BY SUSAN LONDON
Elsevier Global Medical News
Breaking News

SAN FRANCISCO (EGMN) – MDV3100, new oral inhibitor of androgen receptor signaling, reduces the risk of death by more than a third after a failure of docetaxel chemotherapy in men with progressive castration-resistant prostate cancer, according to results of the randomized AFFIRM trial.

Interim data for the trial, which was conducted in nearly 1,200 men, showed that those given the investigational drug lived 4.8 months longer than their counterparts who had been given a placebo, corresponding to a 37% reduced risk of death, lead investigator Dr. Howard I. Scher reported at the Genitourinary Cancers Symposium. This positive finding triggered early trial closure.

Additional analyses revealed that men treated with the drug were significantly more likely to have a soft tissue response and to have at least a halving of their prostate-specific antigen (PSA) level. At the same time, there was no increase in the rate of higher-grade adverse events; seizures (a potential concern from earlier research) occurred at low frequency.

“MDV3100 now joins the list of drugs demonstrating a survival benefit in a phase III trial post docetaxel,” adding to abiraterone (Zytiga) and cabazitaxel (Jevtana), Dr. Scher maintained. “The risk-benefit ratio will likely position this as the frontline agent post docetaxel therapy.”

“I’m not the [Food and Drug Administration], but I would say that when you see this kind of survival benefit and safety profile – and looking at a prior drug [investigation] that I had a privilege of leading – I would say that this should be approved relatively quickly,” he commented in a press briefing.

“I have only one comment: wow! That’s very impressive,” said Dr. Nicholas J. Vogelzang, the moderator of the briefing and the chair and medical director of the Developmental Therapeutics Committee of US Oncology. The median survival and dramatic rates of PSA reduction seen with MDV3100 are “unprecedented. This is going to definitely change the way we take care of patients every day in the office.”

“This is a landmark study,” Dr. Adam S. Kibel agreed in an interview at the meeting. “I think this is a drug that will be widely used, assuming it gets FDA approved.”

Initially, MDV3100 is likely to be used in the postdocetaxel space, said, Dr. Kibel, chief of urology at Brigham and Women’s Hospital and the Dana Farber Cancer Institute and a professor at Harvard Medical School, all in Boston. “I imagine that it would probably be the first-line drug because it appears to have a little less side effect profile than abiraterone and certainly lower than cabazitaxel.”

“The one tripper in there is, will insurance pay for it and how much is it going to cost?” said Dr. Kibel.

MDV3100 is also being tested in patients who have not yet received docetaxel. “I will be shocked if [those data] are not positive,” he commented. And should it perform well there, “it will move prior to docetaxel, because it appears to be very well tolerated from the data presented.”

The AFFIRM trial enrolled 1,199 men with castration-resistant prostate cancer who had experienced progression after receiving docetaxel – a population for whom there was no standard of care at the time the trial began, Dr. Scher noted. They were assigned in 2:1 ratio to once-daily treatment with MDV3100 (manufactured by Medivation) or placebo.

The first-in-class drug has a three-pronged mechanism of action, as well as some advantages over other antiandrogen agents, according to Dr. Scher, chief of the genitourinary oncology service and D. Wayne Calloway Chair in Urologic Oncology at the Memorial Sloan-Kettering Cancer Center in New York.

It “binds more tightly [to the androgen receptor] than the currently available agents, but is also unique in that it inhibits nuclear translocation [of the receptor] as well as the association of the receptor with DNA, inducing cell death,” he explained.

The patients studied had a median age of 69 years. Most (90%) had bone metastases, and the large majority (70%) also had soft tissue metastases.

Main results showed that men given MDV3100 lived 18.4 months, whereas their counterparts given the placebo lived 13.6 months (hazard ratio, 0.63; P less than .0001). Stratified analyses showed similar benefit across most patient subgroups.

Men treated with the drug also had longer median radiographic progression free survival (8.3 vs. 2.9 months; HR, 0.40) and were more likely to have a soft tissue response on imaging (29% vs. 4%) and at least a halving of their PSA level (54% vs. 2%) (all P less than .0001).

There was no increase with MDV3100 in the rate of grade 3 or higher adverse events (45% vs. 53%) or the overall rate of treatment discontinuation due to adverse events (8% vs. 10%).

Seizures occurred in 0.6% of patients given the drug, compared with none of those given the placebo. “Obviously, these cases were studied very, very carefully. In four of the five cases, there were other potential confounders,” including brain metastases and receipt of intravenous lidocaine for a biopsy, Dr. Scher noted. “This is an extremely low frequency, and considering this patient population who are symptomatic post docetaxel, for us, it’s really a nonissue.”

The symposium is sponsored by the American Society of Clinical Oncology, the American Society for Radiation Oncology, and the Society of Urologic Oncology.

Medivation Inc. sponsored the trial. Dr. Scher disclosed that he is a consultant to and receives research funding from Medivation. Dr. Vogelzang disclosed relationships with numerous companies. Dr. Kibel reported that he is a consultant to Dendreon and Sanofi-Aventis.

Subject Codes:
nephrology_urology; top_stories; new_drugs; oncology;


http://www.imng.com


February 03, 2012   12:52 PM EST

Howard I. Scher

BY ALICIA AULT
Elsevier Global Medical News
Breaking News

NEW ORLEANS (EGMN) – Patients with a very low or a very high hematocrit are at higher risk for death after a stroke, and anemic patients are at greatest risk, according to a study presented at the International Stroke Conference sponsored by the American Heart Association on Feb. 2.

Previous studies have shown that extremes of hematocrit increase mortality after myocardial infarction, congestive heart failure, and kidney disease. Dr. Jason J. Sico of the VA Connecticut Healthcare System and researchers from the Department of Veterans Affairs medical system explored whether there was a similar association in stroke. Previous stroke studies had not adjusted for stroke severity or a large number of comorbidities.

They found that “among stroke patients, severe anemia is a potent predictor of dying throughout the first year after a stroke,” said Dr. Sico, who is also an assistant professor of neurology at Yale University, New Haven, Conn.

The researchers abstracted medical records for a sample from 131 Veterans Health Administration (VHA) hospitals of 3,965 patients admitted for a confirmed diagnosis of ischemic stroke in fiscal 2007. Patients with unavailable hematocrits, those who received thrombolytics, or those whose charts had inconsistent death dates were also excluded.

The hematocrit, taken from 24 hours of admission, was divided into six tiers: less than or equal to 27% (defined as severe anemia); 28%-32% (moderate anemia); 33%-37% (mild anemia); 38%-42% (normal); 43%-47% (normal); and greater than or equal to 48% (polycythemia).

Researchers adjusted for age, National Institutes of Health Stroke Scale (NIHSS) score, comorbidities (including pneumonia, hypertension, hypercholesterolemia, diabetes, and history of cancer and heart disease), and Acute Physiology and Chronic Health Evaluation (APACHE)-III scores.

A total of 2% of the 3,750 patients analyzed had severe anemia, 6.2% had moderate anemia, and 17.9% had mild anemia. About 64% were in the normal categories. A total of 9% had a high hematocrit of greater than or equal to 48%.

People with lower hematocrits tended to be older and have higher APACHE scores, a higher Charlson index, a history of heart disease, and were more likely to have diabetes.

The risk of death was 2.5 to 3.5 times higher for patients with severe anemia (P = .013 for in-hospital and 30-day mortality; P = .002 at 6 months and P = .001 at 1 year). A high hematocrit was independently associated only with in-hospital mortality (OR 2.9, P = .004).

The study showed that having a history of severe anemia put stroke patients at a higher risk of death than having a history of other conditions, including cancer and heart disease, said Dr. Sico.

There are several potential mechanisms to explain why anemia might increase the risk of death, he said in an interview. With lower hematocrits, less blood and less oxygen circulate to various parts of the body. Long-term anemia also impairs the ability of the brain’s blood vessels to respond appropriately to a stroke.

A higher hematocrit also decreases blood flow to brain, said Dr. Sico. It causes a more turbulent blood flow to the brain, which could predispose the stroke patient to having a bad outcome.

Dr. Sico said that the study’s findings were limited to men because no women had been analyzed.

But he concluded that stroke patients with low or high hematocrits should be evaluated for potentially reversible causes, and that they should also be closely monitored during the post-stroke period.

Dr. Sico reported having no financial disclosures. The study was funded by the VA Health Services Research and Development Quality Enhancement Research Initiative.

Subject Codes:
top_stories; cardiology; neurology;


http://www.imng.com


February 03, 2012   10:04 AM EST

BY MICHELE G. SULLIVAN
Elsevier Global Medical News
Breaking News

NEW ORLEANS (EGMN)– Compared with warfarin, the new-generation anticoagulant rivaroxaban was associated with a 40% lower risk of intracranial hemorrhage in patients with atrial fibrillation who were taking the agents to prevent stroke.

Since its approval by the Food and Drug Administration last fall, rivaroxaban has been deemed an alternative to warfarin, especially among those patients who have trouble maintaining a stable international normalized ratio, who have warfarin side effects, or who find the constant warfarin monitoring untenable, Dr. Graeme Hankey said at an international stroke conference.

Rivaroxaban also doesn’t involve the medication and food interactions that can make warfarin problematic, said Dr. Hankey, head of the stroke unit at Royal Perth Hospital, Western Australia.

“Many patients don’t want to take warfarin for these reasons,” he said in an interview. “Rivaroxaban doesn’t have these interactions. It has a stable, predictable effect with once-a-day dosing and doesn’t require this constant monitoring.”

Dr. Hankey’s subanalysis of the pivotal ROCKET-AF study, which compared rivaroxaban with warfarin, also determined that some patients had up to a 4-fold increased risk of an intracranial bleed while taking either of the anticoagulants.

The initial study – Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation or ROCKET AF – included 14,264 patients with atrial fibrillation; a history of stroke, TIAs, or systemic embolism; and at least two of the following stroke risk factors: heart failure or a left ventricular ejection fraction of 35% or less; hypertension; an age of 75 years or more; or the presence of diabetes mellitus. Patients were randomized to receive dose-adjusted warfarin or rivaroxaban. Those with normal creatinine clearance received 20 mg daily of the study drug; those with a decreased clearance received 15 mg rivaroxaban daily.

The study’s main end point – a combination of stroke or systemic embolism – was similar in both groups (about 2% per year). The rates of myocardial infarction, and major bleeding also were not significantly different. Vascular mortality and all-cause mortality were nearly identical. However, there was a significant difference in intracranial hemorrhage, favoring rivaroxaban (0.8%; 55 vs. 1.2%; 84). (N. Engl. J. Med 2011;365:883-91). Fatal bleeding occurred in less than 1% of each group.

Dr. Hankey’s subanalysis examined the drug’s effect on intracranial hemorrhage, “probably the most-feared complication of anticoagulation,” according to the investigator. It also examined independent risk factors for intracranial hemorrhage regardless of which drug the study patients took.

He and his colleagues found 172 intracranial hemorrhages in ROCKET-AF – a rate of about 7% per year. Of these bleeds, 128 were intracerebral, 5 subarachnoid, 38 subdural, and 1 extradural. Patients taking rivaroxaban were 40% less likely to have an intracranial hemorrhage than were those taking warfarin.

The subanalysis identified factors that significantly increased the risk of an intracranial bleed. The largest by far were race and concomitant use of clopidogrel. Compared with whites, blacks were more than 400% more likely to have a brain bleed (odds ratio, 4.2), while Asians were 200% more likely. Those taking clopidogrel plus either warfarin or rivaroxaban were 250% more likely to have a bleed than were those not taking an additional anticoagulant (OR, 2.50).

Other significant associations with brain bleeds were as follows:

• High diastolic blood pressure – 21% increased risk for every 10 mm/Hg above normal.

• Poor kidney function – 10% increased risk for every 10 mL/min decrease in creatinine clearance.

• History of stroke or transient ischemic attack – 55% increased risk.

• Low platelets – 8% increased risk;

• Low albumin – 37% increased risk.

The FDA approved rivaroxaban in 2011, to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation.

Dr. José Biller, chairman of neurology at Loyola University, Maywood, Ill., said that although rivaroxaban is another tool in the armamentarium for patients at risk of stroke, he thinks it’s premature to make a paradigm shift away from warfarin.

“Clearly, ROCKET-AF showed us that rivaroxaban was noninferior to warfarin,” said Dr. Biller, the lead author on a recently published review of the new-generation anticoagulation drugs (Expert Rev. Neurother. 2012;12:179-90). “This subanalysis showed that rivaroxaban also had a decreased rate of intracranial hemorrhage, compared with warfarin, but we must keep in mind that the drug did not affect the ROCKET-AF trial’s primary end points of stroke or systemic embolism, nor did it decrease mortality, compared with warfarin.

“One of the biggest concerns about rivaroxaban and some of the other new antithrombotic agents is that we have no established protocol to deal with bleeding, should it occur, as we do with warfarin. At this point, we really don’t know the best way to deal with a bleed. This is something we will learn only with more time,” he said. And compared with the other new-generation anticoagulants apixaban and dabigatran, rivaroxaban seems to have a few more side effects, such as nausea and increased liver enzymes.

“Rivaroxaban and these other drugs do have benefit of being fixed-dose medications taken once or twice a day, and which don’t require the monitoring that warfarin does. But they are going to be more expensive.

“If a patient is under treatment with warfarin and is stable, and if the monitoring schedule is acceptable and there are no major INR fluctuations, I don’t think there is any indication to shift treatment. If the patient has difficulty maintaining a therapeutic INR or if the monitoring is inconvenient, then I suspect patients might welcome the use of one of these fixed-dose agents,” Dr. Biller said.

ROCKET-AF was supported by Johnson & Johnson Pharmaceutical Researchand Development and by Bayer HealthCare. Dr. Hankey was an investigator on the trial and has received honoraria for speaking on the study drug. He is also a consultant for Boehringer Ingelheim and Bayer, which make dabigatran and rivaroxaban, respectively.

Dr. Biller had no disclosures.

Subject Codes:
top_stories; new_drugs; general_primary; cardiology; neurology;


http://www.imng.com


February 02, 2012   08:10 PM EST

BY ALICIA AULT
Elsevier Global Medical News
Breaking News

NEW ORLEANS (EGMN) – Continuous cardiac outpatient telemetry monitoring for at least 21 days may be necessary to accurately identify atrial fibrillation as the cause of cryptogenic stroke, according to the results of a single-center, retrospective study.

Identifying these patients is important because many could be treated with anticoagulants that would reduce their stroke risk, said Dr. Daniel J. Miller, a neurologist at Henry Ford Hospital, Detroit.

About a third of all strokes are of unknown etiology. Paroxysmal atrial fibrillation (AF) is a potential cause of cryptogenic stroke and transient ischemic attacks (TIAs), and carries a high risk of future strokes, Dr. Miller said during a press briefing at the International Stroke Conference.

Physicians have not been sure about the best way to monitor these patients or how long to monitor them.

He and his colleagues followed-up on two small studies: one conducted by Dr. Ashis H. Tayal and colleagues (Neurology 2008;71:1696-1701) and another by Dr. Archit Bhatt and associates (Stroke Res. Treat. 2011 [doi:10.4061/2011/172074]). The Tayal study showed a 23% AF detection rate in cryptogenic stroke patients monitored for longer than 21 days. The Bhatt study found a similar AF rate in cryptogenic stroke.

Dr. Miller and his coinvestigators reviewed the records of 156 Henry Ford Hospital patients who’d had a cryptogenic stroke or TIA and had undergone monitoring with the Cardionet Mobile Cardiac Outpatient Telemetry (MCOT) device, which is commonly used at Henry Ford

The patients had a mean age of 68 years and half were women. The vast majority (97%) were not taking an anticoagulant. Hypertension was common, present in 87% of the patients. They had a fairly low mean score of 3 on the National Institutes of Health Stroke Scale (NIHSS), indicating that the stroke had not been severe.

After monitoring, 27 (17.3%) of the 156 patients had paroxysmal AF. The AF events lasted less than 30 seconds in two-thirds of the patients and longer than 30 seconds in 26%. The remaining 8% had persistently occurring AF. This finding was not surprising and was consistent with the Tayal report, Dr. Miller said in an interview. The monitors are very sensitive, in particular for those events longer than 30 seconds, but they might miss some episodes of less than 30 seconds, he said.

The review showed that the rate of AF detection rose with increased duration of monitoring. The detection rate on a Kaplan-Meier curve was estimated to be 4% at 48 hours, 9% at 7 days, 14% at 14 days, and 20% by 21 days. “Our study does show that in order to capture all these events you should continue to monitor for at least 21 days,” Dr. Miller said.

A multivariate Cox regression analysis showed that for all patients, female gender (P = .002), premature atrial complexes (PAC) on electrocardiogram (P = .001), a 1-cm increase in the diameter of the left atrium (P = .033), and a 10% decline in left ventricular ejection fraction (P = .008) all were associated with increased risk of AF. For stroke patients, female gender, PAC, and increasing stroke severity on the NIHSS were all associated with increased risk.

PAC, a premature beat from the atrium, has been shown to be associated with AF. It was an especially strong predictor of AF in this study, Dr. Miller said.

He urged further study to determine optimal monitoring beyond 21 days for patients with cryptogenic stroke or TIA.

Subject Codes:
top_stories; cardiology; neurology;


http://www.imng.com


February 02, 2012   05:06 PM EST

BY DIANA MAHONEY
Elsevier Global Medical News
Breaking News

Unemployed veterans with post-traumatic stress disorder experience better employment outcomes when they receive individual job placement and support services, compared with standard vocational rehabilitation services, new research shows.

Recipients of evidence-based individual placement and support (IPS) were significantly more likely to gain competitive employment than were recipients of the standard Vocational Rehabilitation Program (VRP) services, Dr. Lori L. Davis of the Tuscaloosa (Alabama) Veterans Affairs Medical Center and her colleagues reported Feb. 2 online ahead of print in Psychiatric Services. Additional employment outcomes, including time worked and total earnings, also favored IPS, they wrote (Psychiatric Serv. 2012 [doi:10.1176/appi.ps.201100340]).

The study is the first to examine employment outcomes for veterans with PTSD who received IPS, compared with those with PTSD enrolled in the VRP, which is offered by the U.S. Department of Veterans Affairs.

For the prospective study, 85 unemployed veterans with PTSD aged 19-60 years at the Tuscaloosa VA Medical Center from 2006 to 2011 were randomized to either IPS-supported employment (42) or VRP treatment as usual (43). The employment rates and occupational outcomes of the veterans were followed for 12 months. All of the subjects were medically cleared to participate in a work activity, were interested in competitive employment, and were planning to remain within a 100-mile radius of the medical center for the duration of the study, the authors wrote.

Excluded from the study were veterans with a severe disorder resulting from severe traumatic brain injury; those diagnosed with schizophrenia, schizoaffective disorder, bipolar I disorder, or dementia; those with an immediate need for alcohol or drug detoxification; or those with pending active legal charges with expected incarceration, the researchers wrote.

The main tenets of the evidence-based IPS supported employment model are client choice, rapid job finding where appropriate, competitive education programs, integrated education and work settings, and follow-along supports. The individualized client-centered services are provided by a multidisciplinary team that integrates and coordinates treatment and rehabilitation, according to the authors. Standard VRP care includes routine prevocational testing and evaluation; vocational rehabilitation therapy comprising a work regimen and the use of special employer incentives; on-the-job training; apprenticeships; and on-paid work experience. Limited supportive rehabilitation and independent living services are also included, they stated.

At baseline, all of the study participants underwent a psychiatric and general medical evaluation, including a medical history, psychiatric history, and family psychiatric history. A clinical research coordinator also evaluated each participant for PTSD and other Axis I disorders using the Mini-International Neuropsychiatric Interview and at baseline and 1-, 2-, 3-, 4-, 6-, 8-, 10- , and 12-month follow-up visits. In addition, the coordinator reviewed subjects’ job logs, which included their employment status, number of hours worked, wages earned, and reasons for missed work.

An analysis of the study results showed that the 85 subjects had been employed for a mean18.9 months and, in addition to PTSD, 89% of the subjects had major depressive disorder, 20% had dysthymia, 54% had agoraphobia, 59% had panic disorder, 28% had social phobia, 42% had alcohol dependence, 21% had alcohol abuse, 37% had drug dependence, and 18% had drug abuse, the authors reported.

With respect to employment outcomes, 32 (76%) of the 42 IPS participants gained competitive employment, compared with 12 (28%) of the 43 VRP participants. Thus, the authors wrote, “... veterans with PTSD who participated in IPS were 2.7 times more likely to gain competitive employment than those who received VRP.” The number needed to treat was 2.07, they noted. “In other words, if three individuals received IPS and three received VRP, one more individual in the IPS intervention would get a competitive job.”

Of the eligible weeks during the study, IPS participants worked in a competitive job an average of 42%, compared with 16% for the VRP participants, the authors reported. Further, the mean total gross 12-month income for the IPS group was $9,264 – significantly higher than the mean $2,601 earned by the VRP group.

The study findings are limited by the single-site design and the exclusion of nonveterans, the authors acknowledged. “A multisite trial with a larger and more diverse study sample would confirm the results and allow examination of secondary outcomes, such as PTSD symptoms, quality of life, and other such outcomes,” they wrote. “In addition, a larger study could evaluate the cost effectiveness of the IPS intervention.”

The investigators disclosed financial relationships with AstraZeneca, Sunovion, Pfizer, MedAvante, and Roche.

Subject Codes:
top_stories; mental_health;


http://www.imng.com


February 02, 2012   12:01 AM EST

BY ALICIA AULT
Elsevier Global Medical News
Breaking News

NEW ORLEANS (EGMN)–There may be a correlation between infection and stroke in children, according to research presented at the International Stroke Conference.

Acute infection is considered to be a risk factor for stroke in adults, so researchers from the University of California, San Francisco, decided to study whether it might also be a potential risk in children, who experience frequent infections.

Stroke, however, is still extremely rare in children: The incidence of acute arterial ischemic stroke is 2.4 per 100,000 children annually in the United States. A large proportion of those cases have no known cause, said Nancy K. Hills, Ph.D., assistant adjunct professor of neurology at UCSF, at a press briefing. Many of those children, however, have an underlying arteriopathy.

Dr. Hills and her colleagues found that children who had a stroke were eight times more likely to have visited a health provider for an infection within 1 month before the stroke, compared with controls. More than 1 month before the stroke, however, there was no difference in the number of visits for infection between cases and controls. The researchers could not prove a direct link between infection and stroke. “We really believe it’s not the infection that’s causing the stroke,” Dr. Hills said.

“It’s not something that parents of healthy children need to worry about,” she said, adding that the infections are “probably a trigger for something else.” The researchers believe that the children who had infection and stroke “probably have some underlying predisposition that causes them to have an unusual response to a common infection.”

The retrospective study examined medical records for 2.5 million children – aged 29 days to 19 years – who were members of Kaiser Permanente from 1993 to 2007. The investigators identified 126 acute ischemic strokes, and then randomly selected 378 age-matched controls (three controls per case) from the Kaiser population. The median age was 10.5 years, and there was a relatively similar mix of male and females. All races were proportionately represented, said Dr. Hills.

The researchers looked at both diagnosed infections and symptoms that were indicative of infection. Any history of infection after a stroke diagnosis was excluded. Once the index stroke was established, the researchers categorized infectious visits according to time frames: 0-2 days, 3-7 days, 8-28 days, 1-3 months, 3-6 months, 6-12 months, and 12-24 months before the stroke.

They found that children who had a stroke were much more likely to have had a visit for infection within 1 month of the index stroke (odds ratio, 8.37). The odds ratio increased to 182 for a visit for infection within 2 days of the stroke. Twenty-nine percent of those who had a stroke had a visit in the 2 days prior to the stroke, compared with 1% of controls for the same dates. In the 3- to 7-day window, 13% of children who had a stroke had an infection, compared with 2% of controls.

The authors concluded that the risk of stroke is substantially elevated within the week after a visit for infection, but that it is likely that these children have some susceptibility to stroke, and that the infection puts them in a prothrombotic state, Dr. Hills said at the meeting, which was sponsored by the American Heart Association.

She pointed out several limitations to the study, including the fact that the number of infections in both the cases and controls was likely underestimated. Also, the infections were not generally confirmed by lab data; they were based on empirical diagnoses.

The study was funded by the National Institute of Neurological Disorders and Stroke. The authors reported no relevant financial conflicts.

Subject Codes:
infectious; top_stories; pediatrics; neurology;


http://www.imng.com


February 01, 2012   08:07 PM EST

BY MICHELE G. SULLIVAN
Elsevier Global Medical News
Breaking News

NEW ORLEANS (EGMN) –Memory is already impaired years before a stroke occurs, declining most rapidly in people destined to suffer a fatal stroke, according to a population-based study of more than 11,000 people.

“For every year that passed [after age 50 years], those who survived a stroke lost their memory at twice the rate as controls. And for those who didn’t survive, their annual memory loss was 3 to 4 years faster than the controls,” said Dr. Maria Glymour of the Harvard University School of Public Health, Boston.

Dr. Glymour and her colleagues examined the relationship between memory and stroke using data from the national Health and Retirement Study (HRS) cohort of people aged 50 years or older.

Interviews with the study’s participants occurred every 2 years, starting in 1998. In their 10-year follow-up study, the investigators focused on 1,456 people who had survived a stroke, 364 who died from a stroke, and 9,994 who did not have a stroke. An immediate and delayed word list recall task, included in the HRS, served as the proxy for working memory among the group.

As expected, Dr. Glymour and her associates found trajectories showing age-related memory decline among all subjects after their baseline interview.

There were also baseline differences between the groups. People who had a stroke – both survivors and nonsurvivors – had significantly poorer memory function at the beginning of the follow-up period.

“More than half of the memory gap between recent stroke survivors and stroke-free adults of similar age was evident before the stroke,” she said during a press briefing at the International Stroke Conference.

The groups continued to separate as the years progressed, although individuals in all three groups had trajectories of at least some age-related memory decline during the 10-year follow-up period.

The study did not assess total cognitive ability, so Dr. Glymour could not say how many in each group already had some basis for memory impairment. But even among the stroke groups, many subjects started out with high function, she noted. “It was the rate of decline that was the key factor.”

“We are really interested to know what’s going on in the brains of these people that seems to be related to having a stroke. My guess is that there is a physiologic basis – that there might be some subclinical strokes that have already occurred that affect memory.”

Another possibility could be memory-related behavioral issues, she said. “If people are already having trouble with memory, they might have a harder time controlling their stroke risks – for example, taking their blood pressure medications.”

Dr. Steven Greenberg, director of the Hemorrhagic Stroke Research Program at Massachusetts General Hospital, Boston, and an American Heart Association spokesman, agreed.

“The cause and effect are still a little unclear. But one possibility is this idea of unnoticed strokes going on over time that cause people to have such a bad trajectory of memory loss. When they do have a symptomatic stroke, they have very little reserve left.”

The study was sponsored by the National Institutes of Health. None of the investigators or Dr. Greenberg had any relevant financial disclosures.

Subject Codes:
top_stories; mental_health; general_primary; neurology; gerontology;


http://www.imng.com


February 01, 2012   06:53 PM EST

BY MARY ANN MOON
Elsevier Global Medical News
Breaking News

Short-term therapy with ulipristal acetate, a selective progesterone-receptor modulator, is superior to placebo and noninferior to leuprolide at controlling the bleeding, reducing the volume, and improving the pain of uterine fibroids, according to two reports in the Feb. 2 issue of the New England Journal of Medicine.

In two parallel international phase-III clinical trials, the duration of treatment with ulipristal acetate (PGL4001) was restricted to 13 weeks and limited to patients who were planning to undergo surgery for fibroids. “More data are needed to inform the benefits and risks of long-term treatment with ulipristal,” as well as to compare the outcomes with therapy against those with surgery, said Dr. Jacques Donnez of the Cliniques Universitaires Saint-Luc Catholic University of Louvain, Brussels, and his associates in the PEARL I and PEARL II studies.

In the PEARL I (PGL4001 [Ulipristal Acetate] Efficacy Assessment in Reduction of Symptoms Due to Uterine Leiomyomata) study, 242 premenopausal women with severe menorrhagia and associated anemia were randomly assigned to receive 5 mg ulipristal, 10 mg ulipristal, or placebo tablets once daily for 13 weeks. The study subjects were treated at 38 academic medical centers in six countries.

Excessive bleeding was controlled in 91% of the women who received the 5-mg dose and 92% of those who received the 10-mg dose, compared with only 19% of those who received placebo. Moreover, excessive bleeding was controlled rapidly – within 8 days – in more than 75% of women taking either dose of ulipristal, compared with only 6% of those taking placebo, the investigators said (N. Engl. J. Med. 2012;366:409-20).

Most of the women in both ulipristal groups but few in the placebo group achieved amenorrhea after 4 weeks of treatment. Half of the patients receiving 5 mg and 70% of those receiving 10 mg of ulipristal became amenorrheic within 10 days.

At the same time, hemoglobin and hematocrit levels rose significantly higher in both ulipristal groups, compared with the placebo group. A significantly greater proportion of patients taking ulipristal showed reductions in fibroid volume of at least 25%, and more reported reduced pain.

The rate of adverse events was not significantly different among the three study groups. All patients showed modest changes in LDL and HDL cholesterol. There were no consistent effects on glucose, estradiol, corticotropin, or prolactin levels, and no differences between active treatment and placebo groups in liver function results or endometrial thickness.

Endometrial biopsies at the end of treatment showed nonphysiologic changes in 62% of women taking 5 mg ulipristal and 57% taking 10 mg ulipristal, compared with only 6% taking placebo. These changes had disappeared by the 6-month follow-up biopsy.

The PEARL II study was a noninferiority trial comparing the same two doses of daily oral ulipristal against once-monthly leuprolide injections for the preoperative treatment of fibroids in 307 women.

After 13 weeks of treatment, 90% of the patients receiving 5 mg ulipristal, 98% of those receiving 10 mg ulipristal, and 89% of those receiving leuprolide achieved control of excessive bleeding, indicating the noninferiority of both doses of ulipristal, Dr. Donnez and his colleagues said (N. Engl. J. Med. 2012;366:421-32).

Excessive bleeding was controlled much more rapidly with ulipristal than with leuprolide, and amenorrhea also was induced more rapidly. The median time to achieving amenorrhea was 7 days with 5 mg ulipristal, 5 days with 10 mg ulipristal, and 21 days with leuprolide, they reported.

All patients reported similar improvements in pain and quality of life, and all showed similar rebounds in hemoglobin levels.

All three treatments significantly reduced uterine volume, but leuprolide produced a significantly greater reduction (47%) than did either dose of ulipristal (20% and 22%).

Estradiol dropped to postmenopausal levels only in the women who received leuprolide. Accordingly, 40% of the leuprolide group reported moderate to severe hot flashes, compared with 11% of the women taking 5 mg ulipristal and 10% of those taking 10 mg ulipristal, Dr. Donnez and his colleagues wrote.

There were no significant differences among the three study groups in other adverse events. As in the PEARL I study, ulipristal induced benign endometrial changes that had disappeared at the 6-month follow-up.

Neither ulipristal nor leuprolide showed any clinically relevant effects on corticotropin, thyrotropin, prolactin, or glucose levels.

Ulipristal May Prove Effective as Intermittent Therapy

In an editorial comment accompanying the reports, Dr. Elizabeth A. Stewart said that, if future studies confirm that the endometrial changes associated with progesterone-receptor modulators like ulipristal are indeed benign and resolve after treatment ends, “women with symptomatic fibroids may have the option of a unique intermittent therapy that maximizes efficacy while minimizing safety concerns.”

It must be noted, however, that the PEARL studies were limited by the short 13-week duration of treatment. They also were limited in that they included very few black women, who have a greater risk of fibroids and a more severe phenotype, and involved patients with only moderately enlarged uteri, said Dr. Stewart of the division of reproductive endocrinology and infertility at the Mayo Clinic, Rochester, Minn. (N. Engl. J. Med. 2012;366:471-3).

Both the PEARL I and PEARL II studies were funded by PregLem, manufacturer of ulipristal acetate. Dr. Donnez reported ties to PregLem, Serono, Merck, Organon, and Ferring; his associates reported ties to numerous industry sources. Dr. Stewart reported ties to Bayer HealthCare, Abbott, Columbia Laboratories, Gynesonics, and InSightec.

Subject Codes:
top_stories; womens_health;


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February 01, 2012   05:00 PM EST

BY MARY ANN MOON
Elsevier Global Medical News
Breaking News

Antigen therapy with glutamic acid decarboxylase 65 formulated with alum failed to induce immunologic tolerance and stem the loss of stimulated serum C-peptide in a phase III clinical trial of new-onset type 1 diabetes, according to a report in the Feb. 2 issue of the New England Journal of Medicine.

The treatment also failed to improve clinical outcomes during the 15-month study, said Dr. Johnny L. Ludvigsson of the department of clinical and experimental medicine, division of pediatrics, Linkoping (Sweden) University, and his associates.

In a previous phase II study, treatment with the 65-kD isoform of glutamic acid decarboxylase (GAD65) formulated with alum (GAD-alum) had preserved stimulated C-peptide levels and fasting C-peptide levels for 4 years in a subgroup of patients who were treated immediately after diagnosis (Diabetologia 2011;54:634-40). However, a more recent phase II trial of GAD-alum did not show any clinical benefit, the investigators noted.

Dr. Ludvigsson and his colleagues performed their phase III clinical trial at 63 clinics in Finland, France, Germany, Italy, the Netherlands, Slovenia, Spain, Sweden, and the United Kingdom. The 327 study subjects were aged 10-20 years and had been diagnosed as having type 1 diabetes within the preceding 3 months.

The patients were randomly assigned in double-blind fashion to receive one of three regimens of subcutaneous injections: four doses of GAD-alum (on days 1, 30, 90, and 270), two doses of GAD-alum (on days 1 and 30), or four doses of placebo.

The primary outcome was preservation of the stimulated serum C-peptide level after 15 months. Stimulated C-peptide levels showed progressive declines in all three groups throughout the study. The declines were not significantly different among the three groups at any time point, including at the conclusion of the study, the investigators said (N. Engl. J. Med. 2012;366:433-42).

Moreover, there were no differences among the three groups in mean daily insulin dose, glycated hemoglobin levels, or several other clinical outcomes.

The rates of adverse events also were similar among the three study groups.

“Much as treatments for diseases such as childhood cancer and immunotherapy of allergy have developed in a stepwise, gradual manner through the combination of existing therapies, treatment for type 1 diabetes will most likely be based on the knowledge gained from this and other studies, as well as future studies, of single agents or combination therapies for both intervention and prevention,” Dr. Ludvigsson and his associates said.

They added that patients who develop stiff person syndrome have been shown in previous studies to carry elevated levels of GAD65 autoantibodies. In this study, all the subjects underwent periodic neurologic assessments, and no symptoms suggestive of stiff person syndrome were seen.

This study was supported by Diamyd Medical and the Swedish Child Diabetes Foundation. Dr. Ludvigsson reported ties to Johnson & Johnson, GlaxoSmithKline, Sanofi-Aventis, and Novo Nordisk; his associates reported ties to Merck Sharp and Dohme, Bristol-Myers Squibb, Eli Lilly, Medtronic, Tolerx, and Andromeda Biotech.

Subject Codes:
top_stories; diabetes; new_drugs; endocrinology;


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February 01, 2012   05:00 PM EST

Johnny L. Ludvigsson

BY SUSAN LONDON
Elsevier Global Medical News
Breaking News

The 2012 Genitourinary Cancers Symposium, to be held Feb. 2-4, will feature potentially practice-changing data on two novel agents – MDV3100 and radium-223 chloride – in prostate cancer.

• Results of the phase III AFFIRM trial, to be reported in full Feb. 2, show that the investigational oral androgen–receptor signaling inhibitor MDV3100 prolongs overall survival in progressive castration-resistant prostate cancer after failure of docetaxel (Taxotere).

Men given this agent lived on average nearly 5 months longer than their counterparts given a placebo, according to a press preview of data by the American Society of Clinical Oncology (ASCO). There was no increase in rates of grade 3 or higher adverse events or serious adverse events with MDV3100. The rate of seizures was 0.6% with the drug and 0% with placebo.

• Results of the placebo-controlled phase III ALSYMPCA trial show that the first alpha-particle–emitting drug to target bone, radium-223 chloride (Alpharadin), prolonged overall survival by nearly 3 months (prompting early trial closure) and delayed the time to skeletal-related events by about 5 months in men with bone-only metastatic castration-resistant prostate cancer who had received or were not candidates for docetaxel.

Radium-223 chloride was well tolerated, and there were no cases of leukemia. The U.S. Food and Drug Administration has granted Fast Track status to this investigational agent.

In addition, two large observational studies using linked Surveillance, Epidemiology, and End Results (SEER) and Medicare data, will likely add to the debate regarding the most cost-effective treatment for prostate cancer, and in particular, the pros and cons of various radiation therapy options.

• Investigators at the University of North Carolina at Chapel Hill and University of North Carolina Hospitals will report findings in more than 12,000 men with localized prostate cancer, showing a lower rate of subsequent cancer treatment with intensity-modulated radiation therapy (IMRT) vs. conformal radiation therapy; bowel toxicity and hip fracture were less common with the former, whereas erectile dysfunction was less common with the latter. In addition, proton therapy did not yield a significantly lower rate of subsequent cancer treatment vs. IMRT, and also had a higher rate of bowel toxicity.

• Investigators at the Cleveland Clinic and Kaiser Permanente will report outcomes after a median follow-up of 71 months in 137,427 men with prostate cancer of various stages, showing that of three common therapies – prostatectomy, external-beam radiation therapy (EBRT), and brachytherapy – EBRT was associated with the highest cumulative incidences of gastrointestinal and genitourinary therapy–related toxicity necessitating intervention and also was the most costly.

In another study of note, also being reported in full Feb. 2, researchers will present findings regarding the impact of vigorous exercise on gene expression in the prostate gland that may help explain its benefit in reducing progression.

• This study in a low-risk prostate cancer population under active surveillance has found that a set of 184 genes in normal prostate tissue are differentially expressed between men who exercise vigorously at least 3 hours a week and men who exercise less intensively, according to results to be presented in a poster session. A number of tumor suppressor genes were upregulated in the vigorous exercisers, and pathway analysis showed that the DNA repair and cell cycle pathways were positively modulated.

For ongoing coverage of these and other presentations at the ASCO Genitourinary Cancers Symposium, visit The Oncology Report.

For earlier reports on these new prostate cancer agent, click on:

• Radium-223 Could Alter Metastatic Prostate Cancer Management

A report from the European Multidisciplinary Cancer Congress in September 2011.

• Positive Data on Alpharadin Could Accelerate Filing Timeline

A report on early halting of the radium-223 trial in June 2011

• Prostate Cancer Drug

A video interview with Dr. Howard Scher on the importance of early MDV3100 data presented at the Genitourinary Symposium in 2009.

Subject Codes:
nephrology_urology; top_stories; new_drugs; oncology;


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January 31, 2012   06:00 PM EST

BY ALICIA AULT
Elsevier Global Medical News
Breaking News

The Food and Drug Administration on Jan. 31 approved the drug ivacaftor (Kalydeco) for cystic fibrosis patients aged 6 years and older who have the G551D mutation.

According to ivacaftor maker Vertex Pharmaceuticals, the approval is one of the fastest ever at the FDA. It took only 3 months from submission of data to approval.

Ivacaftor targets the G551D mutation in the cystic fibrosis transmembrane regulator (CFTR) gene. CFTR proteins regulate the flow of salt and water across the cells. A defective CFTR protein causes thick, sticky mucus to build up in the lungs, digestive tract, and other parts of the body, which can lead to respiratory and digestive problems and other complications.

The Vertex drug, taken orally twice a day, is a CFTR potentiator. It targets abnormal CFTR protein channels and opens them to allow chloride ions to move into and out of the cell; that, in turn, thins the mucus and the airways become less clogged, according to Vertex.

