By Alicia Ault
Elsevier Global Medical News
Breaking News

Allergan agreed on Sept. 1 to plead guilty to charges that it had illegally promoted Botox Therapeutic for uses not approved by the Food and Drug Administration.

The U.S. Department of Justice announced the plea and said that the company would pay a total of $600 million – $375 million in criminal fines and $225 million in a civil settlement with the federal government and all of the states.

The plea came as the result of three lawsuits filed by five “whistle-blowers,” including Dr. Amy Lang, a pain management physician in Lawrenceville, Ga. The whistle-blowers will receive $37.8 million from the federal settlement.

In a statement, the Department of Justice said Allergan had made it a “top corporate priority” to maximize Botox off-label sales. The company was cited for promoting the therapy for headache, pain, spasticity, and juvenile cerebral palsy.

Allergan also held workshops to teach physicians and their staffs how to bill for off-label uses, wined and dined physicians in an effort to encourage off-label use, and “created a purportedly independent online neurotoxin education organization to stimulate increased use of Botox for off-label indications,” according to the statement.

Allergan “demanded tremendous growth in these off-label sales year after year, even when there was little clinical evidence that these uses were effective,” said Sally Q. Yates, U.S. Attorney for the Northern District of Georgia, in a statement. The Georgia district is prosecuting the criminal case.

As a result of the investigation and settlement, Allergan has entered into a Corporate Integrity Agreement with the U.S. Department of Health and Human Services. Under the terms of the 5-year agreement, its board will be charged with reviewing the company’s compliance each year.

The company will also have to post information on its Web site disclosing payments to physicians and send a letter to physicians notifying them about the settlement.

Last fall, Allergan sued the FDA, claiming that restrictions on discussions of off-label use violated the company’s first amendment right to freedom of speech, and its ability to “proactively share truthful and relevant information with the medical community,” according to a company statement.

Subject Codes:
top_stories; general_primary; pain; womans_health; neurology;


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September 01, 2010   06:11 PM EDT

By Mary Ann Moon
Elsevier Global Medical News
Breaking News

Intensive blood pressure control doesn’t slow the progression of chronic kidney disease any better than standard blood pressure control in most patients, according to a report in the Sept. 2 New England Journal of Medicine.

It appears that the more intensive approach may benefit only patients who have proteinuria with a protein:creatinine ratio greater than 0.22, a value that is compatible with the widely accepted threshold of 300 mg/day for absolute urinary protein excretion, said Dr. Lawrence J. Appel of Johns Hopkins University, Baltimore, and his associates in the AASK (African-American Study of Kidney Disease and Hypertension) Collaborative Research Group.

Until now, “few trials have tested the effects of intensive blood pressure control [compared with conventional control] on the progression of chronic kidney disease, and the findings from such trials have been inconsistent. Despite a lack of compelling evidence, numerous guidelines recommend a reduced blood pressure target in patients with CKD,” they wrote.

Previous studies have rarely followed patients beyond 5 years, even though it typically takes longer than that for end-stage renal disease (ESRD) to develop in patients with CKD.

The AASK study compared outcomes between the two approaches to BP control in 1,094 black adults with mild to moderate hypertensive chronic kidney disease (defined as diastolic BP greater than 95 mm Hg and a glomerular filtration rate of 20-65 mL/min) but without marked proteinuria. Patients with diabetes were excluded from the trial.

In the first phase of the AASK investigation, patients were randomly assigned to either intensive BP control with a target of 92 mm Hg or lower mean arterial pressure (that is, lower than the usual target of 130/80 mm Hg recommended for CKD patients) or to conventional BP control with a target of 102-107 mm Hg mean arterial pressure (which corresponds to the conventional BP target of 140/90 mm Hg).

Throughout this initial phase of the trial, which lasted approximately 4 years, mean blood pressure was significantly lower in the intensive-control group (130/78 mm Hg) than in the standard-control group (141/86 mm Hg), yet there was no significant difference in the primary outcome of progression of kidney disease, development of ESRD, or death. Likewise, there was no significant difference between the two approaches in secondary or clinical outcomes.

In the second phase of the AASK investigation, patients who had not yet developed ESRD were invited to continue in a cohort portion of the trial, in which the BP target was 140/90 mm Hg. In 2004, when national guidelines were changed, this target was amended to lower than 130/80 mm Hg.

After a cumulative follow-up of 8-12 years, there still was no significant difference in primary or secondary outcomes between those who were initially assigned to the intensive-control and the standard-control groups. More intensive BP control did not slow the rate of progression of CKD, Dr. Appel and his associates reported (N. Engl. J. Med. 2010;363:918-29).

However, the intensive-control approach did benefit one subgroup of patients with proteinuria: those who had a protein:creatinine ratio of more than 0.22 at baseline. These patients showed a significant reduction in the primary outcome of progression of kidney disease, development of ESRD, or death, as well as in secondary and clinical outcomes.

The reason for this discrepancy is not known. “Overall, it is hard to develop a coherent, biologically plausible argument for a qualitative interaction between harm in patients without proteinuria and benefit in those with proteinuria,” the researchers said.

In an accompanying editorial, Dr. Julie R. Ingelfinger, chief of pediatric nephrology at Massachusetts General Hospital, Boston, and a deputy editor of the New England Journal of Medicine, wrote that the study lends hope to the concept that intensive treatment will improve renal outcomes in at least some patients with hypertension, chronic kidney disease, and microalbuminuria (N. Engl. J. Med. 2010;363:974-6). She noted that the Modification of Diet in Renal Disease trial showed that intensive BP control, compared with standard control, benefited patients who had more than 1 g of proteinuria at baseline. The ESCAPE (Effect of Strict Blood Pressure Control and ACE Inhibition on the Progression of Chronic Renal Failure in Pediatric Patients) trial also demonstrated that intensive BP control with a fixed dose of an ACE inhibitor significantly slowed the progression of renal disease, with the largest effects seen in children who had substantial proteinuria, hypertension, and a reduced GFR at baseline. And intensive BP control was beneficial in a recent study of adults in Italy who had idiopathic glomerular diseases associated with hypertension and proteinuria, Dr. Ingelfinger wrote.

The study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases, the Office of Research in Minority Health, and the National Institutes of Health. King Pharmaceuticals provided financial support and donated antihypertensive medications to each clinical center. Pfizer, AstraZeneca, GlaxoSmithKline, Forest Laboratories, Pharmacia, and Upjohn also donated antihypertensive drugs. None of these companies had any role in the design of the study, the accrual or analysis of data, or the preparation of the manuscript. Some of the investigators reported being in consultant and/or advisory board roles or receiving funds from numerous companies including Daiichi-Sankyo, Novartis, Amgen, King Pharmaceuticals, Abbott, Boehringer-Ingelheim, Litholink, Eli Lilly, Takeda, Merck, and Watson. Dr. Ingelfinger reported having no conflicts of interest.

Subject Codes:
nephrology_urology; top_stories; general_primary; cardiology;


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September 01, 2010   05:00 PM EDT

By Elizabeth Mechcatie
Elsevier Global Medical News
Breaking News

Long-term use of the weight loss drug sibutramine was not associated with an increased risk of death; however, the drug was associated with a significantly increased risk of nonfatal myocardial infarctions and strokes among overweight and obese people with preexisting cardiovascular conditions, based on data from the Sibutramine Cardiovascular Outcomes (SCOUT) trial.

The rate of nonfatal MIs associated with sibutramine was increased by 28% and the rate of nonfatal stroke was increased by 36%, compared with placebo in the randomized, double-blind multicenter study, which was conducted in Europe, Central and South America, and Australia from January 2003 through March 2009 (N. Engl. J. Med. 2010 Sept. 1;363:905-17).

Abbott Laboratories, which has marketed the drug in the United States as Meridia since its approval in 1997, funded SCOUT. Sibutramine is a norepinephrine and serotonin reuptake inhibitor that induces satiety and is known to be associated with modest increases in blood pressure and resting pulse rates.

The results indicate sibutramine “should continue to be excluded from use in patients with pre-existing cardiovascular disease,” concluded Dr. W. Philip T. James of the London School of Hygiene and Tropical Medicine, and the other authors of the study.

In an accompanying editorial, titled “Sibutramine – Another Flawed Diet Pill,” Dr. Gregory Curfman and his coauthors wrote that this conclusion is “based on a narrow interpretation of the SCOUT data, in which only the patients with preexisting cardiovascular disease had an increase in the risk of new cardiovascular events.” While this was a “defensible interpretation” of the data, they pointed out that marketing of sibutramine in the European Union was withdrawn in January 2010 based on early results of SCOUT (N. Engl. J. Med. 2010 Sept. 1;363:972-4).

The SCOUT results will be reviewed at a September 15 meeting of the Food and Drug Administration’s Endocrinologic and Metabolic Drugs Advisory Panel.

While noting the need for safe and effective weight loss medications, the authors of the editorial stated: “Given that sibutramine has minimal efficacy for weight loss, no apparent benefit for clinical outcomes, a worrisome cardiovascular risk profile, and a plausible mechanism to explain the cardiovascular risk, it is difficult to discern a credible rationale for keeping this medication on the market.”

The study compared the primary outcome – nonfatal MI, nonfatal stroke, resuscitation after cardiac arrest, or cardiovascular death – in about 9,000 obese or overweight men and women. All were randomized to receive placebo or 10 mg/day of sibutramine after both groups had received sibutramine as part of a weight management program for 6 weeks. Study participants were aged 51-88 years (mean age, 63 years) and had preexisting cardiovascular disease, type 2 diabetes, or both. During the initial 6-week phase, the mean weight loss was 2.6 kg. Those who stayed on sibutramine lost a mean of another 1.7 kg after 1 year (for a total of 4.3 kg, or 9.5 pounds), while those on placebo had a mean weight gain of 0.7 kg.

Over a mean 3.4 years of treatment, the rate of the primary outcome was 11.4% among those on sibutramine, compared with 10% among those on placebo, an increased risk of 16% that was statistically significant. There were no significant differences in the cardiovascular death rates and the rate of death from any cause (a secondary outcome) among those on sibutramine, compared with those on placebo.

The nonfatal MI rate in the sibutramine-treated patients was 4.1%, compared with 3.2% in the placebo group, and the rate of nonfatal stroke was 2.6% among those on sibutramine, compared with 1.9% among those on placebo. The rate of resuscitation after cardiac arrest was 0.2% or less in the two groups.

The risk of nonfatal events was increased among sibutramine users with preexisting cardiovascular disease and with cardiovascular disease and type 2 diabetes. Risk was not increased among those with type 2 diabetes alone. The increase in nonfatal events might be caused by the “recognized effect of increased blood pressure on cardiovascular outcomes, and the combined peripheral and central sympathomimetic effects” of the drug, the authors wrote.

During the initial 6 weeks, when all patients were receiving sibutramine, systolic blood pressure dropped by a mean of 4.7 mm Hg and diastolic blood pressure dropped by a mean of 1.7 mm Hg. These values remained below the initial measurements in both groups during the remainder of the study, but were “consistently higher” among those on sibutramine, with mean differences of 1 mm Hg-2 mm Hg.

The mean pulse rate among those on sibutramine was also “consistently higher” than among those on placebo, with mean differences of 2.2 to 3.7 beats per minute.

The SCOUT authors cite several limitations of the study. The enrollment of mostly high-risk patients meant that most of the study patients did not meet the treatment criteria in the drug’s label, which warns against the use of sibutramine in patients with preexisting cardiovascular disease.

The editorialists observed that after 1 year, those on sibutramine gained back about 0.5 kg, so had a net weight loss of about 4 kg – almost 9 pounds – from an average of 96 kg (211 pounds) at baseline. “Thus, in exchange for an average weight loss of less than 4 kg, a subject had a 1 in 70 chance (or a 1 in 52 chance for those with known cardiovascular disease) of having a myocardial infarction or stroke – an unattractive benefit-to-risk ratio,” they wrote.

The study was funded by sibutramine manufacturer Abbott Laboratories. Author disclosures included having received lecture fees and travel reimbursement from Abbott. Abbott employees were among the authors of the study. The lead author has served on advisory boards for and has received travel reimbursements from GlaxoSmithKline, the manufacturer of orlistat, another weight loss drug.

The coauthors of the editorial were Stephen Morrissey, Ph.D., and Dr. Jeffrey Drazen. The authors of the editorial declared no conflicts of interest.

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


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September 01, 2010   05:00 PM EDT

By Mary Ann Moon
Elsevier Global Medical News

An automated assay designed for use in Third World regions rapidly and accurately detected Mycobacterium tuberculosis infection and resistance to rifampin, according to a report published online Sept. 1 in the New England Journal of Medicine.

In a multicenter, prospective trial in South Africa, Peru, India, and Azerbaijan involving 1,730 patients suspected of having TB, the Xpert MTB/RIF correctly identified 72% of patients whose sputum smears were negative, as well as 98% of those with positive smears. It also correctly identified 98% of rifampin-resistant bacteria and 98% of rifampin-sensitive bacteria, said Dr. Catharina C. Boehme of the Foundation for Innovative New Diagnostics (FIND), Geneva, and her associates.

“Only a small fraction” of patients worldwide with drug-resistant TB currently has access to sufficiently sensitive diagnostic testing and drug-susceptibility testing, Dr. Boehme noted, because of the complex technologies required for mycobacterial culture and nucleic-acid amplification (N. Engl. J. Med. 2010 Sept. 1 [doi: 10.1056/NEJMoa0907847]).

“Globally, ineffective tuberculosis detection and the rise of multidrug resistance and extensively drug-resistant TB have led to calls for dramatic expansion of culture capability and drug-susceptibility testing in countries in which the disease is endemic,” Dr. Boehme and her colleagues noted. “Unfortunately, the infrastructure and trained personnel required for such testing are not available except in a limited number of reference centers, and results of testing are often not available for at least 4 months, which dramatically reduces its clinical utility.”.

FIND developed the new assay to address those needs. FIND also designed, supervised, and sponsored the study evaluating the assay’s performance.

The Xpert MTB/RIF kit includes a disposable plastic cartridge that contains all the reagents needed for bacterial analysis, nucleic acid extraction, PCR amplification, and amplicon detection. The only manual step is the “nonprecise” addition of a bactericidal buffer to sputum before transferring the sample to the cartridge. Because the cartridge is never reopened, there is little chance of amplicon contamination, the investigators noted. In addition, the sputum is inactivated at the same time it is liquified, thus making a biosafety cabinet unnecessary.

The cartridge is then inserted into the GeneXpert device, which delivers test results within 2 hours. Relatively unskilled health care workers at all the study locations became proficient in the assay’s use after a brief training session. Recent data from a separate study confirm that the assay generates no infectious aerosols, which obviates the need for laboratories equipped for advanced biosafety.

Of the 1,462 patients (4,386 sputum samples) assessed, 567 patients had smear-positive and culture-positive TB; 174 had smear-negative but culture-positive TB; 105 had clinically defined but smear-negative, culture-negative TB; and 616 had no clinical, smear, or culture evidence of TB. The remaining 268 patients were excluded from the study for a variety of reasons, including 103 who had an inadequate number of sputum samples and 10 who had an inadequate volume of sputum samples.

Overall sensitivity of the device among patients with culture-positive TB was 97.6%, with no significant variation in performance across the study sites. That suggests that the study findings “are likely to be widely applicable,” Dr. Boehme and her associates said.

Sensitivity was 99.8% for smear-positive and culture-positive cases, and 90.2% for smear-negative but culture-positive cases. The assay was specific in 604 of the 609 patients who proved not to have TB (99.2%).

In addition, “the MTB/RIF test correctly detected rifampin resistance in 209 of 211 patients (99.1% sensitivity)” and correctly identified rifampin susceptibility in all 506 patients who had it (100% specificity).

“In view of the low sensitivity of smear microscopy for the diagnosis of TB in patients with HIV infection, the increased sensitivity of the MTB/RIF test – notably, among patients with smear-negative tuberculosis – at the two South African sites with 60% to 80% prevalence of HIV infection is encouraging,” the researchers noted.

It is not yet known whether the results can be replicated “in microscopy centers, health posts, and other point-of-treatment settings where temperature and electricity supply will be more variable and training issues will be more relevant,” the investigators cautioned.

“Large-scale projects to show the feasibility and effect of MTB/RIF testing at such sites are under way,” they added.

The study was designed and supervised by the sponsor (and maker) of the Xpert MTB/RIF, FIND, with additional development support provided by the National Institutes of Health, Cepheid, and the Bill and Melinda Gates Foundation. The investigators reported no additional disclosures.

In an editorial accompanying Dr. Boehme’s report, Dr. Peter M. Small and Dr. Madhukar Pai said that the Xpert MTB/RIF assay has the potential to revolutionize the diagnosis of tuberculosis and has several critical advantages over conventional nucleic acid amplification tests.

The assay is “simple to perform with minimal training, is not prone to cross-contamination, requires minimal biosafety facilities, and has a high sensitivity in smear-negative TB (the last factor being particularly relevant in patients with HIV infection),” they noted (N. Engl. J. Med. 2010 Sept. 1 [doi:10.1056/NEJMe1008496]).

However, “because Boehme et al. used the test at reference laboratories, their study offers only indirect proof of concept for use in [other] settings. Critical to rapid scale-up of the test will be the results of additional studies to determine how it performs in such settings and whether its use improves outcomes for patients in a cost-effective manner,” Dr. Small and Dr. Pai added.

“If an improved rapid nucleic acid amplification test is adopted globally, it could help avert more than 15 million TB-related deaths by 2050,” they noted.

Dr. Small is at the Global Health Program of the Bill and Melinda Gates Foundation and the Institute for Systems Biology, both in Seattle. Dr. Pai is in the department of epidemiology and biostatistics at McGill University and at Montreal Chest Institute.