The FDA said that about 1,200 people – 4% of the 30,000 with cystic fibrosis in the United States – have the G551D mutation. Ivacaftor can help only those with the mutation. The agency and Vertex recommend FDA-approved molecular diagnostic testing before starting the therapy.

“Kalydeco is an excellent example of the promise of personalized medicine – targeted drugs that treat patients with a specific genetic makeup,” said Dr. Margaret A. Hamburg, FDA commissioner, in a statement.

Added Dr. Janet Woodcock, director of the FDA’s Center for Drug Evaluation and Research, “Kalydeco is the first available treatment that targets the defective CFTR protein, which is the underlying cause of cystic fibrosis. This is a breakthrough therapy for the cystic fibrosis community because current therapies only treat the symptoms of this genetic disease.”

The FDA’s approval was based on two 48-week, placebo-controlled clinical studies that enrolled 213 patients. One study was in patients aged 12 years and older, and the other was in patients aged 6-11 years.

They all had at least one copy of the G551D mutation. The ivacaftor-treated groups had significant and sustained improvements in lung function, as well as in weight gain and some quality of life measurements, compared with those who received placebo, according to Vertex. They also had fewer pulmonary exacerbations.

The most common side effects were upper respiratory tract infection, headache, stomach ache, rash, diarrhea, and dizziness.

Vertex said it would begin shipping ivacaftor to U.S. pharmacies this week.

Subject Codes:
top_stories; new_drugs; pediatrics; pulmonology;


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January 31, 2012   03:10 PM EST

BY MARY ANN MOON
Elsevier Global Medical News
Breaking News

Rates of re-excision after initial breast-conserving surgery for invasive breast cancer vary greatly across surgeons and across medical centers, according to a report in the Feb. 1 issue of JAMA.

These variations are only partly explained by the basic clinical and demographic factors that dictate treatment decisions, such as tumor size and patient age. The remaining reasons for the profound differences in re-excision rates remain unexplained.

Nevertheless, these variations certainly are a barrier to consistent, high-quality, cost-effective care for breast cancer. “Outcomes such as local recurrence and even overall survival could be affected by variability in initial surgical care,” said Dr. Laurence E. McCahill of the Richard J. Lacks Cancer Center, Van Andel Research Institute, and department of surgery at Michigan State University, Grand Rapids, and his associates.

Noting that “currently, there are no readily identifiable quality measures that allow for meaningful comparisons of breast cancer surgical outcomes among treating surgeons and hospitals,” the investigators examined re-excision rates across four geographically diverse health systems. Their chief goal was to determine whether significant variations existed, which would in turn determine whether the re-excision rate is a meaningful measure of surgical quality.

They assessed detailed data on initial and subsequent surgeries for invasive ductal carcinoma or invasive lobular carcinoma in 2,206 women who underwent an initial breast-conserving procedure for incident cancer.

Overall, 509 patients (23%) underwent re-excision of the affected breast during 5 years of follow-up. A total of 454 women had a single re-excision, 48 had two re-excisions, and 7 had three re-excisions. Approximately 9% of the study subjects (190 women) underwent total mastectomy after the initial breast-conserving surgery.

The rate of re-excision varied greatly from one surgeon to another, ranging from 0% to 70%. This implies that patients with the same clinical presentations are likely to undergo re-excision based on who is doing their procedure, not on their clinical traits, the investigators said (JAMA 2012;307:467-75).

This study was designed to determine whether such variations exist, not the reasons why they exist. But the researchers suggested that “differences in surgical training, surgeon confidence in their operative technique in localizing tumors, utilization of intraoperative assessment of margins, and surgeon’s and pathologist’s coordination of specimen orientation and margin interpretation” may all play a role.

Surprisingly, the volume of procedures a surgeon performs did not affect his or her re-excision rate in this study, so surgical experience may not play an important role in these variations, Dr. McCahill and his colleagues added.

The rate of re-excision also varied greatly from one medical center to another, ranging from 1.7% at the center with the lowest rate to 21% at the center with the highest rate. In particular, the rate of re-excision for cases with positive margins ranged from 74% to 94%. Any variation in this statistic is surprising because positive margins are known to correlate with local recurrence and are “almost always” re-excised, the researchers said.

Again, this study was not designed to determine why re-excision rates differ so greatly between medical centers, but the investigators suggested that “institutional variation in surgeon’s training, regional variation in interpretation of the required criteria for [re-excision], or both” may account, at least in part, for the variation.

The need for re-excision in patients who have negative (pathologically clear) margins at the initial surgery is controversial, because “there is no clear consensus on the appropriate distance required for a clear margin to be deemed adequate.” So perhaps it should not be surprising that almost half of the re-excisions (242 of the 509) in this study were performed in patients who had negative margins, the researchers said.

One major limitation of this study was that some factors that greatly influence treatment decisions, including patient preferences, were not included in the data and so could not be factored into the analysis, they noted.

This study was funded by the National Institutes of Health under the American Recovery and Reinvestment Act. The authors reported no financial conflicts of interest.

Variations in Surgeons’ Attitudes and Practices

One reason for the profound variation among surgeons in re-excision rates is the lack of consensus as to what constitutes the optimal negative margin width, Dr. Monica Morrow and Dr. Steven J. Katz noted in an editorial (JAMA 2012;307:509-10).

Prospective randomized clinical trials haven’t addressed this question, and a substantial number of re-excisions (approximately half in the study by Dr. McCahill and colleagues) are performed on patients with negative margins, merely to obtain a more widely clear margin.

Moreover, some surgeons may have artificially low re-excision rates because they only offer breast-conserving surgery to patients with tumors of 1 cm or smaller, rather than those with tumors up to 4 cm in size. Other surgeons will have artificially low re-excision rates because they intentionally remove very large amounts of normal tissue during the initial lumpectomy, Dr. Morrow and Dr. Katz noted.

Dr. Morrow is at Memorial Sloan-Kettering Cancer Center, New York. Dr. Katz is in the departments of medicine and health management and policy at the University of Michigan, Ann Arbor. They reported no financial conflicts of interest.

Subject Codes:
top_stories; general_primary; oncology; womens_health; surgery;


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January 31, 2012   04:00 PM EST

Dr. Laurence E. McCahill

BY MARY ANN MOON
Elsevier Global Medical News
Breaking News

Emergency departments at “safety-net” hospitals showed timelines similar to those of EDs in other hospitals for admitting, discharging, or transferring patients, according to a national survey published in the Feb. 1 issue of JAMA.

Several measures of ED length of stay have been proposed as indicators of quality of care, including the interval from patient arrival to admission and the interval from admission to discharge or transfer to another facility. Some organizations have suggested that length of stay before discharge should be less than 4 hours and length of stay before admission should be less than 8 hours.

EDs that fail to meet these deadlines would be considered poor performers, and EDs at safety-net hospitals – which provide a disproportionate share of services to poor, uninsured, and Medicaid patients – might be singled out unfairly. “If these measures are tied to pay-for-performance, chronically underfunded safety-net EDs could be at risk of further reductions in funding, which could only exacerbate the lack of resources available in those settings,” said Dr. Christopher Fee of the department of emergency medicine, University of California, San Francisco, and his associates.

To examine the issue, the investigators assessed length of stay measures for 24,719 adult ED visits at hospitals across the United States in 2008, the most recent year for which data are available. They used data from the annual National Hospital Ambulatory Medical Care Survey conducted by the Centers for Disease Control and Prevention’s National Center for Health Statistics.

Approximately 42% of these visits were to safety-net EDs and 58% were to non–safety-net EDs.

There were no significant differences between these two types of EDs in any of the median length of stay measures assessed. “Our results show that both safety-net and non–safety-net EDs perform well on the ED length of stay goals that have been proposed, with median ED lengths of stay ... well under 8 hours for admissions and under 4 hours for discharges,” Dr. Fee and his colleagues said (JAMA 2012;307:476-82).

The overall length of stay was 269 minutes for safety-net EDs and 281 minutes for non–safety-net EDs. The overall length of stay for critical care admissions was 236 minutes and 248 minutes, respectively.

For discharged patients, the median ED length of stay was 156 minutes in safety-net EDs and 148 minutes in non–safety-net EDs.

It is important to note that although these data are the most current available, they were collected before the economic recession. The recession may well have increased the uninsured and Medicaid populations, which may have affected ED visit volume and length of stay. In addition, the “effects of the sweeping health care reform currently under way remain to be seen,” the investigators said.

This study was supported by a grant from the National Institutes of Health/National Center for Research Resources/University of California, San Francisco Clinical and Translational Science Institute and the Robert Wood Johnson Foundation Physician Faculty Scholars Program. Dr. Fee reported ties to Google, and a coauthor is an employee of the National Quality Forum.

Subject Codes:
top_stories; emergency_trauma;


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January 31, 2012   04:00 PM EST

BY NASEEM S. MILLER
Elsevier Global Medical News
Breaking News

To ensure appropriate implementation and use of transcatheter aortic valve replacement in medical centers across the United States, four leading cardiovascular organizations have pooled their knowledge and issued a consensus document.

The document comes 2 months after the Food and Drug Administration approved the first minimally invasive transcatheter aortic valve replacement (TAVR) system (J. Am. Coll. Cardiol. 2012 Jan. 31; doi:10.1016/j.jacc.2012.001).

The document reviews in detail several aspects of the procedure, including the current state of evidence, patient selection, management of complications and steps to integrating TAVR into practice.

“Our goal in crafting this expert consensus document is to provide a clear road map for the use of TAVR as it reaches patients across the United States,” Dr. Michael J. Mack, medical director of cardiovascular surgery at Baylor Health Care System, Heart Hospital Baylor Plano (Tex.), president of the Society of Thoracic Surgeons, and vice chair of the writing committee, said in a statement.

The report also recommends establishment of a national registry by cardiovascular organizations and not the industry, to create standard definitions and data specifications and to avoid the potential for conflict of interest.

In the expert consensus, the organizations also stress that the procedure’s rollout is a “key issue” in the United States. “The rollout is influenced by the societal beliefs in a free market, convenient and timely access to medical care, patient and physician expectations, as well as return on investment by companies and institutions alike,” according to the report.

What complicates the rollout, they added, is the proliferation of advanced cardiovascular facilities.

Take, for instance, Los Angeles County, which has 33 cardiovascular surgical and primary ST-elevation myocardial infarction centers. If all these centers were to offer TAVR, the result would be “the dilution of concentrated experience,” the report stated.

So, establishment of specialized centers of excellence should be a top priority, the report advised.

“As this technology is introduced into practice, detailed and agreed upon protocols are needed to ensure we achieve optimal clinical results,” Dr. David R. Holmes, professor of medicine at Mayo Clinic in Rochester, Minn., president of the American College of Cardiology, and chair of the writing committee, said in a statement.

Nearly 45,000 patients have received TAVR around the world, but the experience with the procedure in the United States lags far behind that in Europe. Five different valves are currently in widespread use across Europe. In the United States, the first valve, Edwards Sapien, was approved in 2011 for use in inoperable patients with severe aortic stenosis. Other use of the Sapien valve is limited to clinical trials. Medtronic’s CoreValve is also in being studied in large U.S. trials. The report lists several next-generation devices under investigation.

“TAVR innovation is a major advance in treating aortic stenosis and sick, elderly patients should have access to this new treatment so they can resume normal, active lives,” Dr. Mack said in a statement. “These guidelines are a coordinated effort from the cardiovascular community to help ensure the appropriate use of TAVR therapy for optimum patient safety.”

The American College of Cardiology Foundation, the American Association for Thoracic Surgery, the Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons were the main authors of the consensus document. Eight other medical and consumer groups were involved in the writing and endorsement of the document.

Dr. Mack and Dr. Holmes reported no relevant disclosures.

Subject Codes:
top_stories; cardiology; surgery;


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January 31, 2012   02:23 PM EST

The hybrid elements of transcatheter aortic valve replacement should feel the benefit of this consensus document on proper TAVR procedure.

BY SHARON WORCESTER
Elsevier Global Medical News
Breaking News

Metformin use was associated with a decreased risk of pancreatic cancer in women, but not in men, in a large case-control study involving more than 19,300 U.K. primary care patients.

Additionally, use of insulin and sulfonylureas was found in the study to be associated with increased risk of pancreatic cancer in both men and women, Dr. Michael Bodmer of the University of Basel, Switzerland, and his colleagues reported online in the Jan. 31 issue of the American Journal of Gastroenterology.

Overall, metformin use was not found to be associated with pancreatic cancer in 2,763 patients with a first-time diagnosis of pancreatic cancer, compared with 16,578 matched controls with no such diagnosis – all from the U.K.-based General Practice Research Database, which includes data on more than 8 million individuals (adjusted odds ratios, 1.01, 0.92, and 0.87 for those who received 1-9, 10-29, and 30 or more metformin prescriptions, respectively), the investigators said.

The findings were similar when analysis was restricted to cases with pancreatic surgery, radio/chemotherapy, or with a specific oncology code, and also when analysis was restricted to diabetic patients. However, in an analysis by gender, long-term metformin use was associated with a decreased risk of pancreatic cancer in women (adjusted OR, 0.43), but not in men (adjusted OR, 1.59), they found (Am. J. Gastroenterol. 2012 Jan. 31 [doi10.1038/ajg.2011.483]).

As for long-term use of sulfonylureas and insulin, the overall analysis demonstrated a “materially increased risk of pancreatic cancer (adjusted OR, 1.90 and 2.29, respectively), and as with metformin, the findings were closely similar in those with pancreatic surgery, radio/chemotherapy, or an oncology code, while in the analysis restricted to patients with diabetes, the adjusted odds ratios for long-term use of sulfonylureas and insulin were 1.59 and 1.69, respectively.

In contrast with the findings regarding metformin, the increased risk of pancreatic cancer among long-term users of sulfonylureas was mainly restricted to women (adjusted OR, 3.05), the investigators said.

Cases in this study were individuals with a first-time diagnosis of pancreatic cancer before the age of 90 years between 1995 and 2009. Controls had no diagnosis of pancreatic cancer and were matched based on calendar time, age, sex, general practice, and number of years of active history in the database before the index date. The average age was 70 years, and 46% were men.

The analyses were conducted using the index date shifted back in time by 2 years to account for cancer latency, the investigators explained.

Using that same shifted index date, the investigators also looked for a link between diabetes history and the risk of pancreatic cancer, and found one. “Overall, the adjusted odds ratio of pancreatic cancer associated with a recorded diagnosis of diabetes mellitus was 1.22. When we stratified the risk of pancreatic cancer by diabetes duration, the odds ratio decreased with increasing duration of diabetes; the odds ratios for a diabetes history of less than 2, 2-5, 5-10, or greater than 10 years were 1.71, 1.21, 0.94, and 0.71, respectively,” they said.

In the analysis using the recorded index date, rather than the shifted date, the overall odds ratio for pancreatic cancer in diabetic patients compared with nondiabetic patients was 1.60, and for those with disease duration of less than 2 years, 2-5 years, 5-10 years, and greater than 10 years were 3.30, 1.13, 0.72, and 0.56, respectively.

The finding of an effect modification by gender for the use of metformin was “somewhat unexpected and could not be explained by confounding by use of estrogens,” the investigators said, noting that the finding should be interpreted with caution since it is based on a limited number of exposed cases and controls, and since there is no obvious pathophysiologic explanation.

Also, the findings regarding metformin differed somewhat from those of prior smaller studies showing an overall decrease in pancreatic cancer with long-term metformin use.

The findings regarding sulfonylureas and insulin, however, support those of prior studies, and as with metformin, effect modification by gender seemed to have a role: The increased risk with long-term use of sulfonylureas was mainly seen in women, and the increased risk with insulin was mainly seen in men.

“Of importance, in our study, neither short-term use of metformin or sulfonylureas, nor insulin was associated with altered relative risk estimates for pancreatic cancer, indicating that our study design effectively eliminated detection bias and/or bias by intensification of antidiabetic therapy due to undiagnosed pancreatic cancer,” they said.

Also the finding of a link between diabetes mellitus and increased risk for pancreatic cancer, which was restricted to those with newly diagnosed diabetes, strongly supports the hypothesis suggested by other authors that short-term diabetes mellitus is likely caused by pancreatic cancer.

“Although uncontrolled confounding by dietary habits or physical activity may be of importance, these findings do not support a causative role for diabetes mellitus for development of pancreatic cancer,” they noted.

This study was partially funded by the Swiss Cancer League and the Research Fund of the University of Basel, Switzerland. None of the authors had relevant disclosures.

Subject Codes:
top_stories; gastroenterology; diabetes; general_primary; endocrinology; womens_health; cardiology;


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January 31, 2012   08:00 AM EST

BY MARY ANN MOON
Elsevier Global Medical News
Breaking News

For pediatric burn patients, the percentage of total body surface area affected remains the strongest predictor of survival, according to a report published online Jan. 31 in the Lancet.

“We have established that, in a modern pediatric burn care setting, a burn size of roughly 60% total body surface area is a crucial threshold for postburn morbidity and mortality,” wrote Dr. Robert Kraft of Shriners Hospitals for Children, Galveston, Texas, and his associates.

For decades, burn size has been the main prognostic factor for both adults and children with burn injuries. But recent improvements in burn care – including novel drug treatments, new grafting techniques and materials, and improved life-support systems and monitoring methods – have dramatically improved survival, according to the investigators. Because treatment decisions, including whether to transfer a patient to a specialized burn center, are based on the probability of survival, it was important to determine whether burn size was still predictive of major complications and mortality under current treatment conditions.

To do so, Dr. Kraft and his colleagues examined outcomes in all 952 patients admitted over a 1-year period to Galveston’s Shriners Hospital with burns involving 30% or more of their total body surface area. Most of the study patients were burned on 40%-49% of their bodies.

Burn size proved to be the strongest predictor of survival, with mortality rising significantly as burn size increased. “In patient groups with burns smaller than 60% total body surface area, there were only minor increases in mortality starting at 3% and reaching up to 7%,” the investigators wrote.

A large increase in mortality was noted when burn size reached 62% of the total body surface area. Such patients had a tenfold higher risk of death, compared with those who had smaller burns, the investigators reported (Lancet 2012 [doi:10.1016/S0140-6736(11)61345-7]).

Large burns also were associated with significant increases in multiorgan failure, infection during ICU stay, and the need for more surgeries to excise tissue. The rate of multiorgan failure was 6%-12% and the rate of sepsis was only 2%-6% for burns involving up to 59% of the body surface area. These rates ballooned as high as 27%-45% for multiorgan failure and 15%-26% for sepsis when burns involved 60% or more of the body surface area.

In addition, blood glucose and insulin levels rose significantly with burns involving 60% or more of the total body surface area, as did resting energy expenditure. Together with concomitant changes in liver structure and function, these findings reflect a massive hypermetabolic response to burn injury, Dr. Kraft and his associates reported.

Cytokine levels also differed by size of burn. With burns involving 60% or more of the body surface area, the levels of interleukin-6, -8, -10, and -13; macrophage inflammatory protein 1beta; tumor necrosis factor–alpha; granulocyte colony-stimulating factor; interferon-gamma; granulocyte-macrophage colony stimulating factor; and C-reactive protein rose substantially for an extended period of time.

Given these findings, “we recommend that pediatric patients with greater than 60% total body surface area burns be immediately transferred to a specialized burn center. Furthermore, at the burn center, patients should be treated with increased vigilance and improved therapies, in view of the increased risk of poor outcome associated with this burn size,” the researchers wrote.

After burn size, the presence of inhalation injury in addition to external burn injury was a significant predictor of mortality. Patients who sustained inhalation injury had a threefold higher risk of death than did patients with no inhalation injuries. “We recommend that the treating physician [keep] in mind that the presence of inhalation injury significantly affects postburn outcomes,” they noted.

Patient age and sex showed no association with survival, and neither did the time interval between sustaining the burn and presenting for admission.

It was noteworthy that mortality rates in this study were relatively low, even among patients who had the most extensive burns. “In our opinion, [high survival was] attributable to an improved and aggressive treatment regimen,” they added.

Important Cutoff Defined

This study shows that children with burns involving less than 62% of total body surface area can be treated successfully with standard procedures, but larger burns require the novel surgical wound management and advanced monitoring available at specialized burn centers, commented Dr. Ronald G. Tompkins, chief of the burn service at Massachusetts General Hospital and the Sumner M. Redstone Professor of Surgery at Harvard Medical School, both in Boston. .

In an editorial accompanying Dr. Kraft’s report, he said it is also important to note that overall survival in this study was quite high. Even among children with burns involving 90% of total body surface area, half survived their injuries. And even the youngest children can be expected to survive as well as older children, now that pediatric intensive care has learned to compensate for their physiological and anatomical differences (Lancet 2012 [doi:10.1016/S0140-6736(11)61626-7]). This means it is time to think beyond mere survival to survivors’ quality of life, he noted.

This study was supported by Shriners Hospitals for Children, the National Institutes of Health, the National Institute on Disability and Rehabilitation Research, the Institute for Translational Sciences, the CFI Leaders Opportunity fund, and Physicians’ Services Incorporated Foundation. The investigators reported having no financial conflicts of interest. Dr. Tompkins reported no financial conflicts of interest.

Subject Codes:
top_stories; dermatology; pediatrics; general_primary; surgery; emergency_trauma;


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January 30, 2012   06:30 PM EST

BY ALICIA AULT
Elsevier Global Medical News
Breaking News

The Food and Drug Administration has approved vismodegib, an oral, once-daily medication for adults with locally advanced and metastatic advanced basal cell carcinoma on Jan. 30.

Vismodegib (Erivedge) is the first medication approved for metastatic BCC and was approved ahead of its March 8 statutory review date, according to a statement from the FDA.

The drug works by inhibiting the hedgehog pathway, which is active in most BCCs. “Our understanding of molecular pathways involved in cancer, such as the hedgehog pathway, has enabled the development of targeted drugs for specific diseases,” said Dr. Richard Pazdur, director of the FDA’s Office of Hematology and Oncology Products, in a statement.

“Today’s approval provides a new treatment for people with advanced basal cell carcinoma who, until now, had no approved medicines to help shrink disfiguring or potentially life-threatening lesions,” Dr. Hal Barron, Genentech’s chief medical officer and head of global product development, said in a statement.

The FDA based its approval on a single-arm, multicenter phase II study, ERIVANCE BCC. The open-label study enrolled 104 patients with locally advanced or metastatic BCC but, according to the FDA, approval was based on evaluations of 96 patients. Study participants took 150 mg vismodegib once daily.

The primary end point was objective response rate, that is, the percentage of patients who experienced complete and partial shrinkage or disappearance of the cancerous lesions after treatment. A total of 43% of patients with locally advanced BCC had partial or complete response (27 of 63) and 30% with metastatic disease had a partial response (10 of 33), according to Genentech. The median duration of response was 7.6 months.

The most common side effects were muscle spasms, hair loss, weight loss, nausea, diarrhea, fatigue, distorted sense of taste or loss of taste, decreased appetite, constipation, vomiting, and aching joints.

Vismodegib will carry a boxed warning about a potential risk of death or severe birth effects to a fetus. The FDA is not requiring a birth defects risk management program for vismodegib, but Genentech is advising female patients to use “highly effective” birth control before, during, and for 7 months after the last dose of treatment. Men should use a condom with spermicide, even if they have had a vasectomy, during sex with female partners during treatment and for 2 months after the last dose.

The company said that pregnant women are being encouraged to participate in the Erivedge pregnancy pharmacovigilance program, which collects information about exposure to that drug during pregnancy and the effects on the mother and her unborn child.

Vismodegib will be available in the United States within a few weeks and will be distributed through specialty pharmacies, according to Genentech.

Subject Codes:
top_stories; new_drugs; dermatology; oncology;


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January 30, 2012   03:12 PM EST

BY KRISTIN ATKINS, M.D.
Elsevier Global Medical News

Recurrent pregnancy loss can have a significant emotional impact on women or couples who are attempting to have a baby.

Unfortunately, we are able to determine the reason for recurrent pregnancy loss (RPL) only 50% of the time, and there is minimal evidence-based guidance available for the evaluation and management of this distressing obstetric complication.

Although there are many areas of uncertainty regarding the etiology of RPL, some potential causes – from anatomical, genetic, and molecular abnormalities to endocrine disorders and antiphospholipid syndrome – can and should be investigated.

In all situations, our psychological support is essential, and when a likely cause can be found, we then are able to provide the woman or the couple with a reason and hopefully support their next pregnancy in a way that will result in a live birth.

There are various definitions for RPL and, therefore, evaluation can occur after differing numbers of losses. The American Society for Reproductive Medicine defines RPL as disease distinct from infertility that involves two or more failed pregnancies. It recommends some evaluation after each miscarriage of unknown etiology, and a thorough evaluation after three or more losses (Fertil. Steril. 2008;89:1603).

Many experts believe, however, that a work-up should occur after two consecutive losses. The incidence of spontaneous miscarriage in all pregnancies is 0%-15%. Overall, the risk of further miscarriages increases after each successive pregnancy loss. However, the recurrence rate after the loss of three pregnancies is only marginally increased, compared with the increased risk after two losses. This is why I and many other experts in the field now consider two consecutive losses sufficient for a thorough investigation.

Etiology

RPL has been associated with many factors and pathologies. Most women with RPL have early first-trimester losses, although some have recurrent losses in the second trimester. The causes of these first- and second-trimester RPLs are often different and require different types of investigations. Here, we focus on recurrent first-trimester loss.

Structural abnormalities of the uterus have been associated with RPL in many cases. In one recently published study, postabortal evaluation of the uterine anatomy with hysteroscopy revealed approximately 20%-40% with congenital or acquired abnormalities of the uterus. These included congenital uterine abnormalities such as partial or complete uterine septum or arcuate uterus, as well as acquired uterine abnormalities, such as intrauterine adhesions, myomas, or polyps (Eur. J. Obstet. Gynecol. Reprod. Biol. 2011;156:101-4).

The investigators did not find any statistically significant differences between hysteroscopic findings and the number of miscarriages. Intrauterine causes are important to evaluate, as many of these conditions can be surgically corrected and often result in successful subsequent pregnancies.

It is well known that chromosomal abnormalities are the predominant cause of miscarriage, and that the rate of chromosomally abnormal specimens from pregnancy loss increases with age. It has been reported across numerous investigations that 50%-70% of abortuses have a karyotypic chromosomal abnormality. Given the increased incidence of nondysjunction in women as they age, the incidence of recurrent miscarriage in women older than 35 years may be explained by this phenomenon.

For some couples, one partner may carry a balanced chromosomal rearrangement, and thus a karyotypic evaluation of each partner may reveal a cause. Karyotypic evaluation of the products of conception may be helpful as well. If the karyotype is normal, then other causes of recurrent miscarriage may be considered more likely to be contributing factors.

Certain endocrine disorders also are associated with RPL, although routine testing has not been recommended in the absence of clinical symptoms. Poorly controlled diabetes, for instance, increases the risk of first-trimester miscarriage, and if diabetes is not controlled in a subsequent pregnancy, miscarriage may occur again. There is no established norm for progesterone levels in the first trimester, but luteal phase defect or progesterone deficiency also have been implicated in RPL.

Thyroid dysfunction has been implicated in RPL as well, and recent reports on thyroid autoimmunity and miscarriage in women with normal thyroid function also are worthy of consideration. In one meta-analysis, 28 of 31 studies evaluating miscarriage showed a positive association between the presence of thyroid autoantibodies and miscarriage (BMJ 2011;342:d2616). The authors of another recent meta-analysis similarly found that the presence of thyroid autoimmunity was associated with an increased risk of miscarriage in euthyroid women, although the investigators also pointed out that the relationship is not necessarily casual (Clin. Endocrinol. [Oxf.] 2011;74:513-9).

The role of inherited thrombophilias in RPL is rather controversial, with a recent shift away from the belief that all thrombophilias put women at risk for RPL. Initial case-control studies were suggestive of increased risk for women with inherited thrombophilias, including factor V Leiden deficiency, prothrombin gene mutation, antithrombin III deficiency, protein C deficiency, and protein S deficiency. However, subsequent prospective evaluations have shown that these genetic disorders are more likely to be associated with later pregnancy loss and not early recurrent loss.

Antiphospholipid syndrome (APS) continues to be considered a major contributor to RPL, causing up to 15% of recurrent miscarriages. This disorder is an autoimmune disorder that manifests itself in vascular events or adverse pregnancy outcome in addition to the presence of antiphospholipid antibody. The diagnosis is made with the presence of one or more clinical scenarios and the presence of antibodies when the patient is tested on two occasions, at least 12 weeks apart.

Evaluation and Management

Given the wide array of potential causes of RPL, evaluation can be lengthy and potentially unfruitful.

On the other hand, because a significant number of uterine abnormalities are correctable, hysterosalpingogram, sonohysterography (also known as hysterosonography), or hysteroscopy are often worth performing. In a study of 60 nonpregnant patients with a history of at least three previous recurrent miscarriages, hysterosonography was found to have higher diagnostic accuracy in the detection of uterine cavity anomalies and was better tolerated by the patients, compared with the other two methods (Arch. Gynecol. Obstet. 2006;274:284-8). In the event that there is a congenital uterine malformation or an acquired abnormality, these can be managed with surgical correction of the abnormality.

Furthermore, if karyotype is available from any of the products of conception involved in the miscarriages, then karyotypic evaluation may be possible. An aneuploidy result in the setting of advanced maternal age may lead the clinician to suspect that nondysjunction is a factor in the RPL. In the event that the karyotype is normal, further investigation into other causes may be fruitful.

Parental karyotyping will reveal a balanced translocation 3%-6% of the time. However, as the authors of a case vignette point out, such karyotyping is expensive, and treatment options (IVF with preimplantation genetic diagnosis) have not been shown to improve outcome over spontaneous conception (N. Engl. J. Med. 2010;363:1740-7). These realities lead some couples to forego this type of testing.

Testing for diabetes and thyroid disease is not recommended as a screening measure in RPL unless the patient has symptoms suggestive of either condition. Although some experts might recommend testing for thyroid autoimmunity, the value of routine screening for thyroid autoantibodies in euthyroid women with RPL is unclear at this point. There is some evidence that treatment with levothyroxine can significantly reduce the risk of miscarriages (as described in the two previously cited meta-analyses) so for now, the reported association between thyroid autoimmunity and miscarriage is at least worthy of our consideration.

With regard to thrombophilias, the focus is increasingly on screening specifically for APS, and treating accordingly, rather than on screening more broadly for thrombophilias. Although some providers continue to evaluate for inherited thrombophilia in women with RPL, others now recommend that evaluation for inherited thrombophilia not take place outside a research setting.

Most people with inherited thrombophilias do well with pregnancies, and research thus far has not shown any clear benefit to heparin thromboprophylaxis (with or without aspirin) in women with inherited thrombophilia and RPL. A 2009 Cochrane review concluded that there is insufficient evidence to recommend the use of anticoagulants in women without antiphospholipid syndrome (Cochrane Database Syst. Rev. 2009 Jan. 21 [doi:10.1002/14651858.CD004734.pub3]).

Two more recent, controlled, randomized trials of women with unexplained RPL similarly showed no improvement in live-birth rates with the use of either low-dose aspirin or low-dose aspirin combined with low-molecular-weight heparin (N. Engl. J. Med. 2010;362:1586-96; Blood 2010;115:4162-7).

On the other hand, trials of women with antiphospholipid antibody syndrome have shown that pregnancy outcomes are improved with the use of aspirin plus heparin. A Cochrane review that covered 13 qualifying studies concluded that combined unfractionated heparin and aspirin may reduce pregnancy loss by 54% (Cochrane Database Syst. Rev. 2010 Jan. 20 [doi:10.1002/14651858.CD002859.pub2]).

Investigators are still exploring the potential differences between unfractionated and low-molecular-weight heparin (LMWH) in the setting of antiphospholipid syndrome. However, these formulations are used interchangeably so frequently in other settings that either can be selected for treatment of RPL. We favor the use of LMWH because dosing is once daily, as opposed to the twice-daily dosing schedule required for unfractionated heparin.

Luteal phase defects and progesterone deficiencies are difficult to diagnose. Although endometrial biopsy was once used to attempt to assess progesterone function, this has been not been shown to be beneficial in the evaluation of couples with RPL. However, a recent Cochrane review of progesterone for preventing miscarriage found that although there is no evidence to support the routine use of progesterone to prevent miscarriage in general, there appears to be evidence of benefit in women with a history of recurrent miscarriage (Cochrane Database Syst. Rev. 2009 July 8 [doi:10.1002/14651858.CD003511.pub2]). Regardless of the route of administration, progesterone supplementation was associated in this review with a statistically significant decrease in the miscarriage rate compared with placebo or no treatment in women with RPL (odds ratio, 0.38).

An Individualized Approach

In order to appropriately counsel and care for these patients, a thorough obstetric history is important and should help to guide evaluation and management. It is important to be sensitive to the emotional factors that come in to play for many couples who are going through the evaluation of pregnancy loss. I often reassure these women that this is a common problem and that even with repeated miscarriages they may still have successful pregnancies in the future without any intervention.

I give them a thorough explanation of the etiology of RPL, and emphasize that a cause might not be found. If a patient has any symptoms suggestive of diabetes, then I consider a fasting glucose or hemoglobin A1C test to confirm a diagnosis. Evaluation of the uterine cavity should be undertaken for all women with RPL.

I also recommend evaluation for antiphospholipid syndrome with lupus anticoagulant, anticardiolipin antibodies, and beta2-glycoprotein I antibodies. (See box.) In addition, I generally discuss with patients the controversy over testing for inherited thrombophilias. If there is any family history suggestive of thrombophilia, I will test for these. Otherwise, I discuss the potential for this testing and will often leave this up to the patient to decide.

After all the testing is complete, management is driven by the results, and when there are no positive results, progesterone supplementation can be offered.

Referral patterns likely vary by community, with either reproductive endocrinologists or maternal fetal medicine specialists providing consultation for these patients. It is important to appreciate, however, that general ob.gyns. – armed with the proper time and information – are also in the position to evaluate and work up an RPL case, and to provide the supportive care, empathy, and encouragement that patients need.

This column, “Master Class,” regularly appears in Ob.Gyn News, an Elsevier publication. Dr. Atkins is an assistant professor in the department of obstetrics, gynecology, and reproductive sciences, and the division of maternal/fetal medicine, at the University of Maryland in Baltimore. Dr. Atkins said she had no relevant financial disclosures.

Subject Codes:
top_stories; womens_health;


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January 30, 2012   02:41 PM EST

Rick Nishimura

BY MARY ANN MOON
Elsevier Global Medical News
Breaking News

A difference of 15 mm Hg or more in systolic blood pressure between a patient’s arms may signal the presence of asymptomatic peripheral vascular disease, according to a meta-analysis published online Jan. 30 in the Lancet.

Patients with this finding on physical examination might benefit from further assessment for peripheral vascular disease, much as those found to have reduced ankle-brachial pressure do. But simultaneous measurement of systolic BP in both arms is more easily done in the primary care setting, since such measurement in one arm is already routine and doesn’t require the time, experience, and training necessary for ankle-brachial pressure assessment, said Dr. Christopher E. Clark of the institute of health services research, University of Exeter (England), and his associates.

The most recent National Institute for Health and Clinical Excellence (NICE) guideline for hypertension states that a difference of 20 mm Hg or more between the arms is “unusual” and is often associated with underlying vascular disease, but doesn’t address smaller differences. The guideline also has advised routinely checking BP in both arms for several years, but most primary care physicians in the United Kingdom do not follow that advice, Dr. Clark and his colleagues said.

To establish whether small differences (10-15 mm Hg) in systolic blood pressure between the arms is associated with peripheral or cardiovascular disease, they performed a meta-analysis of 20 studies addressing the issue.

The investigators found that a difference of 10-15 mm Hg occurred in 12%-15% of the study subjects and was associated with peripheral vascular disease, with a low sensitivity but a very high specificity. This overall prevalence corresponds to published estimates in community studies, implying that findings of the meta-analysis are generalizable, they noted.

In particular, five studies that correlated systolic BP with findings on invasive angiography showed that a difference of 10 mm Hg or more was strongly associated with subclavian stenosis on the side with the lowest pressure (Lancet 2012 Jan. 30 [doi:10.1016/S0140-6736(11)61710-8]).

In pooled findings from studies with noninvasive assessments of vascular disease, a difference of 15 mm Hg or more was associated with not only peripheral vascular disease (sensitivity of 15% and specificity of 96%), but also with cerebrovascular disease (sensitivity of 8% and specificity of 93%) as well as increased cardiovascular and all-cause mortality.

In five studies, a difference as low as 10 mm Hg was associated with peripheral vascular disease (sensitivity of 32% and specificity of 91%).

These findings remained consistent across studies that used different methods of measuring BP, regardless of whether the cohorts comprised high-risk hospital-recruited patients or average-risk people living in the community.

Because this study was a misanalysis rather than a randomized clinical trial, “what constitutes a clinically important difference in systolic BP between arms is [still] unclear. However, we have associated a difference with an increased likelihood of peripheral vascular disease and with prospective differences in survival. Further research is needed to establish the upper limit of normal between-arm differences,” Dr. Clark and his associates wrote.

In an editorial accompanying this report, Dr. Richard J. McManus and Dr. Jonathan Mant wrote: “The high specificity (96%) of the association between a difference in systolic BP between arms of more than 15 mm Hg and peripheral vascular disease justifies the use of this measure as a sign of disease” (Lancet 2012 Jan. 30 [doi:10.1016/S0140-6736(11)61926-0]).

Ascertaining such differences should become part of routine care, “as opposed to a guideline recommendation that is mostly ignored,” said Dr. McManus of the department of primary care health sciences at the University of Oxford (England) and Dr. Mant of the department of public health and primary care at the University of Cambridge (England).

However, “the low sensitivity (15%) shows that measurement of differences is of little value as a screening test for peripheral vascular disease, and ankle-brachial pressure indices will still be necessary for diagnosis,” they noted.

Neither Dr. McManus nor Dr. Mant reported having any relevant financial disclosures.

This study was funded by the Royal College of General Practitioners, the South West GP Trust, and the Peninsula Collaboration for Leadership in Applied Health Research and Care. The investigators reported that they had no relevant financial disclosures.

Subject Codes:
top_stories; general_primary; cardiology;


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January 30, 2012   12:43 PM EST

A meta-analysis showed that systolic blood pressure difference between a patient’s arm could mean there is asymptomatic peripheral vascular disease.

BY JANE ANDERSON
Elsevier Global Medical News
Breaking News

Only 55% of parents with children aged 4-8 years always have their child use a car booster seat when driving with other children in the car, according to a study published Jan. 30 in Pediatrics.

The researchers surveyed 681 parents with 4- to 8-year-old children to ask about their safety seat practices, especially when carpooling. They found that most parents – 76% – reported using a booster seat when riding in the family car.

However, among the 64% of parents who carpool, 45% said they do not always have their child use their booster seat when driving with friends who don’t have boosters. “These findings suggest that social norms and self-efficacy for booster seat use may be influential in carpooling situations,” wrote Dr. Michelle L. Macy of the University of Michigan, Ann Arbor, and her associates (Pediatrics 2012;129:290-98).

Still, 54% of parents who frequently carpool said they would always ask another driver to use a booster seat for their child; that percentage rose to 64% in parents who occasionally carpool. In addition, parents who occasionally carpool were significantly more likely than were parents who carpool frequently to report their child always uses a booster seat, they found.

Physician should ask not just about use of size-appropriate child safety seats during office visits, but also whether parents consistently use them for their children and if there are any barriers to their use, such as perceived difficulty making arrangements to have booster seats available for other people’s children or problems transferring child safety seats between vehicles, Dr. Macy and her colleagues said.

Dr. Macy and her associates said they had no relevant financial disclosures. This research was conducted as part of the C.S. Mott Children’s Hospital National Poll on Children’s Health, sponsored by the department of pediatrics and communicable diseases at the University of Michigan and the University of Michigan Health System. The study was funded by a grant from the Michigan Center for Advancing Safe Transportation Throughout the Lifespan.

Subject Codes:
top_stories; pediatrics; general_primary;


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January 30, 2012   12:01 AM EST

BY SHARON WORCESTER
Elsevier Global Medical News
Breaking News

The incidence of renal scarring did not differ significantly in children with acute pyelonephritis and scintigraphy-documented acute lesions who were treated with oral antibiotics, compared with those treated with sequential intravenous and oral antibiotics in a prospective multicenter trial.

Although the trial wasn’t statistically powered to demonstrate noninferiority of oral treatment, compared with sequential intravenous/oral treatment, the findings confirm those of prior studies and support the use of oral antibiotics for primary acute pyelonephritis (APN) in this population, Dr. Nathalie Bocquet of Assistance Publique-Hôpitaux de Paris and her colleagues reported Jan. 30 in Pediatrics.

In 85 children randomized to receive treatment with oral antibiotics and in 86 randomized to receive sequential treatment with intravenous and oral antibiotics, the incidence of renal scarring based on per protocol analysis was 30.8% and 27.3%, respectively, the investigators said (Pediatrics 2012;129:e269-75).

Participants were infants and children aged 1-36 months who presented with a first case of febrile urinary tract infection (UTI) between August 2004 and April 2008 and who were found to have renal involvement based on serum procalcitonin measurement. All had normal ultrasound findings prenatally, no known uropathy, and no suspected uropathy after ultrasound examination at study inclusion. Dimercaptosuccinic acid (DMSA) scintigraphy was performed within 8 days of inclusion, and those found to have acute lesions underwent follow-up and scintigraphy 6-8 months later.

Treatment for those in the oral antibiotics group included 10 days of cefixime, consisting of an initial double dose of 8 mg/kg administered in the emergency department, followed by 4 mg/kg twice daily. Those in the sequential treatment group received 50 mg/kg of IV ceftriaxone for 4 days followed by oral cefixime at a dose of 4 mg/kg twice daily for 6 days.

After the initial 10-day treatment, antibiotic prophylaxis with co-trimoxazole or another antibiotic adapted to prevent bacterial resistance was continued for up to 1 month until voiding cystography (VCG) could be performed; prophylaxis was discontinued if the VCG findings were normal.

“The frequencies of renal scarring in our treatment groups are comparable with those of previous trials, which reported renal scarring frequencies of 15%-20% and 45%-60%,” the investigators noted.

Because high serum procalcitonin concentrations have been shown in prior studies to correlate with acute renal defects on DMSA scintigraphy, they used serum procalcitonin to identify children at high risk for renal involvement.

“Because one of our inclusion criteria was a PCT [procalcitonin] greater than or equal to 0.5 ng/mL, 85.4% of the patients in our study had positive acute phase scintigraphies,” they said, noting that in the prior studies, the rates ranged from 60.5% to 63.3%.

“Consistent with what has been previously reported, we found that serum PCT concentrations were significantly higher in children who developed scars than in those who had acute abnormalities but no definitive damage. For this reason, monitoring PCT levels in children afflicted with APN could help to identify those at risk for renal complications even in the absence of a suspected or documented uropathy,” they said.

Additionally, they noted that all pathogens isolated in this study were Escherichia coli, which is usually the main pathogen isolated in UTI.

“Antimicrobial treatment with cefixime is a safe choice as long as the likelihood of infection with an E. coli strain that is resistant to third-generation cephalosporins remains low,” they said, adding: “Our results support the use of a completely oral cefixime treatment for initial episodes of APN involving a gram-negative bacteria strain in infants and children aged 1 month to 3 years who are without urological abnormalities and without clinical hemodynamic impairment.”

This approach to treatment can be proposed for children with serum PCT concentrations greater than 0.5 ng/mL who are at high risk for renal involvement, as well as for those with lower PCT concentrations, despite their low risk for acute renal involvement, they said.

“Oral treatment can facilitate outpatient management of young children with APN because it reduces cost, familial disruption, and nosocomial disease exposure,” they concluded.

The findings by Dr. Bocquet and her colleagues provide additional support for the guidelines published last summer by the American Academy of Pediatrics for the treatment of infants and children with a first febrile UTI (Pediatrics 2011;128:e749-70), Dr. Daniel T. Coghlin said in an interview.

The guidelines note that oral antibiotics are just as effective as intravenous antibiotics are and in this study no significant difference was seen in regard to the rates of kidney scarring with oral vs. sequential intravenous/oral antibiotic treatment. Other studies that have looked at this same outcome from different angles all have come to the same conclusion, Dr. Coghlin of the department of pediatrics at Brown University, and a pediatric hospitalist at Hasbro Children’s Hospital, both in Providence, R.I., said.

“What’s different is that in this study the authors looked at children with elevated serum levels of procalcitonin, indicating elevated risk for pyelonephritis and even, with this increased risk, no difference in renal scarring was evident between the treatment groups,” he said, noting that although the study was too small to definitively show noninferiority, the weight of the available evidence is in favor of this approach.

Some have argued that the guidelines are not proactive enough in advocating the kind of testing that has been done traditionally and thus may lead to missing children who could potentially benefit from aggressive therapies that could be initiated sooner to help prevent kidney injury.

“In fact, most studies over the past 5-10 years have shown that we have probably been over-testing and over-treating children with UTI,” he said.

In one study published last year by Salo et al. (Pediatrics 2011;128:840-7), the investigators found no link between chronic UTIs in childhood and chronic kidney injury in adulthood. Of those cases showing even a possible link, all had some kind of structural problem that would have been found on ultrasound. This suggests that even if a difference in the rates of renal scarring was found in this new study, it’s not obvious that that matters, Dr. Coghlin said.

“The guidelines are the best tool for pediatricians to reference when they are deciding how to work up a first- time febrile UTI in an infant, and this study is supportive of those guidelines,” he added.

This study was supported by the Ministry of Health, the Direction de la Recherche Clinique, and the Unit of Clinical Research in Hospital Necker. Only one of the study authors, Dr. Vincent Gajdos had disclosures to report: He has received consulting fees from GlaxoSmithKline. Dr. Coghlin said he had no disclosures to report.

Subject Codes:
nephrology_urology; infectious; top_stories; pediatrics;


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January 30, 2012   12:01 AM EST

BY ELIZABETH MECHCATIE
Elsevier Global Medical News
Breaking News

Axitinib, a kinase inhibitor, received approval for the treatment of advanced renal cell cancer and is the seventh drug approved for metastatic or advanced kidney cell cancer since 2005, the Food and Drug Administration announced on Jan. 27.

“Collectively, this unprecedented level of drug development within this time period has significantly altered the treatment paradigm of metastatic kidney cancer, and offers patients multiple treatment options,” Dr. Richard Pazdur, director of the FDA’s Office of Hematology and Oncology Products, said in the FDA statement.

The approved indication for axitinib is for the treatment of advanced renal cell carcinoma (RCC) “after failure of one prior systemic therapy.” Approval was based on a single randomized, open-label, multicenter clinical study of 723 patients whose disease had progressed on or after treatment with one prior systemic therapy, according to the FDA statement.

In the study, median progression-free survival was 6.7 months among those treated with axitinib, compared with 4.7 months for those treated with sorafenib, a standard treatment for the disease. Both sorafenib (Nexavar), approved in 2005, and axitinib are selective inhibitors of vascular endothelial growth factor (VEGF) and are administered orally twice a day.

Axitinib has an antiangiogenic effect. It inhibits the proangiogenic cytokines vascular endothelial growth factor (VEGF) and platelet-derived growth factor receptors (PDGF), according to the National Cancer Institute.

Axitinib will be marketed as Inlyta by Pfizer. Axitinib inhibits receptor tyrosine kinases, including vascular endothelial growth factor receptors (VEGFR)-1, VEGFR-2, and VEGFR-3 at therapeutic plasma concentrations. These receptors are implicated in pathologic angiogenesis, tumor growth, and cancer progression. VEGF-mediated endothelial cell proliferation and survival were inhibited by axitinib in vitroand in mouse models. Axitinib was shown to inhibit tumor growth and phosphorylation of VEGFR-2 in tumor xenograft mouse models.

The other targeted treatments for advanced RCC that have been approved are VEGF-receptor inhibitors sunitinib (Sutent) and pazopanib (Votrient), the anti-VEGF antibody bevacizumab (Avastin), and the mammalian target of rapamycin (mTOR) inhibitors temsirolimus (Torisel) and everolimus (Afinitor).

The most common side effects reported to occur among more than 20% of patients treated with axitinib included diarrhea, hypertension, fatigue, decreased appetite, nausea, dysphonia, hand-foot syndrome (palmar-plantar erythrodysesthesia), weight loss, vomiting, asthenia, and constipation.

The warnings and precautions section of the label advises that blood pressure should be well controlled before patients start treatment with axitinib and should be monitored during treatment.

At a meeting on Dec. 7, 2011, the FDA’s Oncologic Drugs Advisory Committee unanimously recommended that axitinib be approved for advanced RCC, based on the study findings, although the efficacy findings were driven primarily by the results among patients previously treated with cytokines, a population less likely to be seen in the United States.

Subject Codes:
nephrology_urology; top_stories; oncology;


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January 27, 2012   04:06 PM EST

Elsevier Global Medical News

An article titled “Lansoprazole Disappoints for Poorly Controlled Asthma in Kids,” published January 24, 2012, used an incorrect pronoun when referring to Dr. Nicola Hanania.

Subject Codes:
top_stories; gastroenterology; new_drugs; pediatrics; allergy; pulmonology;


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January 27, 2012   03:00 PM EST

BY FRANCES CORREA
Elsevier Global Medical News
Breaking News

The American College of Physicians is calling on Congress to do away with the automatic, across-the-board budget cuts called for by the Budget Control Act and to replace the Medicare Sustainable Growth Rate formula.

“While we are pleased there is progress being made to improve access, reduce costs, and address physician shortages, recent and proposed cuts in federal funding for many critical health programs threaten to turn back the clock,” Dr. Virginia Hood, ACP president, said at a briefing to release the organization’s State of the Nation’s Health Care 2012 report.

Dr. Hood said that, while the Affordable Care Act has gone far to improve health care, the automatic cuts called for by the Budget Control Act would negate that progress, starting in 2013.

Included in the cuts is a 2% Medicare pay cut to physicians, hospitals, and other providers. That’s on top of the impending 27.5% cut to physician fees called for by the Sustainable Growth Rate (SGR) formula, set to go into effect March 1.

To solve the impending crisis in Medicare physician fees, ACP advocates an SGR replacement plan that includes a 2% pay increase for primary care physicians each year for 5 years. Specialist pay would be protected from any further reductions. ACP suggests using dedicated funds no longer needed for overseas military operations to fund this interim solution. The plan also calls on the Centers for Medicare and Medicaid Services to assess new value-based payment models.

After 5 years, physicians would be required to transition to the payment model found to be most effective.

ACP is also submitting a list of questions to Republican presidential candidates and President Obama about the future of the Affordable Care Act.

Questions to Republican hopefuls include what health reform provisions they would consider maintaining and what strategies they would have to increase access to health insurance. Questions to Mr. Obama include how he would address concerns that the health reform law gives the government too much power.

Bob Doherty, ACP Senior Vice President of Governmental Affairs and Public Policy, said at the briefing that political infighting surrounding health care is blocking progress and disheartening the American people.

“Regrettable though, a broken political culture that demands confrontation over compromise has made it impossible for congress to achieve agreements and some common sense, common ground bipartisan approaches,” Mr. Doherty said. “The 2012 elections unfortunately will likely result in more inflammatory and misleading rhetorical attacks intended to fire up voters, causing even more cynicism, polarization and a lack of confidence in the ability of elected government to deal responsibly with healthcare.”

Mr. Doherty said that it’s critical for Congress take immediate action to address the flawed SGR system this year.

“Congress has punted on this issue every year since 2002. It makes no sense to do that again, especially if the consequence of that is another round of deep cuts,” Mr. Doherty said.

The ACP plan also outlines strategies for reducing defensive medicine costs by enacting caps on noneconomic damages and authorizing a pilot of no-fault health courts. Lastly, the plan lists strategies for promoting cost-effective, value-based care. Recommendations include creating a single deductible for Medicare Parts A and B, providing patients and clinicians with information on effectiveness of different procedures, and negotiating prescription drug prices under Medicare part D.

Subject Codes:
top_stories; general_primary;


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January 27, 2012   02:10 PM EST

Virginia Hood

BY ELIZABETH MECHCATIE
Breaking News

U.S. cancer screening rates in 2010 were below national targets for 2020, particularly among Asians and Hispanics, according to a report issued Jan. 26 by the Centers for Disease Control and Prevention and the National Cancer Institute.

“It is troubling to see that not all Americans are getting the recommended cancer screenings, and that disparities continue to persist for certain populations,” Dr. Sallyann Coleman King, the study’s lead author and an epidemic intelligence service officer in the CDC’s Division of Cancer Prevention and Control, said in a statement.

The study’s authors used data from the 2010 National Health Interview Survey, which is monitoring progress toward the screening goals in Healthy People 2020 (MMWR Morb. Mortal. Wkly. Rep. 2012;61:41-5). That initiative has set objectives for improving the health of Americans – including the use of screening tests for breast, cervical, and colorectal cancer, as recommended by the U.S. Preventive Services Task Force.

This is the first federal study that has identified disparities in cancer screening rates among Asian and Hispanic groups, according to the CDC.

The results illustrate “the particular need for finding ways to increase the use of breast, cervical, and colorectal cancer screening tests among Asians, Hispanics, as well as adults who lack health insurance or a usual source of health care,” noted study coauthor Carrie Klabunde, Ph.D., an epidemiologist in the NCI’s Division of Cancer Control and Population Sciences.

The Health People 2020 screening goals for breast, cervical, and colorectal cancer are:

– 81.1% of women aged 50-74 years undergo breast cancer screening via mammography every 2 years.

– 93% of women aged 21-65 years with a cervix undergo Pap smear testing every 3 years to screen for cervical cancer and precancerous lesions.

– 70.5% of both men and women are screened regularly for colorectal cancer between the ages of 50 years and 75 years.

In the new study, Dr. King and her associates found that:

– The overall rate of breast cancer screening was 72.4%. Between 2000 and 2010, screening rates for breast cancer were “relatively stable,” according to the CDC, with no more than a 3% variation during that time.

– The overall rate of cervical cancer screening was 83%. However, during the decade, the rate of women who said they had had a Pap test within the previous 3 years dropped by 3.3% – a small but statistically significant reduction.

– The overall rate of colorectal cancer screening among men and women was 58.6%. During the 2000-2010 period, colorectal cancer screening rates “increased markedly” for both sexes, and were almost identical for men (58.5%) and women (58.8%). The rate for women had increased slightly faster during the decade, to catch up with the rate for men.

Among Asians (Chinese, Filipino, or other Asians), screening rates for all three cancers were significantly lower: 64.1% for breast cancer, 75.4% for cervical cancer, and 46.9% for colorectal cancer. Among Hispanics (Puerto Rican, Mexican, Mexican-American, Central or South American, or other Hispanics), the screening rates were lower for cervical (78.7%) and for colorectal cancer (46.5%), compared with non-Hispanics (83.8% and 59.9%, respectively).

Not having a usual source of health care or health insurance was associated with “considerably” lower rates for screening of all three cancers.

Among women with no usual source of health care or no health insurance, mammography rates were much lower, at about 36%-38%. And although immigrant women who had lived in the United States for a decade were nearly as likely as were women born in the United States to have had a mammogram (about two-thirds), 46.6% of women who had lived in the United States for less than 10 years said they had been screened in the previous 2 years.

While financial barriers to screening “might explain some of the disparities in cancer screening rates,” the report referred to national programs that provide free or low-cost breast, cervical, and colorectal screening. The study’s authors also noted that the Affordable Health Care Act is expected to help people who can’t afford screening by expanding insurance coverage.

“Efforts should be made to improve screening rates in all population groups,” including targeted efforts for groups with particularly low screening rates, the report authors said. In addition, “other efforts are needed, such as developing systems that identify persons eligible for cancer screening tests, actively encouraging the use of screening tests, and monitoring participation to improve screening rates.”

The study authors provided no disclosure information.

Subject Codes:
top_stories; general_primary; oncology; womens_health;


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January 26, 2012   03:28 PM EST

A report on U.S. cancer screening rates in 2010 noted that the overall rate of breast cancer screening was 72.4%, well under the 81.1% target of screening via mammogram (pictured above) for 2020.

by mary ellen schneider
Elsevier Global Medical News

Two years from now, millions of previously uninsured Americans will gain health coverage through the Medicaid program. With that in mind, section 2701 of the Affordable Care Act instructs officials in the Health and Human Services Department to design a voluntary quality measurement program focused on the care of new adults coming into the program. On Jan. 4, HHS published the initial core set of health care quality measures for Medicaid-eligible adults. The initial set includes 26 quality indicators that cover adult health, maternal/reproductive health, complex health care needs, and mental health and substance use. Measures were selected based on recommendations from the Agency for Healthcare Research and Quality, which convened a committee of state Medicaid representatives and health care quality experts to pare down a list of about 1,000 possible measures.

Matt Salo, executive director of the National Association of Medicaid Directors, shared his thoughts on how HHS did in assembling the list of core measures and how the quality program could affect the success of the Medicaid expansion.

Question: Participation in the program is voluntary. Does that make it less effective?

Mr. Salo: I would argue that it’s voluntary largely for political reasons. When you’re trying to push adoption of any kind of change, whether that’s changing state Medicaid programs or the behavior of physicians, making that change voluntary is a lot more politically palatable. I don’t think it makes it less effective. One of the things that we’ve learned is that quality measures are constantly evolving. The concept of measuring quality is by no means a new one; we’ve been doing this for decades. But what we measure, who we measure it on, and how we measure it is constantly changing. As a result, it’s actually very difficult for anyone to say, ‘yes, we know what the absolute answer is and we’re going to carve it into stone and everyone has to do it now.’ The voluntary nature of this is kind of a testament to that. You will see people adopting it and maybe tweaking it slightly, but they will get there.

Question: Will this program help states to prepare for the 2014 Medicaid expansion?

Mr. Salo: Yes, in part. This is a very small slice of what states are going to need to do to prepare for 2014. But it is relevant because the bulk of people who will be coming into the Medicaid program in 2014 are going to be adults, which is in contrast to the bulk of people who are on Medicaid today: pregnant women and children.

Question: How do Medicaid programs currently evaluate quality of care?

Mr. Salo: Every state measures quality today; it’s just that they do it in different ways. They measure different things. They measure different populations. They measure them in different time periods and in different quantities. This program helps because it starts to give quality measurement a little bit more structure. As HHS was going about putting these measures together, they looked at thousands of different quality measures from numerous different sources and were able to sift through to find the ones that really make a difference and are accurate and effective and narrow that down to a fairly small number. By doing that, it does give states something of a road map to try to narrow down the diversity of approaches they are taking and start to provide more commonality across states and across programs and across providers.

Question: Would you add or delete anything from the core list of measures?

Mr. Salo: At this point, I wouldn’t change anything from that list. I think it’s a really solid first effort. Once put into practice, we may start to see that there’s something that was missed or a measure that isn’t really useful. But I think at this stage of the game they’ve done a really good job.

Question: Physicians are being asked to measure their performance by many payers already. Will this create an additional burden for them?

Mr. Salo: Medicaid directors are frequently inundated with new requirements from Congress or HHS, so this is something that we grapple with too. We are very sensitive to the potential for overburdening physicians on this. My sense, though, is that this is actually going to go in the opposite direction. There really aren’t, or at least there shouldn’t be, any physicians out there who aren’t participating in some kind of quality measurement. This effort should help focus and streamline the future of quality reporting for physicians. I see this as potentially reducing the burden, not increasing it. It’s going to provide some really useful tools that the states will use, that insurance plans will use, but that physicians can use too. Obviously physicians care very deeply about how they are performing compared to the practice down the street or across the state. This is going to start creating a lot more apples-to-apples comparisons that physicians are going to be able to use to find out more. I think that’s a good thing no matter how you slice it.

Subject Codes:
top_stories;


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January 26, 2012   01:07 PM EST

Matt Salo

BY BRENDA SANDBURG
“The Pink Sheet”
Breaking News

Generic drug manufacturer Ranbaxy Laboratories Ltd. will have to withdraw all drug applications that contain data generated at one of its facilities in India and relinquish 180-day marketing exclusivity for three pending abbreviated New Drug Applications under a consent decree for permanent injunction filed Jan. 25 by the U.S. Department of Justice.

The decree follows a lengthy investigation by the DOJ and the U.S. Food and Drug Administration that found numerous problems at three Ranbaxy facilities in India and one facility in Gloversville, N.Y.

According to the DOJ, the problems with Ranbaxy’s drug manufacturing and testing include failure to keep records showing that drugs had been manufactured properly; failure to investigate evidence indicating that drugs did not meet their specifications; failure to adequately separate the manufacture of penicillin drugs from nonpenicillin drugs in order to prevent cross-contamination; lack of adequate procedures to prevent contamination of sterile drugs; and inadequate testing of drug to ensure that they maintained strength and effectiveness until their expiration date.

The government also said that Ranbaxy submitted false data in drug applications, including backdating tests and submitting test data for which no test samples existed.

The consent decree is unprecedented in its scope, according to DOJ officials.

“This action against Ranbaxy is groundbreaking in its international reach – it requires the company to make fundamental changes to its plants in both the United States and India,” Assistant Attorney General Tony West said in a statement. “Submitting false data to the FDA in drug applications will not be tolerated.”

Ranbaxy said in a statement that the consent decree would not affect the company’s recently launched generic atorvastatin, because it is not manufactured in the facilities cited in the decree.

“Today’s announcement is the next step in the process of finalizing our agreement with the FDA to resolve this legacy issue,” according to Arun Sawhney, managing director of Ranbaxy Laboratories. “We are pleased with the progress we have made in upgrading and enhancing the quality of our business and manufacturing processes and remain committed to ensuring that all of our facilities and products meet the high standards that patients, prescribers and the public have come to expect from Ranbaxy.”

Ranbaxy announced earlier that it had entered into the consent decree with the FDA and had set aside $500 million to settle the related DOJ investigation. The consent decree itself does not mention the size of the settlement, although it does note that “if defendants fail to comply with any provision of the law or this decree at any covered facility and/or with respect to any affected application, then [they] ... shall pay to the United States of America $15,000 in liquidated damages for each day such violation continues.”

The company also agreed to relinquish the 180-day marketing exclusivity that it might have for three pending generic applications, but did not specify which drugs would be affected. The company also agreed to relinquish any 180-day marketing exclusivity that it may have for several additional generic applications if it fails to meet certain decree requirements by specified dates.

The manufacturing plants cited in the consent decree are the Paonta Sahib, Batamandi, and Dewas facilities, all in India, and the now-closed facility of Ranbaxy’s Ohm Laboratories subsidiary in Gloversville, N.Y. Import alerts for more than 30 products manufactured at the Paonta Sahib and Dewas sites have been in place since September 2008.

The consent decree also prevents Ranbaxy from manufacturing drugs for introduction to the U.S. market and for the President’s Emergency Plan for AIDS Relief Program at the four facilities.

Brenda Sandburg is a reporter for “The Pink Sheet.” This news organization and “The Pink Sheet” are owned by Elsevier.

Subject Codes:
top_stories; dermatology; cardiology;


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January 26, 2012   01:48 PM EST

BY HEIDI SPLETE
Elsevier Global Medical News
Breaking News

The prevalence of oral human papillomavirus is nearly three times higher in men than in women, according to data from more than 5,000 individuals in the United States.

The findings were simultaneously published online in JAMA and presented at the Multidisciplinary Head and Neck Cancer Symposium in Phoenix on Jan. 26 (JAMA 2012;307: [doi: 10.1001/jama.2012/101]).

Oral HPV infection causes a subset of oropharyngeal squamous cell carcinoma (OSCC) that has increased in several countries, including the United States, over the past 3 decades, said Dr. Maura L. Gillison of the Ohio State University, Columbus, and her colleagues. “HPV has been directly implicated as the underlying cause,” they noted. However, the epidemiology of OSCC has not been well studied.

The researchers conducted a cross-sectional study of HPV infection as part the National Health and Nutrition Examination Survey (NHANES) for 2009-2010. The study population included 5,579 men and women aged 14-69 years who were tested for HPV at mobile centers.

Overall, the prevalence of any HPV infection was 6.9%, and the prevalence of HPV type 16 (the type associated with OSCC) was 1%. The prevalence of any HPV infection was significantly higher in men than in women (10.1% vs. 3.6%, P less than .001). The peak prevalence of oral HPV occurred in people aged 30-34 years (7.3%) and 60-64 years (11.4%).

Infection in either gender was significantly more common in those with a history of any sexual contact (7.5%), compared with those who had no history of sexual contact (0.9%). The risk of infection also increased significantly as the number of sex partners for any type of sex increased. “One in five individuals with more than 20 lifetime sexual partners was infected,” the researchers said.

Univariate associations between risk of oral HPV infection and alcohol and marijuana use did not remain significant in a multivariate analysis. However, cigarette smoking remained independently associated with an increased risk of oral HPV infection. The risk significantly increased with the number of cigarettes smoked daily for both men and women, but this trend was stronger in women.

In a multivariate analysis, age, gender, number of sexual partners, and number of cigarettes smoked daily remained independently associated with an increased risk of oral HPV infection.

“Our data provide evidence that oral HPV infection is predominantly sexually transmitted,” the researchers said. Although HPV-positive OSCC has been associated with oral sex in particular, this study could not associate infection with a particular sexual behavior, they added.

The findings were limited by the emphasis on Alpha-papillomaviruses only, which likely underestimates the prevalence of oral HPV infection, the researchers said. But the findings suggest that vaccine trials to test the efficacy of the current HPV vaccine against oral HPV may be warranted. “Such trials could inform ongoing discussions regarding the benefits of HPV vaccination for males, given the higher prevalence of oral HPV infection demonstrated here as well as higher incidence of HPV-positive OSCC among men,” they said.

“Human papillomavirus–positive oropharyngeal tumors are increasing in incidence and exceed the number of tumors caused by the more traditional risk factors of tobacco and alcohol abuse,” said Dr. Hans P. Schlecht in an editorial accompanying Dr. Gillison’s study (JAMA 2012 [doi: 10.1001/jama.2012.117]). The findings are noteworthy because they estimate oral HPV prevalence based on sexual experience, smoking history, and immune suppression, he said. In addition, the researchers found that HIV-negative individuals had lower rates of HPV infection of the mouth than at other sites, he said.

Additional research is needed to study how HPV-related oropharyngeal dysplastic lesions develop, said Dr. Schlecht, who is affiliated with the division of infectious diseases and HIV medicine at Drexel University in Philadelphia. But “there is meaningful hope that prevention efforts will ameliorate the effects of HPV-related oropharyngeal cancer,” he said.

Although HPV vaccination may eventually play a role in reducing cancers related to oral HPV infection, such an impact will take time, Dr. Schlecht noted. Meanwhile, “clinicians should encourage their patients who engage in oral sex to use barrier protection,” he said. In addition, clinicians should be alert to signs of oropharyngeal cancer, including problems with speech or swallowing, ear pain, neck masses, and unexplained weight loss, he said.

The Multidisciplinary Head and Neck Cancer Symposium is sponsored by the American Society for Radiation Oncology.

Study sponsors included the Ohio State University Comprehensive Cancer Center and the National Cancer Institute. Dr. Gillison has served as a consultant to study sponsor Merck and to GlaxoSmithKline. Dr. Schlecht reported no conflicts of interest.

The incidence of HPV-positive oropharyngeal cancers increased 225% – from 0.8/100,000 to 2.8/100,000 – between 1988 and 2004, according to a presentation by Dr. Gillison at the annual meeting of the American Society of Clinical Oncology in June 2011. Click here for a report on the earlier findings.

Subject Codes:
infectious; top_stories; oncology;


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January 26, 2012   09:00 AM EST

BY SHARON WORCESTER
Elsevier Global Medical News
Breaking News

Adding bevacizumab to neoadjuvant chemotherapy in patients with early-stage HER2-negative breast cancer significantly improves pathological complete response, according to preliminary reports from two large randomized clinical trials.

The published results are likely to reopen debate over the recent U.S. Food and Drug Administration decision to revoke an indication for bevacizumab (Avastin) in metastatic breast cancer and the use of surrogate end points for survival in breast cancer trials.

Findings from the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-40 trial and the GeparQuinto (GBG44) trial appear in the Jan. 26 issue of The New England Journal of Medicine.

Docetaxel-Based Chemo in NSABP B-40

In NSABP B-40, 1,206 patients were enrolled between Jan. 5, 2007 and June 20, 2101 and randomly assigned to receive docetaxel (Taxotere), docetaxel plus capecitabine (Xeloda), or docetaxel plus gemcitabine (Gemzar) for four cycles. All groups received doxorubicin and cyclophosphamide for an additional four cycles, and the participants were additionally assigned to receive or not receive bevacizumab (Avastin) – an antiangiogenic monoclonal antibody against vascular endothelial growth factor (VEGF), for the first 6 of the 8 treatment cycles.

The addition of the antimetabolites capecitabine or gemcitabine had no significant effect on pathological complete response in the breast, with, respectively 29.7% and 31.8% of patients achieving that primary end point, compared with 32.7% of those receiving only docetaxel, Dr. Harry D. Bear of Virginia Commonwealth University, Richmond and his colleagues reported (N. Engl. J. Med. 2012;366:310-20).

Adding bevacizumab, however, increased the rate of pathological complete response in the breast significantly from 28.2% to 34.5%. Subgroup analysis indicated the effect was more pronounced in patients with hormone receptor–positive tumors (the rate increasing significantly from 15.1% without bevacizumab to 23.2% with bevacizumab) than in hormone receptor–negative tumors (47.1% and 51.5%, respectively), the investigators said. The benefit of bevacizumab tended to be seen more in patients with a high tumor grade.

Epirubicin-based Chemo in GeparQuinto

In the GeparQuinto trial, 1,948 patients were enrolled from November 2007 through June 2010 and randomized to receive neoadjuvant epirubicin (Ellence) and cyclophosphamide followed by docetaxel either with or without bevacizumab.

Pathological complete response occurred in 18.4% of those who received bevacizumab, compared with 14.9% of those who did not (odds ratio, 1.29), Dr. Gunter von Minckwitz of the German Breast Group, Neu-Isenburg, Germany and his colleagues reported. (N. Engl. J. Med. 2012;366:299-309). After adjusting for age, clinical tumor and nodal stage, hormone-receptor status, tumor grade, and histologic type, the odds ratio was 1.36.

In contrast with the findings from NSABP B-40, the greatest effects of bevacizumab in GBG44 were seen in the 633 patients with triple-negative tumors (27.9% without vs. 39.3% with bevacizumab), compared with the 1,262 patients with hormone-receptor-positive tumors (7.8% and 7.7%, respectively). The test for interaction for this finding was not significant, but the study was not powered to show these differential effects, the investigators noted.

Investigators from both trials suggested that possible reasons for the divergent findings between the studies include differences in inclusion criteria and drug dosing and/or sequencing.

The NSABP B-40 investigators noted that “the increased rate of pathological complete response in patients with hormone receptor–positive tumors is encouraging, since this group tends to have low rates of pathological complete response with chemotherapy.”

Bevacizumab was associated with toxic effects in both studies, including hand-foot syndrome, mucositis, hypertension, and left ventricular systolic dysfunction in NSABP B-40, and with bleeding, febrile neutropenia, mucositis, hand-foot syndrome, infection, and hypertension in GBG44.

Survival Results Pending

The NSABP B-40 investigators said that the potential for bevacizumab to improve patient outcomes should be clarified when disease-free and overall survival results become available for those who underwent surgery in this study, and for those in other ongoing studies.

They also noted that “the collection of tissue samples from all our patients before treatment, a major advantage of the neoadjuvant approach, offers an opportunity to discover molecular markers that might predict a benefit from bevacizumab.”

The GBG44 investigators noted that because of the short follow-up in their study, it cannot be confirmed that the observed increases in the rate of pathological complete response will translate into a survival advantage.

“However, given that pathological complete response has been shown to be highly correlated with outcome, particularly in patients with triple-negative disease, we speculate that the beneficial effects will be sustained,” they said, adding, “Long-term follow-up data are needed before this treatment option can be fully understood.”

Dosing in the studies was as follows:

In NSABP B-40, docetaxel was administered intravenously at 100 mg/m² on day 1 of the cycle every 3 weeks in the docetaxel-only group, followed by four cycles of doxorubicin-cyclophosphamide at 60 mg/m² and 600 mg/m², respectively, administered intravenously every 3 weeks. Docetaxel was administered at a dose of 75 mg/m² on day 1 in the docetaxel plus capecitabine or gemcitabine groups followed by the doxorubicin-cyclophosphamide. The capecitabine dose was 825 mg/m² twice daily on days 1-14; the gemcitabine dose was 1,000 mg/m² on days 1 and 8. The bevacizumab dose was 15 mg/kg administered intravenously for the first six cycles.

In GBG44, epirubicin was administered at a dose of 90 mg/m²and cyclophosphamide was administered at a dose of 600 mg/m²– both on day 1, every 3 weeks for four cycles, followed by four cycles of docetaxel a dose of 100 mg/m² on day 1, every 3 weeks. As in NSABP B-40, bevacizumab was administered at a dose of 15 mg/kg intravenously. In this study, however, it was administered every 3 weeks starting on day 1 of the first epirubicin-cyclophosphamide cycle for 8 cycles.

While the results of these studies are particularly timely given the U.S. Food and Drug Administration’s revocation in November of its 2008 approval of bevacizumab in combination with paclitaxel for the treatment of metastatic breast cancer, they do little to quell the controversy surrounding bevacizumab, Dr. Alberto J. Montero and Dr. Charles Vogel of the University of Miami Sylvester Comprehensive Cancer Center said in an accompanying editorial (N. Engl. J. Med. 2012;366:374-5).

The studies were designed based on the “plausible assumption” that a surrogate clinical end point such as progression-free survival – the end point used in the trials on which bevacizumab was initially approved – should be used in cases of metastatic breast cancer.

“The unresolved issue is whether significant improvements in a surrogate end point ... in the absence of a benefit for overall survival, are potentially predictive of curative benefits in patients with earlier-stage breast cancer,” they said; only data on recurrence and survival from ongoing trials will resolve this issue.

The controversy also involves broader questions about the use of surrogate end points, as well as about economic factors such as the ever-increasing cost of new cancer drugs.

“It is through this lens that the NSABP B-40 and GBG44 trials should be viewed, since each of these trials reports a significant improvement with bevacizumab in another putative surrogate clinical end point: pathological complete response,” they said, adding that if such surrogate end points are ultimately shown to predict survival benefits in earlier-stage disease, their use in clinical research will be vindicated – and the FDA’s recent action will be further called into question.

“However, in the context of unsustainable expenditures for cancer care in the United States, any survival benefit of bevacizumab, or other molecularly targeted drugs, will be balanced against the considerable development costs of modern molecularly targeted oncology drugs,” they said.

NSABP B-40 was supported by grants from the National Cancer Institute, the Department of Health and Human Services, the Public Health Service, F. Hoffman-La Roche, Genentech USA, and Eli Lilly. GeparQuinto was supported by grants from Sanofi-Aventis and Roche, Germany. Dr. Vogel had several disclosures. Detailed individual author disclosures are available with the full text of the articles at NEJM.org.

Subject Codes:
top_stories; oncology; womens_health;


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January 25, 2012   05:00 PM EST

Gunter von Minckwitz

BY SHARON WORCESTER
Elsevier Global Medical News
Breaking News

Adults with an optimal cardiovascular risk profile at age 55 have a substantially lower risk of death from cardiovascular disease through age 80 years, and a lower lifetime risk of fatal coronary heart disease, nonfatal myocardial infarction, and stroke, compared with those who have two or more major risk factors, according to a meta-analysis of 18 studies involving more than 257,000 adults.

The findings, which have important disease prevention and public health implications, were consistent across race and diverse birth cohorts, Dr. Jarett D. Berry of the University of Texas Southwestern Medical Center, Dallas and his colleagues report in the Jan. 26 issue of The New England Journal of Medicine.

The investigators conducted their meta-analysis at the individual level using data from studies that included black men and women and white men and women who were assessed for cardiovascular risk factors at ages 45, 55, 65, and 75 years. Patients were stratified into five mutually exclusive risk categories based on blood pressure, cholesterol level, smoking status, and diabetes status; only about 5% of participants comprised the optimal risk category, and about two-thirds comprised the two highest-risk groups.

The risk of cardiovascular disease-related death through age 80 years was 4.7% and 6.4% in men and women, respectively, who were nonsmokers without diabetes, and who had a total cholesterol level of less than 80 mg/dL, and blood pressure less than 120 mm Hg systolic and 80 mm Hg diastolic at age 55 years. The risk was 30% and 21% in men and women, respectively, with two or more major risk factors at that age, they said (N. Engl. J. Med. 2012;366:321-9).

The risk of fatal coronary heart disease or nonfatal MI was 3.6% and less than 1% in men and women, respectively, with the optimal risk factor profile, compared with 37.5% and 18.3% in men and women, respectively, with two or more major risk factors. The risk of fatal or nonfatal stroke was 2.3% and 5.3% in men and women with the optimal profile, compared with 8.3% and 10.7% in those with at least two major risk factors.

Similar patterns were seen based on assessments at other ages.

Significant, but expected, differences in the burden of risk factors were seen between older and younger birth cohorts, such as a higher prevalence of diabetes, a lower prevalence of smoking, and lower mean total cholesterol and systolic blood pressure in 55-year-old men born after 1920, compared with those born before 1920. Also, the burden of risk factors was higher among blacks than among whites, when participants were stratified according to race.

This approach to characterizing the lifetime risk of cardiovascular disease provides a more comprehensive assessment of overall disease burden in the general population than does the more common approach that calculates global, 10-year risk estimates, the investigators said, explaining that the majority of adults in the U.S. who are considered to be at low risk in the short-term, are actually at high risk across their lifespan.

It is an approach applauded by Dr. Paul D. Thompson, director of cardiology at Hartford Hospital, who said in an interview that many in the field have been troubled by the tendency to use 10-year risk estimates.

“Nobody wants to live just 10 years,” he said, adding that it’s important to be able to provide younger patients with a broader picture of lifetime risk.

“This study does not give us the ability to calculate 20- and 30-year risk, but it does introduce that concept,” he said.

It also introduces the intriguing and somewhat novel concept of primordial prevention, he said.

According to the investigators, the findings “strongly reinforce the influence of traditional risk factors on the lifetime risk of cardiovascular disease” and despite the development of notable secular trends in the prevalence of risk factors over the past 4 decades, the effect of those risk factors remained remarkably consistent across birth cohorts, they said.

In fact, they concluded that it is the presence or absence of traditional risk factors, rather than race or birth cohort, that appears to be the most consistent determinant of long-term cardiovascular disease risk – a conclusion based in part on a finding that despite an overall higher prevalence of risk factors in black than in whites, the lifetime risks of end points related to cardiovascular disease were similar in blacks and whites when risk factor profiles were similar.

This is not a surprising finding, Dr. Thompson said, noting that the study emphasizes “the classic risk factor model we’ve talked about all along,” and debunks some myths about age, race, and other factors.

“I think that’s a useful message,” he said.

The findings, according to the investigators, have important implications for clinical disease prevention and public health practice.

“First, the effect of untreated risk factors has been fairly constant for decades. Therefore, the present estimates of lifetime risk, made on the basis of current or projected risk-factor levels, may be important in estimating the future burden of cardiovascular disease in the general population. Second, efforts to lower the burden of cardiovascular disease will require prevention of the development of risk factors (primordial prevention) rather than the sole reliance on the treatment of existing risk factors (primary prevention),” they wrote.