Subject Codes:
infectious; top_stories; general_primary; pulmonology;


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September 01, 2010   03:39 PM EDT

By Elizabeth Mechcatie
Elsevier Global Medical News
Breaking News

Alternatives to tigecycline “should be considered” when treating patients with serious infections because the intravenous antibiotic has been associated with an increased mortality rate in this population, according to a safety alert issued by the Food and Drug Administration on Sept. 1.

In a pooled analysis of 13 clinical trials of patients with different types of infections, treatment with tigecycline (Tygacil) was associated with increased mortality when compared with other antibiotics, according to the FDA statement. The increased risk was seen “most clearly” in patients with hospital-acquired pneumonia (HAP), and particularly ventilator-associated pneumonia (VAP); tigecycline is not approved for either condition. Among patients with HAP, 14.1% of those on tigecycline died, compared with 12.2% of those treated with other antibiotics. In the subgroup of patients with VAP, 19.1% of those treated with tigecycline died, compared with 12.3% of those treated with other antibiotics.

But there was no difference in the mortality rates among the rest of the patients with HAP, who were classified as having non–ventilator associated pneumonia, which was 12.2% among both those treated with tigecycline and among those treated with other antibiotics.

Mortality was also increased in patients who were treated with tigecycline for complicated skin and skin structure infections (cSSSI) and complicated intra-abdominal infections (cIAI) – both approved indications – and diabetic foot infections – an unapproved indication – when compared with other antibiotics: Among those with cSSSI, 1.4% of those treated with tigecycline died, compared with 0.7% of those who received other antibiotics. The mortality rate among those with cIAI treated with tigecycline was 3%, compared with 2.2% of those treated with other antibiotics.

The mortality in patients with diabetic foot infections was 1.3% among those who were treated with tigecycline, compared with 0.6% of those treated with other antibiotics.

Tigecycline, a tetracycline antibacterial, also is approved for the treatment of community-acquired pneumonia. Mortality rates were similar among those patients with CAP treated with tigecycline and those treated with other antibiotics.

The cause of the excess deaths in these studies is “often uncertain, but it is likely that most deaths in patients with these severe infections were related to progression of the infection,” the statement said.

A letter to the manufacturer, Pfizer Pharmaceuticals Inc., posted on the FDA’s Web site in July also notes that in some studies, QT prolongation was more common among patients in the tigecycline arm and requests that Pfizer conduct a QTc study of patients treated with tigecycline.

Serious adverse events associated with tigecycline should be reported to the FDA’s MedWatch program or at 800-332-1088.

Subject Codes:
infectious; top_stories; gastroenterology; diabetes; dermatology; general_primary; endocrinology; pulmonology;


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September 01, 2010   03:53 PM EDT

By Bruce Jancin
Elsevier Global Medical News
Breaking News

STOCKHOLM (EGMN) – Use of the oral factor Xa inhibitor apixaban slashed the risk of stroke or systemic embolism by more than half, compared with daily aspirin, in patients with atrial fibrillation who were candidates for but unable to take warfarin, in the phase III AVERROES trial.

Moreover, this substantial benefit was achieved without an increase in major bleeding in the apixaban arm of the 5,600-patient AVERROES (Apixaban Vs. Acetylsalicylic Acid to Prevent Strokes) trial, Dr. Stuart J. Connolly reported at the annual congress of the European Society of Cardiology.

“In general, apixaban was well tolerated compared to aspirin, which is usually a pretty well-tolerated drug. There was less discontinuation of apixaban compared to aspirin,” he noted.

AVERROES was a double-blind study conducted at 522 sites in 32 countries. The 5,600 participants had atrial fibrillation (AF) and one or more risk factors for stroke, but were deemed unsuitable for warfarin or other vitamin K antagonists. They were randomized to apixaban at 5 mg twice daily or usual guideline-driven care with aspirin at 81-324 mg/day, with the dosing left to physician discretion.

The trial was halted earlier this year after a planned interim analysis detected a treatment effect so large it was deemed unethical to continue.

The primary study end point – he annual rate of stroke or systemic embolism – was 4.0% in the aspirin arm and 1.7% with apixaban. A prespecified secondary end point comprising stroke, systemic embolic events, MI, or vascular death occurred at an annual rate of 6.2% on aspirin and 4.1% on apixaban, for a highly significant 33% relative risk reduction. Cardiovascular hospitalizations (another secondary end point) occurred at an annual rate of 14.9% in the aspirin arm, compared with 11.8% with apixaban, for a 21% relative risk reduction, reported Dr. Connolly of McMaster University in Hamilton, Ont.

The annual rate of major bleeding was 1.2% with aspirin and 1.4% with apixaban, a nonsignificant difference. However, minor bleeds not involving physician intervention or discontinuation of therapy were more frequent in the apixaban arm, by a margin of 5.2% per year, compared with 4.1% per year.

Dr. Connolly estimated that treating 1,000 AF patients for 1 year with apixaban instead of aspirin would prevent 18 strokes, most of which would be large and disabling. It would also prevent 10 deaths and 31 cardiovascular hospitalizations. These benefits would come at a cost of two major hemorrhages.

Like the other factor Xa inhibitors in the developmental pipeline, apixaban is under study for multiple potential indications, including for patients with an acute coronary syndrome and for prevention of deep vein thrombosis after orthopedic surgery. The much-anticipated ARISTOTLE (Apixaban for the Prevention of Stroke in Subjects With Atrial Fibrillation) trial comparing the investigational factor Xa inhibitor head to head against warfarin is due to report next year.

Discussant Dr. Harald Arnesen of Ullevål University Hospital in Oslo called AVERROES “a landmark trial.” The study shows that apixaban is quite capable of filling the major unmet need for more effective alternatives to aspirin for stroke prevention in patients with AF who ought to be on warfarin but can’t take it. It has been estimated that up to 50% of AF patients who should be on warfarin are not on the drug, most often because of difficulty in controlling their INR, bleeding problems, [or] drug-drug interactions, or because they find it too much of a hassle.

Comparing the AVERROES results to those for the investigational direct thrombin inhibitor dabigatran in the 18,000-patient RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy) study (N. Engl. J. Med. 2009;361:1139-51), for which Dr. Connolly was also principal investigator, Dr. Arnesen said it appears the two drugs achieve similar reductions in stroke, but that dabigatran has a higher major bleeding rate: 2.7% per year when given at 110 mg twice daily and 3.1% per year at 150 mg twice daily, compared with 1.4% for apixaban in AVERROES. But such cross-trial comparisons aren’t really scientifically valid, and not too much should be made of them, Dr. Arnesen was quick to add.

He predicted that when apixaban reaches the market, the AF management guidelines will have to be revised because of AVERROES. “The use of aspirin will probably be drastically reduced,” the cardiologist added.

Session co-chair Dr. Ralph Brindis went even further in an interview: “I think when these anti-Xa drugs become commercially available, warfarin is going to basically just go away. Formularies will be very hard pressed not to include them. Patients and doctors will insist on it. The patients have been begging for a replacement for warfarin,” said Dr. Brindis, the current president of the American College of Cardiology and senior advisor for cardiovascular disease for Northern California Kaiser Permanente, Oakland.

As for AVERROES, he considers the study of value mainly as proof of safety.

“I would have been shocked if it didn’t show efficacy. We already know that an antithrombin is going to be more effective than aspirin; there’s nothing new there,” the cardiologist said.

AVERROES was sponsored by Bristol-Myers Squibb and Pfizer. Dr. Connolly disclosed receiving research grants and lecture and consulting fees from the two companies. Dr. Arnesen and Dr. Brindis reported no financial conflicts.

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


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September 01, 2010   02:21 PM EDT

Stuart J. Connolly

By Michele G. Sullivan
Elsevier Global Medical News
Breaking News

The first human trial of metformin for precancerous colorectal lesions hints that the diabetes drug may be poised for a second incarnation – this time as a chemopreventive agent for several cancers, including lung, colon, and prostate cancers, and even breast malignancies.

The small study, published in the September issue of Cancer Prevention Research, found that after 1 month of oral metformin, nondiabetic patients who already had at least one colorectal adenoma removed experienced a significant reduction in their number of colorectal aberrant crypt foci – an endoscopic finding that some consider a precursor of adenomatous colon polyps.

A second study, published in the same issue of the journal, found that mice who received the drug after exposure to a potent lung carcinogen developed significantly fewer lung tumors than did those who received a placebo.

In light of these data, physicians may want to look closely at metformin when choosing an oral antidiabetic agent for their patients, Dr. Phillip Dennis of the National Cancer Institute said during a press briefing Sept. 1.

“It’s true that we don’t have an indication for metformin as a cancer chemopreventive,” said Dr. Dennis, lead author of the mouse study. “But a clinician who has four different oral agents for diabetes has to make a choice for his patients, and in that process, this early evidence that metformin may have an oncologic benefit will certainly play a role.”

A growing body of data suggests that metformin reduces the risk of several types of cancer, but thus far the only human evidence had come from observational studies of patients with diabetes. Three epidemiologic studies suggest that metformin decreases the incidence of cancer and cancer-related deaths in diabetic patients by 15%-77% (Euro. J. Cancer 2010;46:2369-2380). In vitro and animal studies suggest similar reductions.

The study released today shows the drug’s potential not only to reduce the number of precancerous lesions, but also to decrease the level of proliferating cell nuclear antigen (PCNA), a marker of tumor virulence, wrote Dr. Kunihiro Hosono of the Yokohama City University School of Medicine, Japan, and colleagues: “This first reported trial of metformin for inhibiting colorectal carcinogenesis in humans provides preliminary evidence that metformin suppresses colonic epithelial proliferation and rectal aberrant crypt foci, suggesting its promise for the chemoprevention of colorectal cancer” (Cancer Prev. Res. 2010;3:1077-83).

The murine study examined metformin’s potential to prevent lung cancers. Mice that had been exposed to tobacco carcinogens and consumed or were injected with metformin had up to 72% fewer lung tumors than did placebo-treated mice, reported Dr. Dennis and his colleagues (Cancer Prev. Res. 2010;3:1066-76).

Although the new data are exciting, metformin is not ready to grab the spotlight, Dr. Ernest Hawk cautioned in an interview.

“The story is quite compelling, suggesting that metformin may have a role in therapy or in maintenance treatment for cancer survivors,” said Dr. Hawk, division head of Cancer Prevention and Population Sciences at the University of Texas M.D. Anderson Cancer Center, Houston. “Before we make any assumptions, though, we need many more trials to figure out if it will live up to the potential it seems to have.”

The Japanese study included 23 nondiabetic patients who had an average of five adenomas removed during a screening colonoscopy. Nine of the patients were treated with 250 mg/day of metformin for 1 month; the remaining 14 did not receive any treatment.

At baseline, the 23 patients had a mean of eight aberrant cryptal foci (ACF). “ACF are tiny lesions that develop in the earliest stage of colorectal carcinogenesis and consist of large, thick crypts,” Dr. Hosono and his team wrote. “ACF have been shown to be precursor lesions of the adenoma-carcinoma sequence in humans, and have been suggested as a suitable surrogate end point for colorectal chemoprevention.”

After the treatment period, patients were examined again; ACF were detected by methylene blue staining of rectal mucosa. The number of lesions decreased significantly in the active group, from a mean of nine per patient to six (P = .007). There was no change in the untreated group (mean of seven at each exam). The mean number of ACF considered dysplastic also decreased significantly in the treated group, while again, there was no change in the untreated group. The drug also proved safe, with no patient experiencing hypoglycemia.

The researchers also examined rectal epithelial proliferation by proliferative cell nuclear antigen (PCNA) immunoassay. The PCNA index decreased significantly in the treated group but remained steady in the untreated group. However, the drug did not affect the percentage of cells undergoing apoptosis.

Dr. Hawk, who is also the T. Boone Pickens Distinguished Chair for Early Prevention of Cancer at M.D. Anderson, cautioned against overinterpreting the results. The short duration and small study size should temper enthusiasm somewhat – as should the debate about whether ACF are indeed precursors of colorectal cancer and whether affecting them in any way eventually affects cancer risk.

“Frankly, the Japanese are very good at these ACF studies. And while they have been very reproducible in animal models, human results have been much more difficult to confirm. A number of American investigators have tried to replicate earlier Japanese ACF studies using aspirin, a known colorectal cancer chemopreventive agent, and have not been able to get the same results.”

It’s unclear whether the difference lies in the treatment time, study design, or even the basic differences between a homogeneous Japanese population and the typical heterogeneous American study group, Dr. Hawk said. “Whatever it is, whether the results can be reproduced is the most important question.”

While larger studies are necessary to discover the unknowns of metformin, he said, the drug already has a lot going for it terms of the known. “We have so much data on metformin, and it has such a strong track record of safety, that I believe it’s an agent worth exploring.”

A review co-released with the studies suggested that metformin may be a more effective chemopreventive agent in patients with hyperinsulinemia. “There is evidence indicating that the growth of untransformed epithelial cells and a subset of cancers is stimulated by insulin, and that the systemic insulin-lowering action of metformin might inhibit the proliferation of these cancers,” wrote Dr. Michael Pollak of McGill University and Jewish General Hospital, Montreal. Cancers stimulated by insulin include endometrial, cervical, breast, and prostate cancers, as well as lung and colorectal malignancies. “This action of metformin shares mechanistic features with the manner by which caloric restriction inhibits the growth of certain cancers,” he said (Cancer Prev. Res. 2010;3:1060-5).

If Dr. Pollak’s theory is correct, Dr. Hawk said, metformin or other biguanides may help stem the flood of obesity- and diabetes-related cancers that researchers have predicted for several years. A recent study concluded that obesity could soon become the leading cause of cancer in women – possibly overtaking smoking as the leading cause (Int. J. Cancer 2010;126:692-702).

“The rise of diabetes-related cancer speaks to the importance of pursuing this investigation vigorously,” Dr. Hawk said. “We know that this is a problem of enormous impact for our future.”

Dr. Hosono, Dr. Dennis, and Dr. Hawk had no financial declarations. Dr. Pollak disclosed that he is a consultant for Merck, Novo Nordisk, Pfizer, and Sanofi-Aventis.

Subject Codes:
nephrology_urology; top_stories; gastroenterology; OncologyEX; diabetes; new_drugs; general_primary; endocrinology; womans_health; pulmonology;


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September 01, 2010   01:12 PM EDT

By Denise Napoli
Elsevier Global Medical News
Breaking News

In patients with hepatitis C genotype 2 or 3, a polymorphism in the region of the interleukin 28B gene on chromosome 19 was associated with a sustained virologic response following treatment with peginterferon-alpha and ribavirin, Dr. Alessandra Mangia and her colleagues reported in the September issue of Gastroenterology.

The finding mirrors similar results among genotype 1 hepatitis C patients with the mutation, who are more than twice as likely to respond to prolonged treatment as patients without it, and could point to a “potential role for IL28B genotyping in selecting non-[rapid virologic response] patients for standard 24-week therapy or more prolonged therapy,” she and her colleagues wrote.

Dr. Mangia, of the liver unit at the IRCCS Casa Sollievo della Sofferenza Hospital, San Giovanni Rotondo, Italy, studied 213 genotype 2 patients and 55 genotype 3 patients, for a total of 268 patients with hepatitis C, in a multicenter, randomized controlled trial (Gastroenterology 2010 Sept 1 [doi:10.1053/j.gastro.2010.05.079]).

Patients were randomly assigned to either standard 24-week therapy (68 patients) or “variable” treatment, which depended on their response (200 patients). The 122 patients in the variable treatment group who had a rapid virologic response at week 4 received treatment for 12 weeks, while the remaining 78 underwent 24 weeks of therapy. Rapid virologic response was defined as undetectable serum/plasma hepatitis C RNA, according to an assay that has a lower limit of detection of less than 50 IU/mL.

All patients received peginterferon alpha-2b, 1.0 mcg/kg/wk, plus ribavirin, 1,000 mg daily (1,200 mg if body weight was greater than 75 kg).

The researchers then determined the patient genotypes. “The genomic region associated with hepatitis C virus treatment response lies on chromosome 19 and contains multiple [single nucleotide polymorphisms, or SNPs] in linkage disequilibrium around the IL28B gene,” they wrote. “We selected the most strongly associated SNP, rs12979860, located 3 [kilobases] upstream of the IL28B gene, for genotyping in the cohorts.”

Patients could be either homozygous for the gene (CC), heterozygous (CT), or not have it at all (TT).

For all the genotypes combined, 201 patients (75%) attained a sustained virologic response: 51/68 (75%) in the standard treatment arm and 150/200 (75%) in the two variable treatment arms combined, they wrote.

Within the variable treatment arms, 98/122 (80%) of rapid response patients in the 12-week arm had a sustained response, and 52/78 (67%) of the non-rapid response patients in the 24-week arm attained a sustained virologic response (P = .1).

However, when patients were stratified according to genotype, Dr. Mangia found that 82% of those with the CC genotype had a sustained virologic response, compared with 75% with the CT genotype and 58% with the TT genotype (odds ratio 1.8, 95% confidence interval 1.2-2.7, P = .0046).

Moreover, although roughly equivalent proportions of each genotype had a rapid virologic response (165 patients total; 53%, 66%, and 59% for CC, CT, and TT patients, respectively), this effect was “largely driven” by those patients in the variable treatment arm who did not have a rapid response, wrote the authors.

Indeed, among those patients who did not have a rapid response, the link between CC genotype and sustained response was even stronger (87% of CC patients, vs. 67% of CT patients, vs. 29% of TT patients; OR 4.0, 95% CI 1.9-8.5, P = .0002).

The link was independent of whether the patient had hepatitis C genotype 2 or genotype 3.

Current guidelines recommend 12 weeks of therapy for all hepatitis C genotype 2 and 3 patients with a low viral load, irrespective of their IL28B status, according to the authors.

“It is tempting to speculate that such treatment would be most suitable for CC patients,” they said, but “prospective studies randomizing patients according to IL28B-type will be necessary.”

Several authors, not including Dr. Mangia, disclosed that they are coinventors of a patent application based on IL28B. The researchers also reported financial and research support from the Duke Clinical Research Institute, Richard B. Boebel Family Fund, National Health and Medical Research Council of Australia, Gastroenterology Society of Australia, and Royal Australasian College of Physicians.

Subject Codes:
infectious; top_stories; gastroenterology; general_primary;


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September 01, 2010   10:31 AM EDT

By January W. Payne
Elsevier Global Medical News
Breaking News

All health care workers should be vaccinated annually against influenza, and doing so should be a condition of new or continued employment, according to a position paper from the Society for Healthcare Epidemiology of America.

This is the first time the organization has recommended mandatory vaccination of all health care workers; and its position was also endorsed by the Infectious Diseases Society of America.

“I am very hopeful that this guideline will encourage the adoption of more mandatory policies at all health care institutions,” said Dr. Neil Fishman, president of SHEA and director of health care epidemiology and infection control for the University of Pennsylvania Health System, Philadelphia.

A variety of vaccinations already are required at health care facilities, including measles, mumps and rubella, and some facilities also require vaccination against chickenpox, pertussis, and hepatitis B. “So there are precedents for having vaccines as a condition of employment,” Dr. Fishman said.

The hope is that SHEA’s new recommendation – published Aug. 31 in the journal Infection Control and Healthcare Epidemiology – will improve the current influenza vaccination rates for health care workers, which now hover in the 30%-40% range, Dr. Fishman said. The recommendation applies to all workers, students, and volunteers in all health care facilities, regardless of whether they have direct patient contact.

Under the SHEA position paper, the only exceptions to the mandatory vaccination policy would be for medical reasons, such as a severe allergy to eggs, Dr. Fishman said.

The Centers for Disease Control and Prevention currently recommends that all health care professionals get an annual influenza vaccine and that health care facilities provide the vaccine to its workers with a goal of vaccinating 100% of staff.

Some health facilities and systems already require influenza vaccination as a condition of employment. The University of Pennsylvania Health System, where Dr. Fishman works, has required flu vaccination for its workers since 2009.

Researchers at the Virginia Mason Medical Center, Seattle – believed to be the first in the country to institute mandatory influenza vaccination for its health care workers in 2005 – recently studied their institution’s efforts to improve influenza vaccination rates.

They found that in the first year after the mandatory influenza requirement was put in place, 97.6% of the facility’s 4,703 health care workers were vaccinated, followed by adherence rates of more than 98% in the following 4 years. Less than 0.7% of the center’s workers were exempted from vaccination for medical or religious reasons, and less than 0.2% refused vaccinated or left employment at the center (Infect. Control Hosp. Epidemiol. 2010;31:881-8).

“Influenza vaccination of health care providers is a professional and ethical obligation ... to prevent the spread of influenza, an infection that can spread rapidly through an institution,” Dr. Fishman said.

Dr. Fishman reported no conflicts of interest. The authors of SHEA’s position paper reported having served as consultants for or having received honoraria from various companies that make vaccines, influenza diagnostics, and pharmaceuticals.

Subject Codes:
infectious; top_stories; general_primary; pulmonology; emergency_trauma;


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August 31, 2010   04:01 PM EDT

By Mary Ann Moon
Elsevier Global Medical News
Breaking News

Among births that occur during the term and postterm range of 37-44 weeks’ gestation, the risk of cerebral palsy is lowest at 40 weeks and highest at the “early” extreme of 37-38 weeks and the “late” extreme of 42 weeks or more, according to a report in the Sept. 1 issue of JAMA.

This indicates that there is “a robust U-shaped association” between CP risk and gestational age, not just for deliveries during the whole of pregnancy but also for deliveries at term, said Dr. Dag Moster of the University of Bergen, Norway, and his associates.

Preterm delivery is a well-established risk factor for CP, but there is scant information on CP risk within the term range, even though most cases of CP occur in children born at term. Dr. Moster and his colleagues examined the issue using data in a nationwide Norwegian registry covering 1,682,441 singleton live births at 37-44 weeks that took place between 1967 and 2001, as well as a medical registry of all the disabled people in the country born during the same period.

There were 1,938 infants in this cohort who were eventually diagnosed as having CP, for an overall prevalence of 1.15 cases per 1,000 live births (JAMA 2010;304:976-82).

Delivery at 40 weeks was associated with the lowest CP risk, with a prevalence of 0.99 cases per 1,000 live births.

In comparison, the prevalence of CP at 37 weeks’ gestation was 1.91 per 1,000 (for a relative risk of 1.9) and at 38 weeks was 1.25 per 1,000 (for a relative risk of 1.3). Similarly, the prevalence of CP at 42 weeks was 1.36 per 1,000 live births (for a relative risk of 1.4) and after 42 weeks was 1.44 per 1,000 live births (for a relative risk of 1.4).

Children with CP had lower mean birth weights (3,437 g), compared with children without CP (3,585 g) and smaller head circumferences (35.1 cm), compared with children without CP (35.3 cm). Children with CP were 82 times more likely to have had low Apgar scores (less than 4) and were eight times more likely to have been transferred to pediatric units after delivery.

Results were essentially the same in a further analysis of the data after adjustment for possible confounders such as maternal age, marital status, and education level.

“One possible interpretation is that delivery too early or too late, even within the limited range of term and postterm births, increases the risk of CP.

“However, an equally plausible interpretation is that fetuses predisposed to CP have a disturbance in the timing of their delivery, which causes them to be more often delivered early or late,” Dr. Moster and his associates said.

“This apparently happens with other fetal conditions: There is a U-shaped pattern in the risk of congenital anomalies with gestational age after 37 weeks. Since congenital anomalies are not caused by the timing of delivery, the most plausible explanation is reverse causation: Malformed infants experience disruptions in their time of delivery, with increased chance of delivery either earlier or later than 40 weeks,” the researchers said.

“Although the forces that regulate timing of a normal delivery are poorly understood, it appears that the types of malformations most likely to disrupt the timing of delivery often involve cerebral function. For example, anencephalic fetuses have a tendency to be born post term, children with Trisomy 18 to be born preterm or post term, and children with Down syndrome to be born early.

“It is possible that cerebral damage later expressed as CP similarly disrupts time of delivery,” Dr. Moster and his associates said.

The lower birth weight and smaller head circumference among CP cases in this cohort “suggest that these children differ from non-CP infants even before birth,” they added.

The investigators emphasized that it would be incorrect to extrapolate from these study findings that intervening to alter the time of delivery could reduce the rate of CP.

This study was sponsored by the National Institutes of Health, the National Institute of Environmental Health Sciences, the Unger-Vetlesen Charitable Fund, the U.S.-Norway Fulbright Foundation, the Norwegian Society of Pediatricians, the University of Bergen, and the Research Council of Norway. No financial conflicts of interest were reported.

Subject Codes:
top_stories; pediatrics; womans_health; neurology;


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August 31, 2010   04:00 PM EDT

By Mary Ann Moon
Elsevier Global Medical News
Breaking News

Prophylactic mastectomy and salpingo-oophorectomy significantly decrease mortality as well as the risks of breast and ovarian cancer among women who carry BRCA1 or BRCA2 mutations, according to a report published in the Sept. 1 issue of JAMA .

These risk-reducing surgeries benefit both carriers who have not yet developed malignancies and those who have already been treated for breast or ovarian cancer and are still at risk for further primary disease, said Dr. Susan M. Domchek of the University of Pennsylvania, Philadelphia, and her associates.

Most previous studies that examined whether the prophylactic excisions actually impact mortality did not address their efficacy according to subjects’ mutation status or prior cancer diagnosis. With no proof of such efficacy, some clinicians and patients may have avoided the surgeries. Some may have believed that the excisions conferred little added protection against further malignancies, especially in the setting of chemotherapy-induced menopause or hormonal therapy, Dr. Domchek and her colleagues said.

The investigators assessed outcomes in a cohort of 2,482 BRCA1 and BRCA2 mutation carriers identified at 22 medical centers in North America and Europe that were participating in the Prevention and Observation of Surgical Endpoints (PROSE) consortium. The study subjects were enrolled in 1974-2008 and followed through the end of 2009 (median follow-up, 3.65 years).

Approximately 10% of these women underwent prophylactic mastectomy, and 40% underwent prophylactic salpingo-oophorectomy.

No breast cancers developed in mutation carriers who underwent prophylactic mastectomy, whereas breast cancers did develop in 7% of those who declined prophylactic mastectomy. This confirms that prophylactic mastectomy is highly effective at significantly reducing breast cancer in women at high risk, the investigators said (JAMA 2010;304:967-75).

Among women who underwent prophylactic salpingo-oophorectomy, only 1% subsequently developed ovarian cancer, and only 11% subsequently developed breast cancer. In contrast, among women who declined prophylactic salpingo-oophorectomy, about 6% subsequently developed ovarian cancer, and 19% subsequently developed breast cancer.

Prophylactic salpingo-oophorectomy cut the risk of ovarian cancer by 70% in the subgroup of women who did not have prior breast cancer and decreased it even further, by 85%, in those who did have prior breast cancer. This finding illustrates why breast cancer patients may want to know about their BRCA mutation status even if they have undergone bilateral mastectomy: Prophylactic salpingo-oophorectomy may well protect them from developing a new primary malignancy in the ovaries.

Among women with no prior breast cancer, prophylactic salpingo-oophorectomy reduced breast cancer risk by 37% in carriers of the BRCA1 mutation and by 64% in carriers of the BRCA2 mutation.

Prophylactic salpingo-oophorectomy also decreased all-cause mortality, which was only 3% among women who underwent the procedure, compared with about 10% among those who did not. The prophylactic excision also significantly reduced breast cancer mortality (2% vs. 6%) and ovarian cancer mortality (0.4% vs. 3%), compared with no prophylactic salpingo-oophorectomy.

In an editorial accompanying this report, Dr. Laura Esserman and Dr. Virginia Kaklamani said that only 10% of the subjects in this study chose prophylactic mastectomy, and only 38% chose prophylactic salpingo-oophorectomy (JAMA 2010;304:1011-2). Now that the study results confirm that these procedures reduce not just cancer risk but also mortality, “women who test positive for BRCA1 or BRCA2 can make more informed choices about whether to consider prophylactic surgery or to opt for intensive surveillance,” and “women considering prophylactic interventions should be aware that options have changed and improved,” the physicians wrote.

Laparoscopic salpingo-oophorectomy in this setting is relatively low risk and can be done on an outpatient basis; invasive node sampling is no longer required as part of the procedure, said Dr. Esserman of the University of California, San Francisco, and Dr. Kaklamani of Northwestern University, Chicago.

Cosmetic options also have improved for prophylactic mastectomy. A total skin-sparing approach provides a more natural appearance, is safe and reliable, and now is routine in many major breast centers.

For women who worry that positive results on genetic testing will raise their insurance premiums, clinicians can reassure them that the Genetic Information Nondiscrimination Act of 2008 protects them from insurance and employer discrimination based on genetic profiles, said Dr. Esserman and Dr. Kaklamani.

Among the institutions providing support for the study were the University of Pennsylvania, the U.S. National Cancer Institute, the Cancer Genetics Network, the Dana-Farber/Harvard Cancer Center, and the U.K. National Institute for Health Research. Dr. Domchek, Dr. Esserman, and Dr. Kaklamani reported no financial conflicts of interest.

Subject Codes:
top_stories; OncologyEX; general_primary; womans_health; surgery;


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August 31, 2010   04:00 PM EDT

By Bruce Jancin
Elsevier Global Medical News
Breaking News

STOCKHOLM (EGMN) – The use of fondaparinux as an antithrombotic agent in percutaneous coronary intervention for acute coronary syndromes could get a major boost in clinical practice now that the optimal dose of adjunctive unfractionated heparin has been carefully defined in the large randomized FUTURA/OASIS-8 study.

It’s clear from FUTURA/OASIS-8 that standard-dose unfractionated heparin, not low-dose, is the right way to go for PCI in ACS patients treated with fondaparinux, Dr. Sanjit S. Jolly said in presenting the trial results in a high-profile Hotline session at the congress.

Many interventional cardiologists have balked at using fondaparinux, a synthetic factor Xa inhibitor, despite its impressive performance in the earlier Organization to Assess Strategies in Acute Ischemic Syndromes (OASIS-5) trial, in which it halved major bleeding and produced a 17% reduction in mortality compared with enoxaparin (N. Engl. J. Med. 2006;354:1464-76).

The concern among interventionalists has been that catheter thrombosis rates were higher with fondaparinux in OASIS-5. Although adjunctive unfractionated heparin will prevent that problem, the optimal dose of heparin needed in order to avoid catheter thrombosis and ischemic complications without compromising fondaparinux’s impressively low rate of major bleeding has been unclear – that is, until FUTURA/OASIS-8, explained Dr. Jolly of McMaster University, Hamilton, Ont.

The Fondaparinux Trial With Unfractionated Heparin During Revascularization in Acute Coronary Syndromes (FUTURA)/OASIS-8 trial was a double-blind, randomized study involving 2,026 patients undergoing PCI within the next 72 hours for high-risk ACS at 179 hospitals in 18 countries. All patients received 2.5 mg of fondaparinux subcutaneously once daily; after entering the catheterization lab, they were randomized to adjunctive standard- or low-dose unfractionated heparin. Standard-dose heparin was defined as 60 U/kg in the event a glycoprotein IIb/IIIa inhibitor was used and 85 U/kg if not, with dosing guided by activated clotting time (ACT). Low-dose heparin was given at 50 U/kg regardless of glycoprotein IIb/IIIa inhibitor therapy, and without ACT measurement.

The primary study end point, comprising major or minor bleeding or major vascular access-site complications within 48 hours after PCI, occurred in roughly 5% of both study arms. But there was a nominally significant difference between the two treatment groups in the key secondary end point: periprocedural major bleeding and the 30-day rate of death, MI, or target vessel revascularization. This occurred in 3.9% of the standard-dose unfractionated heparin group, compared with 5.8% of those on low-dose heparin (P = .05), representing a 51% increased risk with low-dose therapy.

The risk of major bleeding within 48 hours was 1.1% in the standard-dose unfractionated heparin arm and 1.2% with low-dose heparin in FUTURA/OASIS-8, compared with 3.6% with enoxaparin in OASIS-5, he noted.

Dr. Jolly said many fondaparinux skeptics have commented that they wanted to see reassuring data with larger patient numbers before changing their practice in the cath lab. Now they’ve got it.

“We believe FUTURA/OASIS-8 will definitely improve uptake in the community and amongst interventional cardiologists,” he said.

Hotline co-chair and current American College of Cardiology president Dr. Ralph Brindis agreed.

“This could be a paradigm change,” he predicted in an interview.

“We have been very leery, at least in the United States, in utilizing fondaparinux in ACS patients we’re going to take to the cath lab, despite the incredible benefits shown in OASIS-5. There was the catheter thrombosis issue. Plus, intuitively you’d think that, in transitioning between two different antithrombotic agents or adding one on another, there would be a greatly increased bleeding hazard. But they’ve shown in FUTURA/OASIS-8 that you can do so safely and effectively. I think this is going to be very helpful in the cath lab,” added Dr. Brindis, an interventional cardiologist who is senior advisor for cardiovascular disease at Northern California Kaiser Permanente in Oakland.

Simultaneous with the Stockholm presentation of the FUTURA/OASIS-8 results, the study was published online (JAMA 2010 Aug. 31 [doi:10.1001/jama.2010.1320]).

Dr. Jolly, the principal investigator in FUTURA/OASIS-8, declared having received honoraria and research grants from GlaxoSmithKline, the trial sponsor. Dr. Brindis reported having no financial conflicts.

Subject Codes:
top_stories; general_primary; cardiology;


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August 31, 2010   03:32 PM EDT

Ralph Brindis

By Mitchel L. Zoler
Elsevier Global Medical News
Breaking News

STOCKHOLM (EGMN) – Four simple clinical conditions play the biggest role in risk-stratifying outpatients with stable atherothrombotic disease, based on a 45,000-patient, international registry followed for 4 years.

Polyvascular disease heads the list of four factors, followed by history of an ischemic event within the past year, history of an ischemic event at any time, and diabetes, Dr. Deepak L. Bhatt said Aug. 30 at the annual congress of the European Society of Cardiology. The registry results notably showed polyvascular disease to pose the strongest risk for a subsequent ischemic event, and placed diabetes below the risk from a prior ischemic event, a finding that further dislodges diabetes from its perch as a myocardial infarction risk equivalent, said Dr. Bhatt, chief of cardiology at the VA Boston Healthcare System.

“It’s an important point, but unfortunately the myth lingers on” that diabetes is a myocardial infarction risk equivalent, he said. It is a myth Dr. Bhatt dates to studies reported more than a decade ago.

In the more contemporary database studied by Dr. Bhatt and his associates, with patients followed from 2003 to 2008, patients with diabetes may have been better managed. “It’s not that diabetes is not an important risk factor, but a prior ischemic event trumps diabetes,” he said in an interview. The new analysis shows “only a myocardial infarction is a myocardial infarction risk equivalent.”

The 4-year results from the Reduction of Atherothrombosis for Continued Health (REACH) registry also added new evidence on the role of polyvascular disease, the study’s “most potent predictor of future ischemic events. Reach is the largest and longest registry” to show a strong polyvascular effect, a risk factor that until now has been underappreciated, Dr. Bhatt said.

“A patient with angina and claudication [ischemic disease in two vascular beds] may look stable, but the message from these data is that these patients are at exceedingly high risk for something bad happening over the next 4 years,” and so need even tighter medical control of lipids, blood pressure, and other treatable risks.