Also, the findings are consistent with prior observations that the decline in cardiovascular event rates in the general population reflect changes in risk factor prevalence as opposed to treatment effects alone.

“For example, 44.3% of the overall decline in the U.S rates of death from coronary heart disease in 1980 and 2000 was attributed to population changes in levels of serum total cholesterol (24.2%) and systolic blood pressure (20.1%). The effects of clinical treatment on these risk factors were more modest, with statin and antihypertensive therapy accounting for 4.9% and 7.0% of the decline, respectively.”

“These observations were extended to long-term risk estimates, showing that changes in the prevalence of risk factor profiles strongly influence lifetime risk estimates in the general population,” the authors wrote.

Although the concept of primordial prevention is intriguing, the findings don’t obviate the need for maintaining a focus on primary prevention. The treatment effects mentioned by the investigators are small, but given the number of patients who get heart disease, they represent an enormous effect, Dr. Thompson said.

This study was supported by grants from the National Heart, Lung, and Blood Institute and the American Heart Association, and by funding from the Dedman Family Scholar in Clinical Care endowment at the University of Texas Southwestern Medical Center. Dr. Thompson is a consultant, has done research, or has received speaking honoraria numerous manufacturers of lipid-lowering drugs, including GlaxoSmithKline, Merck, Pfizer, and AstraZeneca. Individual author disclosures are available with the full text of the article at NEJM.org.

Subject Codes:
top_stories; diabetes; general_primary; cardiology; gerontology;


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January 25, 2012   05:00 PM EST

BY ALICIA AULT
Elsevier Global Medical News
Breaking News

Although the Republican primaries this year have been anything but predictable, one thing is fairly certain: Health care issues will play a more prominent role in the Florida primary on Jan. 31 than they have so far.

Florida is a coveted win for the GOP contenders in part because 50 delegates are at stake, but also because the state is more diverse – racially, ethnically, and politically – than Iowa, New Hampshire, and South Carolina, where primaries have already been held. As such, it’s considered a better reflection of the general election.

With its large elderly population and hard-hit economy, social welfare programs like Social Security, Medicare, and Medicaid are very important to Florida voters.

“Medicare is certainly the third rail in Florida among the sizeable senior population, but so too is Medicaid,” said Daniel A. Smith, Ph.D., professor of political science at the University of Florida, Gainesville.

Many seniors depend on both Medicare and Medicaid for their health care needs: Medicare for basic doctor and hospital care and Medicaid for long-term care, Dr. Smith pointed out.

That means Republican candidates should consider treading lightly when they talk about Social Security, Medicare, or Medicaid, he said, noting that in 1992, Ross Perot’s presidential bid was derailed in Florida after he said he would favor having wealthier Americans pay more for Social Security and Medicare.

“Retirees aren’t interested in dismantling the welfare state,” Mr. Smith said. “Even those Floridians of means are not interested in having their benefits cut.”

Health Care Platforms

At the Republican debate in Tampa on Jan. 23, Rick Santorum went after putative front-runner Mitt Romney for creating what he called a “government-run” health care plan when Mr. Romney was governor of Massachusetts. Mr. Santorum, a former senator from Pennsylvania, called that plan “RomneyCare,” a play on the dismissive “Obamacare” moniker that Republicans have given to the Affordable Care Act.

In the past, Mr. Santorum, who at press time was polling a distant third in Florida, has supported a plan by Rep. Paul Ryan (R-Wisc.) to essentially privatize Medicare. On his official campaign website, he says his first priority as President would be to repeal the Affordable Care Act. He also has said he would encourage the purchase of health insurance across state lines, push for block grants to states for Medicaid, and bolster health savings accounts. Mr. Santorum also backs medical liability reform.

Like Mr. Santorum, Newt Gingrich is calling for more competition in health care, block grants for Medicaid, and a repeal of the ACA. But the former Speaker of the House presents a more detailed plan for health care that includes reforming the Food and Drug Administration, investing more in health research, and putting a premium on quality of care.

Mr. Gingrich and Mr. Romney have traded the lead in Florida for the last several months, with Mr. Romney leading fairly broadly before the South Carolina primary on Jan. 21. Then, just as Mr. Romney won New Hampshire, Mr. Santorum was belatedly declared the winner in Iowa. Mr. Gingrich handily beat Mr. Romney in South Carolina, 40% to 28%.

According to the University of Florida’s Dr. Smith, Mr. Romney has actively courted health care executives in Florida. But it may not be enough to fend off continued brickbats thrown at him for the Massachusetts plan. He has repeatedly disavowed the notion that the plan was the model for the Affordable Care Act. On his website he says his first priority will be a repeal of Obamacare. Mr. Romney, like the other candidates, says he supports less regulation, more competition, and medical liability reform.

Although his platform makes no overt mention of Medicare, analysis by the Center on Budget and Policy Priorities noted that, if enacted, Mr. Romney’s proposal to cap total spending and balance the budget would lead to a 17%-24% cut to Medicare by 2016.

Interestingly, the American Federation of State, County and Municipal Employees has purchased air time in Florida to attack Mr. Romney for what it calls “Medicare fraud.”

The 30-second spot says that, while Mr. Romney worked for the Damon Corp., the company defrauded Medicare. The spot then goes on to morph Mr. Romney’s face into that of Florida Governor Rick Scott’s, with the tag line, “Sound familiar?”

Gov. Scott, a Republican, was the CEO of HCA (then called Columbia/HCA) during a period when the company was found guilty of defrauding Medicare. He was forced to resign and the company paid a record fine to the government. Gov. Scott has seen his approval ratings in Florida bottom out, in part because he proposed to finance public education through reductions in Medicaid payments to hospitals.

Gov. Scott has not endorsed any of the GOP candidates. “He knows that his poll numbers are quite toxic. As a result I don’t think his endorsement behooves anyone right now,” Dr. Smith said.

The Doctors Stand Clear

Several major physicians’ organizations have so far demurred on endorsing any of the candidates. A spokesperson said that the Florida Medical Association did not feel it was appropriate to even comment on a potential endorsement, given that its membership holds a variety of views.

Dr. John A. Gross, a member of the board of the Florida Academy of Family Physicians (that state’s chapter of the American Academy of Family Physicians), said that the FAFP would not be endorsing any candidates at this time either.

The FAFP is “looking for candidates that are willing to stand up for the patient,” said Dr. Gross, who chairs the group’s government relations committee. Family physicians would be interested in candidates who support the patient-centered medical home and new models that provide high quality care.

Tort reform also is a huge issue for Florida physicians, Dr. Gross noted. In a recent poll, physicians in the state estimated that 1 of every 3 health care dollars in Florida is spent on so-called defensive medical costs. The poll was conducted by Patients for Fair Compensation, a nonprofit established by the for-profit physician staffing company Jackson Healthcare.

Dr. Gross said that medical liability reform is a priority issue for the FAFP every year.

The latest bill to address tort reform was introduced in mid-January in the Florida House and Senate.

Abortion is also a hot-button issue in Florida. The state is regarded as anti-choice by NARAL Pro-Choice America.

Mr. Santorum describes himself as strongly pro-life. Mr. Gingrich has said he supports ending federal subsidies for abortion and defunding Planned Parenthood. Mr. Romney had a much-publicized change in position, seemingly going from supporting a woman’s right to choose to being against abortion. He does not have an official stance listed on his campaign website.

This is the first in a series of articles looking at the Republican presidential primaries through the eyes of physicians. Next up: The race moves on to Minnesota and Colorado, which hold their primaries Feb. 7.

Subject Codes:
nephrology_urology; infectious; top_stories; sports; ophthalmology; gastroenterology; mental_health; diabetes; dermatology; orthopaedics; pediatrics; general_primary; oncology; endocrinology; womens_health; pain; allergy; pulmonology; cardiology; rheumatology; surgery; otolaryngology; neurology; emergency_trauma; gerontology;


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January 25, 2012   03:19 PM EST

With Florida’s large elderly population and hard-hit economy, health care issues should play a prominent role in the Republican primary on Jan. 31.

BY DIANA MAHONEY
Elsevier Global Medical News
Breaking News

Discharge rates for nontraumatic lower extremity amputation among diabetic individuals aged 40 years and older declined 65% from 1996 to 2008, according to a study by the Centers for Disease and Prevention, announced by the agency on Jan. 24 and also published in the February issue of Diabetes Care.

The CDC’s study is the first comprehensive study to examine trends in nontraumatic lower extremity amputation (NLEA) rates and characteristics associated with diabetes-related NLEAs in the U.S. population, Yanfeng Li, MPH, and colleagues at the CDC in Atlanta analyzed data from two nationally representative surveys – the National Hospital Discharge Survey (NHDS) and the National Health Interview Survey (NHIS) – and determined that the age-adjusted NLEA discharge rate per 1,000 persons among diabetic individuals aged 40 years or older decreased from 11.2 in 1996 to 3.9 in 2008, while rates among nondiabetic individuals remained similar. However, even with the dramatic decline, the age-adjusted NLEA rate in the diabetic population remained approximately eight times higher than the rate observed in the nondiabetic population, at 3.9 vs. 0.5 per 1,000 persons, respectively, the authors wrote (Diabetes Care Feb. 2012;35:273-7).

When analyzed by demographic characteristics within the diabetic population, the NLEA rates decreased significantly in all of the demographic groups considered. Throughout the 12-year study period, however, the rates were significantly higher among diabetic patients 75 years or older, compared with those aged 40-64 years and those aged 65-74 years, the authors reported. They were also significantly higher among men than women and among blacks than whites, they stated.

Although the findings are limited by several factors, including the underestimation of the size of the total diabetic population (estimates did not include individuals with undiagnosed disease or those in nursing homes); the lack of inclusion of data on NLEAs performed in long-term hospitals, Veterans Affairs hospitals, or outpatient settings; possible duplicity of patients hospitalized more than once in a given year; and the absence of a racial designation for a large proportion of patients, they nevertheless indicate that increased attention to risk-factor management, patient education, and appropriate foot care in recent years have led to a reduction in NLEA hospitalizations, the authors wrote. The persistent racial disparities and continued increased risk for NLEA among diabetic patients suggest more can be done. “Further decreases in rates of NLEA will require continued awareness of diabetes and its complications among patients and providers as well as comprehensive interventions to reduce the prevalence of risk factors for NLEA and to improve foot care and overall care for people with diabetes, particularly for those in subpopulations at higher risk for NLEA,” they concluded.

The authors reported having no relevant conflicts of interest.

Subject Codes:
top_stories; diabetes; general_primary; endocrinology;


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January 24, 2012   08:55 PM EST

BY SHARON WORCESTER
Elsevier Global Medical News
Breaking News

Germline mutations in the tumor suppressor genes BRCA1 and BRCA2 – and particularly those in BRCA2 – are associated with higher 5-year overall survival rates among patients with confirmed invasive epithelial ovarian cancer, according to a pooled analysis of data from 26 observational studies involving nearly 3,900 women.

The 5-year overall-survival rate was 36% for 2,666 non-BRCA carriers, 44% for 909 BRCA1 carriers, and 52% for 304 BRCA2 carriers, Kelly L. Bolton, Ph.D., of the National Cancer Institute, Bethesda, Md., and her colleagues reported on behalf of EMBRACE, KConFab Investigators, and the Cancer Genome Atlas Research Network.

The findings are reported in the Jan. 25 issue of JAMA.

After adjustment for study and year of diagnosis, BRCA1 carriers were significantly more like to survive than were noncarriers (hazard ratio, 0.78), and their advantage improved slightly after additional adjustment for stage, grade, histology, and age at diagnosis (HR, 0.73), the investigators said (JAMA 2012;307:382-90).

BRCA2 carriers had an even greater advantage when compared with noncarriers (HR, 0.61), particularly after adjustment for other prognostic factors (HR, 0.49). The differences between BRCA1 and BRCA2 carriers were statistically significant.

Although prior smaller studies have also demonstrated survival advantages among invasive epithelial ovarian cancer patients with BRCA2, with some also showing an advantage for those with BRCA1, the current study is the largest to date to assess survival in patients with invasive epithelial ovarian cancer based on BRCA1/2 carrier status.

The studies used in the analysis were reported as 10 from the United States, 6 from Europe, 2 from Israel, 1 each from Hong Kong, Canada, and Australia, and 5 from the United Kingdom. Participants were enrolled between 1987 and 2010 and were actively followed for a mean of 38 months.

Several significant differences were seen in regard to clinical features of BRCA1 and BRCA2 carriers compared with noncarriers. For example, tumors in carriers were more likely to be of serous histology and less likely to be of mucinous histology, and carriers were more likely to have stage III/IV tumors and poorly differentiated or undifferentiated tumors, compared with noncarriers. BRCA2 carriers were more likely than were BRCA1 carriers to have stage III/IV tumors. Also, BRCA1 carriers were younger at diagnosis than noncarriers, and BRCA2 carriers were slightly older.

The investigators also found that the survival advantage of BRCA1/2 carriers, compared with noncarriers, was attenuated in women who had a family history of ovarian cancer, breast cancer, or both.

“The improved survival or BRCA1/2 carriers relative to noncarriers, and the survival advantage of BRCA2 carriers relative to BRCA1 carriers, could be related to intrinsic biological differences, their response to therapeutic agents, or both,” the investigators said, noting that in addition to differences in stage, grade, and histology, BRCA1/2 carriers could have differences in other aspects of tumor biology that were not measured in this study.

Although the study is limited by factors associated with the study design such as a heterogeneous population, the sample size and the magnitude of the differences observed between carriers and noncarriers are a testament to the robustness of the findings, they said.

The results have potentially important implications for the clinical management of patients with epithelial ovarian cancer, including immediate use by health care professionals for patient counseling regarding expected survival, they said, adding:

“BRCA1 and BRCA2 carriers with EOC respond better than noncarriers to platinum-based chemotherapies and have improved survival despite the fact that the disease is generally diagnosed at a later stage and higher grade. If patients could be stratified based on their BRCA status, their treatment could be tailored to reflect this, with noncarriers targeted for more aggressive treatment.”

Epithelial ovarian cancer clinical trials should be stratified by BRCA status, they said, explaining that this would not only allow more appropriately targeted therapy, but also would allow avoidance of potential bias introduced by unequal numbers of carriers in treatment groups or between study cohorts.

“Furthermore, given the important prognostic information provided by BRCA1 and BRCA2 status and the potential for personalized treatment in carriers, the routine testing of women presenting with high-grade serous EOC may now be warranted,” they said.

Numerous funding sources and author disclosures were reported. The complete list is available with the full text of the article www.jama.com.

Rethinking Ovarian Cancer Research

The findings of this study provide “the latest evidence that ovarian cancer is a much more genetically and biologically heterogeneous disease than previously appreciated,” Dr. David M. Hyman and Dr. David R. Spriggs wrote in an accompanying editorial.

The paper –“by far, the largest study of BRCA-associated ovarian cancer outcomes reported to date” – has important implications for the future of ovarian cancer research and treatment, they said:

“Phase [III] studies that do not stratify by BRCA mutation status or account for this factor in a preplanned statistical analysis risk possible confounding because approximately 15% of unselected patients with serous ovarian cancer will carry germline BRCA1/2 mutations.”

The findings also provide impetus for rethinking the current approach to the development of targeted agents in molecularly defined subsets of ovarian cancer, according to the editorial (JAMA 2012;307:408-10). Trials of poly (ADP-ribose) polymerase (PARP) inhibitors, which block base excision repair, have shown promise in BRCA-associated and sporadic ovarian cancers. Investigators should consider whether the unknown mechanisms underpinning the differences in survival of BRCA1- and BRCA2-associated ovarian cancers, as demonstrated in this study, “may also result in differential sensitivity to agents that target the resultant homologous recombination defects.”

“In the future, even germline BRCA status may not be sufficient to fully subclassify ovarian cancers and select the best treatment,” said Dr. Hyman and Dr. Spriggs.

Additional study, in similarly large data sets, is needed to improve the understanding of the effects of somatic and epigenetic alterations in BRCA gene function and the complex interactions with other inherited alleles, they added, concluding that “the accelerating availability of detailed somatic and germline genetic information will challenge all physicians who stand at the bedside of patients with cancer and struggle to deliver compassionate, individualized care.”

Dr. Hyman and Dr. Spriggs are with Memorial Sloan-Kettering Cancer Center and Cornell University, both in New York. Neither had disclosures to report.

Subject Codes:
top_stories; oncology; womens_health;


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January 24, 2012   04:00 PM EST

BY SHARON WORCESTER
Elsevier Global Medical News
Breaking News

The proton pump inhibitor lansoprazole was no better than placebo for improving symptoms and lung function in a randomized, placebo-controlled trial involving more than 300 children with poorly controlled asthma without overt gastroesophageal reflux.

Those treated with lansoprazole did, however, experience significantly more respiratory infections (relative risk, 1.3), sore throats (RR, 1.3), and episodes of bronchitis (RR, 2.2) than did those receiving placebo during the course of the 24-week study. The treatment group also experienced more activity-related bone fractures (6 vs. 1 in treatment vs. placebo groups, respectively), although this difference did not reach significance, Dr. Nicola Hanania and her colleagues from the Writing Committee for the American Lung Association Asthma Clinical Research Centers reported in the Jan. 25 issue of JAMA.

The mean difference in change in Asthma Control Questionnaire scores between the 149 children treated with 15-30 mg/day of lansoprazole depending on weight and the 157 who received placebo in the Study of Acid Reflux in Children With Asthma was 0.2 units, which was less than the meaningful clinically important difference in both groups (–0.1 for lansoprazole, and –0.2 for placebo), and was not statistically significant. Mean differences in change for secondary outcomes, including forced expiratory volume in the first second, asthma-related quality of life, and rate of episodes of poor asthma control, also did not differ significantly between the groups, Dr. Hanania of Baylor College of Medicine, Houston, and her colleagues reported (JAMA 2012;307:373-81).

Additionally, lansoprazole had no treatment effect, compared with placebo, in a subanalysis of 49 study participants (20 in the placebo group and 29 in the lansoprazole group) who were found on esophageal pH studies to have gastroesophageal reflux (GER), they noted.

Untreated GER has been considered a possible cause of inadequate asthma control in children treated with inhaled corticosteroids, but proton pump inhibitors (PPIs) have not been well studied with respect to their use for asymptomatic GER in children with refractory asthma.

For the current double-masked study, children were enrolled between April 2007 and September 2010 at 19 academic clinical centers throughout the United States. They had a mean age of 11 years (range 6-17 years), 50% were black, 65% were boys, and all were using inhaled corticosteroids. Most had required an intervention for asthma symptoms in the year prior to enrollment, and the mean Asthma Control Questionnaire score was high, at 1.6 for both groups, which is consistent with poor asthma control.

The lansoprazole dose used for the study was based on weight, with patients weighing less than 30 kg receiving 15 mg/day, and those weighing 30 kg or more receiving 30 mg/day.

The findings indicate that the drug has no effect on asthma control measures, the investigators wrote. “This was the case even though GER was prevalent in the study sample,” they noted. It was also the case in subgroups defined by markers of asthma severity.

“The results of this clinical trial are uniformly negative regarding the benefit of acid suppression therapy on symptom relief, lung function, airways reactivity, or quality of life,” they said, concluding that in light of previous negative findings from a study of omeprazole, the use of PPI therapy in children with poorly controlled asthma is unwarranted.

The findings also raise important questions about the adverse effects of lansoprazole in children, and along with other concerning data that have led to two Food and Drug Administration Advisory Board Reviews in the past 2 years, they underscore the need for continued study of PPI safety in children, they said.

Although the activity-related fractures in the lansoprazole group were not significantly more common than in the placebo group (6 of 149 [4%] vs. 1 of 157 [less than 1%]; P = .06), they are a cause for concern. Of the seven fractures, one occurred on the day of randomization; the others occurred after 2 months (n = 1), 5 months (n = 3), and 6 months (n = 2) of follow-up. The affected children were 7-14 years old, and all had been taking inhaled corticosteroids during the trial; two had taken oral prednisone as well (one in each group).

Findings Highlight Problem of “Therapeutic Creep.” In an accompanying editorial, Dr. Fernando D. Martinez wrote that despite “unimpressive evidence” derived largely from anecdotal experience in regard to a consistent role of gastroesophageal reflux in asthma morbidity, children with asthma often are treated with antireflux medications (JAMA 2012;307:406-7). One study demonstrated that 13- to 14-year-old children with asthma were more than eight times more likely to be treated with antireflux therapy than those without asthma, said Dr. Martinez, who is at the Arizona Respiratory Center, BIO5 Institute and Clinical and Translational Science Institute at the University of Arizona, Tucson.

The practice represents “therapeutic creep” – or the extension of the use of a treatment with real or suggestive therapeutic effects observed in a certain age group or certain disease phenotype to other patients in whom the efficacy has never been demonstrated – and its perils and costs are highlighted in this study by Dr. Hanania and her colleagues, Dr. Martinez said.

Children in the study who were treated with lansoprazole were more likely than those treated with placebo to experience a number of adverse effects, including respiratory infections – without any improvement in asthma symptoms. Of even greater concern was a finding of increased activity-related bone fractures in the lansoprazole group, Dr. Martinez said, noting that this is the first large randomized controlled trial to look at this potential complication of PPIs in children.

Although the finding didn’t reach statistical significance, it should be considered “in the framework of a substantial body of evidence that has prompted the U.S. Food and Drug Administration to issue an advisory about the risk of fractures in adults taking PPIs chronically,” he said.

The findings of this study should strongly discourage the generalized use of PPIs for treating asthma, and a tentative recommendation by the current National Heart, Lung, and Blood Institute guidelines for an empirical trial of antireflux therapy in patients with poorly controlled asthma – based on the few data available at the time the guidelines were written – should be promptly revised, Dr. Martinez concluded. (The discussion continues in an exclusive video interview with Dr. Janet T. Holbrook, of The Johns Hopkins University.)

This study was supported by the American Lung Association Asthma Clinical Research Centers, as well as by grants from the National Institutes of Health/National Heart, Lung, and Blood Institute. Lansoprazole and placebo were provided by Takeda Pharmaceuticals; albuterol was provided by GlaxoSmithKline. Dr. Hanania and her coauthors had no disclosures to report.

Dr. Martinez has served as a consultant to MedImmune and has presented at an Abbott-sponsored seminar.

Subject Codes:
top_stories; gastroenterology; new_drugs; pediatrics; allergy; pulmonology;


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January 24, 2012   04:00 PM EST

BY JEFFREY S. EISENBERG
Elsevier Global Medical News
Breaking News

Anaphylaxis in children following immunizations is extremely rare, with no events associated with infant and preschool schedule vaccinations and a delayed onset of symptoms in other children, according to a study published online Jan. 23 in Archives of Disease in Childhood.

Anaphylaxis may follow exposure to allergens from many sources, including vaccines made up of a mixture of compounds. Because anaphylaxis is rare, however, it is usually very difficult to pick this up as a potential side effect of a new treatment during clinical trials. Manufacturers have to rely on data collected after the product has come to market.

Dr. Michel Erlewyn-Lajeunesse of Children’s Allergy Clinic, University Hospital Southampton NHS Trust, and colleagues wanted to estimate the incidence and clinical presentation of anaphylaxes as an adverse event following immunization. Pediatricians in the United Kingdom and Ireland were asked to report all cases of suspected anaphylaxis in children younger than age 16 years following an immunization to the British Paediatric Surveillance Unit between September 30, 2008, and September 30, 2009 (Arch. Dis. Child 2012 [doi:10.1136/archdischild-2011-301163]). Reporting physicians also completed an online survey or patient questionnaires on the case presentation, diagnosis, management, and subsequent outcome.

During this time, physicians reported 15 cases of suspected anaphylaxis following vaccination, 7 of which the researchers confirmed. Six children required an injection of adrenaline, three received intravenous fluids, and all seven children fully recovered.

These included 2 cases among more than 16,000 single-component measles vaccines administered, for an incidence of 12 cases per 100,000. [No single-component measles vaccines are currently available in the United States.]

“A higher rate of anaphylaxis following single-component vaccines has been previously observed, although there is no obvious explanation for this,” the researchers said. “Measures should be taken to record the use of non-routine vaccines so that the public may be protected.” No cases of anaphylaxis occurred among the 5.5 million infants and preschool-age children who received normally scheduled vaccines, including measles, mumps, and rubella (MMR) and influenza. “This is extremely reassuring data for the general public and healthcare workers alike,” they said.

There also were three cases of anaphylaxis among more than 2 million doses of human papillomavirus (HPV) vaccine, for an incidence of 1.4 cases per million doses.

Three children already carried injectable adrenaline to treat idiopathic anaphylaxis or multiple food allergies. “We suggest that children with idiopathic anaphylaxis are immunized in a center used to treating anaphylaxis and are observed for at least an hour following the procedure,” Dr. Erlewyn-Lajeunesse and associates said.

The onset of symptoms was 15 minutes in three cases and 30 or more minutes in four cases (120 minutes in one case). The latter finding, observed in other studies, “is in keeping with an idiosyncratic non-immunoglobulin E-mediated reaction,” they said. Although there is no standard observation time, the researchers said that an observation time of up to 60 minutes may be appropriate in children with a history of idiopathic anaphylaxis.

“Anaphylaxis remains a very rare adverse event following immunization,” the researchers said. “There is a clear need for international surveillance using standardized methodologies and case definitions.”

The U.S. Vaccine Adverse Event Reporting System (VAERS) recorded 452 reports of “anaphylactoid reactions” in over 1.9 billion doses of vaccine given over a 10-year period, for an estimated incidence of 0.2 cases per million doses.

Timing of Anaphylaxis Following Injection Is Noteworthy

This latest research confirms that anaphylaxis is a rare adverse event following immunization. Estimates put the incidence at 0.2-1 case per million doses, said Dr. Michael Pichichero.

One finding of note in this study: the delayed onset of anaphylaxes, which typically occurs within minutes after exposure the precipitating antigen. “Delayed anaphylaxis, occurring beyond 30 minutes after a presumed exposure to a precipitating antigen, casts some doubt on the cause and effect association of the putative precipitating antigen,” said Dr. Pichichero, a specialist in pediatric infectious diseases who is director of the Rochester (N.Y.) General Research Institute.

“Moreover, a close timing between exposure to a vaccine and anaphylaxis does not guarantee that the vaccine was the cause. One could eat a sandwich, get in an automobile, and have an accident, but the close timing of that association does not mean that the sandwich definitely caused the person to have the accident. The same applies to the timing of vaccination and anaphylaxis; there is a chance that the association was coincidental,” he said.

The study authors commented that the extreme rarity of these delayed reactions did not make it practical to recommend longer observation times. “This is reasonable because it appears that a number occurred beyond any reasonable observation time,” said Dr. Christopher Harrison, director of the Infectious Disease Research Laboratory and professor of pediatrics at the University of Missouri-Kansas City.

Also of particular interest, Dr. Harrison noted, was that there were no such reactions among those receiving the recommended infant vaccines, including the combination measles, mumps, and rubella (MMR) vaccine.

“Of interest is the observation that several such reactions were seen among a smaller number of young children receiving single components of the measles, mumps, and rubella vaccines,” he added. “This increased frequency with single components is of marginal real importance, however, but should not encourage those with fear of rare reactions to seek out single components of MMR as safer. And, single components are not available in the Unites States now, in any case.”

Also, many of the severe reactions occurred in individuals with a history of severe idiosyncratic or allergic reactions who already carried self-administered epinephrine devices at the time of the reactions, based on these prior severe reactions to other exposures that were not vaccines. “So one message is that one should consider extra counseling for patients who have this history and a need for any vaccine,” Dr. Harrison said.

This study was funded by an unrestricted educational grant from Sanofi Pasteur MSD. Dr. Erlewyn-Lajeunesse reported having received reimbursement from GlaxoSmithKline and Wyeth to attend scientific meetings. Coauthor Dr. Paul T. Heath is an investigator for clinical trials conducted on behalf of St. George’s, University of London, sponsored by vaccine manufacturers. Coauthor Dr. Adam Finn undertakes clinical trails and related research, consulting, lecturing, and chairing for all the major manufacturers and has received reimbursement of travel, accommodation, registration and living expenses relating to these activities. Dr. Pichichero said he had no relevant financial disclosures.

Subject Codes:
infectious; top_stories; pediatrics; allergy;


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January 23, 2012   06:30 PM EST

A new study has shown that anaphylaxis remains a very rare adverse event following immunization.

BY MARY ELLEN SCHNEIDER
Elsevier Global Medical News
Breaking News

Obstetricians and gynecologists should screen all of their patients for intimate partner violence at periodic intervals such as at annual visits or during prenatal care, according to a new recommendation from the American College of Obstetricians and Gynecologists.

The prevalence of the problem and the long-term health consequences for women are driving the need for routine screening, members of the American College of Obstetricians and Gynecologists (ACOG) Committee on Health Care for Underserved Women wrote in Committee Opinion #518 in the February issue of Obstetrics & Gynecology (Obstet. Gynecol. 2012;119:412-7).

More than 1 in 3 women (36%) in the United States have experienced rape, physical violence, or stalking by an intimate partner at some point during their lives, according to figures published in 2010 by the Centers for Disease Control and Prevention. Intimate partner violence (IPV) extends beyond just physical and sexual violence. The term also includes psychological abuse and reproductive coercion, ranging from name calling and threats to isolation and sabotaging efforts at contraception.

The consequences of IPV are wide-ranging, too, and include acute injuries, chronic headaches, sleep and appetite disturbances, and recurrent vaginal infections. Among pregnant women who experience IPV, the abuse has been associated with stillbirth, placental abruption, fetal injury, preterm delivery, and low birth weight.

Ob.gyns. are in a “unique position” to aid women who experience IPV because of their special physician-patient relationship and because of the many opportunities for intervention, according to the committee opinion.

“Women of all ages experience intimate partner violence, but it is most prevalent among reproductive-age women,” Dr. Maureen G. Phipps, chair of the College’s Committee on Health Care for Underserved Women, said in a written statement. “We have a prime opportunity to identify and help women who are being abused by incorporating this screening into our routine office visits with each and every patient.”

ACOG advised ob.gyns. to screen all patients, and do it periodically because some women will not disclose abuse the first time they are asked about it. Other signs that should prompt an IPV assessment include depression, substance abuse, mental health problems, or requests for repeat pregnancy tests at a time when the patient does not wish to be pregnant. During pregnancy, obstetric patients should be screened at the first prenatal visit, at least once a trimester, and at the postpartum visit, according to ACOG.

As part of its recommendation, ACOG provides a set of sample screening questions for IPV. The Committee Opinion suggests starting the conversation with a framing statement such as, “We’ve started talking to all of our patients about safe and healthy relationships because it can have such a large impact on your health.” This lets the patient know that the screening is universal and isn’t being done because IPV is suspected. It’s also important to let patients know about the confidentiality of the discussion, and tell them exactly what state laws mandate that physicians disclose.

“We need to start normalizing the conversation about abuse with all of our patients, much as we’ve done with HIV testing,” Dr. Phipps said. “Many women will not admit to being abused, but bringing up the subject in a caring and straightforward manner over time may encourage them to eventually seek help.”

The committee opinion also emphasizes that physicians do screening for IPV in private, integrate the questions into routine intake forms, and ensure that the office staff is regularly trained about IPV.

IPV screening is part of the list of recommended preventive services for women that most health plans will be required to cover starting on Aug. 1. The preventive services coverage requirement was part of the Affordable Care Act, and the Department of Health and Human Services recently issued the list of recommended services with input from the Institute of Medicine.

Physicians should offer patients information that includes community resources (mental health services, crisis hotlines, rape relief centers, shelters, legal aid, and police contact information) and appropriate referrals, according to the committee opinion. But such information should not be forced upon unwilling patients or slipped unknowingly into their belongings, where their abusers might find them. Offering abused patients a private phone to call the National Domestic Violence Hotline can be very helpful because abusers often monitor cell phone logs or Internet use; the hotline is “a multilingual resource that can connect a patient to local domestic violence programs, help with safety planning, and provide support” (1-800-799-SAFE [7233]).

Physicians who wish to learn about how to help patients dealing with IPV may want to go to the Futures Without Violence website, which provides “educational materials, IPV assessment and safety assessment tools (including scripts for clinical assessment of IPV and reproductive coercion), and free technical assistance specifically for health care providers and settings,” according to the committee opinion. (Visit the website at www.futureswithoutviolence.org, click on Our Work, then click on the Health section.)

But not all groups support routine universal screening. The U.S. Preventive Services Task Force found in 2004 that there is insufficient evidence to recommend for or against routine screening for IPV among women without injuries or symptoms of abuse. Similar groups in Canada and the United Kingdom have found insufficient evidence to recommend one way or another on routine IPV screening.

A 2009 report in JAMA looked at the issue and found that screening for IPV produced a small benefit to abused women in quality of life and depression (JAMA 2009;302:493-501). But that difference was not statistically significant after accounting for women lost to follow-up. The randomized controlled trial, which included more than 6,700 women, also found that many women had to be screened in order to identify a single woman who disclosed abuse.

“While U.S. organizations continue to recommend universally screening for exposure to partner violence all women who visit a health care setting, it should be clear that those recommendations are based on the hope that identifying women in this way will get them on a path to seeking help, if indeed help is available. Current research evidence does not demonstrate that universal screening improves women’s health or well-being, or decreases their exposure to violence,” Dr. Nadine Wathen of the University of Western Ontario, London, one of the authors of the 2009 JAMA study, said in an interview.

Until evidence emerges in support of routine screening, Dr. Wathen said many groups recommend that ob.gyns. become knowledgeable about the signs and symptoms of abuse, and screen for IPV in those cases. “What’s urgently needed is development and evaluation of health-related interventions that can help women who’ve been abused,” she said.

Subject Codes:
top_stories; womens_health;


http://www.imng.com


January 23, 2012   05:00 PM EST

BY SHARON WORCESTER
Elsevier Global Medical News
Breaking News

Cognitively stimulating activity, particularly in early and midlife, is associated with lower brain deposition of the major protein constituent of amyloid plaques in Alzheimer’s disease later in life, based on findings from a cross-sectional clinical study.

The study’s direct association between cognitive activity and beta-amyloid (A-beta) protein suggests that the lifestyles of those with greater cognitive engagement may play a role in the onset and progression of Alzheimer’s disease (AD), particularly because participation in cognitively stimulating activities has been linked with other lifestyle practices associated with reduced Alzheimer’s disease risk, Susan M. Landau, Ph.D., of the University of California, Berkeley, and her colleagues reported online Jan. 23 in Archives of Neurology.

PET imaging of the binding of the radiopharmaceutical carbon 11–labeled Pittsburgh Compound B ([¹¹C]PiB) to A-beta protein showed comparable A-beta deposition in older adults in the highest cognitive activity tertile and young controls. On the other hand, older adults in the lowest cognitive activity tertile had mean cortical [¹¹C]PiB uptake comparable with the Alzheimer’s patients, the investigators said (Arch. Neurol. 2012 Jan. 23 [doi:10.1001/archneurol.2011.2748]).

The researchers defined cognitively demanding activities in terms of activities that depended minimally on socioeconomic status, such as reading books or newspapers, writing letters or e-mails, and playing games.

The greatest association was seen between higher past cognitive activity scores (based on levels from ages 6 to 40 years, compared with those from ages 40 and older) and lower [¹¹C]PiB uptake, but the association between cognitive activity and lower [¹¹C]PiB uptake existed across the life span after age, sex, and years of education were taken into account, the investigators noted.

Although previous epidemiologic studies have also demonstrated a link between cognitive stimulation throughout life and a reduced risk of cognitive decline and Alzheimer’s disease, these findings “suggest a novel mechanism in which increased cognitive activity may play a direct role in reducing A-beta before disease onset,” they wrote.

The notion that cognitive activity influences the development of Alzheimer’s disease pathology is supported by recent findings of reduced hippocampal atrophy – another biomarker of Alzheimer’s pathology – in cognitively normal older adults with greater lifelong complex mental activity levels, they said.

“Our cognitive activity measurement is likely just one of a variety of interrelated lifestyle factors that are difficult to quantify. Cognitive activity and (marginally) years of education were associated with [¹¹C]PiB uptake (although cognitive activity and years of education were not related to one another), suggesting that these measurements may reflect a broader underlying tendency to engage in intellectual, occupational, social, and recreational activities,” Dr. Landau and her coauthors wrote.

The study’s 75 older adults included 65 healthy participants with normal cognition and a mean age of 76 years and 10 with Alzheimer’s disease who had a mean age of 75 years. A total of 11 young control participants had a mean age of 24.5 years.

The healthy older adults underwent [¹¹C]PiB PET imaging and completed an extensive neuropsychological battery between Oct. 31, 2005, and Feb. 22, 2011. They self-reported their levels of cognitively demanding activities and physical activity.

Although physical activity was associated with cognitive activity in this study, it was not associated with [¹¹C]PiB uptake. The addition of physical activity to the model also did not reduce the association between cognitive activity and PiB. This indicates that cognitive activity was the primary variable driving the association because physical activity was measured as a current function and cognitive activity was assessed as a lifelong engagement. Dr. Landau and her associates then proposed that the association between [¹¹C]PiB and cognitive (but not physical) activity “may thus reflect a time-sensitive neural process in which early- and midlife practices have a greater influence on AD pathology than later-life practices.”

It is plausible, they said, that people who participate in a variety of cognitively stimulating activities throughout life may develop more efficient neural processing that results in less A-beta deposition – an idea supported by findings in transgenic A-beta–expressing mice.

“It is unlikely that our results reflect a single unitary cause of AD, which is a complex disease with many potential pathogenetic processes. ... However, the present findings extend previous findings that link cognitive stimulation and AD risk (an indirect downstream effect of A-beta) by providing evidence that is consistent with a model in which cognitive stimulation is linked directly to the AD-related pathology itself,” they concluded.

This study was supported by grants from the National Institutes of Health and the Alzheimer’s Association. The authors reported no relevant financial disclosures.

Subject Codes:
top_stories; mental_health; neurology;


http://www.imng.com


January 23, 2012   04:00 PM EST

Dr. Susan Landau

BY JENNIE SMITH
Elsevier Global Medical News
Breaking News

The Food and Drug Administration has identified a new risk factor for progressive multifocal leukoencephalopathy, a life-threatening brain infection associated with the use of natalizumab, an immunomodulatory agent used to treat multiple sclerosis and Crohn’s disease.

Testing positive for anti–John Cunningham virus (JCV) antibodies raises the risk of developing progressive multifocal leukoencephalopathy (PML), particularly when patients have been on natalizumab treatment for more than 2 years and have previously taken immunosuppressant medicines such as mitoxantrone, azathioprine, methotrexate, cyclophosphamide, or mycophenolate mofetil. When all three risk factors are present – 2 or more years of natalizumab therapy, anti-JCV, and prior immunosuppressant use – the incidence of PML is estimated to be 11 in 1,000 patients, FDA said in a drug safety communication Jan. 20.

When patients have anti-JCV antibodies but have been on natalizumab less than 2 years and have no prior immunosuppressant use, PML incidence is less than 1 in 1,000, the FDA said. PML incidence is estimated at 2 of every 1,000 anti–JCV positive patients with less than 2 years on natalizumab and with prior immunosuppressant use. For those with anti-JCV antibodies and more than 2 years treatment but no prior immunosuppressants, incidence is about 4 in 1,000, the FDA communication said. The FDA, which already had a black box warning on natalizumab (Tysabri, Biogen Idec, and Elan) describing increased PML risk, said Jan. 20 that it had changed the product labeling to reflect the newly stratified risk information, and also announced in a news release that it had approved a new test, called the Stratify JCV Antibody ELISA test (Focus Diagnostics), to detect anti-JCV antibodies in people deemed at risk of developing PML.

In most people, JCV is harmless; however, those on immunomodulatory agents like natalizumab are at risk of death or serious disability from PML caused by JCV exposure.

The agency stressed that patients on natalizumab may be at risk for developing PML even without a positive test for JCV antibodies, because the infection can occur at any time, or because false negative results can occur. Patients should be monitored carefully and natalizumab treatment should be stopped at the first sign of PML. While there is no treatment for PML, stopping treatment early may allow the immune system to recover and fight JCV infection.

Natalizumab, a monoclonal antibody administered by intravenous infusion, works by blocking a protein that is found on the surface of leukocytes, preventing their movement from the blood into the brain and reducing the inflammation and nerve damage caused by MS. In Crohn’s disease, it works by blocking adhesion and migration of leukocytes into the gut. For both indications it is administered by intravenous infusion of 300 mg every 4 weeks.

In 2004, the FDA approved natalizumab as a treatment for MS in patients who had failed other therapies; however, it was withdrawn the following year by its manufacturer due to safety concerns related to PML. In 2006, it was returned to market under a restricted prescribing program to treat relapsing forms of MS and was granted marketing authorization by the European Medicines Agency (EMA) to treat highly active relapsing MS. In 2008, it was approved in the United States for the treatment of Crohn’s disease, also under a restricted prescribing program, in patients failing other therapies.

The EMA in 2007 refused to grant marketing authorization to natalizumab for Crohn’s, citing an unfavorable risk-benefit profile. In 2010 the EMA concluded a review of the risks of natalizumab for relapsing MS following increasing reports of PML cases. The EMA retained natalizumab’s marketing authorization for relapsing MS but strengthened its warnings about PML risk.

Subject Codes:
top_stories; gastroenterology; general_primary; neurology;


http://www.imng.com


January 23, 2012   12:25 PM EST

BY JENNIE SMITH
Elsevier Global Medical News
Breaking News

Less than half of U.S. teenagers were vaccinated against hepatitis A in 2009 – a rate that may leave a large portion of young people susceptible to hepatitis A infection in adulthood, a study has shown.

Nationally, the vaccination rate in 2009 was only 42% among 13- to 17-year-olds nationwide, although 70% of vaccinated teens had received the second dose necessary for durable immunity against hepatitis A. Just over half of vaccinated teens had received the vaccine before age 10 years, and 48% had been vaccinated at age 11 years or older.

In contrast, coverage rates in 2009 among teens for the tetanus toxoid–acellular pertussis vaccine and meningococcal conjugate vaccine were 55.6% and 53.6%, respectively.

The findings are from the first study to use provider-reported data to evaluate hepatitis A vaccination coverage.

Hepatitis A morbidity and mortality are more severe among adolescents and adults than children, noted Dr. Christina G. Dorell of the Centers for Disease Control and Prevention and her colleagues (Pediatrics 2012;129:213-21).

Although hepatitis A infections are not common in the United States, 1,987 cases were reported nationally in 2009, with the highest rates of disease among young adults between 20 years and 29 years of age. When unreported and asymptomatic cases are considered, the actual incidence of hepatitis A infections in 2009 was more than 10 times greater than the reported number, according to CDC estimates.

Dr. Dorell and her colleagues likened the potential threat of low hepatitis A coverage to that presented by measles outbreaks in undervaccinated population pockets.

To determine hepatitis A vaccination coverage rates, the researchers used data from the 2009 National Immunization Survey–Teen, a randomized telephone survey of parents that then sought additional data from vaccine providers identified by the parents. Nearly 35,000 parents completed telephone surveys, 20,066 of which could be matched with adequate provider information and entered into analysis.

Vaccine coverage varied widely depending on the adolescents’ state of residence. The 33 states (and the District of Columbia) that were the latest to adopt universal childhood hepatitis A vaccination recommendations (in 2006) saw the lowest rates of coverage as of 2009 – collectively, only 27.8%. However, those states also had the highest proportion of adolescents vaccinated at 11 years of age or older, likely because of recent adoption of the universal-vaccination recommendations.

In contrast, the 11 states that had adopted hepatitis requirements earlier (in 1999) saw nearly three-quarters (74.3%) of adolescents covered by one or more doses in 2009. The six states that in 1999 adopted a weaker recommendation to “consider” early childhood hepatitis A vaccination saw an overall vaccination rate of 54% in 2009.

Adjusted prevalence ratios of vaccination initiation were highest for states with a vaccination requirement and for adolescents whose providers recommended vaccination, the researchers found.

In some states, adolescents of American Indian, Hispanic, black, or Asian ethnicity were more likely to have hepatitis A coverage, possibly related to outreach in those groups. In other states, adolescents in rural areas were less likely to be vaccinated than those living in urban areas, where pediatrician-to-children ratios are higher. Poverty was not generally seen as bearing on vaccination rates, possibly because of a federal program providing free vaccines to lower-income families.

Study limitations included the fact that the parent telephone surveys were conducted exclusively on landlines, while a quarter of U.S. adolescents live in homes without landlines. Other limitations included potential recall bias in parent reports, as well as incomplete provider data or vaccination histories.

The study authors also noted that adolescents with inadequate provider data were excluded from the analysis – teens who may have had less access to primary health care and therefore were less likely to have received vaccine.

“Excluding this group may have resulted in elevated vaccination coverage estimates,” the researchers cautioned. Thus, overall coverage in fact could be even less than the already low 42% reported.

Dr. Dorell and her colleagues said they had no relevant financial disclosures.

Subject Codes:
infectious; top_stories; gastroenterology; pediatrics;


http://www.imng.com


January 23, 2012   12:01 AM EST

In the United States, the vaccination rate in 2009 was only 42% among 13- to 17-year-olds, and 70% of those vaccinated had received the second dose necessary for durable immunity against hepatitis A.

BY JENNIE SMITH
Elsevier Global Medical News
Breaking News

Attitudes toward sun exposure – and behaviors – change between childhood and adolescence, researchers have found, suggesting that children in this age bracket may be critical targets for physicians to advise.

Among children who were interviewed at age 10 years and again at 13, those in the elder group were only half as consistent in their sunscreen use as they had previously been, and were significantly more likely to report liking the appearance of a tan or seeking to become tan. Actual incidence of sunburn and tanning, meanwhile, remained high and largely unchanged between ages 10 and 13 years, with recent sunburns reported by more than half of children at both ages.

The findings, published online Jan. 23 in Pediatrics, were the first to examine sunburn and sun behaviors prospectively in this age group.

Stephen W. Dusza, Dr.P.H., of Memorial Sloan-Kettering Cancer Center in New York, led SONIC (Study of Nevi in Children), which used self-reported data from 360 students who were enrolled as fifth graders in Framingham, Mass., schools in 2004 and had complete data upon follow-up in 2007. High-resolution photography of the back was conducted for all subjects at both points. Almost three-fourths (74%) of the subjects analyzed were white, and males accounted for more than half the sample (62%).

At baseline in 2004, 53% of subjects reported having had a sunburn (defined as “pink or red skin”) at least once the previous summer, and this proportion remained similar (55%) at follow-up, a nonsignificant difference. Actual incidence of tanning also changed little. At both baseline and follow-up, about 85% of students reported having gotten a tan the previous summer (Pediatrics 2012;129:309-17).

Sunscreen use, meanwhile, dropped sharply. In 2004, 50% of students reported that they used sunscreen “often or always” when outside for 6 or more hours in the summer. By 2007, only 25% reported the same, a significant difference.

The children in the study with the highest risk of developing skin cancer – those with pale skin – experienced the sharpest increase in reported sunburns, Dr. Dusza and his colleagues found. In 2007, fair-skinned children were 40% more likely to report two or more recent sunburns than in 2004. By contrast, children with light olive to black skin were 70% less likely to report two or more recent burns at follow-up, compared with baseline.

Some 53% of students reported “liking a tan” at age 10, but 66% did by age 13, a significant difference. And although 22% of 10-year-olds reported deliberately spending time in the sun to get a tan, a full 40% did so at follow up, also a significant difference. Girls were twice as likely to report liking a tan in 2007, compared with 2004 (odds ratio, 2.4). Boys also were more likely to report liking a tan when they reached age 13 (OR, 1.5).

The researchers acknowledged as weaknesses their study’s reliance on self-reported sun behaviors by children, noting that these reports have been shown to have “fair to moderate agreement” with direct observation.

Moreover, they said, nearly one-fourth of the children recruited in 2004 dropped out of the study because of relocation, and could not be included in the analysis. Among these were a disproportionate number of children with darker skins, an understudied group as far as sun behaviors are concerned. And finally, because the study did not seek reasons for sunscreen use or nonuse, “it was beyond the scope of this study to ascribe reasons for the drop in sunscreen use during these 3 years.”

Despite these limitations, the findings strongly underscore the necessity of “new and creative messages” in both schools and physicians’ offices, with an aim to promote consistent sunscreen use and to deter tanning in this important age bracket, Dr. Dusza and his colleagues wrote in their analysis. In the United States, melanoma is reported to be one of the two most common cancers of young people, so it is important to encourage strong sun protection practices at young ages, the researchers noted.

In addition, “further studies are required to learn how to interweave enhanced sun-protection policies in settings such as beaches, after-school sites, and sporting events frequented by preadolescents and adolescents,” the researchers wrote. Particular effort is needed to reach this group, they added, because adolescence “is a period of flexing independence, coupled with feelings of invincibility.”

It also is important because the use of tanning beds, particularly for girls, is reported to begin at age 14, Dr. Dusza and his colleagues said.

Dr. Dusza and colleagues’ study was funded by the National Institutes of Health, as part of an ongoing study of nevi in children. Dr. Dusza and colleagues reported that they had no relevant financial disclosures.

Subject Codes:
top_stories; dermatology; pediatrics;


http://www.imng.com


January 23, 2012   12:01 AM EST

Despite the possible damage to their skin, children increasingly prefer the appearance of a tan as they grow older.

BY JEFFREY S. EISENBERG
Elsevier Global Medical News
Breaking News

Children currently diagnosed with an autism spectrum disorder are more likely to have coexisting psychiatric or neurodevelopmental conditions than are children with a past but not current diagnosis, and these conditions might lead to a change in ASD diagnosis, suggest the findings of a cross-sectional study in the February issue of Pediatrics.

An estimated 1% of 8-year-old children (typically the peak age of prevalence) have an ASD, such as autistic disorder; pervasive developmental disorder, not otherwise specified (PDD-NOS); or Asperger’s syndrome, according to the Centers for Disease Control and Prevention. Co-occurring conditions often include attention-deficit/hyperactivity disorder, learning disability, depression, anxiety, and seizures. Also, more than 10% of children diagnosed with an ASD at age 2 years no longer have the diagnosis by age 9 years.

To provide an appropriate diagnosis and opportunities for early intervention, clinicians must be able to differentiate between the core features of an ASD and any coexisting conditions.

Using cross-sectional data from the National Survey of Children’s Health 2007 (NSCH), Heather A. Close, of the Center for Autism and Developmental Disabilities Epidemiology at Johns Hopkins University, Baltimore, and her colleagues examined the relationship between co-occurring conditions and changes in diagnosis of an ASD (Pediatrics 2012;129:305-16 [doi:10.1542/peds.2011-1217]). This study consisted of 1,366 children from the NSCH with a parent-reported current or a past but not current (PBNC) diagnosis of an ASD.

The study authors found that the type of co-occurring conditions varied by age. For example, 3- to 5-year-old children currently diagnosed with an ASD were 11 times more likely to have a moderate or severe learning disability and 9 times more likely to have a moderate or severe developmental delay than children with a PBNC diagnosis. They were nearly 5 times more likely to have two or more current co-occurring conditions than children with a PBNC diagnosis of an ASD.

Meanwhile, children aged 6-11 years with a current ASD diagnosis were almost 4 times more likely to have had a past speech problem and 3.5 times more likely to have current moderate or severe anxiety than children with a PBNC diagnosis. And, they were more than 3 times as likely to have two or more current co-occurring conditions as those with a PBNC diagnosis.

Finally, adolescents aged 12-17 years with a current ASD diagnosis were almost 4 times more likely to have moderate or severe speech problems and 10 times more likely to have current mild seizures or epilepsy than children with a PBNC diagnosis of ASD.

Children and adolescents with a current ASD diagnosis were more likely to have two or more co-occurring conditions than those with a PBNC diagnosis.

The study results suggest that some co-occurring conditions might, in part, lead to a change in an ASD diagnosis, although the underlying mechanisms for this change are unclear. In this study, the researchers focused on the possible impact that neurodevelopmental and psychiatric conditions could have on the continuation of ASD diagnosis by comparing groups who currently have an ASD diagnosis to groups with a PBNC diagnosis.

“Our results are in line with the few studies that have researched differences between current or past ASD diagnoses in the context of co-occurring conditions,” Ms. Close and her colleagues wrote.

Children with ASDs have impaired communication, including delays in speech and acquisition of language, or delays in age-appropriate social skills. With increasing age, these symptoms appear more consistent with ASD than with what might have been considered a speech or hearing problem or a nonspecific developmental delay.

“This can also be true in the opposite direction, in which a child might have been diagnosed with an ASD because of the presence of common ASD co-occurring conditions or diagnoses and then was later reclassified as not having an ASD,” the researchers said.

Possible reasons for reclassifying children previously diagnosed with an ASD include developmental improvements as the child ages, such as in IQ or adaptive social abilities, or a child no longer meeting the diagnostic criteria as a result of early intervention. “Improvements leading to a loss of an ASD diagnosis also occur more commonly in children diagnosed at an early age with PDD-NOS rather than with autistic disorder,” the researchers said.

The limitations of this study included the fact that information was based on parent-reported diagnoses obtained through one telephone interview; the different outcomes among children and adolescents with autism, Asperger’s syndrome, and PDD-NOS; the small sample size for some variables of interest; and a lack of information on individual interventions for each study. Also, the study investigated children with a current or previous ASD diagnosis but did not specifically look at the change from never having a diagnosis to having a diagnosis.

A prospective, longitudinal, population-based retrospective study of adults that asks similar questions could offer a detailed profile of the ages at which an ASD diagnosis changes, as well as co-occurring conditions and interventions, the researchers said.

The authors had no financial relationships to disclose.

Subject Codes:
top_stories; mental_health; pediatrics; neurology;


http://www.imng.com


January 23, 2012   12:01 AM EST

BY ELIZABETH MECHCATIE
Elsevier Global Medical News
Breaking News

SILVER SPRING, MD. (EGMN)–The majority of a Food and Drug Administration advisory panel recommended against approval of an 8% vaginal formulation of progesterone gel for use in reducing the risk of preterm birth in women with a short cervix.

The Reproductive Health Drugs Advisory Committee on Jan. 20 voted 13 to 4 that the product did not have an acceptable risk-benefit profile and that the manufacturer had not provided sufficient evidence to conclude that the gel reduced the risk of preterm birth in women with a singleton gestation and a short cervix at mid-trimester – the proposed indication.

Panelists were not concerned about safety. But those voting against approval said that while they agreed the treatment appeared to have potential and recognized the need for such a product, they were not convinced that it had been shown effective in the pivotal, international study. The overall results were not robust enough to convince them the treatment was effective in reducing preterm birth, they noted, adding that no benefit was seen in the study participants from the United States.

The study compared progesterone gel 8% with placebo, administered daily, in 450 women with a short cervix (1.0-2.0 cm). All women had singleton pregnancies and enrolled from 19 to almost 24 weeks’ gestation. The rate of preterm birth before 33 weeks’ gestation, the primary end point, was 8.9% among those randomized to receive the gel, compared with 15.2 % among women randomized to placebo. This was a statistically significant difference that represented a 44% reduction in risk, according to the manufacturer, Columbia Laboratories Inc.

In the subgroup of women enrolled in the United States, however, the differences between the two groups in the preterm birth rate was not significant (16.8% in the gel group vs. 19.2% in the placebo group) – a major concern raised by the FDA reviewers. The overall compliance rate among the U.S. women was lower than among those enrolled internationally (23% vs. 2%), which the company said could have affected the results.

The FDA analysis, which adjusted for different factors, did not find a significant effect of the gel in reducing the risk of preterm birth, and raised concerns about the generalizability of the results to the U.S. population and variations of the treatment effect in different countries.

The product is a bioadhesive formulation of progesterone packaged in a prefilled, single use vaginal applicator that delivers 90 mg of progesterone. It has been on the market since 1997 and is approved for use in treating infertility in women with progesterone deficiency; it’s also approved as a treatment for secondary amenorrhea in women who have not responded to a 4% formulation. (For these indications, it is marketed as Crinone, by Watson Pharmaceuticals, which is in a partnership with Columbia Laboratories).

Currently, no product is approved for reducing preterm birth in women with a short cervix, a well-recognized predictor of preterm birth. Last year, an injectable progesterone formulation, hydroxyprogesterone caproate (Makena), was approved to reduce preterm birth in women with a singleton pregnancy who have a history of spontaneous preterm singleton birth. That product has been controversial because of its extremely high cost.

The FDA usually follows the recommendations of its advisory panels. Panelists have been cleared of potential conflicts of interest related to the topic of the meeting. Occasionally, a panelist may be given a waiver, but not at this meeting.

Subject Codes:
top_stories; womens_health;


http://www.imng.com


January 20, 2012   08:34 PM EST

BY ELIZABETH MECHCATIE
Elsevier Global Medical News
Breaking News

In 2010, an estimated 20% of adults aged 18 years and older in the United States – almost 46 million adults – had experienced “any mental illness” in the past year, with those aged 18-25 years, women, and the unemployed among the groups most affected, according to a report issued Jan. 19 by the Substance Abuse and Mental Health Services Administration (SAMHSA).

A “relatively high” prevalence rate of mental illness during the previous year, a strong association between mental illness during the previous year and substance abuse, as well as a “substantial unmet need” for mental health care during the previous year are among the key findings, the report concluded.

The report also found that that 8% of adolescents aged 12-17 years (almost 2 million individuals) had experienced a major depressive episode in the past year, and that illicit drug use was more than twofold greater among these adolescents than among those who had not used illicit drugs (37% vs. 18%). In addition, 12% of people in this age group (almost 3 million individuals) had received treatment or counseling for emotional or behavioral problems in an inpatient or outpatient mental health setting. “Feeling depressed” was the most common reason for using these services, in almost 50% of cases, the report said.

The SAMHSA report defined “any mental illness” as having had, at the current time or at any time during the past year, “a diagnosable mental, behavioral, or emotional disorder (excluding developmental and substance use disorders) of sufficient duration to meet diagnostic criteria” specified in the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV), regardless of functional impairment. The 20% figure in adults was similar to the rate of the previous year. Nearly 30% of the adults aged 18-25 years and 22% of those aged 26-49 years had had a mental illness in the past year, compared with 14% of those aged 50 years and older. Unemployed people were also more likely to have had a mental illness in the past year (28%), compared with people who worked full time (17%) or part time (23%).

The rate of “serious mental illness” – which was defined the same way as “any mental illness,” but one that was “of sufficient duration” to meet diagnostic DSM-IV criteria and had “resulted in serious functional impairment, which substantially interferes with or limits one or more major life activities” – followed a similar pattern.

An estimated 5% of adults aged 18 years and older (about 11.4 million adults) had had a serious mental illness, similar to the rate of the previous year. The rate of serious mental illness was highest among those aged 18-25 years (8%), followed by those aged 26-49 years (6%), compared with 3% of those aged 50 years and older. Almost 8% of unemployed adults had a serious illness, compared with 4% of those who were employed full time and 6% of those who were employed part time.

Women were more likely to be affected than men by any mental illness (23% vs. 17%) and serious mental illness (7% vs. 3%).

Less than 40% of the adults who had experienced any mental illness and almost 61% of those with a serious mental illness had received mental health services during the past year.

Substance abuse was more than threefold higher among adults who had had any mental illness in the past year: 20% of the adults who had had any mental illness and 25% of those who had had a serious mental illness met the criteria for substance abuse or dependence, compared with 6% of those who had not had any mental illness during that time.

Among the other findings included in the report was that almost 4% of adults had had serious thoughts about suicide, similar to the rate of the previous year. The rates were about the same for men and women, but were higher among the younger age groups: 7% in those aged 18-25 years, 4% in those aged 26-49 years, and 2.5% in those aged 50 and older.

“Mental illness is a significant public health problem in itself, but also because it is associated with chronic medical diseases such as cardiovascular disease, diabetes, obesity, and cancer, as well as several risk behaviors including physical inactivity, smoking, excessive drinking, and insufficient sleep,” Ileana Arias, Ph.D., principal deputy director of the Centers for Disease Control and Prevention, said in a SAMHSA statement announcing the report on Jan. 19. The report, she added, “provides further evidence that we need to continue efforts to monitor levels of mental illness in the United States in order to effectively prevent this important public health problem and its negative impact on total health.”

The results are based on the mental health–related results from the 2010 National Survey on Drug Use and Health (NSDUH), an annual survey of about 67,500 people aged 12 years and older in the United States.

Subject Codes:
top_stories; mental_health; general_primary;


http://www.imng.com


January 19, 2012   12:01 PM EST

BY SHARON WORCESTER
Elsevier Global Medical News
Breaking News

Lithium is associated with an increased risk of reduced urinary concentrating ability, hypothyroidism, hyperparathyroidism, and weight gain, but, despite widespread belief to the contrary, it may not be associated with congenital malformations, alopecia, skin disorders, or clinically significant reductions in renal function, according to findings from a systematic review and meta-analysis of data from 385 studies.

The review was undertaken in part because new evidence confirming the efficacy of lithium in bipolar disorder has led to suggestions that it be used more widely. Although it is considered an effective long-term therapy for bipolar disorder, its use has declined in recent years as new, more commercially promoted – but not always equally or more effective – drugs have become available. Concerns about potential teratogenic and other adverse effects, particularly on renal function, and have also contributed to declining use, Dr. Rebecca F. McKnight of the University of Oxford (England) and her colleagues reported online in the Jan. 20 issue of the Lancet.

To provide clinicians and patients with accurate evidence of lithium’s harms and benefits, the investigators set out to provide “a clinically informative systematic toxicity profile for lithium” they said (Lancet 2012 Jan. 20 [doi: 10.1016/S0140-6736(11)61516-X]).

Based on a hierarchy of evidence from the 22 randomized controlled trials, 197 cohort studies and case-control studies, and 166 case reports included in the review and meta-analysis, the investigators found that overall, glomerular filtration was reduced by –6.22 mL/min and urinary concentrating ability was reduced by 15% of normal maximum in patients receiving lithium, compared with controls.

“Data for the most clinically important outcome, renal failure, were scarce,” the investigators said, noting that the only substantial cohort study showed that only 0.5% of patients receiving lithium were treated with renal replacement therapy.

As for clinical hypothyroidism, those taking lithium were significantly more likely than those on a placebo to develop the condition (odds ratio, 5.78), and based on a meta-analysis of the case-control studies, thyroid-stimulating hormone (TSH) concentrations were also significantly greater in those taking lithium (weighted mean difference, 4.00 IU/mL). Also, based on findings from 60 studies, blood calcium and parathyroid hormone levels were increased by about 10% over normal values in those taking lithium.

Clinically significant weight gain was also more frequent among those taking lithium than in controls (OR, 1.89), the investigators noted.

The evidence indicated, however, that lithium has little effect on hair or skin, with no significant difference seen in the incidence of alopecia in 24 publications reporting on the condition, and with no significant difference found in the prevalence of skin disorders between those taking lithium and controls in a meta-analysis of 77 publications.

Of note, six case-control studies that measured the association between Ebstein’s anomaly and lithium exposure found no link between the two. Although those estimates are unstable because of the low number of events, a case-control study of nearly 10,700 infants with a major congenital abnormality and more than 21,500 healthy controls also showed no significant association between lithium and congenital abnormalities.

Though limited by the quality and quantity of the primary evidence used in this study, which involved the screening of nearly 6,000 abstracts, the findings represent a “reasonable amount of evidence that allows cautious conclusions to be drawn about the safety of lithium,” according to the investigators.

“This review provides a comprehensive synthesis of the evidence of harm that should inform clinical decision and draw attention to key questions in urgent need of further clarification,” they said.

Based on their findings, the investigators developed the following recommendations for monitoring of lithium in clinical practice:

Before the start of lithium therapy, the risk of major adverse events should be discussed with the patient, a serum calcium level should be added to baseline blood tests, and uncertainty about the risk of congenital malformations to women of childbearing age should be explained. The latter two of these recommendations mark a change from current U.K. guidelines, the authors noted.

Also, during lithium therapy, renal, parathyroid, and thyroid function (at least glomerular filtration rate, TSH, and calcium) should be repeated at least every 12 months – and more frequently if an abnormal result is found or if the patient has a family history of endocrine disease; blood tests should all be repeated immediately in the event of a change in mood state; the occurrence of adverse effects should be routinely recorded; and women who would like to conceive or who have become pregnant during therapy should be advised that the increased risk of congenital malformation is uncertain, and the balance of risks between harm to the baby and maternal mood instability should be discussed before making a decision to discontinue lithium. All but the recommendation regarding repeat blood tests in the setting of mood state changes mark a change from current U.K. guidelines.

This study was funded by the National Institute for Health Research Programme Grant for Applied Research. The authors had no disclosures to report.

Lithium Reaffirmed as Treatment of Choice

In an accompanying editorial, Dr. Gin S. Malhi and Dr. Michael Berk wrote that “the authors of this review should be congratulated for the systematic quantification of the potential risks associated with lithium” (Lancet 2012 Jan. 20 [doi:10.1016/S0140-6736(11)61703-0]).

This detailed review and analysis provides meaningful and reassuring advice for clinicians and identifies areas in need of additional research in regard to the safety of lithium, wrote Dr. Malhi of the University of Sydney and Dr. Berk of the University of Melbourne. They noted that while the available evidence is far from ideal, the study – in the context of efficacy data upgrading the ranking of lithium, and new data that “recalibrate the safety risks of alternative drugs” – provides “timely clarification of the toxicity associated with lithium therapy, and on balance, reaffirms its role as a treatment of choice for bipolar disorder.”

“The renal side-effects of lithium are of greatest concern to both clinicians and patients, and in this regard, the analysis is reassuring in that, even with long-term lithium use, the risk of renal toxicity, specifically end-stage renal failure, is fairly low (0.53% compared to 0.2% in the general population),” they wrote.

However, since the data on dosing and its relationship with toxicity were insufficient, matters of dose-related side-effects cannot be informed by the findings, said Dr. Malhi and Dr. Berk.

“Instead, the study provides useful guidance for clinicians considering lithium treatment, and redirects the focus of research to dosage and safety monitoring,” they wrote.

Dr. Malhi has received research support from, and/or served as a speaker or consultant for AstraZeneca, Eli Lilly, Organon, Pfizer, Servier, Wyeth, Janssen-Cilag, Lundbeck, and Ranbaxy. Dr. Berk has received research support from, and/or served as a speaker or consultant for Medical Benefits Funds of Australia, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Organon, Novartis, Mayne Pharma, Servier, Janssen-Cilag, Lundbeck, Merck, Pfizer, Sanofi-Synthelabo, Solvay, and Wyeth.

Subject Codes:
nephrology_urology; top_stories; mental_health; diabetes; dermatology; general_primary; endocrinology; womens_health;


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January 19, 2012   06:30 PM EST

BY DIANA MAHONEY
Elsevier Global Medical News
Breaking News

A 2009 measles outbreak linked to an unvaccinated child who was treated in the emergency department of a hospital in southwestern Pennsylvania highlights both the potential for measles transmission in health care settings and the need for clinicians to include the disease in differential diagnoses of patients with fever and rash. Hospitals should document employees’ immunity and be otherwise prepared to limit outbreaks, according to a report released today by the Centers for Disease Control and Prevention in Morbidity and Mortality Weekly Report.

In March of 2009, a physician report to the Pennsylvania Department of Health of a measles case involving an unvaccinated child – followed within 5 days by reports of four additional reported cases, including three unvaccinated children and one physician, who had been in the same community hospital ED on the same day earlier in the month – led to an electronic medical record review to identify the source patient.

The source was also a child (the brother of the initially diagnosed patient) who had recently arrived in the United States with his family from India, and who had been treated previously in the ED for a rash diagnosed as viral exanthema and released, the CDC reported (MMWR 2012;61:30-2).

The discovery led to an extensive and expensive regional search and investigation of the approximately 4,000 individuals who had been in contact with all six of the patients during the incubation period. A review of employee health records to identify exposed personnel without serologic evidence of measles immunity was also conducted. The investigation did not identify any additional measles cases, but did identify 72 of 168 potentially exposed employees with no documented measles immunity who were then required to undergo serologic testing and, if necessary, vaccination, according to the report. Testing found that eight did not have measles IgG antibodies, and of those, five were furloughed for 18 days after exposure.

Of note, the authors wrote in an editorial note, “of the six cases, only the index patient initially was suspected of having measles; therefore, he was the only patient for whom isolation precautions were taken,” despite 2007 guidelines issued by the Hospital Infection Control Practices Advisory Committee (HICPAC) recommending precautions against airborne transmission for any patient who has a maculopapular rash accompanied by cough, coryza, and fever. The failure to readily identify potential measles cases may be attributable to U.S. clinicians’ limited experience with the contagious disease – itself an unintended consequence of the high U.S. vaccination coverage levels and the efficacy of the measles-mumps-rubella vaccine, they wrote.

In addition to the public health implications, health care–associated measles outbreaks pose a substantial burden on public health resources and health care facilities, in terms of the time and cost of extensive record reviews, contact tracing, and requisite communications, the authors wrote.

Fortunately, the scope of the Pennsylvania outbreak was limited, possibly because of high rates of measles immunization in the community, the fact that the affected children did not attend school or child care, and intense public health control efforts, they stated.

In addition to improving clinicians’ awareness of measles and the necessary isolation procedures, “all health care facilities should follow [Advisory Committee on Immunization Practices] ACIP and HICPAC guidelines that health-care facilities should ensure that their employees are fully vaccinated from measles or have laboratory evidence of immunity,” the authors stressed. “This can minimize the need for emergency testing and furlough of employees exposed to measles and associated outbreaks.”

Subject Codes:
infectious; top_stories; dermatology; pediatrics; emergency_trauma;


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January 19, 2012   03:03 PM EST

This photo shows the skin of a patient after 3 days of measles infection. A series of measles cases in a Pennsylvania emergency department led to an extensive and expensive regional search and investigation of the approximately 4,000 individuals who had been in contact with all six of the patients during the incubation period.

BY KERRI WACHTER
Elsevier Global Medical News
Breaking News

WASHINGTON (EGMN) –Members of a national advisory council on Alzheimer’s disease have identified preliminary goals and specific recommendations for a national strategic plan to slow or even halt the expected rise in new cases.

The plan aims to prevent and effectively treat the disease by as early as 2025. Its goals include enhancing care quality and efficiency, expanding patient and family support, enhancing public awareness and engagement, and improving data to track disease progress.

The plan is part of the National Alzheimer’s Project Act that was signed into law on Jan, 4, 2011, by President Obama. The law established the Advisory Council on Alzheimer’s Research, Care, and Services and requires the secretary of the Department of Health and Human Services and the advisory council to create and maintain a national plan to overcome Alzheimer’s disease. Members of the council’s subgroups on long-term services and supports (LTSS), clinical care, and research met Jan. 17-18 to comment on and provide recommendations for the plan’s draft framework.

Long-Term Services and Supports

Members of the LTSS subgroup noted that the importance of caregivers and family to Alzheimer’s patients warrants the inclusion of services to maintain their health and vitality. In addition, the subgroup proposed that robust dementia-capable systems of LTSS be culturally appropriate, available in every state, and accessible to younger people with Alzheimer’s disease – a group often forgotten in discussions of Alzheimer’s disease. The LTSS subgroup also recommended that new guidelines for diagnosis be used whenever someone is admitted for LTSS or assessed for eligibility. The process of diagnosis also should include engaging the patient and family in advance care planning. End of life considerations should be incorporated into all surveillance and quality indicators.

Council members recommended that federal funds be made available to support a lead agency in every state to coordinate all available LTSS provided through various public and private mechanisms. The agency could use these funds to build and monitor quality indicators and the capacity to maximize the positive impact of services on patients and caregivers.

The council advised that state education agencies and professional organizations include key information about Alzheimer’s disease in all curricula for any profession or career track affecting LTSS, as well as key information about Alzheimer’s disease for any staff working in human service agencies. Patients and caregivers also should be informed of state, local, and private housing resources, and states should provide adult day services as an option under Medicaid, the council said.

Clinical Care of Alzheimer’s Disease

The clinical care subgroup said the overall goal of clinical care is to ensure that individuals with Alzheimer’s have their disease detected and diagnosed at an early stage, receive care planning, and have access to coordinated and high-quality health care throughout the course of the disease.

In particular, members recommended changes to Medicare coverage and physician reimbursement to encourage the diagnosis of Alzheimer’s disease and to provide care planning to diagnosed individuals and their caregivers. In addition, quality indicators for the care and treatment of individuals with Alzheimer’s should be developed. The subgroup proposed medical home pilot projects specifically targeted at improving medical management for individuals with Alzheimer’s using grants from the Center for Medicare and Medicaid Innovation (CMMI).

The subgroup also recommended addressing palliative care by forming a blue-ribbon panel of experts to recommend one or more models of care for people with advancing dementia, which would cover eligibility criteria and financing mechanisms. CMMI also could be tapped to supply grants to implement these models.

In addition, the subgroup advised improving and expanding the National Family Caregiver Support Program and other evidence-based caregiver support models. Members also recommended that a specific round of grants for pilot projects to reduce potentially preventable emergency department visits and hospitalizations for individuals with Alzheimer’s be funded through CMMI. They recommended exploring the use of public-private partnerships to develop and evaluate ways to improve hospital care for people with Alzheimer’s and other dementias.

Greater funding and incentives should be offered to individuals to pursue careers in geriatric specialties, they noted.

Research Goals

The research subgroup said their stated goal – the ability to prevent, effectively treat, and substantially delay the onset or slow the progression of Alzheimer’s disease – could be reached through three key strategies:

• Aggressively committing resources, with appropriate accountability, to Alzheimer’s disease research to match the current and growing impact of the disease on society.

• Accelerating public access to new therapeutic interventions by compressing the current average time of identifying and validating therapeutic targets and developing and testing the efficacy and safety of interventions.

• Exploring the possibility of providing incentives to private industry to invest in disease-modifying interventions by convening a panel of experts from private industry to help determine the nature of possible incentives that would accelerate discovery. These may include tax reform or incentives to drive greater investment, patent law reform to include pharmaceutical incentives, and enhanced market exclusivity.

The council is scheduled to meet again on April 17, 2012. A final draft is expected to be released in late spring 2012.

Subject Codes:
top_stories; general_primary; neurology; gerontology;


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January 19, 2012   12:22 PM EST

Elsevier Global Medical News
Breaking News

A story titled “Health Spending Continued Historic Decline in 2010,” published January 9, 2012, misstated the period of historically low growth in health spending addressed in the reported data. The specified period started in 2009 and continued through the end of 2010.

Subject Codes:
top_stories; general_primary;


http://www.imng.com


January 19, 2012   12:08 PM EST

BY MARY ELLEN SCHNEIDER
Elsevier Global Medical News
Breaking News

After nearly a decade of steady decreases in abortion, the global abortion rate has leveled off, according to new research from the World Health Organization and the Guttmacher Institute.

Between 2003 and 2008, the abortion rate worldwide was almost unchanged, going from 29 abortions per 1,000 women aged 15-44 years to 28 abortions per 1,000 women. The slight drop follows years of consistent decreases in the abortion rate that occurred from 1995 to 2003, when the abortion rate globally fell from 35 to 29 abortions per 1,000 women.

At the same time, the rate of unsafe abortions being performed around the world has increased. The percentage of unsafe abortions rose from 44% in 1995 to 49% in 2008, reported Gilda Sedgh, Sc.D., of the Guttmacher Institute, New York, and her associates. The definition of unsafe abortion used was “a procedure for termination of an unintended pregnancy done either by people lacking the necessary skills or in an environment that does not conform to minimum medical standards, or both,” as established by WHO.

The research was based on an analysis of official statistics, published reports, hospital records, and surveys, and it was published on Jan. 19 in the Lancet (Lancet 2012 Jan. 19 [doi: 10.1016/S0140-6736(11)61786-8).

The leveling off of the abortion rate between 2003 and 2008 was probably due in part to unmet contraception needs in developing countries, according to the study authors. The stall in the abortion rate between 2003 and 2008 coincides with a plateau in contraceptive use that had previously been increasing, Dr. Sedgh said in a press conference on Jan. 18.

She emphasized that a greater investment in family planning services will be needed to break the stall in abortion rates and reduce unintended pregnancy rates.

Research does not support the enactment of more restrictive abortion laws, she said, noting that restrictive abortion laws were not associated with lower abortion rates. In fact, the opposite was true. In subregions that had more liberal laws governing abortion, the abortion rate was lower. For example, the abortion rate is 32 per 1,000 women in 2008 in Latin America, where abortion is illegal in most cases, compared with 12 per 1,000 in 2008 in Western Europe, where abortion is generally allowed.

The leveling off of the global abortion rate appears to be driven by a similar stall in abortion rates in developing countries. In 2003 and 2008, the abortion rate in the developing world was 29 abortions per 1,000 women in both years. For example, the rate was 29 in Africa in 2008, following a steady decline from 33 in 2003.

“A growing proportion of all abortions are taking place in developing countries, where they are generally illegal and unsafe,” Dr. Sedgh said. “Thirteen percent of all maternal deaths are attributed to unsafe abortion, and virtually all of these deaths occur in the developing world.”

In the developed world, excluding Eastern Europe, the abortion rate dropped somewhat – from 19 per 1,000 women in 2003 to 17 in 2008. In North America, that rate dropped from 21 in 2003 to 19 in 2008. The lowest subregional rate worldwide was in Western Europe at 12 abortions per 1,000 women in 2008. In contrast, Eastern Europe had the highest subregional rate at 43 abortions per 1,000 women the same year.

According to the report, the absolute number of abortions was an estimated 45.6 million in 1995, compared with an estimated 41.6 million in 2003 and 43.8 million abortions in 2008. Although these numbers may be related to population growth, the abortion rate per 1,000 women is not, the researchers said. “About 78% of all abortions took place in the developing world in 1995, and increased to 86% in 2008.” The proportion of women of reproductive age who live in the developing world rose from 80% to 84% during the same time period. “Since 2003, the number of abortions fell by 0.6 million in the developed world, but increased by 2.8 million in developing countries,” they said.

The study was funded by the United Kingdom Department for International Development, the Dutch Ministry of Foreign Affairs, and the John D. and Catherine T. MacArthur Foundation. The authors reported no conflicts of interest.

Subject Codes:
top_stories; womens_health;


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January 18, 2012   06:30 PM EST

BY MARY ANN MOON
Elsevier Global Medical News
Breaking News

Based on available evidence, osteoporosis screening should take place at 15-year intervals for postmenopausal women who have normal bone density or mild osteopenia at their first assessment, at 5-year intervals for those who have moderate osteopenia, and at 1-year intervals for those who have advanced osteopenia, according to a report in the Jan. 19 New England Journal of Medicine.

Screening at shorter intervals is unlikely to improve prediction of the transition to osteoporosis, and thus won’t help clinicians judge when to start osteoporosis therapy so as to avert hip or vertebral fractures, said Dr. Margaret L. Gourlay of the department of family medicine, University of North Carolina, Chapel Hill, and her associates in the Study of Osteoporotic Fractures research group.

Current guidelines do not specify how long to wait between bone mineral density screening with dual-energy x-ray absorptiometry (DEXA), and no U.S. study to date “has addressed this clinical uncertainty,” they noted.

“To determine how the BMD testing interval relates to the timing of the transition from normal [bone mineral density] or osteopenia to the development of osteoporosis before a hip or clinical vertebral fracture occurs, we conducted competing-risk analyses of data from 4,957 women, 67 years of age or older, who did not have osteoporosis at baseline and who were followed longitudinally for up to 15 years in the [Study of Osteoporotic Fractures],” the investigators said.