Dr. Bhatt and his associates are in the final stages of refining a secondary-prevention risk model, a formula to mathematically stratify patients’ risk based on the new REACH analysis. While the model isn’t ready for release yet, it is based on the four major risk factors he reported. Until now, “there really hasn’t been any major attempt to risk-stratify secondary prevention patients, in part because many physicians seem to feel that the risk faced by all secondary-prevention patients is the same. “These data show that’s not true. There is a wide range of risk in this population, and risk stratification is called for.” Higher-risk patients could receive, for example, intensive case management by a nurse, or may be candidates for expensive, new antiatherosclerotic, anti-inflammatory, or antithrombotic therapies, with some nearing the market. “I don’t think we can afford to use [new, expensive treatments] on all patients. This analysis helps identify patients at the highest risk” who make good candidates for efficacy studies.

The REACH registry initially enrolled more than 68,000 people at 5,587 centers in 44 countries during 2003 and 2004. Reports on the baseline and 1-year follow-up data appeared several years ago (JAMA 2006;295:180-9, and JAMA 2007;297:1197-1206).The new analysis used data collected after 4 years’ follow-up from 45,227 of the participants.

The database included 21,890 patients with a prior ischemic event (myocardial infarction or stroke) at the time of enrollment into the registry. Another 15,264 patients entered based on having symptomatic, stable atherosclerosis but no event history. The final 8,073 participants had no documented disease but at least three risk factors off this list: on treatment for diabetes; diabetic retinopathy; an ankle-brachial index below 0.9; asymptomatic carotid stenosis with at least 70% occlusion; carotid intima media thickness at least twice that at adjacent sites; systolic blood pressure of at least 150 mm Hg; hypercholesterolemia; current smoker; age 65 or older in men and 70 or older in women.

The average age of the enrollees at baseline was 68; two-thirds were men. Nearly half had a prior ischemic event, 44% had a history of diabetes, 28% had an ischemic event during the prior year, and 16% had polyvascular disease, defined as atherosclerotic disease in at least two vascular beds: coronary, cerebrovascular, or peripheral. During follow-up, the participants had 5,481 events, either cardiovascular death, myocardial infarction, or stroke.

In a multivariable regression model, polyvascular disease at baseline linked with a twofold increased risk for an ischemic event during follow-up, compared with enrollees with risk factors only. Patients with a history of a recent ischemic event had a 70% higher risk for a follow-up event compared with enrollees without an event history. Patients with diabetes at enrollment had a 44% increased risk for a follow-up event compared with participants without diabetes, which did match the increased risk from an older ischemic event. Heart failure also appeared as a strong risk factor.

“Our analysis provides simple criteria for assessing the risk of cardiovascular events in stable outpatients,” Dr. Bhatt said.

Concurrently with Dr. Bhatt’s report, the results were published online (JAMA 2010 Aug. 30 [doi: 10.1001/jama.2010.1322]). The REACH registry is partially sponsored by Sanofi-Aventis and Bristol-Myers Squibb. Dr. Bhatt reported receiving research grants from AstraZeneca, Bristol-Myers Squibb, Eisai, Ethicon, Heartscape, Sanofi-Aventis, and The Medicines Company.

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


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August 31, 2010   10:35 AM EDT

Deepak L. Bhatt

By Diana Mahoney
Elsevier Global Medical News
Breaking News

One in three first time mothers are being delivered by cesarean section, and prelabor repeat cesarean deliveries contribute almost one-third of cesarean deliveries overall, according to a National Institutes of Health study.

The findings suggest that preventing unnecessary primary cesarean deliveries could substantially reduce the high cesarean delivery rate in the United States – which has increased more than 50% since 1996 and appears to be on a continued upward trajectory, lead investigator Dr. Jun Zhang said Aug. 30 during a NIH telebriefing on the study results.

In collaboration with the Consortium of Safe Labor that comprised 12 clinical centers nationwide, Dr. Zhang of the Eunice Shriver Kennedy National Institute of Child Health and Human Development and his colleagues retrospectively collected and evaluated comprehensive information on 206,969 deliveries from 2002 through 2008 to gain insight into contemporary labor and delivery practices and to shed light on the underlying causes of the nation’s high rate of cesarean deliveries.

The overall rate of cesarean delivery was 30.5%, which is consistent with recently reported national data, Dr. Zhang stated. Among nulliparous women specifically, the cesarean section rate was 31.2%, which was “somewhat surprising,” he said. “We all know that one-third of all deliveries are by cesarean section, but [the finding] that one in three nulliparous deliveries are cesarean sections seems to be high and has consequences for future deliveries.” In fact, 30.9% of all of cesarean sections were attributed to prelabor repeat cesarean deliveries because of a previous uterine scar.

Among women with a previous uterine scar, fewer than 30% attempted vaginal birth after cesarean (VBAC) with a success rate of 57%, which is substantially lower than that observed in previous large studies, Dr. Zhang stated. The reduced success rate may be influenced by other factors, including the fact that, even during a trial of labor, cesarean sections for dystocia were performed before 6 cm of cervical dilation, he said.

Of the women attempting vaginal delivery, 43.8% had induced labor and 21.1% of these had cesarean deliveries – a rate nearly twice as high as that observed among woman who had spontaneous labor, Dr. Zhang reported.

Although the study cannot directly answer the question of whether induction per se or some underlying problem leading to induction causes high rates of cesarean deliveries, “it does provide clues that induction might play some role in the cesarean section rate,” he said. For example, among women whose labor was induced, a high percentage of intrapartum cesarean sections were performed before 6 cm of cervical dilation, when many women might not yet be in active phase, indicating that “people may not be patient enough,” he hypothesized.

The investigators also determined that one-third of cesarean deliveries at the second stage of labor were performed at less than 3 hours in nulliparous women and one-quarter were performed at less than 2 hours in multiparous women. Taking into account “decision to incision” time, these waiting periods appear shorter than the American College of Obstetricians and Gynecologists guidelines, which define arrest of descent as greater than 3 hours in nulliparous women with epidural analgesia and greater than 2 hours in multiparous women with epidural analgesia, the investigators reported online ahead of print in the American Journal of Obstetrics and Gynecology (2010 Aug. 11 [doi: 10.1016/j.ajog.2010.06.058]).

The following results also were observed:

• The overall cesarean rate doubled from 21% among women younger than 20 years to 42% in women 35 years and older, mainly from repeat prelabor cesarean deliveries.

• Obesity was associated with higher cesarean rates in all categories.

• Approximately 66% of multifetal gestations were delivered by cesarean section, compared with 29.9% of singleton pregnancies.

• Term pregnancies with a vertex, singleton fetus and previous uterine scar contributed the most cesarean deliveries (30.9%), followed by term gestations with a singleton, vertex fetus whose labor was induced (19.2%).

• Multifetal gestations and pregnancies with nonvertex presentation accounted for only 6.7% of all births but contributed to one-fifth of all cesarean deliveries.

• Previous uterine scare was the main indication for prelabor cesarean delivery, followed by fetal malpresentation.

• The reason cited for approximately half of the intrapartum cesarean deliveries was “failure to progress” or “cephalopelvic disproportion”; more than one-quarter were performed for indications of nonreassuring fetal testing or fetal distress.

• Nearly 10% of prelabor and 2.1% of intrapartum cesarean deliveries were “truly elective.”

The limitations of these findings include the study’s observational design and the fact that it does not a represent a random national sample, according to Dr. Zhang. “This is a retrospective study. The quality of the information we have, even though we think it’s very good, also relies on what is required in the medical record. The data is only as good as the medical record,” he said.

With respect to the sample, “although we purposely selected sites across the country, it is not a random sample, and academic institutions are over-represented,” Dr. Zhang explained. To alleviate potential bias, the investigators used birth certificate data and assigned some weight so that one institution or ethnic group wouldn’t be overrepresented in the sample. “It’s quite a comprehensive database, but it’s not truly representative of the U.S. population,” he said.

Efforts to reduce the high cesarean delivery rate in the United States should target the prevention of unnecessary primary cesarean deliveries, including decreasing the rate of cesarean deliveries associated with a high rate of labor induction; avoiding cesarean section for dystocia before active phase of labor is established in nulliparous women, induced labor, and VBAC attempts; establishing a clinically accepted indication for performing cesarean delivery; and increasing access to patient education on trial of labor in women with a previous uterine scar and improving the success rate, according to the investigators recommendations in their report.

Dr. Zhang and his colleagues said they had no conflicts of interest to disclose. The Consortium on Safe Labor was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development.

Subject Codes:
top_stories; womans_health;


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August 30, 2010   06:21 PM EDT

By Heidi Splete
Elsevier Global Medical News
Breaking News

Approximately 40% of emergency department visits for sports-related concussions in young athletes occurred in children aged 8-13 years, based on data from concussion-related ED visits in the United States between 2001 and 2005, according to a study published online Aug. 30 in Pediatrics.

There are two main concerns about sports-related concussion in younger children, compared with college athletes and adults, lead study author Dr. Lisa Bakhos of Brown University, Providence, R.I., said in an interview.

“First, many parents, coaches, teachers, and other adults feel that, because these athletes are so young, they could not possibly get seriously hurt. As we have seen time and time again, this is of course not the case,” she said.

“Also, a few good studies have shown that head injury in younger children can have more long-term effects, as you are essentially damaging a developing brain,” she explained. In addition, more data have surfaced about cognitive deficits in older children after concussion, she said, “which leads to conjecture that younger children would suffer the same, if not more, deficits long term.” However, the link between sports-related concussion and cognitive deficits needs further study, she added.

To get a better picture of the scope of sports-related concussion in young athletes, Dr. Bakhos and colleagues reviewed data from the National Electronic Injury Surveillance System (NEISS) from 1997 through 2007, and from the NEISS All Injury Program from 2001 through 2005. The NEISS allows researchers to investigate injury- and product-related ED visits (Pediatrics 2010 Aug. 30 [doi:10.1542/peds.2009-3101]).

Between 2001 and 2005, approximately half of all ED visits for concussion across older and younger age groups were related to sports, including 58% visits in children aged 8-13 years and 46% of visits in those aged 14-19 years. Put another way, approximately 4 in 1,000 children aged 8-13 years and 6 in 1,000 of those aged 14-19 years went to the ED for a sports-related concussion.

During the 10-year period from 1997 through 2007, ED visits for the most popular organized team sports – football, ice hockey, soccer, basketball, and baseball – doubled in 8- to 13-year-olds and increased by more than 200% in 14- to 19-year-olds.

“The take-home message for pediatricians is take concussion seriously even in the very young athlete,” said Dr. Bakhos. “Children with concussion should be followed just as closely as a child with a sprained ankle or a broken bone. Return-to-play guidelines should be followed closely and stressed to parents,” she said.

“We as pediatricians should also stress to parents the importance of concussion prevention in sport as well, mostly the use of helmets at all times,” she emphasized.

The study was limited by the exclusion of sports-related concussions treated in non-ED settings, and by the underreporting of sports-related concussions by young athletes, their parents, and their coaches, the researchers noted.

But the rise in sports-related concussions in younger and older children suggests the need for more research and guidance in preventing and treating these injuries, they added.

The researchers said that they had no financial conflicts to disclose.

Subject Codes:
top_stories; sports; pediatrics; general_primary; neurology; emergency_trauma;


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August 30, 2010   04:03 PM EDT

Emergency department visits due to sports-related concussions are on the rise for young athletes between the ages of 8-13 years, researchers reported.

By Heidi Splete
Elsevier Global Medical News
Breaking News

Black patients who received drug-eluting stents were significantly more likely to develop stent thrombosis compared with nonblack patients, based on data from more than 7,000 adults published online Aug. 30 in Circulation.

To determine the incidence of early, late, and very late stent thrombosis (ST) in black patients compared with nonblack patients, Dr. Sara D. Collins and her colleagues at the Washington (D.C.) Hospital Center reviewed data from 7,236 adults who underwent percutaneous coronary intervention at a single hospital from April 2003 through December 2008.

The study group included 1,594 black patients and 5,642 nonblack patients (Circulation 2010 Aug. 30 [doi:10.1161/CIRCULATIONAHA.109.907998]).

For all patients, the incidence of early ST at 30 days was 0.83%. The cumulative incidence of late ST was 0.24% per year between 30 days and 1 year, which rose to 0.36% per year between 1 and 2 years.

The rates of ST were more than twice as high in blacks vs. nonblacks across all time points. At 30 days, the rate of ST in blacks vs. nonblacks was 1.71% vs. 0.59%. At 1 year, 2 years, and 3 years, the ST rates in blacks were 2.25%, 2.78%, and 3.67%, respectively. In nonblacks, the ST rates were 0.79%, 1.09%, and 1.25%, respectively.

In a multivariate analysis, black race was the strongest significant independent predictor of ST more than 30 days after PCI, and it was a significant predictor of early ST at 30 days.

“Black race is an independent predictor of ST even when accounting for potential confounders such as socioeconomic status and comorbidities,” the researchers said.

Black patients were more likely than nonblack patients to be taking clopidogrel at the time of the ST (88% vs. 78%), although the difference was not significant.

In a univariate analysis, black patients were significantly more likely than nonblack patients to have a history of hypertension, chronic renal insufficiency, diabetes, and heart failure. Black patients were significantly younger than nonblack patients (average age, 63 years vs. 65 years), and the median household income was significantly lower for black patients, the researchers noted.

The results support data from previous studies suggesting that black patients are more likely to experience ST, but this study is the first to control for variables typically associated with racial disparities in health care, the investigators noted.

“Because our analysis adjusts for traditional variables associated with racial disparities in health care, further mechanisms such as genetic polymorphisms and responsiveness to antiplatelet therapy must be pursued,” they said.

The researched said that they had no financial conflicts to disclose.

Subject Codes:
top_stories; general_primary; cardiology;


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August 30, 2010   04:00 PM EDT

Elsevier Global Medical News
Breaking News

In an article titled “Heart Rate Cut With Ivabradine, Trims Heart Failure Deaths in Phase III Study” (published Aug. 30, 2010), mortality was incorrectly described in reference to the study’s primary end point. The sentence should have read: “This safety finding and the significant impact of the investigational drug both on the combined primary end point of the study and on heart failure mortality should give ivabradine a clear path toward U.S. Food and Drug Administration approval, followed by widespread adoption in practice, predicted U.S. heart failure experts.”

Subject Codes:
top_stories; new_drugs; general_primary; cardiology;


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August 30, 2010   03:02 PM EDT

By Bruce Jancin
Elsevier Global Medical News
Breaking News

STOCKHOLM (EGMN) – Patients’ possession of a clopidogrel loss-of-function genetic polymorphism is likely to worsen outcomes when the antiplatelet agent is prescribed for acute coronary syndromes that are likely to be treated with coronary stenting, but not when the drug is given for atrial fibrillation or chronic coronary artery disease.

This was the prevailing interpretation of two high-profile studies that were presented at the annual congress of the European Society of Cardiology with what at first glance seemed to be disparate results.

The studies drew strong interest because they addressed an issue that was brought dramatically to the fore in the Food and Drug Administration’s black box warning for clopidogrel, issued in March 2010: namely, clopidogrel’s reduced effectiveness in protecting against cardiovascular events in patients who are poor metabolizers of the drug because they have loss-of-function alleles of the CYP2C19 gene that is responsible for converting the prodrug into its active metabolite.

The black box warning was based mainly on data from studies of clopidogrel in ACS patients with high rates of coronary intervention. But a study presented at the congress by Dr. Guillaume Pare suggested that the black box may have been painted with too broad a brush. Dr. Pare reported that clopidogrel was consistently more beneficial than placebo, regardless of CYP2C19 loss-of-function carrier status in other sorts of patients (such as those with atrial fibrillation or those with low-risk, conservatively managed ACS).

This suggests that there is no need for genetic profiling studies in such patients in order to identify poor metabolizers of clopidogrel (Plavix) prior to starting the drug, according to Dr. Pare of McMaster University in Hamilton, Ont.

The study involved the genotyping of 5,059 patients with conservatively managed ACS who participated in the CURE (Clopidogrel in Unstable Angina to Prevent Recurrent Events) trial and 1,156 participants in ACTIVE A (Atrial Fibrillation Clopidogrel Trial With Irbesartan for Prevention of Vascular Events A). Both CURE and ACTIVE A were randomized, double-blind, placebo-controlled trials with primary results that have previously been published.

Patients in CURE who carried one or more loss-of-function alleles had an 8.0% rate of the primary efficacy end point consisting of cardiovascular death, nonfatal MI, or stroke, compared with an 11.6% rate with placebo. This translated into a highly significant 31% relative risk reduction, closely similar to the 28% risk reduction seen in noncarriers. A similar pattern was seen among the patients with atrial fibrillation in ACTIVE A.

The other major clopidogrel loss-of-function genotyping study that was presented at the congress was a secondary analysis from the previously reported PLATO (Platelet Inhibition and Patient Outcomes) study. Dr. Lars Wallentin of Uppsala (Sweden) University presented genetic profiling data on 10,285 PLATO participants with ACS who were randomized in double-blind fashion to aspirin plus either 75 mg of clopidogrel once daily or the investigational oral antiplatelet drug ticagrelor (Brilinta) at 90 mg twice daily. In contrast to the CURE study, in which only 14% of ACS patients underwent coronary intervention, invasive treatment was already planned at baseline in two-thirds of PLATO participants.

Among the 39% of subjects with any loss-of-function allele, the 1-year composite primary end point of cardiovascular death, nonfatal MI, or stroke occurred in 8.6% of the ticagrelor group, compared with 11.2% of those on clopidogrel. Among patients without a loss-of-function allele, the rates were 8.8% in the ticagrelor group and 10.0% in the clopidogrel group. In other words, patients on ticagrelor benefited equally from the drug regardless of whether they possessed a loss-of-function mutation, unlike those on clopidogrel, presumably because ticagrelor doesn’t depend upon CYP2C19 for its metabolism.