The appropriate screening interval was defined as the estimated time for 10% of the study subjects in each category of osteopenia severity to make the transition from normal BMD or osteopenia to osteoporosis before fractures occurred and before treatment for osteoporosis was initiated. The three categories of severity were normal BMD/mild osteopenia (T score of greater than -1.50) at the initial assessment, moderate osteopenia (T score of -1.50 to -1.99), and advanced osteopenia (T score of -2.00 to -2.49).

This interval was found to be 15 years for normal BMD/mild osteopenia, 5 years for moderate osteopenia, and 1 year for advanced osteopenia, Dr. Gourlay and her colleagues said (N. Engl. J. Med. 2012;366:225-33).

“Recent controversy over the harms of excessive screening for other chronic diseases reinforces the importance of developing a rational screening program for osteoporosis that is based on the best available evidence rather than on health care marketing, advocacy, and public beliefs that have encouraged overtesting and overtreatment in the U.S.,” they noted.

“Our estimates for BMD testing proved to be robust after adjustment for major clinical risk factors” such as fracture history, smoking status, use of estrogen, and use of glucocorticoids. “However, clinicians may choose to reevaluate patients before our estimated screening intervals if there is evidence of decreased activity or mobility, weight loss, or other risk factors not considered in our analyses,” they said.

This study was supported by the National Institutes of Health. No potential conflicts of interest were reported.

Subject Codes:
top_stories; general_primary; endocrinology; womens_health; rheumatology;


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January 18, 2012   05:00 PM EST

A new report has offered up recommended intervals for bone mineral density screening with dual-energy x-ray absorptiometry.

BY PATRICE WENDLING
Elsevier Global Medical News
Breaking News

Phase III data on regorafenib, the first small-molecule kinase inhibitor to demonstrate a significant survival advantage in colorectal cancer, will be presented at the American Society of Clinical Oncology Gastrointestinal Cancers Symposium opening Jan. 19.

Other noteworthy studies include a reanalysis of the phase III RADIANT-2 trial suggesting that everolimus (Afinitor) may be of greater benefit in neuroendocrine tumors than previously shown, and research that could improve the early detection of esophageal and pancreatic cancer.

CORRECT Trial in Colorectal Cancer

Investigators will present results on Jan. 21 from the phase III CORRECT trial showing that the oral, investigational multikinase inhibitor, regorafenib, plus best supportive care, significantly increased median overall survival by 29% in 760 patients whose metastatic colorectal cancer progressed after standard therapies (hazard ratio 0.773; P value = .0051).

This added a median benefit of just 1.4 months compared with placebo and best supportive care (6.4 months vs. 5.0 months), but lead investigator Dr. Axel Grothey pointed out during a press briefing that the patients were running out of options after failing all standard therapies including bevacizumab and epidermal growth factor receptor inhibitors if they had KRAS-wild type tumors.

The response rate was similar between regorafenib and placebo (1.6% vs. 0.4%), but where regorafenib distinguished itself was in a much higher disease-control rate than placebo (44% vs. 15%).

The median difference in progression-free survival was again small, at just 1.2 months, but this corresponded to a 51% reduction in the risk of progression (HR 0.493; P less than .000001), said Dr. Grothey, professor of oncology at Mayo Clinic in Rochester, Minn. “There is clearly a benefit for about 50% of patients compared to the placebo-control,” he said.

The side effect profile was similar to that observed in the phase I trial and included grade 3 hand-foot skin reactions, fatigue, anorexia, and a class effect of hypertension that was controlled with dose reductions.

The trial was stopped based on the preliminary results from the preplanned interim analysis to allow patients on placebo to cross over to treatment with regorafenib.

Dr. Grothey said regorafenib “identifies itself as a potential new standard of care in this patient population,” and that it will move into earlier lines of therapy. Phase II studies are underway to evaluate the agent in combination with standard chemotherapy backbones such as 5FU and irinotecan.

Presscast moderator Dr. Morten S. Kahlenberg, medical director of Surgical Oncology Associates of South Texas in San Antonio, called results from the late-breaking abstract exciting and very noteworthy, particularly in such a heavily pretreated population, and agreed that the research lays the groundwork for further study to evaluate whether regorafenib could “possibly become a component of standard therapies for colorectal cancer.”

Dr. Grothey suggested that regorafenib may have achieved the results it did in part because it was used as a single agent, whereas trials of other small-molecule kinase inhibitors such as gefitinib (Iressa), sorafenib (Nexavar), and PTK/ZK involved adding the agents to first- or second-line chemotherapy.

“This is not unheard of that adding a kinase inhibitor to chemotherapy does not produce the desired result,” he said, noting that the addition of sorafenib to FOLFOX chemotherapy actually appeared detrimental in patients with metastatic colorectal cancer.

RADIANT-2 Reanalysis

On Jan. 20, Dr. James C. Yao, deputy chair of gastrointestinal medical oncology at M.D. Anderson Cancer Center in Houston, will present a reanalysis of the phase III RADIANT-2 trial in patients with advanced nonpancreatic neuroendocrine tumors.

The analysis identified several prognostic factors that could help physicians better identify which patients should be treated. It could also explain why the addition of everolimus to standard therapy with octreotide LAR (Sandostatin LAR Depot) delayed progression by a median of 5.1 months, but just missed statistical significance.

In multivariate analysis, significant prognostic factors included WHO performance status, bone involvement, lung as primary site, and, most notably, baseline levels of chromogranin A, a secretory protein present in neuroendocrine tissue.

Patients with elevated chromogranin A (CgA) had a significantly shorter progression-free survival of 11.3 months vs. 26.8 for those with nonelevated chromogranin A.

At baseline, there was a significant imbalance in mean and median CgA levels between patients receiving everolimus plus octreotide and those given octreotide alone, he said.

An exploratory analysis that adjusted for these prognostic indicators indicated that everolimus had a significant benefit, changing the reduction in risk of neuroendocrine progression from 23% as originally reported to 38% (HR 0.62). A larger trial, RADIANT-4, is planned to confirm these results, Dr. Yao said.

Dr. Kahlenberg said the results provide clinicians with additional insights on how to determine which patients would benefit from everolimus therapy. “In that providers are really limited by the small number of successful therapies for neuroendocrine tumors, your study is that much more meaningful,” he added.

Flagging Patients at High Risk for Esophageal Cancer

Investigators at the University of Pittsburgh will present data on Jan. 19 describing the use of three optical biomarkers to improve early identification of patients at high risk for esophageal cancer.

The biomarkers were derived using a novel microscopy technique called spatial-domain low-coherence quantitative phase microscopy (SL-QPM) to evaluate tissue samples taken during conventional endoscopic surveillance of 60 patients with Barrett’s esophagus. SL-QPM measures nano-scale changes in the nuclear structure of cells in the esophageal lining.

All three biomarkers – nuclear optical path length, intranuclear uniformity, and intranuclear entropy – were able to distinguish patients with nondysplastic Barrett’s esophagus from those with high-grade dysplasia or esophageal adenocarcinoma. When combined, they had a sensitivity of 89% and specificity of 76%, for an overall accuracy of 86%.

Lead author Dr. Randall E. Brand, professor of medicine at the university, said the biomarkers provide a promising approach for detecting dysplastic/neoplastic Barrett’s epithelium, and could potentially simplify surveillance by identifying patients who warrant intensive surveillance.

“Further, we think this may be useful in monitoring patients after ablative therapy or in determining surveillance frequency,” he said.

Barrett’s esophagus affects about 1% of the U.S. population, and is typically monitored by obtaining multiple random biopsies of the esophagus every 1 to 3 years. Notably, the incidence of esophageal adenocarcinoma in the United States is rising faster than any other type of cancer, with the National Cancer Institute reporting an estimated 16,980 new cases and 14,710 deaths in 2011.

“The ability to have an additional test in patients who may harbor malignancy or a precancerous condition like high-grade dysplasia in the background of Barrett’s is indeed very, very noteworthy, and has a very real chance of modifying how this patient population is followed and treated,” Dr. Kahlenberg told reporters.

Markers Promising for Finding Early Pancreatic Cancer

Finally, three abstracts to be presented at the meeting discuss the use of the monoclonal antibody PAM4 to identify patients with pancreatic ductal adenocarcinoma (PDAC), which accounts for 90% of all patients with pancreatic cancer.

David V. Gold, Ph.D., lead author of abstract 151 to be presented on Jan. 20, said that in a blinded analysis involving about 600 patients, the PAM4 immunoassay confirmed the presence of PDAC in 76% of 298 patients with known PDAC, and that it detected two-thirds of stage I patients. Specificity was high.

The results confirm a prior study in which the immunoassay correctly identified about 80% of roughly 60 patients with known PDAC, and provide a rationale for longitudinal surveillance of patients at high risk for PDAC including those with a history of familial pancreatic cancer or with new-onset diabetes, according to Dr. Gold of the Garden State Cancer Center in Belleville, N.J.

The second abstract (no. 164) reports improved detection rates when the PAM4 immunoassay is combined with the cancer antigen 19-9 test, which is widely used to monitor pancreatic cancer progression.

The final abstract (no. 188) provides detailed specificity analyses for the PAM4 antibody itself. Currently, there is no approved test for the detection and diagnosis of pancreatic cancer.

Dr. Grothey disclosed a consultant/advisory role for Bayer. His coauthors reported financial relationships with several pharmaceutical firms. Dr. Kahlenberg reported honoraria from Genentech. Dr. Yao reported a consultant/advisory role for Ipsen, Pfizer, and Endo Pharmaceuticals; honoraria from Novartis; and research funding from Novartis and Genentech. His coauthors reported several financial relationships including employment with Novartis. Dr. Brand reported no conflicts of interest. Dr. Gold reported no conflicts. His coauthor Dr. David Goldenberg reported employment/leadership and stock ownership with Immunomedics.

Subject Codes:
top_stories; gastroenterology; new_drugs; oncology;


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January 18, 2012   03:01 PM EST

BY JANE ANDERSON
Elsevier Global Medical News
Breaking News

House Democrats have called on the Drug Enforcement Administration and two manufacturers of drugs to treat attention-deficit/hyperactivity disorder to explain shortages of medicines to treat the disorder, especially generic versions of the drugs.

The request comes amid reports that the drug makers may be manipulating the market to force consumers to purchase brand-name products.

Rep. Henry Waxman (D-Calif.), ranking member of the House Energy and Commerce Committee, joined Reps. Diana DeGette (D-Colo.), Frank Pallone, Jr. (D-N.J.), and Chris Van Hollen (D-Md.) to question the DEA as well as Shire Pharmaceuticals and Novartis regarding recent reports of shortages of generic ADHD drugs.

The FDA is reporting current shortages of three drugs that are prescribed to treat ADHD: amphetamine mixed salts immediate-release tablets, dextroamphetamine tablets, and methylphenidate HCI tablets.

“Reports indicate that drug manufacturers may be manipulating the market to create an artificial shortage of the generic ADD drugs and force patients to purchase the more expensive brand-name drugs,” the lawmakers said in a statement. “Reports have also indicated that DEA policies regarding ADD drug quotas may be exacerbating these shortages.”

In a letter dated Jan. 17, the lawmakers asked the DEA for details on how the agency sets the quotas for the drugs involved and how it develops quotas for drugs with rapidly increasing sales, such as amphetamine mixed salts immediate-release tablets. They also asked the DEA to describe any changes in the process it plans to make to address the reported shortages.

Meanwhile, the lawmakers sent separate letters asking Novartis, which produces both branded and generic methylphenidate (Ritalin), and Shire Pharmaceuticals, which makes both branded and generic amphetamine mixed salts immediate-release tablets (Adderall), to provide details on their production of both brand name and generic versions of their ADHD drugs.

Subject Codes:
top_stories; mental_health; pediatrics;


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January 18, 2012   12:04 PM EST

BY ALICIA AULT
Elsevier Global Medical News
Breaking News

Glucarpidase, an intravenously delivered recombinant enzyme, was approved on Jan. 17 for the treatment of patients with toxic levels of methotrexate in their blood due to kidney failure, according to the Food and Drug Administration.

Patients receiving high doses of methotrexate can develop renal failure, which allows the chemotherapy drug to accumulate. Glucarpidase (Voraxaze) rapidly breaks down methotrexate into a form that can then be eliminated from the body, according to the agency.

In addition to kidney failure, prolonged exposure to high levels of methotrexate can result in “liver damage, severe mouth sores, damage to the lining of the intestine, skin rashes, and death due to low blood counts,” Dr. Richard Pazdur, director of the FDA’s Office of Hematology and Oncology Products, said in a statement. “Voraxaze is an important new treatment option for cancer patients aimed at preventing these toxicities associated with sustained high levels of methotrexate,” he added.

According to glucarpidase’s manufacturer, BTG Plc, high-dose methotrexate is used to treat or prevent the recurrence of certain types of cancer, such as osteosarcoma, leukemia, and lymphoma.

Methotrexate also is used to treat rheumatologic conditions, such as rheumatoid arthritis.

The enzyme had been available to some patients under the FDA’s investigational new drug designation. In 2008, Protherics Inc., which previously owned the rights to glucarpidase, was warned by the FDA against promoting the drug before it was approved.

Glucarpidase received orphan drug status, which put it on a priority review track.

Approval was based on two studies: a single clinical study of 22 patients that evaluated effectiveness and a 290-patient trial that evaluated safety.

According to the FDA, treatment was considered successful if methotrexate levels fell below a critical level within 15 minutes and stayed below the critical level for 8 days. That result was seen in 10 of the 22 patients. BTG said that there was a 95% reduction in methotrexate concentration from pretreatment baseline levels, maintained for up to 8 days, in all evaluable patients.

The most common side effects were hypotension, headache, nausea, vomiting, flushing, and paraesthesia.

Louise Makin, chief executive officer of BTG, said in a statement that glucarpidase “is the first product BTG has taken through to approval in the U.S. and we look forward to its launch over coming months.”

Subject Codes:
top_stories; new_drugs; oncology;


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January 18, 2012   11:40 AM EST

BY ALICIA AULT
Elsevier Global Medical News
Breaking News

The Food and Drug Administration has sent recommendations to Congress on establishing user fee programs for generic and biosimilar drugs.

Legislation is required to create the new programs, which would be modeled on the 20-year-old Prescription Drug User Fee Act (PDUFA), according to the agency.

Under PDUFA, the FDA collects fees for certain applications for a new drugs or biologics, and it also assesses fees on certain manufacturing establishments. In fiscal 2012, for instance, a new drug application that includes clinical data costs $1.8 million; establishment fees are $520,000. In return, the FDA agrees to review applications according to set deadlines.

“Human drug user fees have revolutionized the drug review process in the United States since they were adopted 20 years ago, allowing the FDA to speed the application review process without compromising the agency’s high standards,” said FDA Commissioner Margaret Hamburg in a statement.

The PDUFA requires congressional reauthorization every 5 years. The current program expires in September, so the FDA also sent recommendations to Capitol Hill on how the next PDUFA program should look.

A generic drug user fee program is crucial because the agency is being flooded with applications, according to the agency. Generics now account for two-thirds of prescriptions written in the United States. The FDA receives 800-900 generic-drug-related applications each year. With user fees, the agency aims to eliminate a backlog of reviews and “achieve parity between surveillance inspections of foreign and domestic establishments by the 2017 fiscal year.” Many generic products are manufactured overseas.

The Generic Pharmaceutical Association said that under the agency plan, the industry would pay $299 million a year for 5 years, beginning in fiscal 2012. In a statement, GPhA lauded the agency for completing its recommendations.

“This is an important landmark that could not have been achieved without the extraordinary efforts of the FDA, my colleagues in the generic industry, and all other stakeholders,” said GPhA president and CEO Ralph G. Neas.

For biosimilar drugs – essentially generic forms of biologic products – the FDA said that the fees it recommended would apply to products in development now, to “generate revenue in the near-term and to provide FDA with the resources needed to support development-phase meetings with sponsors of biosimilar biological product candidates.”

The agency expects more of these products to come online in the future, in part because the Affordable Care Act created a quicker path to market through a subtitle of the law, the Biologics Price Competition and Innovation Act (BPCI).

The Biotechnology Industry Organization (BIO) did not comment specifically on the biosimilar user fee program, but it has expressed support for the program, with caveats, in the past.

BIO president and CEO Jim Greenwood commended the FDA for completing recommendations on the PDUFA reauthorization, noting in a statement that the law had “contributed to the approval of more than 1,200 new medicines and initially reduced review times for the newest, most innovative drugs by more than a year.”

Mr. Greenwood added, “In light of the scientific and regulatory complexities of modern drug development, the PDUFA V recommendations include a set of enhancements that seek to reinforce FDA’s review performance and get back-to-basics for patients with the goal of minimizing development and review issues that can delay patient access to needed treatments.”

Subject Codes:
top_stories; general_primary;


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January 17, 2012   05:49 PM EST

BY JANE ANDERSON
Elsevier Global Medical News
Breaking News

Children with neurological impairment – especially epilepsy – accounted for more than 21% of all hospital charges in 2006, and their impact on children’s hospitals is growing as utilization shifts to those facilities, according to a retrospective, cross-sectional analysis of multiple years of the Kids’ Inpatient Database.

As more resources are used by children with neurological impairment, particularly at children’s hospitals, the institutions will need to make sure that they provide adequate staffing and education to treat these vulnerable children, Dr. Jay G. Berry of Children Hospital Boston and his coauthors recommended in the study, published online Jan. 17 in PLoS Medicine.

“Children’s hospitals, in particular, will need to ensure that (1) adequate clinical and coordinated expertise is focused on the needs of these children, (2) neurological impairment clinical assessment and care management training is developed for trainees and junior graduates in pediatric postgraduate educational programs, (3) partnerships between families of children with [neurological impairment] and hospitals are developed and implemented, and (4) care treatment strategies of both nervous and non-nervous-system problems are rigorously evaluated for these children,” the authors wrote.

Dr. Jeffrey Buchhalter, pediatric neurologist at Phoenix Children’s Hospital, said in an interview that the study provides real data on trends that he’s seen in his own institution.

“It’s confirmed for me my clinical suspicions that these are very frequent admissions and very expensive admissions. The bulk of the admissions relate to epilepsy,” he said. There are several reasons this could be happening, including increased incidence of neurological impairment, increased severity of the conditions, and an increased desire to deliver medical care, he said.

The investigators analyzed data from more than 25.7 million hospitalizations in the years 1997, 2000, 2003, and 2006 in the Kids’ Inpatient Database. They found that the proportion of hospitalizations attributable to children with neurological impairment – 5.3% in 2006 – did not change significantly over time (PLoS Med. 2012 Jan. 17 [doi:10.1371/journal.pmed.1001158]).

But even though children with neurological impairment represented less than 6% of admissions during that period, they accounted for a significant rise in the proportion of hospital bed days from 12.9% in 1997 to 13.9% in 2006. There was a statistically insignificant rise in hospital charges for children with neurological impairment across all hospitals during this period from 20.8% to 21.6%, the investigators found.

Between 1997 and 2006, the proportion of hospitalizations attributable to children with neurological impairment decreased within non-children’s hospitals, from 3% in 1997 to 2.5% in 2006, but increased within children’s hospitals from 11.7% in 1997 to 13.5% in 2006.

The proportion of bed days at children’s hospitals for children with neurological impairment also grew from 21.8% in 1997 to 25.0% in 2006. Their proportion of hospital charges rose in parallel from 27.1% to 29.0%.

More than 52% of admissions involved a diagnosis of epilepsy. Almost 16% involved a diagnosis of cerebral palsy.

The study’s authors speculated that patients may be gravitating toward children’s hospitals because most U.S. child neurologists work within those hospitals, and multi-disciplinary care coordination clinics have emerged to provide comprehensive care to children with neurological impairment.

In addition, the study found a trend of rising hospitalizations in adolescent children with neurological impairment that was greater than that for children without neurological impairment. Hospitalizations for children aged 13-18 years with neurological impairment rose 27.8% between 1997 and 2006, compared with a decrease of 8.4% among same-aged children without neurological impairment.

The authors said it’s possible that problems with transitioning care from pediatric specialists to adult providers could contribute to this trend.

“U.S. physicians have demonstrated deficiencies in working knowledge of the most common forms of neurological impairment, and negative provider attitudes toward this population are associated with substandard acute care practices,” the authors wrote. “Parents of adolescents with neurological impairment report this as a contributing factor that complicates the transfer of their child’s health care from pediatric to adult providers.”

Dr. Buchhalter said that another way to look at the situation portrayed by the study is to consider it “as a failure of ambulatory care,” adding that more child neurologists are needed to care for these patients. However, he said, “it’s all a matter of funding being available to support residencies and fellowships.” In addition, “reimbursement to be a child neurologist is falling, since it’s mainly a cognitive specialty,” and that leads to fewer medical students pursuing a career in child neurology, he said.

“What these children need is people to think about and organize their care,” Dr. Buchhalter said. “There’s enormous variation in care, and we need evidence-based care guidelines. There’s also a great need for multi-disciplinary care for these children, but that’s not reimbursed well.”

Coauthor Dr. Rajendu Srivastava has received grant funding from the National Institute of Child Health and Human Development, has given talks as Chair of Pediatric Research in Inpatient Settings Network, with his time funded by the Child Health Corporation. He’s also been asked to speak in his capacity as a hospitalist investigator with receipt of an honorarium, and has acted as an expert witness on behalf of a plaintiff for Jackson & Campbell P.C. because of his research with neurological impairment and their care. No other authors had any disclosures.

Subject Codes:
top_stories; pediatrics; neurology;


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January 17, 2012   04:00 PM EST

Jeffrey R. Buchhalter

BY SHARON WORCESTER
Elsevier Global Medical News
Breaking News

Trastuzumab is significantly more effective alone or in combination with lapatinib than is lapatinib alone for the treatment of human epidermal growth factor receptor 2–positive breast cancer in patients receiving neoadjuvant chemotherapy, according to findings from two randomized phase III trials.

The studies – GeparQuinto and the NeoALTTO (Neoadjuvant Lapatinib and/or Trastuzumab Treatment Optimization) trial – underscore the value of testing new therapies in the neoadjuvant setting.

In the GeparQuinto trial, 30% of 307 HER2-positive patients treated with the anti-HER2 humanized monoclonal antibody trastuzumab had a pathological complete response, compared with only 23% of 308 HER2-positive patients treated with the tyrosine kinase inhibitor lapatinib, which targets both HER1 and HER2 (odds ratio, 0.68).

Although the patients randomized to receive trastuzumab had significantly more edema (39% vs. 29%) and dyspnea (30% vs. 21%), those randomized to receive lapatinib experienced significantly more diarrhea (75% vs. 47%) and skin rash (55% vs. 32%), and significantly more patients in the lapatinib group discontinued treatment (33% vs. 14%), Dr. Michael Untch and his colleagues reported in the Jan. 17 issue of the Lancet Oncology.

Women with previously untreated unilateral or bilateral primary invasive breast carcinoma were enrolled in the study between Nov. 7, 2007, and July 9, 2010, at 126 centers in Germany and 1 center in Switzerland. Patients were eligible for inclusion if they had locally advanced tumor stages cT3 or cT4, hormone receptor (HR)-negative tumors, or HR-positive tumors with clinically positive axillary nodes (cN+ for cT2) or pNSLN+ for cT1 disease (Lancet Oncol. 2012 Jan. 17 [doi:10.1016/S1470-2045(11)70397-7]).

They received neoadjuvant treatment including four cycles of epirubicin given at 90 mg/m² intravenously along with cyclophosphamide at a dose of 600 mg/m² intravenously, every 3 weeks, and four cycles of docetaxel at 100 mg/m² intravenously every 3 weeks, plus either trastuzumab or lapatinib throughout all cycles prior to surgery. Trastuzumab was given at a starting loading dose of 8 mg/kg and then at 6 mg/kg intravenously every 3 weeks; the lapatinib dose was 1,000-1,250 mg/day orally.

“Pathological complete response rates were significantly lower with lapatinib treatment than with trastuzumab, irrespective of the definitions of pathological complete response that were used. These results confirm the efficacy of a neoadjuvant regimen containing trastuzumab,” wrote Dr. Untch, of Helios-Klinikum, Berlin-Buch, Berlin, and his colleagues from the German Breast Group and the Arbeitsgemeinschaft Gynäkologische Onkologie-Breast (AGO-B) Study Group.

The investigators noted that lapatinib may provide a lower pathological complete response because of a reduced ability to block the HER2 pathway, compared with trastuzumab. Also, trastuzumab may have additional antitumor efficacy “by inducing an immune response via antibody-derived cellular cytotoxicity,” they wrote.

In addition to providing additional evidence of the feasibility – and low cardiac toxicity – of “exposing the tumor for as long as possible to the synergistic effect of chemotherapy and trastuzumab before surgery,” these findings suggest lapatinib should not be used outside of clinical trials as single anti-HER2 treatment in patients undergoing neoadjuvant chemotherapy, the investigators concluded.

Indeed, these findings “should lead to the conclusion that this regimen [the combination of lapatinib with standard chemotherapy] does not seem to have any advantages compared with a standard trastuzumab-based regimen for the adjuvant treatment of HER2-positive, early-stage breast cancer,” Dr. Stephen K. Chia of the British Columbia Cancer Agency, Vancouver, B.C., wrote in an accompanying editorial (Lancet Oncol. 2012 Jan. 17 [doi:10.106/S1470-2045(12)70013-X]).

Another lesson learned from the GeparQuinto trial, according to Dr. Chia, is that the preoperative setting, which the research community and patients “seem to have embraced as both standard of care therapy and as an important strategy to test new therapeutic regimens,” is ideally suited for this purpose.

“Moving forward into the future, no adjuvant trials should be done without an adequate signal from preoperative trials showing safety, efficacy, target modulation, and, ideally, the identification of predictive biomarkers such that we no longer pick a loser to study in larger and more resource-intensive adjuvant trials,” he said. Dr. Chia noted that the second study demonstrating improved efficacy of trastuzumab – NeoALTTO – is a good example of such a preoperative study supporting the rationale for adjuvant trials with the combination of these agents, in this case the ALTTO (Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization) trial, which is underway. The lapatinib group for ALTTO has been closed due to the demonstration of futility.

In NeoALTTO, which was published concomitantly with GeparQuinto in the Lancet, trastuzumab was more effective – although not significantly – than lapatinib alone for the treatment of HER2-positive breast cancer, but it was most effective in combination with lapatinib, Dr. José Baselga of Massachusetts General Hospital Cancer Center, Boston, and his colleagues from the NeoALTTO Study Team reported.

Pathological complete response in this parallel groups, open-label study, occurred in 51% of 152 patients in the combination treatment group, compared with 30% of the 149 patients in the trastuzumab group and 25% of the 154 patients in the lapatinib group, for an adjusted odds ratio of 2.6 for the combination vs. trastuzumab alone (Lancet 2012 Jan. 17 [doi:10.106/S0140-6736(11)61847-3]).

As in the GeparQuinto Trial, no major cardiac dysfunction occurred, and diarrhea was more frequent in the patients receiving lapatinib (23% and 21% of those in the lapatinib and combination groups, respectively, vs. 2% in the trastuzumab group who had grade 3 diarrhea).

NeoALTTO participants were enrolled between Jan. 5, 2008, and May 27, 2010, at 86 sites in 23 countries. Participants had histologically confirmed invasive HER2-positive breast cancer with tumors at least 2 cm in diameter. Lapatinib was given at 1,500 mg orally to those in the lapatinib-only group, and at 1,000 mg for those in the combination group; trastuzumab was given at a loading dose of 4 mg/m² followed by 2 mg/kg on subsequent doses for both groups.

The anti-HER2 treatments were given alone for 6 weeks, and paclitaxel at 80 mg/m² weekly was then added for an additional 12 weeks.

“Dual targeting of HER2-positive tumors with trastuzumab and lapatinib is undertaken because of primary and acquired resistance to both agents, their partly non-overlapping mechanisms of action, and the well characterized synergistic interaction between them in HER2 breast-cancer models,” the investigators noted.

These findings provide proof of concept that dual inhibition of HER2 is better than a single-agent approach, Dr. Baselga and his colleagues said, noting that the higher pathological complete response rate for the combination was clear across all subgroups tested, which is consistent with the findings from other studies of anti-HER2 treatment in HER2-positive tumors.

“Our study also supports investigation of novel targeted agents for breast cancer in the neoadjuvant setting, when tumors have not yet acquired resistance to therapy and when chances of clinical benefit are highest,” they said.

In an accompanying editorial, Dr. Michael Gnant and Dr. Guenther G. Steger highlighted the NeoALTTO study’s design as a “crucial scientific strength” (Lancet 2012 Jan. 17 [doi:10.106/S0140-6736(12)60068-3]). Delaying chemotherapy for 6 weeks while the targeted anti-HER2 treatment was initiated enabled collection of samples for translational research, as well as assessment of early tumor response without confounding by cytotoxic therapy, wrote Dr. Gnant and Dr. Steger of the Comprehensive Cancer Centre of the Medical University of Vienna.

Dr. Gnant has served on advisory boards for and has received consulting fees from AstraZeneca and Novartis, and has received lecture fees and/or research support from Roche, Schering, Pfizer, Novartis, AstraZeneca, Sanofi-Aventis, GlaxoSmithKline, and Amgen. Dr. Steger has served on advisory boards for and has received consulting fees from AstraZeneca, Roche, and Amgen, and has received lecture fees and research support from AstraZeneca, Novartis, Roche, GlaxoSmithKline, and Amgen.

GeparQuinto was funded by GlaxoSmithKline, Roche, and Sanofi-Aventis; lapatinib was provided free of charge. Dr. Untch said he had no relevant financial disclosures, but several other GeparQuinto investigators made financial disclosures relating to these and other pharmaceutical companies. The NeoALTTO trial was funded by GlaxoSmithKline. Dr. Baselga said he has received honoraria from Roche, and his institution has received funding from GlaxoSmithKline and Roche. Several other NeoALTTO investigators made financial disclosures involving GlaxoSmithKline and/or other pharmaceutical companies. Dr. Chia, the author of the editorial that accompanied the article in the Lancet Oncology on the GeparQuinto trial, disclosed that he has received honoraria from GlaxoSmithKline, manufacturer of lapatinib, and F. Hoffmann-La Roche, manufacturer of trastuzumab, as well as an unrestricted research grant from Hoffmann-La Roche.

Subject Codes:
top_stories; oncology;


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January 17, 2012   03:28 PM EST

BY MARY ANN MOON
Elsevier Global Medical News
Breaking News

Intravenous cangrelor may prove to be a useful “bridge” in patients awaiting nonemergency CABG who must first discontinue their regular antiplatelet therapy, according to the results of the Maintenance of Platelet Inhibition With Cangrelor (BRIDGE) trialreported in the Jan. 18 issue of JAMA.

The practice of discontinuation of antiplatelet therapy is associated with significant morbidity and mortality; in patients who have coronary stents, it raises the risk of stent thrombosis that often leads to myocardial infarction and death. “Cessation of thienopyridine treatment for nearly a week before surgery, with patients not hospitalized or monitored but carrying an excess risk of major ischemic events, has been a troubling and not infrequent problem for clinicians, because it is estimated that approximately 5% of patients will require some type of surgery within the first 12 months after stent implant or [acute coronary syndrome] diagnosis,” said Dr. Dominick J. Angiolillo of the department of cardiology, University of Florida, Jacksonville, and his associates.

In this multicenter clinical trial sponsored by the drug’s maker, cangrelor “achieved and maintained target levels of platelet inhibition known to be associated with a low risk of thrombotic events compared with placebo, without a significant excess in bleeding complications,” the investigators noted.

Cangrelor is an investigational nonthienopyridine adenosine triphosphate analogue that acts as an antagonist of the P2Y12 receptor. It is characterized by “rapid, potent, predictable, and reversible platelet inhibition,” and its extremely short half-life (3-6 minutes) allows “rapid offset of effect.”

The investigators hypothesized that cangrelor would allow patients who must discontinue antiplatelet therapy prior to cardiac surgery, especially if they’re taking a P2Y12 inhibitor such as ticlopidine, clopidogrel, or prasugrel, to go off their usual drug without raising their risk for thrombotic events. They tested this hypothesis in a two-part trial.

The first part was an open-label dose-finding study involving 11 adults, which concluded that the optimal intravenous dose needed to maintain antiplatelet activity without raising bleeding risks was 0.75 mcg/kg per minute.

In the second part of the trial, 210 patients awaiting CABG at 34 medical centers around the world were randomly assigned to receive either cangrelor (106 subjects) or placebo (104 subjects) after thienopyridines were discontinued and throughout the preoperative period – that is, until 1-6 hours before surgical incision. Platelet function was assessed before, during, and after the infusion.

The mean interval between discontinuation of thienopyridines and infusion of the study drug was 29 hours, and the mean duration of the infusion was approximately 3 days.

The primary end point was the percentage of patients who showed platelet reactivity of less than 240 P2Y12 Reaction Units (PRUs) throughout the infusion of the study drug. “This level approximated the levels of platelet reactivity expected to be maintained if a thienopyridine had not been discontinued,” the investigators explained.

This end point was met by 99% of the cangrelor group but only 19% of the placebo group. It was achieved independently of patients’ usual dose of thienopyridines and independently of the length of time since thienopyridines were discontinued, Dr. Angiolillo and his colleagues said (JAMA 2012;307:265-74).

Moreover, cangrelor did not raise the rate of excessive bleeding related to CABG surgery. This safety end point occurred in 22 patients: 11.8% of the cangrelor group and 10.4% of the placebo group, a nonsignificant difference.

The number of minor bleeding events was numerically higher with cangrelor but did not reach statistical significance. Other adverse events, including dyspnea and laboratory abnormalities, also were comparable between the two groups. This favorable safety profile, even with prolonged infusion of up to 7 days, was “reassuring,” the researchers noted.

Ischemic end points prior to surgery were low in both groups, occurring in 2.8% (3 of 106) and 4.0% (4 of 101) of patients in the cangrelor and placebo groups.

“These observations support the hypothesis that intravenous cangrelor is a feasible management strategy, providing prolonged platelet P2Y12 inhibition in patients who must wait for cardiac surgery after thienopyridine discontinuation,” they said.

This study was sponsored by the Medicines Company. Dr. Angiolillo reported ties to Bristol-Myers Squibb, Sanofi-Aventis, Eli Lilly, Daiichi Sankyo, AstraZeneca, Portola, Novartis, Medicure, Accumetrics, Arena Pharmaceuticals, Merck, Evolva, and Abbott Vascular, and his associates reported ties to numerous other industry sources.

Subject Codes:
top_stories; cardiology; surgery;


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January 17, 2012   04:00 PM EST

BY MARY ANN MOON
Elsevier Global Medical News
Breaking News

For the first time, researchers say they have established benchmarks for the rates of in-hospital venous thromboembolism that occur after total or partial hip arthroplasty and after total or partial knee arthroplasty, according to a report Jan. 18 in JAMA.

In a meta-analysis of 47 studies that documented venous thromboembolism (VTE) event rates in nearly 45,000 patients who received recommended prophylaxis during hospitalization for knee or hip arthroplasty, investigators estimated that approximately 1 in every 100 patients undergoing knee arthroplasty and 1 in every 200 undergoing hip arthroplasty will develop symptomatic VTE before they are discharged.

“These estimates are of value to individual patients and clinicians in the consideration of risks and benefits” of the two procedures. They also are important because rates of in-hospital VTE are increasingly used as indicators of patient safety at individual medical centers, even though the expected background rates haven’t been established until now, said Jean-Marie Januel, a registered nurse with the Institute of Social and Preventive Medicine, Lausanne (Switzerland) University Hospital, and his associates.

“Large numbers of patients worldwide undergo hip and knee replacement procedures annually, and VTE is a widely acknowledged complication. Yet no estimate of symptomatic VTE risk prior to hospital discharge is available from the literature that can be conveyed to patients in the informed consent process,” they noted.

Mr. Januel and his colleagues performed a systemic search of the literature to identify studies performed between 1996 and 2011 in which subjects undergoing either hip or knee arthroplasty received VTE prophylaxis according to published guidelines, including either low-molecular-weight heparin or inhibitors of factor Xa or IIa. They found 41 randomized clinical trials and 6 observational studies to include in the meta-analysis.

A total of 22 of the studies were performed in Europe, 14 were in North America, and 11 were in other regions. The mean duration of follow-up after either surgery was 13 days.

This included 21 studies of partial or total hip arthroplasty, 20 of partial or total knee arthroplasty, and 6 studies of both procedures, with a total of 44,844 subjects.

There were 443 cases of symptomatic postoperative VTE that developed before hospital discharge: 288 in the 23,475 knee patients and 155 in the 23,475 hip patients. This included 182 cases of deep vein thrombosis in the knee patients and 93 in the hip patients, as well as 106 cases of pulmonary embolism in the knee patients and 43 in the hip patients.

The pooled incidence rates of VTE were approximately 1% after knee arthroplasty and approximately 0.5% after hip arthroplasty. This means that the background rate of VTE is approximately 1 in 100 knee patients and 1 in 200 hip patients, the investigators said (JAMA 2012;307:294-303).

When the data were broken down by type of VTE, the pooled incidence rates were 0.26% for deep vein thrombosis and 0.14% for pulmonary embolism after knee arthroplasty. The corresponding rates were 0.63% for deep vein thrombosis and 0.27% for pulmonary embolism after hip arthroplasty.

“Given that these rates are based on the results of rigorous studies, they may represent a lower incidence than actual rates observed in clinical practice, in which patients are selected less rigorously and prophylaxis is administered less assiduously,” Mr. Januel and his associates noted.

The pooled incidence rates of deep vein thrombosis were lower for both knee patients and hip patients when factor Xa or IIa inhibitors, rather than low-molecular-weight heparin, were given for prophylaxis. “However, we cannot make assertions regarding comparative efficacy among treatments, because our meta-analysis did not directly compare [these agents] as an efficacy meta-analysis would have done,” they said.

In-Hospital Not as Telling as Post-Discharge VTE Rates

The in-hospital VTE rates reported by Januel et al may be “suboptimal” for assessing both patients’ risks and a facility’s performance in patient safety, as the investigators proposed, said Dr. John A. Heit of the division of cardiovascular diseases at the Mayo Clinic, Rochester, Minn.

The period of VTE risks extends far beyond the hospital stay, with as many as 76% of VTE events occurring during the 3 months following hospital discharge. “From the perspective of the patient contemplating elective total hip replacement or total knee replacement,” the 3-month rate rather than the in-hospital rate of VTE is more important in weighing risks and benefits, he said in an editorial accompanying Mr. Januel’s report (JAMA 2012;307:306-7).

And it can be argued that this cumulative rate of VTE is also more important for the purpose of assessing a facility’s performance, Dr. Heit added.

This study was supported by Alberta Innovates Health Solutions, a government research funding agency, and the International Methodology Consortium for Coded Health Information, a collaboration of health sciences researchers to promote quality of care. Dr. Heit reported ties to Daiichi Sankyo, GTC, Ortho-McNeil-Jansen, the National Heart, Lung, and Blood Institute, the National Human Genome Research Institute, the National Institutes of Health, the Centers for Disease Control and Prevention, and the Mayo Foundation.

Subject Codes:
top_stories; cardiology; rheumatology; surgery; gerontology;


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January 17, 2012   04:00 PM EST

BY MITCHEL L. ZOLER
Elsevier Global Medical News
Breaking News

MIAMI BEACH (EGMN) – Local and regional anesthesia are better options than is general anesthesia for patients undergoing endovascular repair of an abdominal aortic aneurysm, based on findings from a registry with nearly 1,200 patients.

Both local anesthesia and regional anesthesia each surpassed general anesthesia in two periprocedural measures: significantly reducing procedure time, and significantly reducing postoperative hospitalization, Dr. Rutger A. Stokmans said at ISET 2012, an international symposium on endovascular therapy.

In addition, both local and regional anesthesia led to trends in reduced rates of major adverse events during the 30 days following surgery, although these differences did not reach statistical significance. All three anesthesia types linked with similar rates of both technical and clinical success of the aneurysm repairs. Regional anesthesia also led to a significantly lower rate of ICU admission, compared with both general and local anesthesia; local anesthesia showed no significant difference for this measure, compared with general anesthesia.

Based on these findings, local or regional anesthesia should be preferred when performing endovascular aneurysm repair (EVAR), whereas general anesthesia should usually be avoided, said Dr. Stokmans, a vascular surgeon at Catharina Hospital in Eindhoven, the Netherlands.

These findings support the most recent anesthesia recommendations of the European Society for Vascular Surgery, which in 2011 guidelines for managing abdominal aortic aneurysms (AAA) cited local anesthesia as preferred for EVAR, with regional or general anesthesia reserved for patients with contraindications for local anesthesia, he said (Euro. J. Vasc. Endovasc. Surg .2011;41[suppl. 1]:S1-S58). The most recent guidelines for AAA management from the Society for Vascular Surgery suggested using local or regional anesthesia over general anesthesia, he added (J. Vasc. Surg. 2009[suppl.]:50:S2-S49).

But despite these recommendations, the most commonly used anesthesia type worldwide for EVAR repair of AAA has been general anesthesia, followed by regional anesthesia, with local treatment used least often, according to the registry data reported by Dr. Stokmans. Among the 1,199 patients enrolled in ENGAGE (Endurant Stent Graft Natural Selection Global Postmarketing Registry) during March 2009 to December 2010 in 30 countries on five continents, 749 (62%) underwent their EVAR with general anesthesia, 325 (27%) with regional, and 125 (10%) with local anesthesia. (Percentages do not add up to 100% because of rounding.)

The registry data also showed striking regional variations in anesthesia use, with general anesthesia used on about 90% of patients in Canada, Australia, and New Zealand, and on about 70% of patients in Scandinavian countries and the United Kingdom. But in Central Europe, regional anesthesia – used on nearly 70% of EVAR patients – dominated. The only region favoring local anesthesia was South America (Argentina, Columbia, and Uruguay), where about 50% of patients received local, but more than 40% received general anesthesia, he said. The registry contained no U.S. patients, although the Endurant AAA stent graft system is marketed in the United States.

The average age of the EVAR patients in the registry was about 73 years. Those patients who underwent general anesthesia were significantly older, by an average of about 18 months, compared with those who received local or regional anesthesia.

The proportions of patients undergoing general, regional, or local anesthesia were similar in the subgroups of patients with American Society of Anesthesiologists (ASA) physical status scores of 1, 2, or 3. However, among the highest-risk patients included in the study – those with an ASA score of 4 – a significantly greater proportion of patients received general anesthesia. The multivariate models used in the analysis, therefore, were adjusted for age and for ASA score. About 42% of patients were in ASA class 2, and another 42% in class 3.

All patients were hemodynamically stable at the time of their enrollment. The maximum AAA diameter of registry patients was 6 cm, and about 88% of patients had an AAA diameter greater than 5 cm.

Average procedure times were 106 minutes in the general anesthesia patients, 95 minutes in the regional patients, and 81 minutes in the local anesthesia patients – statistically significant differences among the three groups.

The average postoperative hospitalization was 5.2 days in the general anesthesia patients, 4.3 days in the regional patients, and 3.6 days in the local anesthesia patients, differences that were statistically significant among each of the three groups.

The rate of technical surgical success was 98% in all three subgroups, and the rate of clinical success reached 97%-98% in all three groups.

The rates of major adverse events during the 30 days following surgery were 5.1% in the general anesthesia patients, 3.2% in the local patients, and 2.2% in the regional anesthesia patients. None of these differences reached statistical significance. Major adverse events included death, MI, stroke, renal failure, blood loss greater than 1 L, and bowel ischemia. No patients developed paraplegia or respiratory failure.

Postoperative ICU admission occurred for 27% of the regional anesthesia patients, 35% of the general patients, and 42% of the local anesthesia patients. The rate among the regional patients was significantly less than in the other two groups, but the difference in rates between the general and local anesthesia patients did not reach statistical significance.

The ENGAGE registry was organized and sponsored by Medtronic, which markets the Endurant stent. Dr. Stokmans and his associates received an unrestricted research grant from Medtronic. Dr. Stokmans said that he had no other disclosures.

Subject Codes:
top_stories; cardiology; surgery;


http://www.imng.com


January 17, 2012   02:17 PM EST

Rutger A. Stokmans

BY HEIDI SPLETE
Elsevier Global Medical News
Breaking News

Twenty-four percent of 525 pediatricians surveyed agreed that children with attention-deficit/hyperactivity disorder should undergo cardiac screening before taking stimulants, according to a study published online Jan. 16 in Pediatrics.

Although postmarketing reports during the past decade have shown cases of sudden cardiac death (SCD) in children with attention-deficit/hyperactivity disorder (ADHD) who were taking stimulants, findings from studies specifically addressing the topic have been inconsistent, said Dr. Laurel K. Leslie of Tufts Medical Center, Boston, and colleagues.

These studies have been undertaken in the wake of various recommendations for evaluation of cardiac status prior to starting stimulant treatment. In 2008, the American Heart Association “released a policy statement widely interpreted as recommending the routine use of electrocardiograms (ECGs) to evaluate children” prior to starting treatment with stimulant medication (Circulation 2008;117:2407-23).

As a clarification of that policy statement, the American Academy of Pediatrics (AAP) and the American Heart Association subsequently published a joint statement, which was endorsed by the American Academy of Child and Adolescent Psychiatry, that revised the American Heart Association’s original recommendation of the ECG. The joint statement stated that physicians should perform in-depth cardiac history and physicals (H&P) prior to starting stimulant treatment and get ECGs for children with positive findings. It noted that getting an ECG was a Class IIa recommendation so it is reasonable for a physician to consider an ECG, but not mandatory.

Then, the AAP stated in a 2008 policy statement that medications used to treat ADHD had not been shown to cause SCD, and there was not sufficient evidence to justify obtaining routine ECGs before starting treatment with stimulants. The AAP concluded that “until these questions are answered, a recommendation to obtain routine ECGs for children receiving ADHD medications is not warranted” (Pediatrics 2008;122:451-3).

In Dr. Leslie’s current study, 75% of the survey respondents agreed that physicians have a responsibility to inform families about the possible risk of SCD before children begin treatment with stimulants. However, only 30% agreed that the risk of a potential lawsuit was high enough to warrant cardiac screening (Pediatrics 2012;129:222-30).

In addition, 36% of the respondents agreed that informing families about a possible SCD risk might deter them from giving the stimulants to their children.

As part of the survey, each of the respondents reported the cardiac screening practices for his or her most recent patient with ADHD. Nearly all respondents (93%) completed a routine history and physical, and 71% collected an in-depth cardiac history, while 48% completed an in-depth cardiac history and physical.

Less than half (46%) of the physicians discussed cardiac risks with families of a recent patient with ADHD, although most (93%) of the respondents discussed weight loss or appetite suppression as a side effect of stimulants, 87% discussed sleep disturbance, and 75% discussed affective symptoms such as moodiness, irritability, and suicidality.

A total of 77 respondents (15%) reported ordering an ECG for their most recent patient; 42 of these did so because it was standard in their practices. Only 16 (21%) of the physicians who ordered ECGs reviewed the results themselves.

There was a general lack of comfort with cardiac screening procedures. A total of 71% of respondents said that their ability to interpret a pediatric ECG was a barrier to screening, and 18% said that their ability to perform an in-depth cardiac history and physical was a barrier. The respondents reported other barriers including lack of local specialists (18%), a long wait to see a specialist (37%), and patients’ inability to pay for care (52%).

In a multivariate analysis, certain associations emerged among attitudes, barriers, and physician practices, the researchers wrote. “Legal liability and physician responsibility to inform families of SCD risk were positively associated with an in-depth cardiac H&P, whereas barriers in ability to perform an in-depth cardiac H&P were negatively associated,” they noted.

The findings suggest that balancing the potential benefits of stimulants for ADHD children with the obligation to inform families of a possible SCD risk remains a challenge for pediatricians, the researchers said.

“Shared decision-making extends informed consent by not only exchanging information about treatment options, risks, and benefits, but also by sharing viewpoints so that patients, families, and physicians become aware of each other’s perspectives with the goal of achieving a mutually agreed on treatment plan,” Dr. Leslie and colleagues wrote.

The survey was mailed to 1,600 randomly selected AAP members who provide direct patient care to children aged 5-17 years with ADHD. Pediatricians who were retired, trainees, or not based in the United States were excluded. Most who responded were female, non-Hispanic/white, and practicing for an average of 18 years.

The study was limited by the lower-than-expected response rate, the lack of information about the resources available in each practice, and the lack of perspective from families. But the study is the first to ask pediatricians about this topic specifically, and the findings reinforce the ongoing controversy over the potential cardiac risks associated with stimulant use by children with ADHD, Dr. Leslie and colleagues noted.

Dr. Leslie and colleagues reported having no relevant financial disclosures. The study was funded by the National Institutes of Health.

Subject Codes:
top_stories; mental_health; pediatrics; cardiology;


http://www.imng.com


January 16, 2012   12:01 AM EST

BY KERRI WACHTER
Elsevier Global Medical News
Breaking News

Hospitalizations for drowning dropped 51% between 1993 and 2008, according to the results of a study based on data from the Nationwide Inpatient Sample.

The number of hospitalizations fell from an estimated 3,623 in 1993 to 1,781 in 2008. During the same period, the estimated annual incidence rate of pediatric hospitalizations associated with drowning declined 57% – from 4.9 to 2.1 per 100,000, according to findings published online Jan. 16 in Pediatrics (2012;129:1-7)

“Our study provides national estimates of pediatric drowning hospitalizations that can be used as benchmarks to inform drowning prevention efforts and to help target interventions to high-risk areas. Given the significant burden of drowning in both real and human costs, additional monitoring of pediatric drowning is needed,” wrote Stephen M. Bowman, Ph.D., of the center for injury research and policy at Johns Hopkins University in Baltimore, and his coinvestigators.

The researchers used administrative discharge data from the 1993 to 2008 Nationwide Inpatient Sample (NIS). The NIS is created from state inpatient databases provided by public/private statewide data organizations from participating states. The NIS is the largest, longitudinal, all-payer inpatient care database in the United States, with an average of 8 million hospitalizations from approximately 1,000 hospitals each year, the researchers noted. The NIS approximates a 20% stratified random sample of all short-term U.S. community hospitals.

Eligibility for this study was limited to children and adolescents who were aged 0-19 years at admission and who were hospitalized with a primary or secondary ICD-9-CM diagnosis code for drowning injury. Patients who died while hospitalized were included.

The circumstances of drowning were determined based on the external cause of injury code when possible. The circumstances of drowning injury were categorized into five groups: recreational swimming and diving, drowning in bathtubs, other drowning activities, all other codes, and missing. For the incidence rate calculations, the investigators used U.S. Census estimates for the national civilian population at midyears during this time interval. External cause of injury codes were missing for up to 55% of hospitalizations before 1997. For this reason, the investigators compared 2-year aggregate data for the years 1998-1999 and 2007-2008 to evaluate changes in drowning mechanism and intent over time.

Drowning characteristics typically differ by age and sex. Young children (less than 4 years of age) have the greatest mortality rate from drowning and are more likely to drown while bathing or falling into water, the authors noted. Older children are more likely to drown while swimming in open water. In addition, males are four to six times more likely than females to experience a drowning injury, because of factors such as overestimation of swimming ability and greater use of alcohol by adolescent males, Dr. Bowman and his associates said.

The hospitalization rates declined significantly for all ages and for both sexes. However, the rate for males remained greater at each point in time. The total annual hospital days also declined from an estimated 14,570 days in 1993 to approximately 6,295 days in 2008. However no trend in mean hospital length of stay was observed.

“Consistent with decreases in pediatric drowning mortality, we observed a significant decline in the rate of pediatric drowning hospitalizations, primarily because of decreases in the South and West. This is an important finding that provides some evidence of a true decrease in drowning incidents, rather than a possible shift from fatal out-of-hospital drowning to nonfatal in-hospital cases,” Dr. Bowman and his associates wrote. Hospitalization rates decreased significantly across all geographic regions of the United States, although the greatest decline in drowning hospitalization rates occurred in the South. The overall drowning rate fell from 7.5 hospitalizations per 100,000 in 1993-1994 to 3.5 per 100,000 in 2007-2008 in this region.

“Between 1998-1999 and 2007-2008, we observed a significant change in drowning hospitalization rates for selected ages and mechanisms,” they wrote. Overall, there was a significant decline (40%) in bathtub-related drowning hospitalizations in children aged 0-4 years. Drowning hospitalizations due to swimming and diving decreased by nearly half in older children aged 10-14 years.

“Reductions in bathtub drowning hospitalizations among the youngest children may reflect a response to targeted injury prevention efforts that have been aimed at parents and caregivers of young children, encouraging increased vigilance in supervision.

“Interestingly, we did observe a decrease in the rate of in-hospital deaths over the 14-year period, although the in-hospital case fatality did not change significantly,” the researchers noted. In-hospital mortality declined 42% from an estimated 359 deaths in 1993 to 207 deaths in 2008. “Although improvements in treatment might be having an impact on survival, it is not clear from these data what level of neurologic functioning survivors may have. An alternate explanation is that better decision making in the prehospital period may be resulting in more pronouncement of death in the field for unsurvivable cases.”

The study was funded by the National Institutes of Health. Dr. Bowman and his associates reported that they have no relevant financial disclosures.

Subject Codes:
top_stories; pediatrics; emergency_trauma;


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January 16, 2012   12:01 AM EST

BY DIANA MAHONEY
Elsevier Global Medical News
Breaking News

The Food and Drug Administration on Jan. 13 announced that a boxed warning will be added to the label of brentuximab vedotin because of reports of two cases of progressive multifocal leukoencephalopathy associated with the drug’s use in lymphoma patients.

Brentuximab vedotin (Adcetris) was approved in August 2011 for the treatment of Hodgkin’s lymphoma and systemic anaplastic large cell lymphoma. At the time of its approval, the warnings and precautions label described one case of progressive multifocal leukoencephalopathy (PML), a rare and potentially fatal brain infection. These two additional cases prompted the new boxed warning because of the serious nature of the infection, the FDA release stated.

Additionally, a contraindication warning against the use of brentuximab vedotin in combination with the antitumor antibiotic bleomycin (Blenoxane) has been added to the label because of an association with an increased risk of pulmonary toxicity.

Signs and symptoms of PML include mood or behavior changes; confusion; altered cognitive abilities; memory loss; vision, speech, and motor function changes; and unilateral weakness or decreased strength that can develop over several weeks or months, according to the statement.

The new label advises patients who develop signs or symptoms of the condition to notify their health care provider immediately. If PML is suspected, health care professionals are advised to hold dosing pending the diagnosis of PML, and discontinue the drug if the diagnosis is confirmed.

Subject Codes:
infectious; top_stories; oncology;


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January 13, 2012   04:26 PM EST

BY KERRI WACHTER
Elsevier Global Medical News
Breaking News

The Food and Drug Administration is reporting current shortages of three drugs that are prescribed in the treatment of attention-deficit/hyperactive disorder: amphetamine mixed salts immediate-release tablets, dextroamphetamine tablets, and methylphenidate HCl.

The shortage of amphetamine mixed salts immediate-release tablets is primarily attributable to an increase in demand. Supply issues were cited by one manufacturer. The three companies involved are releasing the products as they become available.

The shortage of dextroamphetamine tablets (5 mg and 10 mg), made by Teva Pharmaceuticals, is new. The product will be released as it becomes available, the company reported. Dexamethasone injection presentations (5-mg/mL and 10-mg/mL vial [Carpujet]), made by American Regent Inc., are on hold because of the presence of particulate matter. It has “no estimated release date,” the company reported. West-Ward Pharmaceuticals has the 10 mg/mL formulation of dexamethasone on back order and expects to have it available by the middle of July.

The shortage of methylphenidate HCl is tied to delays that have been reported by several manufacturers, the FDA noted. Sandoz has reported capacity constraints, and expects sporadic back orders for the next couple of months. Mallinckrodt has reported continued recovery as a result of previously unavailable raw material; the company expects all strengths of methylphenidate IR and ER (extended-release) tablets to be increasingly available as supply recovery continues, with most contracted orders being met. UCB has reported increased demand; the company is currently out of its stock of 5-mg IR, 10-mg IR, 20-mg IR, and 20-mg ER products, with resupply expected by February. Watson Pharmaceuticals Inc. has all three strengths available for contracted customers only. Noven Pharmaceuticals Inc. reports that all Daytrana (methylphenidate transdermal system) products are available.

Subject Codes:
top_stories; mental_health; pediatrics;


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January 13, 2012   02:48 PM EST

BY FRANCES CORREA
Elsevier Global Medical News
Breaking News

WASHINGTON (EGMN) – The Medicare Payment Advisory Commission voiced its disappointment with Congress’ failure to find a permanent fix for Medicare’s sustainable growth rate formula (SGR) at its Jan. 12 meeting.

MedPAC Chairman Glenn Hackbarth said the opportunity to pay for an SGR solution is fading. “Repeal of SGR will only get more expensive.” He added that the likelihood that Congress would forgive any debt incurred by the SGR also is fading, as are the Medicare savings that could fund the repeal.

“To say that we can’t repeal SGR without it being offset and then take Medicare savings for other purposes leaves this destabilizing element at the heart of the Medicare program,” Mr. Hackbarth said.

At its October meeting, the commission voted to submit its recommendations to Congress for using Medicare savings to fund an SGR replacement. Key among the recommendations are:

• Repealing the SGR.

• Freezing payments to primary care physicians for 10 years.

• Cutting reimbursements to specialist physicians by 17% over 3 years, followed by a 7-year freeze.

Dr. Ron Castellanos, MedPAC commissioner and a Florida urologist, called on MedPAC to increase their pressure on Congress to find a permanent solution.

“I don’t know how to say more passionately that there needs to be a message from MedPAC that this is just totally unacceptable,” Dr. Castellanos said. He added that if the 27.4% pay cut goes through, it could force Congress to come up with a permanent fix.

“I don’t like the idea of letting the cut go through but certainly if that happens I think we could get an answer,” Mr. Castellanos said.

The commission’s next meeting is March 8.

Subject Codes:
top_stories;


http://www.imng.com


January 13, 2012   12:38 PM EST

BY KERRI WACHTER
Elsevier Global Medical News
Breaking News

The use of selective serotonin reuptake inhibitors by women during pregnancy increases the risk of persistent pulmonary hypertension in newborns, with the risk doubling for use during late pregnancy.

The risk of persistent pulmonary hypertension of the newborn (PPHN) after exposure to any SSRI in late pregnancy was more than doubled (adjusted odds ratio, 2.1). The risk was slightly increased in association with exposure to SSRIs in early pregnancy (adjusted OR, 1.4). The combination of a previous admission to hospital for a psychiatric disorder and exposure to an SSRI in late pregnancy yielded an adjusted OR of 3.1. The findings – from a population-based cohort study of data from registries in five Nordic countries – were published Jan. 12 in BMJ (2011;344:d8012 [doi:10.1136/bmj.d8012]).

“As the risk in association with treatment in late pregnancy seems to be more than doubled, we recommend caution when treating pregnant women with SSRIs. It is essential to plan the treatment and to weigh the risks of persistent pulmonary hypertension of the newborn when treating women in late pregnancy with those of relapse of depression and neonatal abstinence syndrome if therapy is interrupted. For women where treatment with an SSRI is the only or best option, the choice of substance seems to be of minor importance,” said Dr. Helle Kieler, an ob.gyn. at the Centre for Pharmacoepidemiology at the Karolinska Institute in Stockholm, and her coinvestigators.

The researchers included women and their infants born in Denmark, Finland, Iceland, Norway, or Sweden between 1996 and 2007. Each of these countries has national registers with prospectively collected information on the health of all inhabitants. They obtained data from the medical birth registers, the prescription registers, and the cause of death registers from all five countries. Data on the mother’s previous psychiatric diseases and infant diagnoses were included for Denmark, Iceland, Sweden, and Finland and from the Danish Psychiatric Central Register.

The investigators included all singletons born after 33 weeks’ gestation between 1996 and 2007. Births were included only from the years when prescription data were available. They obtained information on PPHN, level of delivery hospital, maternal smoking, body mass index (BMI) in early pregnancy, year of birth, mode of delivery, gestational age at birth, birth weight, meconium aspiration, and maternal diseases recorded during pregnancy from the national registers.

The researchers also collected information about the mothers’ admissions to hospital for a psychiatric diagnosis during the 10 years before giving birth. In addition, they identified women who had filled prescriptions for antidepressants, antidiabetes drugs, or nonsteroidal anti-inflammatory drugs (NSAIDs) from 3 months before the start of pregnancy until delivery.

Dr. Kieler and her associates included six SSRIs in the analyses: fluoxetine (Prozac), citalopram (Celexa), paroxetine (Paxil), sertraline (Zoloft), fluvoxamine (Luvox), and escitalopram (Lexapro). They also performed subanalyses on whether other antidepressants with an effect on serotonin activity or norepinephrine activity would affect the risks of PPHN. Patient use was as “ever use” (3 months before the start of pregnancy until birth), as a filled prescription in late pregnancy (from 140 days after the start of pregnancy until birth), or in early pregnancy only (from 3 months before the start of pregnancy until a pregnancy length of 55 days).

Potential confounders included maternal smoking, age, BMI, purchased NSAIDs and antidiabetes drugs, diseases recorded during pregnancy, level of delivery hospital (university or nonuniversity hospital), and infants’ country of birth, birth year, and birth order.

In total, 1,618,255 singleton births were included. Of these, 0.7% of the mothers had filled a prescription for an SSRI during late pregnancy and 1.1% in early pregnancy only. The mothers with a filled prescription for an SSRI tended to be older and more often smokers than mothers not using SSRIs. Exposed infants had a lower gestational age at birth and were more often classified as small for gestational age. The absolute risk for PPHN for infants to mothers using SSRIs was as low as 3 infants per 1,000 exposed.

In late pregnancy, 627 women had filled a prescription for an antidepressant with an effect on serotonin activity or norepinephrine activity. The corresponding figure for early pregnancy only was 2,503. More than three-quarters (85%) of 63,615 women with a previous psychiatric diagnosis had not filled a prescription for any of the antidepressants during pregnancy.

Among the 11,014 infants exposed to an SSRI in late pregnancy, 33 (0.3%) had a diagnosis of PPHN – three of whom had meconium aspiration. Among 627 infants exposed to antidepressants with an effect on serotonin activity or norepinephrine activity, 3 (0.5%) had a diagnosis of PPHN. Of the 17,053 infants exposed to SSRIs only in early pregnancy, 32 (0.2%) had PPHN; 0.1% of the 1,588,140 infants never exposed to SSRIs were diagnosed with PPHN.

Of the infants with PPHN, 3 of the 33 infants (9%) who were exposed to SSRIs in late pregnancy died, as did 183 (9.5%) of the 1,935 who were never exposed to SSRIs. Among the 63,615 women with a previous admission to hospital for a psychiatric disorder, 114 (1.8%) infants had a diagnosis of PPHN.

The risk estimates of PPHN after exposure to fluoxetine, citalopram, sertraline, or paroxetine in late pregnancy ranged from 2 to 3. While the risk estimate for escitalopram was lower, this number was imprecise. No infants with PPHN had been exposed to fluvoxamine. “Exposure to the other antidepressants with an effect on serotonin activity or norepinephrine activity also generated increased risks,” Dr. Kieler and her associates wrote.

Risks for PPHN were only slightly increased in association with exposure to SSRI in early pregnancy only. Exposure to the other antidepressants with an effect on serotonin activity or norepinephrine activity did not increase the risk of PPHN in early pregnancy only.

After exclusion of infants with meconium aspiration, the risk estimates increased slightly, they said.

This study was funded by the Swedish Pharmacy Company. The authors reported that they had no relevant financial disclosures.

Additional Study Needed

In an accompanying editorial, Dr. Gideon Koren and Dr. Hevig Nordeng noted that “pharmacoepidemiological studies can show an association but cannot prove causation, yet the authors state that SSRI use in late pregnancy increased the risk of this syndrome, implying causation” (BMJ 2011;343:d7642). Dr. Koren and Dr. Nordeng pointed out several problems that are inherent in this type of study and problems with this particular study.

“A major challenge in prescription database studies is to prove exposure. The fact that the drug was prescribed does not mean that it was taken. In this study, the timing of exposure was based on the pharmacies’ date of dispensing and defined daily dosages (which may differ from the prescribed doses), but they did not mention the uncertainty around the timing of exposure and how it was calculated,” they wrote.

“In addition, without having validated the diagnosis or reviewed the medical charts of each case, it is difficult to estimate the quality of Kieler and colleagues’ definition of pulmonary hypertension in the newborn. In [a] 2006 case-control study, 40% of the potential cases were rejected after a neonatologist reviewed the medical records (N. Engl. J. Med. 2006;354:579-87),” wrote Dr. Koren, who is director of the Motherisk Program at the Hospital for Sick Children in Toronto, and Dr. Nordeng, an associate professor of pharmacy at the University of Oslo.

Surprisingly, Kieler et al. excluded neonates with one cause of pulmonary hypertension in the newborn, meconium aspiration, but did not do so with other known causes, they continued. “This decision is not justified, especially when the registries available to the authors included clinical details on all other known causes of the syndrome. By not controlling for these confounding or modifying conditions, the authors have missed an opportunity to calculate the attributable risk of SSRIs in causing pulmonary hypertension in the newborn,” wrote Dr. Koren and Dr. Nordeng.

In addition, “although the authors argue against confounding by indication, their analyses clearly show that women who did not use antidepressants in pregnancy but who had been admitted to hospital for psychiatric reasons were more likely to give birth to infants with pulmonary hypertension in the newborn (OR 1.3).”

Lastly, “an important question is not the relative risk of an SSRI causing the syndrome, but rather absolute attributable risk. As estimated previously, this syndrome may occur in less than one in 100 pregnant women treated with an SSRI. If the infant has no life-threatening known causes of pulmonary hypertension in the newborn – such as meconium aspiration, sepsis, congenital heart disease, or diaphragmatic hernia – the chance of a full recovery is high. Future studies, or additional analyses of Kieler and colleagues’ large cohort, may be able to quantify this risk, or the lack of one,” they wrote.

Dr. Koren and Dr. Nordeng reported that they had no financial disclosures relevant to their editorial.

Subject Codes:
top_stories; mental_health; pediatrics; womens_health; pulmonology;


http://www.imng.com


January 12, 2012   06:30 PM EST

BY ELIZABETH MECHCATIE
Elsevier Global Medical News
Breaking News

GAITHERSBURG, MD. (EGMN)–A Food and Drug Administration advisory panel on Jan. 11 unanimously agreed in a 9 to 0 vote that a laparoscopically implanted device designed to treat gastroesophageal reflux disease has a favorable risk-benefit profile, providing patients who do not get adequate relief from antireflux medications an alternative to more invasive surgery,.

The FDA’s Gastroenterology–Urology Devices Panel also voted 9 to 0 that there was “reasonable assurance” that the device, the LINX Reflux Management System, was safe and effective for the indication proposed by the manufacturer: the treatment for people who are “diagnosed with pathologic gastroesophageal reflux disease (GERD) as defined by abnormal pH testing, and who continue to have chronic GERD symptoms despite anti-reflux therapy.” The panel did not vote specifically on whether to recommend approval.

The sterile, single-use device is designed to augment a weak lower esophageal sphincter (LES), and is composed of titanium beads that have a magnetic core, strung together on a titanium wire, which is placed around the gastroesophageal junction at the LES. Because of the magnetic attraction between the beads, the beads rest against each other and help prevent the LES from opening at rest, therefore preventing reflux. But the magnetic attraction is disrupted when the patient swallows, allowing food and liquids to pass into the stomach. Belching and vomiting are possible, because the device does not compress the esophagus.

The manufacturer, Torax Medical Inc., conducted two prospective, uncontrolled studies of 144 patients with chronic GERD symptoms, despite long-term acid suppression treatment, in the United States and Europe. All patients received the implant.

In the pivotal study of 100 patients, 64% had normalization of pH or at least a 50% reduction in pH 12 months after device implantation, which was the primary efficacy end point. This finding was not statistically significant, based on prespecified cirtieria for significance. But the majority of patients showed improvement in scores on a scale that measures the severity of GERD symptoms and were able to reduce their daily proton pump inhibitor dosage by at least 50% at 12 and 24 months, which were secondary end points.

Almost 80% (76) of the patients had a total of 162 adverse events that were related to the device or the procedure, of which dysphagia was the most common, accounting for 76 events, followed by pain in 24 events. Some cases had to be treated with esophageal dilation, and some required device removal.

In the feasibility study of 44 patients, the majority of patients also had improvements in GERD symptoms and PPI use for up to a 3-year follow-up, with dysphagia the most common side effect, requiring two esophageal dilations and one explant.

Panelists recommended that patients be followed up for longer than the 3 years in postmarketing studies proposed by the manufacturer. The device has been available in the United Kingdom and Germany for about 2 years.

The FDA usually follows the recommendations of its advisory panels, which are not binding. Panelists have been cleared of potential conflicts of interest related to the topic of the meeting. Occasionally, a panelist may be given a waiver, but not at this meeting.

Subject Codes:
top_stories; gastroenterology; general_primary;


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January 11, 2012   08:32 PM EST

BY MARY ANN MOON
Elsevier Global Medical News
Breaking News

Marathon runners’ risk of cardiac arrest is relatively low – equivalent to or lower than that of other athletes engaged in vigorous activity, according to a report in the Jan. 12 issue of the New England Journal of Medicine.

The number of cardiac arrests related to marathon (26.2-mile) and half-marathon (13.1-mile) races has increased in recent years, but that is largely explained by the increase in the number of people who have taken up the sport, said Dr. Jonathan H. Kim of the division of cardiology, Massachusetts General Hospital, Boston, and his associates.

“The growth of long-distance running has been accompanied by studies documenting post-race cardiac dysfunction and numerous reports of race-related cardiac arrest. These unexpected tragedies attract considerable media attention and have led to concerns regarding the health risks of this activity,” the researchers wrote.

Until now, no large studies have examined the incidence, clinical profiles, and outcomes of cardiac arrests that occur during or immediately after long-distances races. The Race Associated Cardiac Arrest Event Registry (RACER) collected data to facilitate such studies. It included information on all marathon or half-marathon races held in the United States between 2000 and May 2010.

Dr. Kim and his associates in the RACER study group identified 59 marathon-related cardiac arrests (out of 10.9 million registered marathon runners) during this period and contacted survivors, as well as the next of kin of nonsurvivors, to ascertain demographic data, exercise history, personal and family medical histories, and pertinent medical records.

The overall incidence of cardiac arrest was 1 per 184,000 participants, and that of sudden death was 1 per 259,000 participants. This translates to 0.2 cardiac arrests and 0.14 sudden deaths per 100,000 runner-hours at risk, assuming an average running time of 4 hours for marathons and 2 hours for half-marathons.

“Thus, event rates among marathon and half-marathon runners are relatively low, as compared with other athletic populations, including collegiate athletes (1 death per 43,770 participants per year), triathlon participants (1 death per 52,630 participants), and previously healthy middle-aged joggers (1 death per 7,620 participants),” the researchers wrote (N. Engl. J. Med. 2012;366:130-40).

The absolute number of marathon-related cardiac arrests rose each year during the study period, but the incidence remained stable because of an annual increase in runners from fewer than 1 million in 2000 to approximately 2 million in 2010, according to the investigators.

Men were more likely than were women runners to have a cardiac arrest or sudden death (0.90 per 100,000 vs. 0.16 per 100,000), which the authors noted is “consistent with reports on other populations and reaffirms a male predisposition to exertional cardiac arrest.”

The distance of a race was a key determinant of the risk of cardiac arrest, since rates were three to five times higher during marathons (1.01 per 100,000 runners) than during half-marathons (0.27 per 100,000). “A possible explanation is that longer races involve more physiological stress and thus a higher likelihood of precipitating an adverse event in a predisposed participant,” the researchers wrote.

The overall case fatality rate was 71%. Sufficient information was available to determine the cause of cardiac arrest in only 31 of the 59 cases.

The most frequent cause of death was hypertrophic cardiomyopathy (8 cases) or possible hypertrophic cardiomyopathy (7 cases). This is also the primary cause of death in young competitive athletes, they pointed out.

“Notably, 9 of the 15 nonsurvivors who had cardiac hypertrophy had an additional clinical factor or postmortem finding: obstructive coronary artery disease (in 3), myocarditis (in 2), bicuspid aortic valve or coronary anomaly (in 2), accessory atrioventricular nodal bypass tract (in 1), or hyperthermia (in 1),” the researchers wrote. The race-related disorders of hyperthermia and hyponatremia, which led to the death of one runner without cardiac hypertrophy, thus are not common causes of cardiac arrest and sudden death, they added.

Among the eight survivors of cardiac arrest, ischemic heart disease was the most frequent cause of the arrest. The strongest predictor of survival of cardiac arrest was bystander-administered CPR, underscoring the importance of onsite medical services.

It was “surprising” that none of the runners with serious coronary atherosclerosis had angiographic evidence of acute plaque rupture or thrombus, because previous studies as well as expert consensus statements have suggest that exercise-induced coronary syndromes result from disruption of atherosclerotic plaque and coronary thrombosis. “In contrast, our findings suggest that demand ischemia (i.e., ischemia due to an imbalance between oxygen supply and demand) may be operative in exercise-related acute coronary events during long-distance running races,” they wrote.

This finding also suggests that the practice of taking aspirin before a race to prevent cardiac arrest is likely ineffective, since acute coronary artery thrombosis is not an important cause of marathon-related cardiac arrest, they added.

Physicians called on to evaluate potential marathon participants “should be aware of the risks of hypertrophic cardiomyopathy and atherosclerotic disease in this patient population.” Prerace exercise testing may detect physiologically significant coronary artery stenosis or may identify patients with exertion-induced myocardial ischemia, the investigators said.

This study was limited in that the researchers were unable to obtain complete clinical information on 45% of the nonsurvivors or on 53% of the survivors.

Dr. Kim reported no financial conflicts of interest, but two of his coauthors reported ties to industry sources.

Subject Codes:
top_stories; sports; general_primary; cardiology;


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January 11, 2012   05:00 PM EST

While it may appear that cardiac arrests related to marathon running have increased, researchers say it’s because more people are participating in the sport. The incidence of cardiac arrests remained stable over the study period.

BY BRUCE JANCIN
Elsevier Global Medical News
Breaking News

Asymptomatic episodes of atrial fibrillation are common in elderly hypertensive patients with pacemakers and no history of clinical AF – and these subclinical atrial tachyarrhythmias are associated with a sharply increased risk of subsequent ischemic stroke.

These were the two major findings of the large, international, randomized ASSERT (Asymptomatic Atrial Fibrillation and Stroke Evaluation in Pacemaker Patients and the Atrial Fibrillation Reduction Atrial Pacing Trial) study.

An important secondary finding was that, disappointingly, continuous atrial overdrive pacing using a programmable algorithm to maintain a paced atrium did not prevent the development of clinical AF, nor did it modify stroke risk, according to Dr. Jeff S. Healey of the Population Health Research Institute at McMaster University in Hamilton, Ont.

ASSERT enrolled 2,580 patients in 23 countries. All were aged 65 years or older, were hypertensive, and had recently received a dual-chamber pacemaker or implantable cardioverter-defibrillator. None of the subjects had a history of AF at enrollment.

In the first 3 months of follow-up, 10.1% of study participants developed device-detected subclinical AF (defined as an atrial rate in excess of 190 beats per minute lasting for more than 6 minutes). As a practical matter, it’s worth noting that the median time to implanted device–detected asymptomatic AF in this subgroup was 36 days. Thus, several days of negative Holter monitoring would have made for false reassurance, the cardiologist noted.

The subgroup with asymptomatic AF during the first 3 months had a 5.6-fold increased risk of developing clinical AF during a mean 2.5 years of prospective follow-up. Moreover, the rate of ischemic stroke or systemic embolism in patients with subclinical AF in the first 3 months was 1.7% per year, compared with 0.69% annually in the rest of the ASSERT participants.

The population attributable risk (PAR) of stroke or systemic embolism associated with asymptomatic AF in the first 3 months was 13%. Of note, that’s similar to the PAR of stroke that is associated with clinical AF in the Framingham Heart Study.

In a multivariate analysis adjusted for the standard predictors of stroke, device-detected subclinical AF during the first 3 months of the study was independently associated with a 2.5-fold increased subsequent risk of stroke. And this may well underestimate the true magnitude of risk, since more than half of ASSERT participants were on aspirin at baseline and 18% of those with early subclinical AF received warfarin during the follow-up period.

Both of these venerable drugs are clearly effective in reducing stroke risk in patients with established clinical AF, although it’s not known whether these agents also have a net benefit in patients with subclinical AF. A randomized trial testing this hypothesis by using these drugs or newer anticoagulants should be a priority, Dr. Healey said (N. Engl. J. Med. 2012;366:120-9).

Subjects with a CHADS2 score greater than 2 plus subclinical AF detected in the first 3 months of the study had a rate of ischemic stroke or systemic embolism of 3.7% per year, compared with 0.97% per year in patients with a similarly elevated CHADS2 score but no early subclinical atrial tachyarrhythmia.

In addition to the 10% of ASSERT participants who developed subclinical AF during the initial 3 months of follow-up, another 24% did so later.

Episodes of asymptomatic AF briefer than 6 minutes were not catalogued in the study, so it remains unknown if they, too, are associated with increased subsequent stroke risk.

At the study’s outset, all subjects with pacemakers were randomized to continuous atrial overdrive pacing or to having this feature switched off for the duration. The atrial pacing intervention did not affect the rate of development of clinical AF, although the trial was underpowered for this outcome.

How Much Atrial Arrhythmia Is Too Much?

In an editorial accompanying the study, Dr. Gervasio Lamas noted that although this “robust” study convincingly demonstrates that device-detected subclinical AF was independently associated with a more-than-doubled annualized risk of stroke or peripheral embolism, the question of cause vs. effect remains open: Are these asymptomatic episodes of AF actually causing cardioembolic stroke, or are they merely a marker of stroke risk, possibly reflecting myocardial fibrosis or structural heart disease (N. Engl. J. Med. 2012;366:178-80)?

It’s noteworthy that the lengthier the longest episode of subclinical AF in the first 3 months of the ASSERT study, the greater the subsequent stroke risk, said Dr. Lamas, chairman of medicine at Mount Sinai Medical Center in Miami Beach. Among those whose longest episode lasted more than 17.7 hours, the risk of stroke or systemic embolism was increased nearly fivefold.

The ASSERT investigators have identified a large and interesting population at increased risk of stroke, he noted. But “until definitive, randomized clinical trials have been carried out demonstrating that anticoagulant therapy is justified for patients with short episodes of device-detected AF, I’m going to continue relying upon the CHADS2 score for guidance in deciding upon whether to prescribe a prophylactic anticoagulant. I’ll consider applying the CHADS2 metric to patients with subclinical episodes of AF lasting for hours.”

The ASSERT study was supported by St. Jude Medical. Dr. Healey disclosed that he has served as a paid consultant to that company, Boehringer Ingelheim, and Bayer, as well receiving grant support from AstraZeneca, Boston Scientific, and Boehringer Ingelheim. Dr. Lamas declared having no relevant financial interests.

Subject Codes:
top_stories; cardiology; neurology;


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January 11, 2012   05:00 PM EST

Dr. Jeff S. Healey

BY MICHELE G. SULLIVAN
Elsevier Global Medical News
Breaking News

Binge drinking appears to be more common in the United States than previously thought, with about 17% of adults aged 18 years and over engaging in the behavior each month.