“These findings emphasize that ticagrelor will be a simple and reliable treatment to further improve survival and reduce the risk of recurrences in almost all patients with acute coronary syndrome without the need for any specific tests of its activity before or during routine treatment,” according to Dr. Wallentin.

He and his colleagues also genotyped the PLATO patients for ABCB1 polymorphisms. The ABCB1 gene is believed to be responsible for clopidogrel absorption. Event rates at 1 year were consistently lower in the ticagrelor than the clopidogrel group in high, intermediate, and low expressers of the ABCB1 polymorphism.

The 30-day event rate in clopidogrel-treated patients was significantly higher in those with any loss-of-function CYP2C19 alleles by a margin of 5.7%, compared with 3.8% in those without such alleles. However, after 30 days and out to 1 year, there were no significant differences in event rates between clopidogrel-treated patients with and without loss-of-function alleles. This supports the notion that the loss-of-function alleles in the CYP2C19 gene are influential in the early phase of ACS, when thrombosis is particularly important, the cardiologist said.

Discussant Dr. Kurt Huber of Wilhelminen Hospital, Vienna, emphatically stated that routine genotyping for loss-of-function alleles is not warranted today in clinical practice, in PLATO-type patients or anyone else. As yet there are no prospective, randomized intervention studies to show that altering treatment on the basis of genetic testing leads to better clinical outcomes. Moreover, the tests are generally not reimbursable and the 2-3 hours required for results are an impediment to fast-track management of high-risk ACS patients.

What makes more sense today is simply to make routine use of more efficient antiplatelet drugs such as prasugrel or ticagrelor, instead of clopidogrel, in patients who are at medium to high risk of thrombotic complications related to stenting, Dr. Huber said. Examples would be individuals with ST-elevation MI, high-risk non–ST-elevation MI, or prior stent thrombosis.

Discussant Robert M. Califf expressed doubt that what he termed the “nirvana” promised by pharmacogenetics proponents will ever come to pass. The notion of using genetic testing to assign patients to the drug they are likely to best respond to, with resultant better outcomes overall at less cost to the health care system, is immensely appealing, but it flies in the face of recent evidence regarding the powerful influence that environment exerts on DNA.

“I predict that for most complex diseases, the proportion explained by genes is going to be quite small and there will be many other factors involved, leaving you always with this question: After you know the genes, is it enough that it would cross a threshold to change clinical practice?” observed Dr. Califf, vice chancellor for clinical research at Duke University, Durham, N.C.

It will probably prove more fruitful to fine-tune various functional assays that measure the integrated output of genes and other factors, he added. Examples include platelet function tests for guidance in antiplatelet therapy and INR measurement in prescribing warfarin.

Simultaneously with Dr. Wallentin’s presentation, the PLATO genetic analysis study was published online in the Lancet (2010 Aug. 29 [doi:10.1016/S0140-6736(10)61274-3]). Dr. Pare’s study was also simultaneously published online (N. Engl. J. Med. 2010 Aug. 29 [doi:10.1056/nejmoa1008410]).

PLATO was funded by AstraZeneca; Dr. Wallentin disclosed that he has received research grants from that company as well as numerous others with an interest in antithrombotic agents. Dr. Pare reported receiving consulting fees from Bristol-Myers Squibb and Sanofi-Aventis, the funders of ACTIVE A and CURE, respectively. Dr. Huber and Dr. Califf disclosed receiving research grants and consulting fees from numerous pharmaceutical companies with an interest in antiplatelet therapies.

Subject Codes:
top_stories; general_primary; cardiology;


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August 30, 2010   01:20 PM EDT

Lars Wallentin

By Mitchel L. Zoler
Elsevier Global Medical News
Breaking News

STOCKHOLM (EGMN) – Patients with moderate to severe systolic heart failure and an elevated heart rate had a marked drop in their rate of heart failure death and hospitalization when they were treated with the heart-rate–lowering drug ivabradine in a phase III, randomized trial with more than 6,500 patients.

In addition to making ivabradine an important new agent for treating many heart failure patients, the findings proved that heart rate is an effective intervention target for this disease. Patients who received the drug on top of a standard heart failure regimen had a 5% absolute and 18% relative drop in their incidence of cardiovascular mortality and heart failure hospitalization, the study’s primary end point, during a median treatment duration of 23 months, Dr. Michel Komajda said on Aug. 29 at the European Society of Cardiology Congress 2010.

Heart failure mortality fell by 2%, a 26% relative drop that was statistically significant, reported Dr. Komajda, head of the cardiovascular department at Pitié-Salpetrière Hospital in Paris. Also well tolerated, ivabradine had a serious adverse event rate of 45%, significantly better than the 48% rate in the placebo arm. “We are very happy to see one positive trial in chronic heart failure after several years of disappointments,” he said.

This safety finding and the significant impact of the investigational drug both on the combined primary end point of the study and on cardiovascular mortality should give ivabradine a clear path toward Food and Drug Administration approval, followed by widespread adoption in practice, predicted U.S. heart failure experts.

“Once you have the mortality benefit, it’s very hard to go back” and do a second placebo-controlled trial, commented Dr. Bertram Pitt, a cardiologist at the University of Michigan in Ann Arbor. “These are compelling data. I would use this” on my patients, he said in an interview.

Analysis of results from SHIFT (Systolic Heart Failure Treatment with the If Inhibitor Ivabradine Trial) also showed the critical role that heart rate played in the rate of the primary end point, both patients’ heart rate at entry into the study, and their achieved heart rate after 4 weeks on ivabradine. When the primary end point analysis dichotomized the enrolled patients by their median baseline heart rate of 77 bpm, those with an entry rate of 76 bpm or lower showed no significant benefit from ivabradine treatment, whereas those at 77 bpm or greater had a significant benefit, leading Dr. Komajda to call patients with a rate of at least 77 bpm the target population for the drug.

In addition, patients with a baseline heart rate of 80-86 bpm had a significant, 80% relative increased rate of the primary end point, compared with patients who entered the study with the lowest heart rates allowed by the enrollment criteria (70-72 bpm). Patients who entered with a rate of 87 bpm or higher had a greater-than-twofold increased risk for the primary end point.

Once treatment started and ran for 28 days, patients who achieved a heart rate lower than 60 bpm had a 17% rate of the primary end point during complete follow-up, whereas those with a heart rate of 75 bpm or greater after 28 days had an eventual 32% rate of cardiovascular death or heart failure hospitalization, also a statistically significant difference. The average achieved heart rate after 28 days was 64 bpm on ivabradine, compared with 75 bpm in placebo patients. At 1 year, the rates averaged 67 bpm and 75 bpm, respectively.

“SHIFT confirms the importance of heart rate in the pathophysiology of heart failure,” commented Dr. Inder Anand, professor of medicine at the University of Minnesota in Minneapolis.

Based on this finding, a physician who treats heart failure patients with ivabradine should titrate the dosage to a target heart rate of 60 bpm, assuming the patient remains tolerant, said Dr. Karl Swedberg, professor of medicine at the Göteborg (Sweden) University, who led the study along with Dr. Komajda.

Simultaneously with the meeting report, the SHIFT results appeared online in two Lancet articles (2010 Aug. 29 [doi:10.1016/S0140-6736(10)61198-1]; 2010 Aug. 29 [doi:10.1016/S0140-6736(10)61259-1]).

SHIFT randomized 6,558 patients with systolic heart failure at 677 centers in 37 countries. (No U.S. center participated.) Patients could have New York Heart Association class II-IV heart failure, with a left ventricular ejection fraction of 35% or less and a heart rate of at least 70 bpm. Their average age was 60 years and their median heart rate was 77 bpm; roughly half had class II heart failure and the other half class III disease.

Given that ivabradine works exclusively by lowering heart rate, specifically targeting the heart-rate controlling “funny” (If) current of the sinus node, the use of beta-blockers by study patients received extra scrutiny, with 89% of enrolled patients receiving a beta-blocker, and with 56% receiving at least half of their target beta-blocker dosage and 26% getting the complete, recommended dosage. In addition, more than 90% of patients received an ACE inhibitor or an angiotensin receptor blocker.

Patients in the study received the highest background dose of a beta-blocker in a heart failure trial outside of a beta-blocker study,” said Dr. Swedberg. “We think they had the best treatment available. This is the best we can achieve today with a beta-blocker.” All patients in SHIFT began a beta-blocker, and only those who were completely intolerant of the drug came off it. The added heart-rate reduction that ivabradine provided on top of the beta-blocker “saved energy in a compromised myocardium,” he explained.

“We encouraged up-titration [of beta-blockers] as much as possible,” Dr. Komajda said.

“It’s unlikely that use of higher beta-blocker doses in SHIFT would have caused a further reduced heart rate. In the real world, clinicians are unable to increase doses of beta-blockers to target levels because of actual or perceived side effects,” Dr. Anand said.

“There are adverse effects from beta-blockers. Sometimes you can’t push high doses,” said Dr. Alfred Bove, a cardiologist and heart failure specialist at Temple University in Philadelphia. Ivabradine “supplements the titration of a beta-blocker when you run out of room because of side effects,” he said in an interview. Dr. Bove said that the 50% prevalence of a heart rate of 77 bpm or greater in the SHIFT patients reasonably reflected the rate in average heart failure patients of the type enrolled, and was a rate indicating inadequately controlled heart failure. Among similar patients who were managed in a more intensive, closely monitored program, perhaps 25% would have such an elevated heart rate and would be good candidates for ivabradine treatment, he said in an interview.

Dr. Anand recommended excluding heart failure patients with atrial fibrillation from ivabradine treatment, but despite that, he estimated that roughly 40% of all heart failure patients with left ventricular systolic dysfunction who were on current, standard-of-care therapy might benefit from the addition of ivabradine to their regimen.

SHIFT was sponsored by Servier Laboratories, which markets ivabradine in Europe under the name Procoralan for the treatment of patients with chronic stable angina. Ivabradine does not have an approved indication from the U.S. Food and Drug Administration. Dr. Komajda and Dr. Swedberg have received fees and research grants from Servier, and two of their coauthors on the study are employees of Servier. Dr. Pitt has received honoraria from and has been a consultant to Merck & Co., Novartis, and Pfizer Inc. Dr. Bove has been an unpaid consultant to Insight Telehealth Systems. Dr. Anand has served on an advisory board for and received research grants from Corventis Inc.

Subject Codes:
top_stories; new_drugs; general_primary; cardiology;


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August 30, 2010   09:48 AM EDT

By Diana Mahoney
Elsevier Global Medical News
Breaking News

Annual estimates of influenza-associated deaths from 1976-2007 varied substantially by season, influenza virus type, underlying cause of death, and age group, according to revised statistical models, the Centers for Disease Control and Prevention reported August 27 in its Morbidity and Mortality Weekly Report.

The “incredible variation” indicates that using a single, average estimate insufficiently communicates the mortality burden of influenza,Dr. David Shay, medical officer with the CDC’s National Center for Immunization and Respiratory Diseases, said in a media briefing.

With a low of 3,349 estimated deaths in 1986-87 and a high of 48,614 deaths in 2003-2004, the estimated annual rate of influenza-associated deaths in the United States from 1976-2007 ranged from 1.4 to 16.7 deaths per 100,000 persons, according to the new models, which update the CDC’s previously published estimates for 1976-2003 and include new data from 2006-2007.

Because of the wide variability across influenza seasons, “it is relatively meaningless to try to summarize [influenza burden] with one number,” Dr. Shay stressed. “There are very few average seasons, so providing a simple average fails to communicate the impact of flu in an understandable fashion.”

For this reason, the CDC advises quantifying influenza-associated deaths in the context of circulating virus strains and underlying causes of death among age groups. Toward this end, the influenza-associated mortality estimates in the CDC’s revised models are provided for three age groups (younger than 19 years, 19–64 years, and 65 years or older) and for two categories of underlying cause of death codes: pneumonia and influenza causes and respiratory and circulatory causes.

For pneumonia and influenza causes, the respective estimated annual average of influenza-associated deaths and the rate of influenza-associated deaths per 100,000 people were 6,309 and 2.4 for the U.S. population overall; 97 and 0.1 for persons younger than 19 years; 666 and 0.4 for adults age 19-64 years; and 5,546 and 17.0 for adults 65 years and older, the report states.

For deaths with underlying respiratory and circulatory causes, the respective estimated number and rate of influenza-associated deaths per 100,000 was 23,607 and 9.0 for the U.S. population overall; 124 and 0.2 for persons younger than age 19 years; 2,385 and 1.5 among adults age 19–64 years; and 21,098 and 66.1 among adults age 65 years and older (MMWR 2010;33:1057-62).

For both causes, “the average mortality rates for the 22 seasons during which influenza A(H3N2) was a prominent strain were 2.7 times higher than for the nine seasons that it was not,” the authors reported. “The average annual number of influenza-associated deaths during influenza A(H3N2) prominent seasons was 7,722 for pneumonia and influenza causes and 28,909 for respiratory and circulatory causes, compared with 2,856 deaths for pneumonia and influenza causes and 10,648 deaths for respiratory and circulatory causes in seasons in which it was not.”

The numbers “confirm that influenza has a substantial burden of mortality each year, but also that the burden can change substantially from year to year,” Dr. Shay stated.

The findings represented in the revised model are limited by a number of factors, including the failure to account for co-circulating pathogens such as respiratory syncytial virus; the possibility that changing virus surveillance data may reduce the relevance of comparing estimates over time; and the possibility that the increase in the number of adults older than age 65 years during the study period could have contributed to an increase in influenza-associated mortality, according to the authors. Also, because the models rely on national death certificate data through 2007, preliminary estimates of 2009 influenza A(H1N1)-associated deaths are not comparable, they wrote.

Subject Codes:
infectious; top_stories; pediatrics; general_primary; pulmonology; emergency_trauma; gerontology;


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August 26, 2010   02:38 PM EDT

By Naseem S. Miller
Elsevier Global Medical News
Breaking News

Children who are underinsured outnumber uninsured children and are almost as likely as uninsured children to have problems with health care access and quality, according to a study published Aug. 25 in the New England Journal of Medicine.

Nearly a quarter of children with continuous health care coverage in 2007 did not have coverage adequate enough to provide access to appropriate services and providers, according to lead author Michael Kogan, Ph.D., of the Health Resources and Services Administration’s Maternal and Child Health Bureau, and his colleagues.

Dr. Kogan and his colleagues analyzed data collected from the 2007 National Survey of Children’s Health, which was conducted by random-digital-dial interviews with the parents or guardians of 91,642 children.

They found that in 2007, 19% (14.1 million) of all U.S. children were underinsured (continuous but inadequate coverage), while 5% (3.4 million) were uninsured, and 10% (7.6 million) were sometimes insured. In contrast, 66% (48.2 million) were fully insured.

Children with private insurance were twice as likely to be underinsured as those with public insurance, for example coverage under either Medicaid or a State Children’s Health Insurance Program (SCHIP), they wrote. Inadequate coverage of charges was the most common source of underinsurance, accounting for 12.1 million children.

Certain groups of insured children were more likely to be underinsured: those older than 6 years, Hispanic and black children, those in the Midwest, and those who had special health care needs.

Underinsured children had no access to a medical home on the same scale as their sometimes insured peers – 55% and 58% respectively. Dr. Kogan and colleagues found a similar situation regarding access to specialty care: 26% of underinsured children had difficulty obtaining specialist care, compared with 29% of sometimes insured children and 25% of uninsured children.

While attention has been focused on the woes of adult underinsurance, less has been paid to childhood underinsurance, according to Dr. Kogan, who added that it is not clear whether the number of uninsured children has been on the rise over the years, because there are no similar studies for comparison.

As implementation of the Affordable Care Act continues, “it may be worthwhile to consider not only the number of uninsured children in the United States but also the adequacy of coverage for those with current insurance,” wrote Dr. Kogan and colleagues.

The study is limited in several ways, the authors wrote. Because the study design was cross-sectional, it is difficult to establish the direction of causality. In addition, the data excludes children in institutions. And, because the study is based on data collected in a phone survey, it is subject to biases, “including the exclusion of household without landlines.”

“What I would hope from policymakers is that they would be aware that this problem is more prevalent than the number of uninsured kids and to take that into account in the future policy considerations,” Dr. Kogan wrote, noting that HRSA plans on repeating the study within the next few years.

In an accompanying editorial, Dr. James Perrin of the MGH Center for Child and Adolescent Health Policy, Boston, noted that the study offers “compelling evidence that underinsured children face major problems in obtaining both the appropriate quality of care and access to that care. Implementation of the Affordable Care Act offers important opportunities to address the problem of underinsurance.”

He added, however, that “the Affordable Care Act may leave chronically ill children with CHIP coverage and newly insured Medicaid population underinsured.” While expansion of benefits is unlikely, “CHIP and the new Medicaid could offer such benefits to persons meeting certain disability criteria [and potentially offer a better federal match to encourage states to include these benefits].”

The study authors and Dr. Perrin disclosed that they have no relevant conflicts of interest.

Subject Codes:
top_stories; pediatrics; emergency_trauma;


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August 25, 2010   05:00 PM EDT

By Jeffrey S. Eisenberg
Elsevier Global Medical News
Breaking News

Fuchs’s corneal dystrophy results from variation in the transcription factor 4 gene, according to research published Aug. 25 in the New England Journal of Medicine.

The condition affects 5% of people in the United States, and is a leading cause of corneal transplantation.

Previous linkage studies have identified chromosomal loci associated with common age-related Fuchs’s corneal dystrophy (FCD). However, they did not identify genetic variation contributing to FCD within these loci.

So, Dr. Keith H. Baratz of the Mayo Clinic, Rochester, Minn., and several colleagues conducted a collaborative genomewide association study of 130 subjects who had FCD matched with 260 control subjects by age and sex. They also performed a replication study with an independent group of 150 FCD patients matched to 150 controls, also by age and sex (NEJM 2010 Aug. 25 [doi:10.1056/NEJMoa1007064]).

Genotyping of archived DNA samples took place at the Center for Inherited Disease Research. Single-nucleotide polymorphisms (SNPs) that had the highest association for FCD were used for the replication study. The researchers imputed SNPs across loci associated with FCD, performed single SNP analyses on genotype distributions using imputed genotype dosage, and conducted haplotype studies using the most likely imputed genotype and score.

Results suggest that two regions of the genome contribute to FCD. The most significant association was seen on the region that spans the gene encoding transcription factor 4 (TCF4), which is located on chromosome 18q21.2 – a finding the researchers confirmed in the replication study. The odds ratio of FCD was 5.5 for those carrying a single risk allele and 30 for those carrying two risk alleles.

A second region, which houses the gene encoding the protein tyrosine phosphatase receptor type G (PTPRG) was strongly associated with FCD in the replication group, the researchers found. This association, however, did not reach genomewide significance, so additional replication studies are necessary.

The genetic variations shown in TCF4 may explain the linkage signal with FCD previously observed on the 18q21 chromosome. “The high impact on disease risk suggests that a pathway regulated by E2-2, the protein encoded by TCF4, is a major contributor to FCD,” the researchers said. E2-2 is expressed in the developing corneal endothelium.

“So far, we have not identified variation in the coding region of TCF4 that is associated with FCD, and we do not know which genetic variation in this region directly drives the associations that we have observed. It is possible that risk is determined by noncoding variants that influence the forms or extent of expression of E2-2.”

The findings suggest several mechanisms of the pathogenesis of FCD, the researchers said. These include decreased endothelial cell count due to senescence, deficient proliferation, or migration; and increased cellular stress through abnormal development of the basement membrane, abnormal ion-channel regulation, or premature senescence.

Dr. Baratz disclosed that his departments received an unrestricted research grant from Research to Prevent Blindness. One of the coauthors receives royalties from Arctic Dx Inc. related to AMD sequence data. The Mayo Clinic may pursue a patent application related to this research.

In an accompanying editorial, Dr. Alan F. Wright of the Western General Hospital in Edinburgh and Dr. Baljean Dhillon of the University of Edinburgh, stated that Dr. Baratz and his colleagues showed a strong association between FCD and variants in the gene encoding transcription factor 4 (TCF4) – a finding they replicated in independent subjects. TCF4 encodes E2-2, a helix-loop-helix transcription factor that is expressed in the cornea (NEJM 2010 Aug. 25 [doi:10.1056/NEJMe1007495]).

“Beyond that, the goal would be to develop a means of disease prevention,” they stated.

Dr. Wright and Dr. Dhillon reported that they had no conflicts of interest.

Subject Codes:
top_stories; ophthalmology;


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August 25, 2010   05:00 PM EDT

By Mary Ann Moon
Elsevier Global Medical News
Breaking News

The use of the antiviral drugs acyclovir and valacyclovir during the first trimester of pregnancy does not appear to be associated with major birth defects, according to a report in the Aug. 25 issue of JAMA.

Exposure to the related drug famciclovir also showed no association with major birth defects in this nationwide Danish cohort study, but the number of cases (26) was too small for definitive conclusions to be drawn regarding this agent, said Bjorn Pasternak, Ph.D., and Anders Hviid, Dr.Med.Sci, of Statens Serum Institut, Copenhagen.

Given that more than 1% of sexually active women acquire herpes simplex during the first trimester of pregnancy and that the incidence of herpes zoster is 1-2 per 1,000 person-years during the reproductive years, a substantial number of women will receive antiviral therapy early in pregnancy, they noted.

Information on the teratogenicity of acyclovir “is mainly based on data from a pregnancy registry managed by the drug manufacturer,” which relies on spontaneous reporting and lacks a valid control group. Information on the teratogenicity of famciclovir is even more sparse, with only four pregnancies reviewed in the literature, and there are no published data at all on cases of exposure to valacyclovir in early pregnancy.

Dr. Pasternak and Dr. Hviid used data from a registry of all the live births in Denmark between 1996 and 2008 to track any possible associations between exposure to antivirals and birth defects. They linked this data with that in two other nationwide registries, one of all prescription drug use and another of all hospital-based diagnoses of chromosomal aberrations, genetic disorders, and birth defect syndromes in infants during the same 13-year period. They excluded 2,944 cases in which the birth defects were associated with other known causes and 259 cases in which the birth defects were possibly related to congenital viral infections.

The final cohort comprised 837,795 live births, which included 19,960 cases of major birth defects during the first year of life. This 2.4% prevalence accords with that expected in the general population.

There were 1,804 pregnancies exposed to acyclovir, valacyclovir, or famciclovir during the first trimester, and 40 of these infants (2.2%) had a major birth defect. In comparison, the rate was 2.4% in unexposed pregnancies, a nonsignificant difference.

The data then were adjusted to account for several potential confounding factors such as the mother’s parity, age at conception, smoking status, education level, socioeconomic class, comorbidities, history of STDs, diabetes status, and use of other drugs. The investigators also excluded subjects with a history of birth defects in siblings. These adjustments did not alter the finding of no association between antiviral use and birth defects.

Analyses of the data on each antiviral agent alone also showed no such association, although the use of famciclovir was very uncommon.

A further analysis in which birth defects were classified by organ system also showed no significant association with antiviral use. However, these analyses were based on a small number of cases of antiviral exposure “and therefore cannot exclude teratogenic effects with certainty,” the investigators said (JAMA 2010;304:859-66).

A supplementary analysis of dermatologic creams containing acyclovir or penciclovir also showed no association with major birth defects.

Finally, several analyses to test the robustness of the results found no associations. These included breaking down the data by the number of doses of antivirals prescribed, as well as restricting the analysis to subjects who filled an antiviral prescription during the period of maximal susceptibility to teratogenic agents (2-8 weeks after conception).

In an editorial accompanying this report, Dr. James L. Mills and Dr. Tonia Carter noted that from a public health perspective, “this study provides fairly strong reassurance that acyclovir is not a major cause of birth defects.”

However, it cannot definitively answer the question of whether acyclovir or related antivirals are teratogens, because of the small number of individual birth defects – “a critical limitation,” wrote Dr. Mills and Dr. Carter, of the division of epidemiology, statistics, and prevention research at the Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Md.

No teratogen produces an increase in all malformations; instead, “each produces a characteristic pattern of malformations, almost a distinctive signature. The Danish data ... have too few birth defects to examine even common defects individually to look for such a pattern,” Dr. Mills and Dr. Carter said (JAMA 2010;304:905-6).

In fact, the data on individual defects “are too sparse even to provide guidance as to which defects are worth more explanation.”

Overall, “the study by Pasternak and Hviid is helpful in demonstrating the safety of acyclovir in pregnancy, but additional strategies must be developed to resolve the remaining issues,” they said.

Dr. Mills and Dr. Carter reported no financial conflicts. Their work was funded by the Intramural Research Program of the National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development.

Dr. Pasternak and Dr. Hviid reported no financial conflicts. Their study was supported by grants from the Danish Medical Research Council and the Lundbeck Foundation.

Subject Codes:
infectious; top_stories; womans_health;


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August 24, 2010   04:00 PM EDT

By Mary Ann Moon
Elsevier Global Medical News
Breaking News

Prophylactic counterpulsation with an intra-aortic balloon pump did not prevent major adverse cardiovascular events from developing in high-risk PCI patients, according to a report in the Aug. 25 issue of JAMA.

In what they described as the first randomized controlled trial to assess the efficacy and safety of the prophylactic use of an IABP in patients at high risk due to severe left ventricular impairment and extensive coronary disease, investigators found no difference in the primary outcome – a composite end point of death, MI, cerebrovascular events, or further revascularization – between patients randomly assigned to planned IABP counterpulsation and those assigned to no planned IABP counterpulsation before PCI.

In addition, “Elective IABP use was associated with significantly fewer procedural complications but more minor bleeding and more access-site complications than when PCI was performed without planned IABP insertion,” said Dr. Divaka Perera of King’s College, London, and his associates.

The researchers performed the study because current international guidelines for PCI do not include any formal recommendations concerning elective IABP use. They only suggest that “IABP support should be reserved only for patients at the extreme end of the spectrum of hemodynamic compromise,” Dr. Perera and his colleagues said.

Nevertheless, several observational studies have reported fewer complications and major adverse cardiovascular events when an IABP is placed prophylactically rather than being placed only in the event that counterpulsation is needed. And clinicians appear to be acting on those results: A recent study showed that the most common reason for IABP insertion “is to electively support patients who are hemodynamically stable at the outset but perceived to be at high risk of major complications during angiography or PCI,” Dr. Perera and his associates noted.

They performed the prospective, open-label trial at 17 interventional cardiology centers in the United Kingdom in 2005-2009. The study involved 301 patients with multivessel disease, impaired left ventricular function, and a large amount of myocardium subtended by stenosed vessels who were scheduled for PCI of either native coronary arteries or bypass grafts.

A total of 151 subjects were randomly assigned to undergo IABP insertion before PCI and 150 were assigned to have no IABP insertion unless the need for counterpulsation developed during PCI. All the subjects were followed until hospital discharge or for 28 days following the procedure.

Four patients in the prophylactic IABP group were not treated as planned. Insertion of the IABP could not be achieved in three of them because of difficulties with vascular access, and the fourth subject was switched from PCI to CABG. Similarly, three patients in the control group were not treated as planned; two underwent IABP insertion before PCI and one was switched from PCI to CABG.

Of the 147 patients in the control group who did not receive prophylactic IABP, 18 (12%) required rescue IABP counterpulsation during PCI, usually because they developed prolonged hypotension during the procedure (13 cases). This underscores the importance of keeping IABP counterpulsation ready as a standby strategy, the investigators said.

The primary end point of major adverse cardiac or cardiovascular events (MACCE) within 28 days occurred in 15% of the patients who had prophylactic placement of an IABP and 16% of those who did not, a nonsignificant difference. There was a 2.8% absolute decrease in mortality at 6 months with prophylactic IABP counterpulsation, but that difference also was nonsignificant, the researchers said (JAMA 2010;304;867-74).

The MACCE rates also did not differ significantly in important subgroups of patients, including those who had impaired kidney function, diabetes, or extremely high risk of PCI-related complications.

Major procedural complications occurred less often in the group with prophylactic IABP (1.3%) than in the control group (10.7%), but bleeding events and access-site complications were more frequent with prophylactic IABP (19.2% vs. 11.3% and 3.3% vs. 0%, respectively).

“These results do not support a strategy of prophylactic placement of an intraaortic balloon catheter during PCI in all patients with severe left ventricular dysfunction” and a high risk of PCI-related complications, Dr. Perera and his associates said.

“In the absence of clear markers that would allow prospective identification of patients who will require rescue IABP insertion, a standby IABP approach is advisable when undertaking PCI in the presence of severe left ventricular impairment and extensive coronary disease, to allow timely emergency placement of a balloon catheter if required,” they added.

The researchers noted that this study was conducted at high-volume centers and that most of the cardiologists were “experienced at performing complex PCIs and using percutaneous hemodynamic support devices. It is unclear whether inclusion of a more heterogeneous group of centers and operators may have affected the incidence of major complications overall and, therefore, the relative efficacy of elective counterpulsation.”

The study was sponsored by the British Cardiovascular Intervention Society, which is funded by Maquet Cardiovascular, Cordis, and Johnson and Johnson, and was supported in part by Lilly. Dr. Perera and an associate received financial support from the U.K. Department of Health.

Subject Codes:
top_stories; cardiology;


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August 24, 2010   04:00 PM EDT

By Mary Ellen Schneider
Elsevier Global Medical News
Breaking News

The American College of Obstetricians and Gynecologists has endorsed federal recommendations to routinely vaccinate girls 11-12 years old against the human papillomavirus using either the quadrivalent or bivalent vaccines.

Echoing the advice of the Advisory Committee on Immunization Practices, ACOG officials said the vaccine can be given to girls as young as 9 years old and that catch-up vaccination should be offered through age 26 years. ACOG outlined its position in the September issue of Obstetrics & Gynecology (2010;116:800-3).

Although ob.gyns. are unlikely to care for girls in the initial vaccination group, ACOG said that ob.gyns. should offer the vaccine to girls in the catch-up group and routinely document human papillomavirus (HPV) vaccine status in the patient’s record.

Two HPV vaccines are currently licensed by the Food and Drug Administration for sale in the United States. Merck’s Gardasil, which is offered as a three-dose course, is a quadrivalent vaccine that provides protection against cervical cancer, cervical dysplasias, vulvar and vaginal dysplasias, and genital warts associated with HPV genotypes 6, 11, 16, and 18.

Last year, the FDA approved the bivalent HPV vaccine Cervarix. This new vaccine, marketed by GlaxoSmithKline, is also offered as a three-dose course and is thought to provide protection similar to that of Gardasil for infections caused by the HPV genotypes 16 and 18. About 70% of all cervical cancer cases are associated with HPV genotypes 16 and 18, and about 90% of genital warts are associated with the HPV genotypes 6 and 11, according to the Centers for Disease Control and Prevention.

In the policy statement issued by ACOG’s Committee on Adolescent Health Care, the organization urged girls to get vaccinated before they are sexually active. “The ideal time for girls to receive the HPV vaccination is before they become sexually active and become exposed to HPV,” Dr. Diane F. Merritt, chair of the committee, said in a statement. “For those already sexually active, we also recommend the HPV vaccination for adolescents and young women up to age 26.”

Dr. Merritt said physicians should counsel patients that the HPV vaccine may be less effective if they have already been exposed to the virus.

ACOG does not recommend that girls and women be tested for HPV before they are vaccinated. Serologic assays to test for HPV DNA are unreliable and aren’t currently commercially available, according to the organization. “More importantly, it’s unlikely that someone would have been exposed to all of the HPV strains that the vaccines protect against, so testing is somewhat pointless,” Dr. Merritt said.

But women should have routine cervical cytology screening, according to ACOG. The organization said cervical cancer screening is needed in all women aged 21 years and older, even if they received the HPV vaccine before becoming sexually active.

HPV vaccination is not recommended during pregnancy, but physicians do not need to routinely perform pregnancy testing before giving the vaccine, according to ACOG. Instead, ACOG officials advised physicians to remind their patients to use contraception while they are receiving the vaccine series. If a woman becomes pregnant while receiving the vaccine, the series should be delayed until the end of the pregnancy. The vaccine is safe for breast-feeding women, ACOG said, because the virus it contains is inactive.

Subject Codes:
infectious; top_stories; pediatrics; general_primary; womans_health;


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August 23, 2010   05:00 PM EDT

By Kerri Wachter
Elsevier Global Medical News
Breaking News

Antimicrobial prophylaxis now should be administered within 60 minutes of the start of a cesarean delivery, rather than after cord clamping, which has been the preferred time for administration.

The recommended change in practice comes from a new opinion released Aug. 23 by the American College of Obstetricians and Gynecologists’ Committee on Obstetric Practice as Committee Opinion No. 465, “Antimicrobial Prophylaxis for Cesarean Delivery: Timing of Administration” (Obstet. Gynecol. 2010;116:791-2).

“Based on the latest data, prophylactic antibiotics given to pregnant women before a cesarean significantly reduce maternal infections and do not appear to harm newborns,” Dr. William H. Barth Jr., chair of the committee, said in a statement.

“Anytime you have invasive surgery, you have an increased risk of developing an infection at the incision site,” he said in the statement. Infection is the most common complication of cesarean delivery and can occur in an estimated 10%-40% of women who undergo cesarean delivery, compared with 1%-3% of women who deliver vaginally, according to ACOG.

The committee recommends antimicrobial prophylaxis for all cesarean deliveries unless the patient is already receiving appropriate antibiotics. When it is not possible to begin administration within 60 minutes of the first incision – as with emergent delivery – prophylaxis should be administered as soon as possible.

Antimicrobial prophylaxis has been a common practice for cesarean deliveries. However, intraoperative antibiotics have been administered after umbilical clamping due to concerns about neonatal exposure to antibiotics. In particular, it has been theorized that antibiotics in neonatal serum could mask positive bacterial culture results in newborns and that fetal antibiotic exposure could lead to increased newborn colonization or infection with antibiotic-resistant organisms.

Older studies had suggested that when prophylactic antibiotics were given before the cesarean, pediatricians tended to do more invasive neonatal sepsis evaluations and costs were increased, Dr. Barth said in an interview. “This was based on the fear that the antibiotics given to the mother would cross rapidly to the fetus and then mask the signs of infection in the newborn child.” Pediatricians feared that the usual signs of sepsis might be masked by these antibiotics. Given this fear, tests such as blood draws and lumbar punctures that are useful in making a diagnosis of newborn sepsis tended to be used more frequently.

“However, based on recent randomized clinical trials and systematic reviews, giving the mother the antibiotics before the cesarean incision does not appear to increase problems in the newborn. None of the studies were large enough to say that definitively, but given the overall benefit to the mother, our committee – which included pediatricians – felt that this was the right thing to do,” said Dr. Barth, chief of maternal-fetal medicine at Massachusetts General Hospital, Boston.

In fact, preoperative antimicrobial prophylaxis “does not appear to have any deleterious effects on mother or neonate,” the committee wrote. Timing really does make a difference. In the studies reviewed, preoperative administration significantly reduced the rates of endometritis and total maternal infectious morbidity, compared with administration after cord clamping. Just as importantly, preoperative administration was not associated with an increase in neonatal infectious morbidity or the selection of antimicrobial-resistant bacteria causing neonatal sepsis.

The committee recommends that the infusion be timed so that a bactericidal serum level is reached by the time of skin incision. Therapeutic antibiotic levels should be maintained throughout the operation. Readministration is indicated at intervals of one or two times the half-life of the drug during longer procedures.

The committee recommends using narrow-spectrum drugs that are effective against gram-positive and gram-negative bacteria and against some anaerobic bacteria – such as first-generation cephalosporins. Notably, obese women may require doses larger than the recommended 1 gram intravenous cefazolin (with a therapeutic dose maintained for 3-4 hours). Clindamycin with gentamicin is an acceptable alternative for women with significant allergies to beta-lactam antibiotics.

Dr. Barth said he had conflicts of interest to disclose.

Subject Codes:
top_stories; womans_health; emergency_trauma;


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August 23, 2010   05:00 PM EDT

By Heidi Splete
Elsevier Global Medical News
Breaking News

Memantine might improve behavioral symptoms and reduce brain deterioration in patients with mild to moderate Lewy body dementia, but not Parkinson’s disease dementia, based on data from a randomized, placebo-controlled trial.

The higher amount of Alzheimer’s disease–like amyloid pathology that is normally observed in patients with Lewy body dementia (DLB) might explain why the drug appears to provide symptomatic relief to that group but not to patients with Parkinson’s disease dementia (PDD), in whom amyloid pathology is encountered less often, Dr. Murat Emre of Istanbul (Turkey) University and his colleagues reported online Aug. 23 in the Lancet Neurology.

Dr. Emre and his coauthors conducted the study of memantine, which is approved for the treatment of moderate to severe Alzheimer’s disease, because previous studies had suggested that the drug might yield similar benefits in patients with Lewy body–related dementias such as PDD or DLB, which have some overlap in clinical presentation and pathology.

The researchers randomized 78 patients with DLB and 121 patients with PDD to a 20-mg dose of memantine once daily or a placebo. Concomitant use of cholinesterase inhibitors was not allowed (Lancet Neurology 2010 Aug. 23 [doi:10.1016/S1474-4422(10)70194-0]).

Patients were assessed when they were screened, at baseline, and at weeks 4, 12, 16, and 24. The study included patients from 30 sites in Austria, France, Germany, the United Kingdom, Greece, Italy, Spain, and Turkey. The average age of the patients was 74 years, and almost 100% were white.

In DLB patients, memantine significantly improved scores on the ADCS-CGIC (Alzheimer’s Disease Cooperative Study–Clinical Global Impression of Change) scale from baseline to 24 weeks, compared with placebo (mean change from baseline, 3.3 vs. 3.9, respectively). In addition, NPI (Neuropsychiatry Inventory) scores improved significantly more from baseline to 24 weeks in memantine-treated patients than in placebo-treated patients (mean change from baseline, –4.3 vs. 1.7, respectively).

Among PDD patients, memantine did not significantly change scores with either measurement, compared with placebo.

“Memantine might exert stronger beneficial effects in patients with more prominent Alzheimer’s disease–type pathology,” the investigators wrote. The differences in effects between DLB and PDD patients also could be accounted for by the range in symptoms and in concomitant drug use between these two patient populations, they added.

The most commonly reported adverse events were falls and sleepiness, which were reported by no more than 10% of the patients in each group. A total of 11 patients (5 with DLB and 6 with PDD) in the memantine group and 12 patients in the placebo group (7 with DLB and 5 with PDD) withdrew from the study because of adverse events, which included two cases of stroke in the memantine group and two cases each of agitation, confusion, and tremor in the placebo group.

Two patients in each group were withdrawn early because they violated the study protocol by not taking any study drug. Another 16 patients in the memantine group and 20 patients in the placebo group withdrew during the study, leaving complete study data on 159 patients. The efficacy analysis included 97 patients in the memantine group and 93 patients in the placebo group.

The study was limited in part by its small sample size, but the low incidence of adverse events and improvements among DLB patients support the use of memantine as a treatment option for this subset of patients, the researchers said.

In an accompanying editorial, Dr. Laura Marsh of Baylor College of Medicine and the Michael E. DeBakey Veterans’ Affairs Medical Center, both in Houston, noted that definitive treatments for Lewy body dementias are lacking (Lancet Neurology 2010 Aug. 23 [doi:10.1016/S1474-4422(10)70208-8]). But she added that the findings from the study by Dr. Emre and colleagues showed that memantine significantly improved global status scores in patients with Lewy body dementia in particular.

The study was funded by Lundbeck, a manufacturer and distributor of memantine. Dr. Emre and some of his coauthors disclosed financial relationships with Lundbeck and other pharmaceutical companies. One author is an employee of Lundbeck. Dr. Marsh has received funding from Forest Research Institute to study the effects of memantine on the treatment of dementia in Parkinson’s disease.

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


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August 22, 2010   06:30 PM EDT

By Michele G. Sullivan
Elsevier Global Medical News
Breaking News

CHICAGO (EGMN) – A drug that targets metastatic melanoma with mutations in the BRAF oncogene may be the first step on a path to individualized chemotherapy for patients with these formerly untreatable cancers.

“We are rapidly unraveling the molecular underpinnings of these tumors, and discovering the mechanisms by which they drive melanoma growth. These insights allow us to develop and select drugs on the basis of every patient’s individual genome,” Dr. Hensin Tsao said at the American Academy of Dermatology’s Academy 2010 meeting.

PLX4032 is the first drug to successfully shrink both cutaneous and internal metastases of BRAF-mutated melanomas, said Dr. Tsao, a dermatologist who is director of the Massachusetts General Hospital Melanoma Genetics Program in Boston. His colleague, Dr. Keith Flaherty, is about to publish data from the drug’s phase II trial of 87 patients; 81% of those with the BRAF-mutated melanoma responded with a 30% or more shrinkage of the targeted lesions.

After a phase I safety and dose-finding trial, investigators settled on an oral dose of 960 mg twice daily for the phase II study. The effect was little short of remarkable, Dr. Flaherty, director of developmental therapeutics at the Massachusetts General Hospital Cancer Center, said in an interview.

“My first responding patient had cutaneous and internal metastases, and the cutaneous metastases were clearly getting better right in front of our eyes,” he said. “We have seen this in some other areas of cancer, but never in melanoma, which before this was a clinical scenario with an unmet need for therapy.”

PLX4032, first engineered by the Berkeley, Calif., company Plexxikon Inc. and being developed in partnership with Roche, is not a foolproof cure, Dr. Tsao said in an interview. “It’s clearly a huge leap forward for the patients who responded so rapidly, yet most are still progressing despite being on the drug. It’s the best stun we’ve ever seen for melanoma, but it’s not a permanent kill.”

Sustained response in the phase I and II trials has varied from only 2 months to up to 2 years, Dr. Flaherty said. He could find no significant predictors of progression or response among the group except for initial tumor number and size. Typically, he said, the patients with the greatest mass of metastatic disease had the shortest duration of response, while those with a smaller tumor burden had a longer duration of response.

“When you have metastatic melanoma, your days are numbered – and numbered in a way we can’t predict when metastatic disease is diagnosed,” Dr. Flaherty said. “What this therapy does is push out the time until the disease worsens. We are not yet smart enough to understand what it is that allows a tumor to work its way around the drug’s activity.”

Chemotherapy-resistant cancers are nothing new, Dr. Tsao noted. What will be new is the full investigation of melanoma’s genetic pathways, and the development of drugs to block them in multiple ways. “The next frontier will be to understand all the ways that melanoma can outsmart treatment. We may have to use multiple therapies to corner it. So a full discovery of all melanoma’s potential vulnerabilities is very important.”

There is already at least a hint that PLX4032 has a very narrow target – only BRAF tumors with the V600E subtype. “There is some laboratory evidence that if you give this drug to a tumor that may be mutated at another gene you may be worsening things,” Dr. Tsao said. “This has yet to be borne out in clinical studies, but bench-side data suggest that you have to be very precise with this drug, because the wrong choice could be potentially deleterious.”

In vitro and in vivo experiments did suggest that PLX4032 was ineffective against non-BRAF melanomas, Dr. Flaherty said. “In a lab, the drug will kill a cancer cell with a BRAF mutation but not with another mutation. Whether it can facilitate the growth of others is an interesting concept supported by some laboratory data, with the observation that this and drugs like it can transiently stimulate other cancer cells with RAS mutations. In these, the drug basically activates the BRAF pathway instead of blocking it. We don’t know the relevance of this finding to humans. It is interesting, but it may have no real clinical impact.”

Discovering the best targets for molecular therapies is typically a long process, Dr. Tsao said, but the race to treat BRAF metastatic melanoma has so far been a fast one. “In 2002, the first BRAF mutation in melanoma was published, and the first drug is already coming to clinical fruition. This is pretty fast for something we’ve been fooling around with ineffectively for 20 years.”

During the 8 years between the mutation’s discovery and Dr. Flaherty’s trial, drug companies have not been idle. “There is now a pipeline of drugs against BRAF. PLX4032 might not be the best or the least toxic, but it’s the first of a host coming down the pike. This is very significant, because now we have a brand-new way of looking at a previously untreatable cancer.”

Roche Pharmaceuticals and Plexxikon sponsored the PLX4032 studies. Dr. Tsao said he had no financial declarations with regard to the drug. Dr. Flaherty has served as a consultant to Roche regarding further development of PLX4032 in melanoma.

Subject Codes:
top_stories; OncologyEX; new_drugs; dermatology;


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August 20, 2010   01:33 PM EDT

By Elizabeth Mechcatie
Elsevier Global Medical News

BETHESDA, Md. (EGMN) – In a split vote, a Food and Drug Administration advisory panel voted 8-6 that the approved pain indications for duloxetine be expanded to include a broader population of patients with chronic pain, at a meeting on August 19.

However, in separate votes, the panel specifically recommended approving the drug for chronic low back pain but not for management of chronic pain from osteoarthritis.

At the meeting of the FDA’s Anesthetic and Life Support Drugs Advisory Committee, the two adult patient populations considered for the expanded approval, based on data from five clinical studies submitted by duloxetine manufacturer, Eli Lilly and Co., were for those with chronic low back pain and those with chronic pain related to osteoarthritis.

Those voting in favor said that they believed the drug could be a valuable treatment for patients with these conditions, while those who did not support approval cited concerns that included questions about the strength of the studies that were conducted.

But in two other separate votes, the panel split on whether the data from the 12-13 week long clinical trials in the two groups of patients provided adequate evidence of efficacy for the two indications: The panel voted 8-5 with 1 abstention that the clinical data provided enough evidence that duloxetine was effective in managing chronic low back pain. The majority of panelists were not convinced by the data on the osteoarthritis pain indication, voting 9-4 with 1 abstention, that the two studies in OA patients did not provide adequate evidence that duloxetine was an effective treatment for chronic pain due to osteoarthritis – largely because only one of the two studies found that treatment was significantly more effective in alleviating pain, compared with placebo.

Duloxetine, a serotonin and norepinephrine reuptake inhibitor (SNRI) marketed as Cymbalta by Eli Lilly, was previously approved for two other pain indications, pain associated with diabetic peripheral neuropathy (2004) and fibromyalgia (2008). It was first approved in 2004 for major depressive disorder, and was also approved for generalized anxiety disorder (2007).

Representatives of Eli Lilly maintained that duloxetine can provide pain relief via a mechanism that is different from opioids and NSAIDs, and that the efficacy of duloxetine in the studies of patients with OA and chronic low back pain was “at least comparable” to existing treatments.

In the three studies of about 1,000 patients with chronic low (nonradicular) back pain (median age was 51-54 years), the average pain severity decreased more in those on 60 mg or 120 mg of duloxetine in all three studies, compared with placebo; the difference was significant in two of the studies. In the two studies of almost 500 patients with osteoarthritis (median age was 62-63 years), the intensity of pain decreased more in those patients on duloxetine, compared with those on placebo, but the difference was significant only in one study, in which patients were allowed to stay on NSAIDs and acetaminophen.

No new safety issues, other than those already included in the label, surfaced during the studies. Duloxetine can cause increases in aminotransferase levels, and a statement added to the label’s warnings and precautions section when the drug was approved for fibromyalgia in 2008 notes that there have been reports of hepatoxicity, sometimes fatal, in patients treated with duloxetine and recommends that treatment be stopped in patients who become jaundiced or have other signs of clinically significant liver dysfunction.

The potential for hepatoxicity was the main safety issue reviewed by the panel, which voted 9-4 that the drug’s safety profile and overall risk-benefit profile supported expanding the approval.

All but two of the panel members did not believe there was evidence that the 120-mg dose was more effective than the 60-mg dose, largely because there were not enough data on the higher dose.

National outpatient prescription data (in retail settings) presented by the FDA indicated that nearly two-thirds of duloxetine use is off label and that 14% of the use of the off-label use is for pain conditions such as musculoskeletal system and connective tissue diseases (7.3%) and headaches and nerve pain (6.5%).

The FDA usually follows the recommendations of its advisory panels. Panel members have been cleared of potential conflicts related to the topic of the meeting, although in some cases, a waiver is granted to a panelist.

Subject Codes:
top_stories; orthopaedics; general_primary; pain; rheumatology; gerontology;


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August 19, 2010   06:27 PM EDT

By Cathy Dombrowski
“The Pink Sheet”
Breaking News

The ability of separate Risk Evaluation and Mitigation Strategies to prevent medication errors when the same active ingredient is marketed under two brand names will be a central question presented to Food and Drug Administration advisory committees on Aug. 20.

The agency will ask the committees to address the issue as they assess an indication for Jazz Pharmaceuticals’ sodium oxybate to treat fibromyalgia. The drug was approved in 2002 as Xyrem for the treatment of cataplexy in patients with narcolepsy, and in 2005 for the treatment of excessive daytime sleepiness in those patients. It is a schedule III central nervous system depressant with hypnotic properties and the potential for misuse and abuse.

For the fibromyalgia indication, the company is proposing to use the trade name Rekinla, and to manufacture the drug, which is an oral solution, in a concentration (375 mg/mL) different from that of Xyrem (500 mg/mL).

The occurrence of medication errors with other drugs that share a common active ingredient and have different brand names raises concerns about the safety of this approach, according to FDA briefing documents. Among the concerns is the possibility of dose calculation errors due to the new concentration.

Expanding use to the fibromyalgia population “will almost assuredly increase the likelihood of abuse and misuse or unintentional exposure” of other household members to the drug, the risk management review team from the FDA’s Office of Surveillance and Epidemiology points out.

Jazz Pharmaceuticals proposes to address risk with individual Risk Evaluation and Mitigation Strategies (REMS) programs for each indication. But the two REMS, with two enrollment forms and separate pharmacy dispensing programs for each indication, “may be confusing for prescribers, pharmacies, and patients and may be burdensome to the health care system,” the review team says.

The safety reviewers concede they are unaware of medication errors occurring when an active ingredient with two names is marketed under a restricted distribution program that closely monitors patients, and this “lessens our concern to some extent.”

But, the team adds, success in mitigating risk depends on timely communication between the various distribution parties and a fully integrated database of patients and prescribers. The information provided by Jazz does not make clear “whether the two REMS programs are able to achieve these goals.”

Xyrem currently is managed through a Risk Minimization Action Plan (RiskMAP) known as the Patient Success Program, in which a single pharmacy is authorized to dispense the medication, and patients and prescribers are enrolled in the safety program. The RiskMAP was “deemed” by the FDA to be a REMS under the FDA Amendments Act, requiring Jazz to propose an actual REMS, which the FDA currently is reviewing.

The REMS proposal for Rekinla is similar to the program for Xyrem, but 15 pharmacies would be authorized to handle the drug. A pharmacy could not stock both products, and prescribers would have to enroll in both programs if they treat patients in both disease categories.

Each REMS would have its own function to verify prescriber and patient eligibility and to validate prescriptions. A data coordinating center would be created to consolidate data to ensure that patients are not receiving drugs for both indications, and to track use.

Elsevier Global Medical News and “The Pink Sheet” are published by Elsevier.

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


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August 19, 2010   01:56 PM EDT

By Denise Napoli
Elsevier Global Medical News
Breaking News

Vaccination coverage among U.S. teens increased nationally by as much as 15% in 2009, compared with 2008, but there is still room for improvement.

The finding, released Aug. 19 from the Centers for Disease Control and Prevention’s MMWR, draws on data from adolescents aged 13-17 years who participated in the National Immunization Survey for Teens, which has been conducted every year since 2006.

To gather the data for the survey, parents of teens were contacted randomly by telephone and were asked for permission to contact the child’s provider for vaccination histories. This year’s national survey included 20,066 individual records from all 50 states, plus the U.S. Virgin Islands (MMWR 2010;59:1018-23).

According to the report’s authors led by Dr. Christina Dorell of the CDC’s National Center for Immunization and Respiratory Diseases, coverage with one or more doses of the Tdap vaccine (tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine) increased significantly from 41% of all U.S. teens in 2008 to 56% in 2009.

There was also a significant rise in coverage of the meningococcal conjugate vaccine (MenACWY), from 42% coverage in 2008 to 54% in 2009.

And, among females, there were similarly significant jumps both in the percentage of girls receiving at least one dose of the human papillomavirus (HPV) vaccine – from 37% to 44% – as well as girls receiving all three recommended doses, from 18% to 27%.

Nevertheless, there were some areas of stagnation. For example, coverage with two or more doses of the measles, mumps, rubella (MMR) vaccine was not significantly different from coverage during 2008 (89.1% in 2009 and 89.3% in 2008).

Looking at chickenpox, in 2009, “75.7% had protection from varicella disease (i.e., history of varicella or received [two or more] doses of VAR),” wrote the authors, up from 73.5% in 2008—an insignificant increase.

And coverage with three or more doses of the hepatitis B vaccine increased only slightly (although significantly), from 88% to 90%.

The report also breaks down vaccination according to state, with Mississippi coming in dead last for coverage with one of more doses of the MenACWY vaccine (19%), with one or more doses of Tdap (23%), and one or more doses of the HPV vaccine (23%).

Dr. Anne Schuchat, director of the CDC’s National Center for Immunization and Respiratory Diseases, called the 2009 data “mixed” in an accompanying CDC press release. A complete breakdown of vaccination rates by state and nationally, going back to 2006, is available at the CDC.

“We can see that more parents of adolescents are electing to protect their children from serious diseases such as pertussis, meningitis, and cervical cancer, but there is clear room for improvement in our system’s ability to reach this age group,” she said. For example, “Pertussis outbreaks in several states and an increase in pertussis-related infant deaths in California highlight how important it is for preteens to receive the Tdap booster.”

Subject Codes:
infectious; top_stories; dermatology; pediatrics;


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August 19, 2010   01:26 PM EDT

By Mary Ellen Schneider
Elsevier Global Medical News
Breaking News

The heat is a serious hazard for teenage athletes that each year results in more than 9,000 illnesses nationwide, according to a heat illness analysis from the Centers for Disease Control and Prevention.

Nearly 71% of those heat-related illnesses occurred among high school football players. They experienced time-loss heat illness – dehydration, heat exhaustion, or heat stroke that resulted in at least 1 day of missed sports – about 4.5 times per 100,000 athlete exposures. That rate is 10 times greater than the average rate for eight other common high school sports. Football players also were more likely to experience a heat-related illness if they were overweight or obese. About 37% of high school football players who were affected by the heat were overweight, and nearly 28% were obese, according to the CDC.

The study, which is the first to report national estimates for time-loss heat illness among high school athletes, was published Aug. 19 in the Morbidity and Mortality Weekly Report (MMWR 2010; 59:1009-13). The researchers used information from the National High School Sports-Related Injury Surveillance Study and specifically analyzed data on 100 high schools from 2005 to 2009. The researchers used those data to produce national estimates.

Many high schools begin preseason sports training in August, which appeared to be the worst month for heat-related illnesses among teen athletes: 66% of illnesses occurring in that month. Time-loss heat illnesses also were more likely to occur during practice than competition, although that is likely because teams spend more time practicing in August, the researchers noted.

The heat-loss illness estimates are conservative and might underestimate the risk to teenage athletes, the investigators said, because the data don’t include heat illnesses in which an athlete was cleared to return to practice the next day. The study also was limited to nine sports and included only schools with certified athletic trainers who were affiliated with the National Athletic Trainers’ Association (NATA).

The researchers urged athletes and coaches to heed existing recommendations from NATA for preventing and treating heat-related illnesses. Those include providing a 14-day acclimatization period during warm-weather sports training, in which the frequency, duration, and intensity of training is increased gradually.

NATA also recommends that athletes be educated about heat-related illnesses and the need for proper hydration before, during, and after sports.

Subject Codes:
top_stories; sports; pediatrics; general_primary; emergency_trauma;


http://www.imng.com


August 19, 2010   12:22 PM EDT

Almost 71% of heat-related illnesses reported in a new analysis occurred among high school football players. Photo: Copyright Fred Hall/iStockphoto.com

By Denise Napoli
Elsevier Global Medical News
Breaking News

Early palliative care in metastatic non–small cell lung cancer led to better quality of life, fewer depressive symptoms, and longer survival, compared with standard therapy, according to the findings of a randomized, controlled trial.

The results “offer great promise for alleviating distress in patients with metastatic disease and addressing critical concerns regarding the use of health care services at the end of life,” Dr. Jennifer S. Temel of Massachusetts General Hospital, Boston, wrote in the Aug. 19 New England Journal of Medicine.

Dr. Temel and her colleagues’ study involved 151 ambulatory patients with newly diagnosed (within 8 weeks) metastatic non–small cell lung cancer seen at MGH between June 7, 2006 and July 15, 2009 (N. Engl. J. Med. 2010;363:733-42).

A total of 77 patients were randomly assigned to the early palliative care group; they met with board-certified palliative care physicians and advanced-practice nurses within 3 weeks of study enrollment and monthly thereafter until death.

“Additional visits with the palliative care service were scheduled at the discretion of the patient, oncologist, or palliative care provider,” wrote Dr. Temel, with all visits thoroughly documented and conducted according to the guidelines set forth by the National Consensus Project for Quality Palliative Care.

The palliative care team assessed the patient from both a physical and psychosocial standpoint, established “goals of care,” helped with decisions regarding treatment, and coordinated patient care “on the basis of the individual needs of the patient.”

The 74 patients assigned to the standard care group did not meet with the palliative care service team unless a meeting was requested by the patient, the family, or the oncologist.

All patients continued to receive routine oncologic care throughout the study.

Both groups had a mean age of 65 years, roughly half were female, and nearly 100% were white.

At baseline, there were no significant differences between groups on any of the outcome measures studied, including the Functional Assessment of Cancer Therapy–Lung (FACT-L) scale (scored from 0-136, with higher scores indicating better quality of life); the Lung-Cancer Subscale (or LCS, scored from 0-28, with higher scores meaning fewer symptoms); or the Trial Outcome Index (TOI), (scored from 0-84, with higher scores indicating better quality of life).

According to Dr. Temel, the average number of palliative care visits in the early palliative care group was four (range, zero to eight), with all patients having at least one visit by 12 weeks follow-up (except one patient who died within 2 weeks of enrollment).

Among the standard care group, there were 10 patients (14%) who had a palliative care consultation in the first 12 weeks – 7 of these patients had just the one visit, while the remaining 3 had two.

By 12 weeks, the 47 patients remaining for analysis in the standard care group had a mean FACT-L score of 91.5. In comparison, the 60 patients in the treatment group had a mean score of 98, indicating a significant moderate effect.

A significant difference between groups also was seen on the lung cancer subscale of the FACT-L. At 12 weeks, the standard treatment group had a mean LCS score of 19.3, compared with 21 in the early palliative care group, which indicated a significant moderate effect.

The most significant between-group difference was seen on the Trial Outcome Index score. By 12 weeks, the standard treatment group’s mean score was 53.0, compared with 59 in the palliative care group.

“In addition, the percentage of patients with depression at 12 weeks ... was significantly lower in the palliative care group than in the standard care group,” wrote the authors, though they added that the proportions of patients receiving new antidepressant prescriptions were similar in the two groups (roughly 18%).

Finally, the authors found a significant – and surprising – difference in survival among groups.

“Despite receiving less-aggressive end-of-life care, patients in the palliative care group had significantly longer survival than did those in the standard care group” (median survival 11.6 months vs. 8.9 months), they wrote.

The authors conceded that the generalizability of their study findings were limited by the fact that it was performed at a single, tertiary care site on patients with one specific type of cancer, and they added that the demographically homogenous sample also limits the applicability of these data to other populations.

However, “the results nonetheless offer great promise for alleviating distress in patients with metastatic disease and addressing critical concerns regarding the use of health care services at the end of life,” they wrote.

According to Dr. Ann S. Kelley and Dr. Diane E. Meier, who wrote in an editorial that accompanied the study, the results show that palliative care is appropriate and potentially beneficial when it is introduced at the time of diagnosis of a serious or life-limiting illness – at the same time as all other appropriate and beneficial medical therapies are initiated.

“Unfortunately, physicians tend to perceive palliative care as the alternative to life-prolonging or curative care – what we do when there is nothing more that we can do – rather than as a simultaneously delivered adjunct to disease-focused treatment,” wrote Dr. Kelley and Dr. Diane E. Meier, both of the Mount Sinai School of Medicine, New York.

The specific components of the study’s palliative care intervention remain unspecified and hence may not be easily reproducible in other practice settings. For example, the salutary effect of additional time with and attention from health care providers and physicians, as opposed to a specific benefit derived from palliative care itself, was not assessed.

Moreover, the reasons for the 2.7-month survival benefit in the palliative care group – a benefit that is equivalent to that achieved with a response to standard chemotherapy regimens – are unknown.

Nevertheless, the study by Temel et al. represents an important step in confirming the beneficial outcomes of a simultaneous care model that provides both palliative care and disease-specific therapies beginning at the time of diagnosis.

The study was supported by the American Society of Clinical Oncology, the Joanne Hill Monahan Cancer Fund, and Golf Fights Cancer. Dr. Temel reported receiving payment for developing continuing medical education programs on behalf of InforMEDical. Another author reported serving on the board of Infinity Pharmaceuticals, receiving consulting fees from numerous drug makers, and developing CME programs for InforMEDical.

Dr. Kelley and Dr. Diane E. Meier were not involved with this study and stated that they had no conflicts of interest to disclose.

Subject Codes:
top_stories; OncologyEX; general_primary; pulmonology;


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August 18, 2010   05:00 PM EDT

Diane Meier

By Denise Napoli
Elsevier Global Medical News
Breaking News

Twice-weekly tai chi exercises led to a statistically significant decrease in fibromyalgia symptoms, compared with wellness education and stretching.

The finding, published online Aug. 18 in the New England Journal of Medicine, is consistent with other studies that have shown the benefits of tai chi for fibromyalgia as well as pain, depression and overall quality of life (N. Engl. J. Med. 2010;363:743-54).

Dr. Chenchen Wang of the division of rheumatology at Tufts Medical Center, Boston, and colleagues looked at patients seen at Dr. Wang’s facility between July 2007 and May 2009. All patients were at least 21 years old and met American College of Rheumatology (ACR) 1990 diagnostic criteria for fibromyalgia, including “history of widespread musculoskeletal pain on the right and left sides of the body as well as above and below the waist, with a minimum duration of 3 months, and tenderness on pressure at 11 or more of 18 specific sites.”

Patients were excluded if they had any tai chi training or serious comorbidities such as rheumatoid arthritis or other conditions that might limit their mobility; if they were pregnant or planning on becoming pregnant; or if they scored less than 24 out of 30 points on the Mini Mental State Examination.

The primary end point was improvement on the Fibromyalgia Impact Questionnaire (FIQ), which scores symptoms from 1 to 100, with 100 being the worst.

Thirty patients completed a 12-week, twice-weekly, 60-minute tai chi program, plus a 24-week evaluation. Participants also were encouraged to practice at home for 20 minutes per day on their own, and “to maintain their tai chi practice, using an instructional DVD, up until the follow-up visit at 24 weeks.”

Meanwhile, 29 control patients completed a twice-weekly, 60-minute wellness education and stretching program, plus the 24-week follow-up. The program included a didactic portion on pain management strategies and nutrition, plus a portion devoted to stretching. Patients also were encouraged to stretch at home each day for 20-minute periods.

Both groups were predominantly female (greater than 85%) and had mean ages of 50 years and 51 years for the tai chi group and the control group, respectively. The mean baseline FIQ score in the tai chi group was 62.9, compared with 68.0 in the control group; the rate of attendance was 77% and 70% for the active treatment and control group, respectively.

According to Dr. Wang, by 12 weeks, the tai chi group had a significantly greater decrease in the total FIQ score, to 35.1 (–27.8 points, 95% confidence interval –33.8 to –21.8) compared with controls, who fell to 58.6 (–9.4 points , 95% CI, –15.5 to –3.4), for a between-group difference of slightly more than 18 points, P less than .001.

The improvement in symptoms held up at 24 weeks, with a change from baseline among the tai chi group of –28.6 points from baseline (95% CI, –34.8 to –22.4), compared with –10.2 among controls (95% CI, –16.4 to –4.0).

Similar to findings at the 12-week mark, that amounted to a between-group difference of more than 18 points, P less than .001.

Dr. Wang also looked at improvement in sleep, as measured on the Pittsburgh Sleep Quality Index, graded on a scale from 0 to 21, with higher score indicating poorer sleep.

At 12 weeks, the tai chi patients had reduced their score by 3.6 points from baseline, compared with 0.7 points for the control group (P less than .001); at 24 weeks, the tai chi practitioners had dropped their score by 4.2 points, compared with 1.2 among controls (P less than .007).

The researchers also saw significant improvement among tai chi patients on the physician global assessment score, the patient global assessment score, the 6-minute walk test, and both the physical and mental components of the Medical Outcomes Study 36-Item Short Form Health Survey.

Only patients’ body mass index and their scores on the Chronic Pain Self Efficacy Scale, which measures patients’ confidence in their ability to perform a particular task, did not change significantly, compared with controls.

The authors pointed out some limitations, including their inability to conduct a double-blind study, since it “would have required the use of sham tai chi, for which no validated approach currently exists,” though they recommended one be developed in the future.

Moreover, the authors stated that patients’ preexisting knowledge and attitudes about tai chi may have led to a placebo effect; to minimize this, they “informed participants only that the study was designed to test the effects of two different types of exercise training programs,” thereby deemphasizing the tai chi to “lessen participants’ expectations.”

In an editorial, Dr. Gloria Y. Yeh said that the study findings showing that tai chi lessened the severity of fibromyalgia symptoms are provocative and in line with findings from small studies of tai chi in other patient populations.

However, still other studies have shown mixed results, she wrote. For example, although an 8-week, randomized, controlled study of mindfulness meditation and tai chi–like movements, known as qigong, in 128 patients with fibromyalgia showed significant reductions in pain, disability, and depression, these improvements were no better than those seen in the control group, which received educational support (J. Rheumatol. 2003;30:2257-62).

Given this background, the positive results across all outcome measures reported by Dr. Wang and associates are striking, Dr. Yeh noted.

Nevertheless, questions remain: How much of the benefit of tai chi is due to a placebo effect? What is an appropriate control for tai chi? And what do these findings mean for clinical practice?

Going forward, replications of this study on a larger scale over longer periods of time are needed, with different practitioners and different styles at multiple sites, as well as determination of the optimal “dose” of tai chi, she said.

Additionally, research should focus on comparisons with similar therapies such as yoga, plus an assessment of cost-effectiveness.

Even so, the potential efficacy and lack of adverse effects now make it reasonable for physicians to support patients’ interest in exploring these types of exercises, even if it is too early to take out a prescription pad and write “tai chi” (N. Engl. J. Med. 2010;363:783-4).

Dr. Wang reported having no financial conflicts of interest. A coauthor reported financial relationships with Pfizer, Lilly, and Forest; several authors reported having received grants from the National Institutes of Health and the National Center for Complementary and Alternative Medicine, which cosponsored the study with the American College of Rheumatology and the Boston Claude D. Pepper Older Americans Independence Center.

Dr. Yeh is in the division for research and education in complementary and integrative medical therapies at Harvard Medical School, Boston, as well as the division of general medicine and primary care at Beth Israel Deaconess Medical Center, Boston. She cowrote the editorial with Mr. Ted J. Kaptchuk, also of Harvard and the division of general medicine and primary care at Beth Israel, and Dr. Robert H. Shmerling, of the division of rheumatology at Beth Israel. The investigators were not involved with this study and stated they had no disclosures relative to their editorial.

Subject Codes:
top_stories; general_primary; pain; rheumatology;


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August 18, 2010   05:00 PM EDT

Tai chi exercises led to improvement in fibromyalgia as well as benefits for pain, depression and overall quality of life. (Photo Copyright: Willie B. Thomas/iStockphoto.com)

By Mary Ellen Schneider
Elsevier Global Medical News
Breaking News

Delays in the time from first contact with the health care system to treatment with primary percutaneous coronary intervention are linked to mortality for patients with ST-segment elevation myocardial infarction, according to an historic follow-up study of more than 6,200 Danish heart patients.

The researchers found that a delay of up to 60 minutes between the time of first contact with emergency medical services (EMS) to the time when patients received guiding catheter insertion during primary percutaneous coronary intervention (PCI) resulted in a long-term mortality rate of 15.4%. When the delay increased to 61-120 minutes, the mortality rate rose to 23.3%. A delay of 121-180 minutes resulted in a long-term mortality rate of 28.1%, and a delay of 181-360 minutes had a rate of 30.8%. When the researchers adjusted for other predictors of mortality, the system delay was still independently associated with mortality, with an adjusted hazard ratio of 1.10 per 1-hour delay.

The study, which analyzed public medical databases for patients with ST-segment elevation myocardial infarction (STEMI) in western Denmark, was published Aug. 18 in JAMA (2010;304:763-71). The team of researchers was led by Dr. Christian Juhl Terkelsen of the department of cardiology at Åarhus (Denmark) University Hospital.

The study may be the first to examine the association between system delay and mortality in an unselected group of patients with STEMI who were transported by EMS and treated with primary PCI, according to the researchers. They analyzed records from 6,209 patients with STEMI or bundle-branch block myocardial infarction who were admitted for primary PCI between Jan. 1, 2002, and Dec. 31, 2008, at three western Denmark high-volume PCI centers. The median follow-up time was 3.4 years. In Denmark, primary PCI has been the recommended treatment for patients with STEMI since 2003.

The researchers also looked at the impact of treatment delay (the time from symptom onset to guiding catheter insertion) and patient delay (the time from symptom onset to contact with EMS). They found that neither of these measures was independently associated with mortality after adjusting for other mortality predictors. The lack of an association may be explained in part by selection bias, as data on patient and treatment delays are available only when the patient survives long enough to make contact with the health care system and only when the patient can recall the exact time of symptom onset, the researchers reported.

However, the elements of system delay – such as prehospital system delay (time from contact with EMS to arrival at the PCI center) and door-to-balloon delay (time from arrival at the PCI center to guiding catheter insertion) – were both associated with mortality.

Door-to-balloon delay has been suggested by some organizations, such as the D2B Alliance, as a quality indicator for STEMI patients who are treated with primary PCI. Although it may be an appropriate measure for PCI centers, the researchers concluded that system delay would be a superior measure for the health care system as a whole, as it encompasses more of the delays that can occur throughout the system. The other advantage of using system delay over other potential measures is that it applies both to patients who have been field-triaged directly from EMS to a PCI center, and to patients who were transferred from local hospitals.

“Increased