About 38 million U.S. adults went on at least one drinking binge in 2010, according to a new federal report. Unfortunately, that number probably represents less than a third of the actual binge drinking that goes on, according to Dr. Robert Brewer of the National Center for Chronic Disease Prevention and Health Promotion (NCCDPH).

“We know that surveys like this one pick up only about 33% of presumed alcohol consumption, based on per capita sales,” he said in a press briefing. Bingeing accounts for half of the country’s alcohol consumption overall, he noted, and up to 90% of that consumed by young people.

The 2010 Behavioral Risk Factor Surveillance System (BRFSS) found bingeing in virtually every state and in every population group, regardless of age, ethnicity, race, and socioeconomic level. Even states with a comparatively lower prevalence showed serious bingeing problems, Dr. Brewer said. “We found a number of states with a low prevalence but a very high frequency or number of drinks per episode. We can’t be lulled into a false sense of security. There are high-risk drinkers in every population, even though it might not look like a big problem,” he said.

The data were compiled through the 2010 BRFSS, an annual nationwide telephone survey. The survey included responses from almost 458,000 civilian U.S. adults in 48 states and the District of Columbia. (South Dakota and Tennessee were not included.) For the first time, cell phone users were included. Binge drinking was defined as four or more drinks for women and five or more drinks for men on one occasion during the past 30 days.

“Physicians need to adopt these numbers – five drinks or more on any occasion for a man and four drinks or more for a woman is unhealthy, unwise, and dangerous,” Dr. Robert L. DuPont, the first director of the National Institute on Drug Abuse, said in an interview when asked about the survey. “There is no other step that can match the power of the nation’s physicians once they make this question a routine part of every patient contact.”

Overall, bingeing prevalence was up 2% from 2009, but that increase probably is attributable to the inclusion of cell phone users, Dafna Kanny, Ph.D., wrote in the Jan. 10 issue of Morbidity and Mortality Weekly Report (2012;61:1-7).

“Cellular telephone–only users typically are young (aged 18-34 years) and male; both groups tend to report a higher prevalence of binge drinking,” wrote Dr. Kanny, also of the NCCDPH.

No group was exempt from the problem, the report found. Men were more likely to binge than women (23.2% vs. 11.4%). Overall, bingeing was most common among those aged 18-34 years (28.2%). But the oldest respondents, those aged 65 years and older, binged the most often, at 5.5 times per month.

Non-Hispanic whites (18%) and Hispanics (17.9%) were significantly more likely to binge than blacks (12.7%).

Education also influenced bingeing. Those who did not graduate from high school had the lowest prevalence (13.7%), but drank more frequently and intensely than those of other educational levels (5.5 times per month with 9.3 drinks per episode).

Respondents with the highest incomes ($75,000 or more) were more likely to binge (20.2%), but those with the lowest incomes ($25,000 or less) drank more frequently and more intensely (5 times per month and 8.5 drinks per episode).

Bingeing also varied by state. Utah had the lowest age-adjusted prevalence (10.9%) and Wisconsin the highest (25.6%) Wisconsin residents also drank the most per episode (9). Bingers drank least often in New Jersey and most often in Kentucky (3.6 vs. 5.9 times per month).

Demographic differences in binge drinking are likely related to laws that affect the price and availability of alcohol, the authors noted. Studies have shows that a 10% price increase can decrease alcohol consumption by 7% in a population.

The Community Preventive Services Task Force has made several recommendations designed to change these factors, including:

• Limiting the density of stores that sell alcohol.

• Holding retailers accountable for harms resulting from sales to minors and already intoxicated persons.

• Maintaining existing limits on times and days of sale.

• Price increases.

• Avoiding further privatization of sales outlets.

From 2001 to 2005, excessive alcohol use accounted for an estimated average of 80,000 deaths and 2.3 million years of potential life lost in the United States, the report noted. Binge drinking accounted for more than half of the deaths, two-thirds of the life/years lost, and three-quarters of the economic costs.

Bingeing also significantly contributes to the incidence of other risky behaviors, like interpersonal violence, unsafe sex, and impaired driving, Dr. Brewer said. “As the number of drinks increases over a short period of time, the risk of these adverse outcomes goes up. Clearly, we have a lot of work to do to bring down the frequency and intensity of binge drinking.”

He also stressed that many binge drinkers don’t meet the medical criteria for alcohol dependence. “You don’t have to be alcohol dependent to experience a whole host of alcohol-related problems. If a person is consuming eight drinks in a short period of time, they are putting themselves and others at a great risk of alcohol-related harm.”

As government employees, Dr. Brewer and Dr. Kanny had no financial conflicts.

Subject Codes:
top_stories; mental_health; general_primary;


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January 10, 2012   04:36 PM EST

A new federal report indicates that roughly 38 million adults went on at least one drinking binge in 2010.

BY MARY ANN MOON
Elsevier Global Medical News
Breaking News

Unlike cigarette smoking, 20 years of typical marijuana smoking doesn’t appear to impair lung function, according to a report in the Jan. 11 issue of JAMA.

“With up to 7 joint-years of lifetime exposure (e.g., 1 joint per day for 7 years or 1 joint per week for 49 years), we found no evidence that increasing exposure to marijuana adversely affects pulmonary function,” said Dr. Mark J. Pletcher of the department of epidemiology and biostatistics and the department of medicine, University of California, San Francisco, and his associates.

While heavier use may impair lung function, the number of such users was too small in this study cohort to allow reliable estimates. The data suggested a detrimental effect with heavier marijuana smoking, they noted.

Previous studies of the pulmonary effects of long-term marijuana use have yielded inconsistent results. On the one hand, they have demonstrated “consistent evidence of airway mucosal injury and inflammation, as well as increased respiratory symptoms such as cough, phlegm production, and wheeze, similar to that seen in tobacco smokers.” But on the other hand, these appear to be short-term effects, and there has been no clear evidence of long-term damage to lung function.

Dr. Pletcher and his colleagues studied the issue using data from a large longitudinal study of coronary risk that closely followed the cigarette and marijuana smoking habits of 5,016 young adults in four U.S. communities from 1985 through 2006. As part of that study, the subjects (aged 18-30 years at baseline) underwent pulmonary function testing at baseline, 2 years, 5 years, 10 years, and 20 years.

Using that data, “we estimated both current intensity and lifetime cumulative exposure to tobacco and marijuana smoking and analyzed their associations with spirometric measures of pulmonary function over the 20 years of follow-up,” the researchers said.

One joint-year of exposure was defined as the equivalent of 365 joints or filled pipe bowls smoked. Secondhand smoke exposure also was accounted for.

As expected, both current and lifetime tobacco smoking were associated with lower forced expiratory volume in 1 second (FEV1) and lower forced vital capacity (FVC). But unexpectedly, both current and lifetime marijuana smoking were associated with higher FEV1 and higher FVC, the authors wrote (JAMA 2012;307:173-81).

“For example, compared with zero exposure, FVC increased with greater lifetime exposure in joint-years, and FEV1 increased with greater lifetime exposure of up to 10 joint-years and then declined to ... greater than zero-exposure level,” the investigators said.

Why marijuana smoking would increase lung capacity is unknown, but other studies have also found this effect. “Some investigators have proposed that the deep inspiratory maneuvers practiced by marijuana smokers could stretch the lungs, resulting in larger lung volumes. Another speculative possibility is strengthening of chest wall musculature or another ‘training’ effect that allows marijuana users to inspire more fully (closer to lung capacity) on spirometry testing,” Dr. Pletcher and his associates said.

In a separate analysis of the data using different statistical methods, “we again found strong, dose-related associations between increasing exposure to tobacco and lower FEV1 and FVC,” but no such associations for marijuana smoking. Only at very high levels of marijuana smoking was a detrimental effect on pulmonary function suggested.

“Hypothetically speaking, a positive effect from marijuana in the short term (the stretch/training effect) and a negative effect in the long term (damage from smoke exposure) should result in a nonlinear association such as the one we observed. According to this explanation, the predominant effect for FEV1 at very high exposure (more than 40 joint-years) reflects cumulative damage; the predominant effect for FVC at all levels of exposure is from the stretch/training mechanism,” they noted.

“Marijuana may have beneficial effects on pain control, appetite, mood, and management of other chronic symptoms. Our findings suggest that occasional use of marijuana for these or other purposes may not be associated with adverse consequences on pulmonary function,” the investigators said.

This study was supported by the National Institute on Drug Abuse and the National Heart, Lung, and Blood Institute. Dr. Pletcher reported no conflicts of interest.

Subject Codes:
top_stories; general_primary; pulmonology;


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January 10, 2012   04:00 PM EST

A new report shows that 20 years of typical marijuana smoking does not impair lung function; in fact, it may actually increase lung capacity.

BY MARY ANN MOON
Elsevier Global Medical News
Breaking News

Current guidelines for correcting serum potassium levels in patients who present with acute MI are out of date and aim for targets that are too high, raising the risk of in-hospital mortality, according to a report in the Jan. 11 issue of JAMA.

In a retrospective study of 38,689 cases of MI in a nationally representative database, there was a U-shaped relationship between serum potassium level at admission an in-hospital mortality. The lowest mortality occurred in patients with potassium levels of 3.5-4.5 mEq/L, with higher mortality in those with potassium levels of 4.5 mEq/L or higher as well as those with levels less than 3.5 mEq/L.

Current practice guidelines recommend raising “low” potassium to 4.0-5.0 mEq/L, “and some experts even advise a higher range of 4.5-5.5 mEq/L,” said Dr. Abhinav Goyal of the schools of medicine and public health at Emory University, Atlanta, and his associates.

“These guidelines are based on small, older studies that focused only on [preventing] ventricular arrhythmias (and not mortality) and were conducted before the routine use of beta-blockers, reperfusion therapy, and early invasive management in acute MI patients. Our data suggest that ... potassium levels of greater than 4.5 mEq/L are associated with increased mortality and probably should be avoided,” they noted.

Dr. Goyal and his colleagues performed their study because measuring and repleting potassium to prevent arrhythmia in patients who present with acute MI is an entrenched practice, despite “the lack of current, adequately powered studies that define the optimal range of serum potassium levels with respect to mortality and other important clinical outcomes.” They used information from the Cerner Corporation’s Health Facts database, which covers nearly 400,000 consecutive MI patients who presented to 67 U.S. hospitals representing all geographic regions of the country in 2000-2008.

A total of 2,679 of these study subjects (6.9%) died during hospitalization.

Compared with the reference group (potassium level of 3.5-4.0 mEq/L), in which in-hospital mortality was 4.8%, patients with levels of 4.0-4.5 had comparable mortality (5.0%).

In contrast, mortality was twice as great (10.0%) for patients with potassium levels of 4.5-5.0 mEq/L, and was even greater at higher levels, the investigators said (JAMA 2012;307:157-64).

“Our findings suggest that overly aggressive repletion of potassium levels (which is often automated through the implementation of hospital order sets) may not be advisable in patients with acute MI ... as potassium levels of at least 4.5 mEq/L are associated with harm,” they noted.

As expected, mortality also was greater for patients with low potassium levels below 3.5 mEq/L.

These associations persisted in further analyses that adjusted for potentially confounding factors such as patient age, sex, and glomerular filtration rate at admission. They also remained robust regardless of whether patients did or did not receive potassium supplementation during hospitalization, and remained robust when the analysis was restricted only to patients who survived past the first 24 hours.

The investigators cautioned that their findings apply only to patients with acute MI and should not be extrapolated to those with other cardiac conditions, including heart failure.

This study was supported in part by Saint Luke’s Mid America Heart Institute, Kansas City, Mo. No conflicts of interest were reported.

Higher Potassium Targets ‘Not Justified’

Potassium repletion to levels higher than 4.5 mEq/L no longer appear to be justified in acute MI, said Dr. Benjamin M. Scirica and Dr. David A. Morrow.

Even potassium levels of 4.0-4.5 mEq/L were associated with increased mortality, compared with levels of 3.5-4.0 mEq/L, and 43% of all the patients in this study fell into that category.

However, it is reasonable to avoid significant hypokalemia (less than 3.5 mEq/L), especially for patients who have significant, sustained, ventricular ectopy or other high-risk features.

Dr. Scirica and Dr. Morrow are at the Levine Cardiac Unit at Brigham and Women’s Hospital and Harvard Medical School, both in Boston. They reported numerous ties to pharmaceutical companies. These remarks were adapted from their editorial comment accompanying Dr. Goyal’s report (JAMA 2012;307:195-6).

Subject Codes:
top_stories; cardiology;


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January 10, 2012   04:00 PM EST

BY KERRI WACHTER
Elsevier Global Medical News
Breaking News

Older people who develop dementia have higher rates of hospitalizations for medical illnesses than do those without dementia. In addition, those with dementia are at greater risk for several conditions that could be treated in the ambulatory setting, potentially reducing hospitalizations.

A total of 494 patients developed dementia during an average follow-up of 8 years; of those, 427 (86%) were hospitalized. In comparison, 2,525 individuals remained dementia-free during 10 years of follow-up; of those, 1,478 (59%) were hospitalized. Forty percent of those with dementia had at least one admission for an ambulatory care–sensitive condition (ACSC), compared with 17% of the dementia-free group. ASCSs were considered to be preventable with proactive outpatient care.

The findings come from a population-based, longitudinal study of aging and the incidence of and risk factors for dementia, involving more than 3,500 members of a large integrated health care delivery system. The study results were published in the Jan. 11 issue of JAMA (2012;307:165-72).

“Three ACSCs – pneumonia, [congestive heart failure], and [urinary tract infections] – accounted for two-thirds of all potentially preventable admissions among persons with dementia. Knowledge of the ACSCs most likely to lead to hospitalization is important, as this information may help clinicians focus their differential diagnostic considerations and thereby permit proactive, early management for these conditions among patients with dementia,” wrote Dr. Elizabeth A. Phelan and her coinvestigators.

“Early detection and outpatient management of acute illness when it is still in its early phases might minimize the need for hospitalization for these conditions and help health care organizations reduce their rates of ACSC admissions and associated costs,” wrote Dr. Phelan of the division of gerontology and geriatric medicine at the University of Washington in Seattle.

Participants were from the Adult Changes in Thought (ACT) cohort, a population-based, longitudinal study of aging and the incidence of and risk factors for dementia that began in 1994. The study involved more than 3,019 members of Group Health Cooperative, a large integrated health care delivery system. Eligible individuals were aged 65 years or older, cognitively intact, and not residing in a nursing home at the time of enrollment in the cohort (mean age at inception was 75 years). Participants have been followed up every 2 years with an in-person interview that includes dementia and health status assessment.

A biennial examination was conducted to identify cases of incident dementia. Participants who scored less than 86 on the Cognitive Abilities Screening Instrument (CASI) or had symptoms suggesting possible new onset of cognitive impairment underwent a standardized dementia diagnostic evaluation consisting of an examination by a study physician and detailed neuropsychological testing.

The results were presented at a consensus conference attended by study physicians, a neuropsychologist, a research nurse, and interviewers, and a consensus diagnosis was recorded based on standardized criteria (Diagnostic and Statistical Manual of Mental Disorders–IV and Neurological and Communicative Disorders and Stroke–Alzheimer’s Disease and Related Disorders Association criteria). Participants with incident dementia underwent one annual follow-up examination for verification of dementia status and dementia type.

The researchers used a retrospective, longitudinal cohort design to assess inpatient admission rates. ACT participants were eligible for these analyses if they did not have dementia at the baseline ACT visit; had completed at least one ACT follow-up visit (to assess for incident dementia); and were enrolled in GHC at the time of a follow-up visit (to ensure availability of hospitalization data).

The primary outcome measure was rate of hospitalization, measured as mean number of admissions per year of follow-up. An admission was defined as a hospitalization requiring an overnight stay. The secondary outcome measure was the rate of hospitalization by type, classified by the principal discharge diagnosis. The researchers identified ACSCs among principal discharge diagnoses to count conditions for which hospitalization might have been prevented with timely, evidence-driven outpatient care. Potential confounders of the association between dementia and hospitalization – sociodemographic characteristics, comorbidities, health behaviors, self-rated health, and place of residence – were ascertained from self-reported data collected at the baseline visit as well as at 2-year follow-up visits.

In terms of baseline differences, those in the group who eventually developed dementia were older at cohort entry by about 3 years and were less likely to have graduated from high school. In addition, larger percentages in this group reported having trouble dressing and reported a diagnosis of depression or Parkinson’s disease.

Probable Alzheimer’s disease (as a single cause) was the most common etiologic diagnosis in the dementia group, followed by vascular dementia alone (16%), and dementia of multiple etiologies (15%). Other etiologies included other medical (7%), substance-related (2%), and other/unknown (2%). The mean age at diagnosis was 84.3 years, with 61% having diagnoses in their 80s. The mean CASI score at time of diagnosis was 76, which is consistent with mild dementia.

The most common reasons for hospitalization – regardless of dementia status – were circulatory, respiratory, and digestive disorders. Among participants with dementia, the average annual admission rate was 419 admissions per 1,000 persons – more than twice that of those without dementia, who averaged 200 admissions per 1,000 persons each year. After age/sex adjustment, the ratio of admission rates was 1.57 and was 1.41 after adjustment for additional covariates.

In the fully adjusted model, admission rates for five types of disorders (circulatory, genitourinary, infectious, neurologic, and respiratory) were significantly greater among participants with dementia, compared with those without dementia. In contrast, those with dementia had significantly lower admission rates for musculoskeletal disorders.

ACSCs were analyzed separately. The admission rate ratio was 1.78, after full adjustment for covariates. Importantly, three ACSCs – bacterial pneumonia, heart failure, and urinary tract infection – accounted for two-thirds of all potentially preventable admissions; admission rates among those with dementia were significantly greater for all three conditions. Admission rates for dehydration and duodenal ulcer, though low overall, also were significantly greater among those with dementia. Admissions for ACSCs accounted for 28% of all hospitalizations among those with dementia vs. only 19% of all admissions among those who remained dementia free.

The authors speculated about why dementia might lead to more frequent hospitalization. First, underlying conditions that increase the risk of dementia such as stroke, or that develop in the setting of dementia, such as trouble swallowing, which raises the risk of pneumonia, might increase the risk of hospitalization.

“Second, because of its primary deleterious effects on global cognition, executive function, expressive language, symptom perception, and awareness of deficits, dementia impairs the ability to self-manage chronic conditions and to pinpoint symptoms and alert others to their presence, thereby creating substantial diagnostic and treatment challenges for primary care clinicians,” the researchers wrote.

Situational factors also might contribute, including a change of living situation, or the temporary or permanent absence of a caregiver who is familiar with the person’s usual habits, behaviors, and ongoing general medical management.

They also cited another potential explanation – the threshold for hospitalizing such persons might be lower because dementia “increases central nervous system vulnerability to the metabolic effects of acute illness, such that for a comparable severity of illness, persons with dementia are in fact sicker.”

The authors reported that they have no conflicts of interest. The ACT study is supported by a grant from the National Institute on Aging.

Many Hospitalizations Are Preventable for Dementia Patients

“In the context of earlier literature, the results of this methodologically rigorous study indicate that in the current U.S. health care environment, patients with dementia are much more likely to be hospitalized than age-comparable peers, especially for conditions such as urinary tract infection, congestive heart failure, dehydration, and bacterial pneumonia,” Dr. Constantine G. Lyketsos noted in an accompanying editorial (JAMA 2012;307:197-8).

The association between comorbidity and progression is poorly understood but probably reflects the “vulnerability of the diseased brain to biologic stresses and to the frequent development of delirium even with mild exacerbations of acute or chronic diseases,” he wrote. Urinary tract infection, upper respiratory tract infections, or brief general anesthesia for routine outpatient procedures, for example, can lead to unforeseen but significant functional declines in patients with dementia, from which it is often difficult for them to recover.” Early detection of these conditions “can often lead to effective management in ambulatory settings, thus preventing hospitalizations. Ambulatory care is the optimal setting to both detect dementia early and manage such conditions” Dr. Lyketsos wrote.

He also wrote that early detection of dementia can lead to effective supports that can help manage comorbidities before they lead to acute hospitalizations. “Involvement by physicians of families and caregivers as partners in this process is critically important,” he wrote.

“Hospital stays are very difficult for patients with dementia as they are more likely to require restraints, develop delirium, or experience falls, thus prolonging stays and increasing costs. Effective ambulatory care that prevents hospitalizations through proactive dementia detection and management is a major and realistic priority in the public health response to dementia.”

Dr. Lyketsos is chairman of the psychiatry department at Johns Hopkins Bayview Medical Center in Baltimore. He reported that he has significant financial relationships with numerous pharmaceutical companies.

Subject Codes:
top_stories; neurology; gerontology;


http://www.imng.com


January 10, 2012   04:00 PM EST

BY SHARON WORCESTER
Elsevier Global Medical News
Breaking News

Memantine is not an effective treatment for dementia in adults older than 40 years with Down syndrome, according to findings from a randomized, placebo-controlled study.

In fact, all of the 173 participants in the Memantine for Dementia in Adults Older than 40 Years with Down’s Syndrome (MEADOWS) trial, regardless of whether they received placebo or active treatment, experienced declines in cognition and function during the 52-week study. Moreover, although the rates of decline did not differ significantly between the groups, they were slightly lower in the placebo group, senior author Dr. Clive Ballard of King’s College London (England) and his colleagues reported online in the January 10 issue of The Lancet.

The findings suggest that therapies that are effective for Alzheimer’s disease in other patient populations are not necessarily effective in those with Down syndrome.

After adjustment for baseline score, participants in the placebo group and treatment group experienced mean changes in scores on the Down syndrome attention, memory, and executive function scales (DAMES) of -1.9 and -5.6 at 52 weeks, respectively. There also was no difference in the mean changes in scores between the placebo and memantine groups in part I of the Adaptive Behavior Scale (-1.7 and -10.7, respectively), which measures independent functioning, or part II (0 and 1.0, respectively), which measures challenging behavior (Lancet 2011 Jan. 10 [doi:10.1016/S0140-6736(11)61676-0]).

The results were similar regardless of the presence of dementia, which had been diagnosed in 35% of individuals in each group at the time of randomization.

The rate of serious adverse events also did not differ significantly between the placebo and treatment groups at 7% and 11%, respectively.

The findings have implications for research strategy in development of treatments for cognitive decline and dementia in individuals with Down syndrome, the investigators said.

Dementia is very prevalent in this population, with nearly 40% of those with Down syndrome receiving a diagnosis of dementia after age 60 years. Additionally, clinically significant Alzheimer’s disease–like pathological features are “almost ubiquitous” by age 40 years in those with Down syndrome.

“Although there is therefore a rationale for the efficacy of pharmacological treatments for Alzheimer’s disease in people with Down’s syndrome, there are some key differences in pathological features that should not be overlooked. For example, people with Down’s syndrome have lifelong overproduction of amyloid-beta compounded with dysregulation of many genes, most of which are not associated with Alzheimer’s disease,” the investigators explained, adding that differences in the neuropathologic features of people with Down syndrome compared with Alzheimer’s disease might affect responses to pharmacologic therapies.

The N-methyl-d-aspartate glutamate receptor antagonist memantine (Namenda) is licensed for the treatment of moderate to severe Alzheimer’s disease and showed promise in two studies in a Down syndrome model in mice. But in the current study it was found to confer no benefit, regardless of whether a formal diagnosis of dementia was available, they said.

Study participants were men and women with Down syndrome aged 40 years or older or individuals of any age with Down syndrome and an established diagnosis of dementia. They were enrolled at four learning disability centers throughout the United Kingdom and Norway. The randomization process involved a computer-generated allocation sequence that ensured balanced allocation based on the prognostic factors of sex, presence of dementia, age group, DAMES score, and center. The investigators escalated the dose of memantine over 8 weeks from 5 mg per day to the optimal therapeutic dose of 10 mg per day with fixed titration.

“The findings of this study are robust and represent an important step in the evidence base for treatment of people with Down’s syndrome with cognitive decline,” the investigators wrote, concluding that research into specific therapies for this patient population needs to be based on an understanding of underlying pathologic processes.

In particular, an adequately powered randomized controlled trial of cholinesterase inhibitors is needed to determine if this class of drug has any role in the treatment of Down syndrome patients with dementia. Cholinesterase inhibitors are approved in the United Kingdom for people with dementia in the context of Down syndrome, but very little evidence exists to support this guidance, they said.

This study was funded by Lundbeck and sponsored by King’s College London. Dr. Ballard reported receiving consultancy and speaking fees from Lundbeck, Janssen, Novartis, and Acadia and grants from Lundbeck and Acadia. Other study authors reported receiving consultancy fees, speaking fees, honoraria, and/or grants from Lundbeck, Novartis, and/or Roche, as well as serving on the advisory board for Lundbeck, providing paid expert testimony for Novartis and Eisai, and receiving funding from the Alzheimer’s Society and the Henry Smith Trust. Detailed disclosures are available with the full text of the article at www.thelancet.com.

Study Lays Groundwork for Future Trials

Though disappointing, the findings of the MEADOWS trial do serve to exclude treatments of little or no benefit for Down syndrome patients with dementia, and thereby prevent potential side effects and depletion of scarce resources, according to Dr. Gill Livingston and Dr. Andre Strydom.

The complexity of Down syndrome likely means that the amelioration of associated pathology will require a combination of treatments, rather than a single drug.

While there is optimism that the cognitive problems and neurodegeneration associated with Down syndrome can be improved with pharmacologic intervention, researchers need a much better understanding of the neurobiology of Down syndrome to design such interventions, they said, adding that potential treatments must be identified through genetic, animal, and cellular studies, and that findings of experiments will need to be interpreted by mapping animal behavioral paradigms to human cognitive functioning.

“Sophisticated outcome measures and practical biomarkers are needed that can be used in trials for accurate measurement of changes in people with severe disability,” they wrote, noting that large scale studies will require international coordination and collaboration through linked Down syndrome research networks, and that the potential effects of new treatment options should be explored thoroughly before undertaking clinical trials.

Dr. Livingston is a professor of psychiatry of older people and Dr. Strydom is a clinical senior lecturer in the department of mental health sciences at University College London (England). They wrote these comments in an editorial accompanying the trial report (Lancet 2011 Jan. 10 [doi:10.1016/S0140-6736(11)61929-6]). Dr. Livingston has been funded by Lundbeck for unrelated research in Alzheimer’s disease. Dr. Strydom is an investigator in a Roche-sponsored trial to improve cognition in adults with Down syndrome.

Subject Codes:
top_stories; neurology;


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January 09, 2012   06:30 PM EST

Clive Ballard

By Alicia Ault
Elsevier Global Medical News
Breaking News

WASHINGTON (EGMN) – The historically low growth in health spending in 2009 and the first half of 2010 continued through the end of last year, driven largely by the recession, Centers for Medicare and Medicaid officials announced Jan. 9.

U.S. health spending grew 3.9% in 2010, to a total of $2.6 trillion or $8,402 per person. That was a 0.1% rise from 2009, which was already at an all-time low growth rate.

As the nation’s economy slumped throughout 2009 and 2010, consumers cut back on elective surgical procedures, emergency room visits, physician office visits, and prescription drug use, according to the officials.

“Even though the recession officially ended in 2009, its impact on the health sector appears to have continued into 2010,” said Anne Martin, an economist with the CMS.

Employers shifted the costs of insurance and care to employees, which drove up out-of-pocket spending in 2010. But consumers overall spent only 1.8% more out-of-pocket in 2010 than they had in 2009, which was a slow rate of growth when compared with historical patterns, Ms. Martin said.

Consumers reacted to cost-shifting by choosing health insurance plans with lower premiums and higher deductibles, and by reducing, where they could, use of personal health care services. Medical prices and the U.S. population remained relatively stable before, during, and after the recession, and yet, personal health spending fell, indicating a willful pullback.

“The slower growth in personal health care spending was mainly driven by the slowdown in the use and intensity of health care goods and services,” Ms. Martin said. The agency documented a shrinkage in use of hospital care and physician services as compared with historical levels.

Hospital spending grew only 5% to $814 billion in 2010, compared to 6% in 2009. There was a decline in median inpatient admissions, and slower growth in emergency department visits, outpatient visits, and outpatient surgeries.

Overall spending on physicians and clinical services – totaling $515 billion in 2010 – accounted for 20% of total health spending. As consumers went to the doctor less frequently, fewer prescriptions were written. And, many of those dispensed were for less expensive generic drugs. These and other factors led to the slowest rate of growth in prescription drug spending ever recorded – a 1% increase from 2009 to $259 billion. The data were published in the journal Health Affairs (Health Aff.2012 [doi: 10.1377/hlthaff.2011.1135]).

Growth in spending on physician and clinical services also was historically low, growing 2.5% in 2010 as compared with 3.3% in 2009, said Ms. Martin.

Meanwhile, as employers and private insurers reduced the amount they spent on health care, the federal government’s share of health spending rose – to 29% or a total of $742 billion in 2010. The rise in federal spending also was attributed to federal subsidies to state Medicaid programs. Medicaid was about 15% of the nation’s health bill in 2010, at $401 billion.

In 2009, the federal government spent 22% more than in 2008; in 2010, spending rose by almost 9%. That compares to a 10% decrease in spending by states and localities in 2008, and a 4% increase in 2010.

Medicare saw an increase in enrollment, both in Medicare Advantage managed care program and traditional fee-for-service Medicare. The increase in traditional enrollment reversed a several-year pattern of decline. Overall, Medicare spending increased 5% in 2010 to $524 billion, but per-enrollee spending did not rise as quickly as it had in 2009.

This is because there was a big reduction in payments for certain types of home health services, but also because of low use of physician services. Small increases in physician fees in 2009 and 2010 also kept a lid on Medicare spending.

Those increases were instituted by Congress in response to cuts that would otherwise have been required by Medicare’s Sustainable Growth Rate formula.

The Affordable Care Act had a negligible impact on overall spending, perhaps accounting for less than 0.1% of the slowdown, according to the CMS economists. This is because few provisions were in effect in 2010, and some, such as coverage for patients with preexisting conditions, did not enroll as many people as had been expected.

Subject Codes:
top_stories; general_primary;


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January 09, 2012   04:00 PM EST

Consumers spent only 1.8% more out-of-pocket in 2010 than they had in 2009, which was a slow rate of growth, compared with historical patterns.

BY MARY ANN MOON
Elsevier Global Medical News
Breaking News

Structured lifestyle interventions based on the U.S. Diabetes Prevention Program’s curriculum were effective at promoting clinically significant weight loss of approximately 4% when applied in real-world settings, according to a meta-analysis in the January issue of Health Affairs.

The U.S. Diabetes Prevention Program conducted a clinical trial in 2002 showing that modest weight loss through caloric restriction and increased physical activity reduced the incidence of diabetes in high-risk patients by 58%. Weight loss was found to be the single most important factor in preventing diabetes from developing over the course of 3 years among patients who were at high risk for the disease. For every kilogram of weight lost, the incidence of diabetes decreased by 16%.

“Yet these results have not been ‘translated’ into routine clinical practice and public health policy,” said Dr. Mohammed K. Ali of Emory University, Atlanta, and his associates.

They performed what they described as the first meta-analysis of U.S. studies in which the structured intervention recommended by they Diabetes Prevention Program was applied to high-risk patients in real-world settings. The meta-analysis included 28 studies published in 2003-2011. In all, 4 were randomized, controlled trials (RCTs), 2 were cluster RCTs, 20 were single-group studies comparing pre-intervention and post-intervention weight, and 2 were nonrandomized, controlled studies.

Most of the studies were conducted in urban areas. In all, 12 were based in community centers, recreation centers, and church organizations, and 11 were based in health care facilities. The total number of patients was 2,916, and the median study duration was 1 year.

Across all the reviewed studies, the mean weight loss was 3.99%, which is considered clinically meaningful, Dr. Ali and his colleagues said (Health Aff. 2012 [doi:10.1377/hlthaff.2011.1009]).

Weight loss was comparable among programs that used medical and allied health professionals to implement the intervention (average 4.27% weight loss), programs that used lay community educators (3.15% weight loss), and programs that used electronic media-assisted interventions (4.20% weight loss).

Moreover, sensitivity analyses showed that programs with lay community educators achieved greater weight loss than those with medical and allied health professionals as educators. That finding “has enormous importance for the scalability and economic sustainability of diabetes interventions,” Dr. Ali and his colleagues noted, because lay educators required lower salaries and their training was neither costly nor time-consuming.

Programs that included more “core sessions” in which patients received counseling maintained the highest attendance rates. And higher attendance rates correlated positively with greater weight loss.

The rate of attrition varied greatly among the studies, ranging from 0% to 49%. In some studies that analyzed patient feedback, it appeared that attrition was more strongly related to patients’ perceptions of their risk and to their readiness to change than it was to specific features of the intervention, such as the number of counseling sessions.

No disclosure information was provided.

Subject Codes:
top_stories; diabetes; general_primary; endocrinology;


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January 09, 2012   04:00 PM EST

BY MARY ANN MOON
Elsevier Global Medical News
Breaking News

The direct thrombin inhibitor dabigatran appears to raise the risk of myocardial infarction or acute coronary syndromes, according to a meta-analysis of seven randomized clinical trials published online Jan. 9 in the Archives of Internal Medicine.

The meta-analysis included randomized clinical trials assessing the noninferiority of dabigatran against various control treatments including adjusted-dose warfarin, enoxaparin, and placebo, in a broad spectrum of patients using the drug for a variety of indications.

“We used several meta-analytic methods and several association measures, and the results were consistent. Although the relative risk increase was 33%, the absolute risk increase was very small, at 0.27%,” said Dr. Ken Uchino and Dr. Adrian V. Hernandez, both of the Cleveland Clinic.

The mechanism by which dabigatran increases the risk of MI or acute coronary syndrome (ACS) is not yet known. It is possible that the drug doesn’t actively raise this risk, but instead lacks some protective effect that the control treatments possess, the investigators noted.

The meta-analysis covered 30,514 study subjects, including patients with atrial fibrillation who used dabigatran to prevent stroke, patients with atrial fibrillation who used it to prevent acute venous thromboembolism, patients with ACS who used it to prevent recurrent ACS, and patients undergoing joint replacement who used it to prevent deep vein thrombosis.

Overall, patients who received dabigatran were at significantly higher risk of MI or ACS than were control patients. The incidence of these events was 1.19% in those taking dabigatran, compared with 0.79% in control subjects, Dr. Uchino and Dr. Hernandez said (Arch. Intern. Med. 2012 [doi:10.1001/archinternmed.2011.1666]).

Since it is possible that dabigatran’s negative effects may increase with longer duration of use, the investigators performed a separate analysis excluding three of the seven studies that had exceptionally short (less than 1 month) exposure times. The risk of MI or ACS remained high and significant in this analysis of the data, they noted.

An important limitation of the meta-analysis is that a single large trial, with a study population of 18,113 patients, overshadowed the findings from the other 6 trials, which had populations of 515 to 2,451 patients. In addition, the large trial followed patients for a median of 2 years, while the smaller trials did so for 6 months or less.

Because of this imbalance, the large trial accounted for 59% of the meta-analysis cohort and 74% of the cardiovascular events, they said.

Overall, the findings indicate that dabigatran’s cardiovascular risks should be investigated further, “especially if [the drug] is used in populations at high risk of MI or ACS,” they added.

The “robust” finding by Dr. Uchino and Dr. Hernandez that dabigatran is associated with increased MI “is alarming and emphasizes the need for continued critical appraisal of new drugs after phase III trials,” Dr. Jeremy M. Jacobs and Dr. Jochanan Stessman wrote in remarks taken from an invited commentary that accompanied the meta-analysis (Arch. Intern. Med. 2012 [doi:10.1001/archinternmed.2011.1721]).

The researchers’ results “suggest that physicians [should] step back for a moment, take their own pulse, and retain a critical view as a powerful new drug enters clinical use on a potentially massive scale,” Dr. Jacobs of the Jerusalem Institute of Aging Research at Hadassah-Hebrew University Medical Center and Dr. Stessman of the Hebrew University–Hadassah Medical School, Jerusalem.

The findings also highlight another deeply concerning issue: “the enthusiasm – nearly to the level of euphoria – to embrace the new,” they added.

All seven studies included in the meta-analysis were sponsored by the drug manufacturer, Boehringer Ingelheim. No financial conflicts of interest were reported among the investigators for this current study.

Dr. Jacobs and Dr. Stessman reported having no financial conflicts of interest.

Subject Codes:
top_stories; cardiology; surgery; neurology;


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January 09, 2012   04:00 PM EST

BY MICHELE G. SULLIVAN
Elsevier Global Medical News
Breaking News

Packaging errors in a Novartis drug plant could cause opioid painkillers to end up in bottles of over-the-counter medications, the Food and Drug Administration said today.

Opioid pills could have been retained in the machinery and then released into bottles of other types of prescription painkillers, or into over-the-counter medications including Excedrin, Bufferin, No-Doze, and Gas-X, according to Dr. Edward Cox, director of the Office of Antimicrobial Products in the FDA’s Center for Drug Evaluation and Research.

“The likelihood of this happening is low, but there is a potential” for mix-ups, Dr. Cox said during a press briefing. Although there have been no reports of stray opioids in other medications, the possibility of a mix-up is so serious that FDA was compelled to issue a public health advisory. Novartis voluntarily closed its Lincoln, Neb., plant that manufactured and packaged opiate products for Endo Pharmaceuticals after a mid-December inspection focused on packaging machinery.

The same manufacturing problem has damaged gel caps and tablets of the over-the-counter medications; these also could be mispackaged among themselves. Because of the problems, Novartis has issued a nationwide recall of all these brands with an expiration date prior to Dec. 20, 2014.

However, the manufacturing problems at the Lincoln, Neb., plant were not a surprise to the FDA. A 13-page document details the results of several federal inspections undertaken from 2009 to 2011. According to the document, Novartis failed to respond to almost 200 consumer complaints about solid drugs made at the plant, including cases in which Excedrin Migraine gel caps and tablets were packed in the same bottle (this was considered a case of “foreign tablets”).

“You have failed to adequately investigate 166 instances of foreign tablets in your drug products since 2009,” the report stated.

Dr. Cox said the latest inspection focused on the packaging machinery and was the impetus for the plant’s closing. Endo Pharmaceuticals, the company that uses the plant to manufacture its opioid products, has received three consumer complaints about the issue since 2009, Dr. Cox said.

These medications will be in short supply, at least temporarily, according to a company spokesman. “We really don’t know how long the situation will go on,” Chris Clark, associate director of marketing and communications at Endo Pharmaceuticals, said in an interview. “We hope the [shut-down time] will be as minimal as possible.”

Mr. Clark said the company is “working proactively” with physicians to conserve the drugs that are still available for patients already taking them. “We’ve issued a health care practitioner letter suggesting that physicians keep patients on their ongoing therapy, but consider limiting starts on new patients, as appropriate.”

The affected medications include:

• OPANA (oxymorphone hydrochloride) Extended Release Tablets CII

• OPANA (oxymorphone hydrochloride) Tablets CII

• PERCOCET (oxycodone hydrochloride and acetaminophen USP) Tablets CII

• PERCODAN (oxycodone hydrochloride and aspirin, USP) Tablets CII

• ENDOCET (oxycodone hydrochloride and acetaminophen USP) Tablets CII

• ENDODAN (oxycodone hydrochloride and aspirin, USP) Tablets CII

• Morphine sulfate Extended-Release Tablets CII

• ZYDONE (hydrocodone bitartrate/acetaminophen tablets, USP) CIII

Endo Pharmaceuticals has posted picture of the medications in question on its website.

Dr. Cox recommended that both pharmacists and patients be extra-vigilant about any of the medications in question. “Check the medication carefully for tablets that are a different size or color, and take them back to the pharmacy if you find this,” he recommended. Pharmacists should carefully inspect medication before dispensing it.

Subject Codes: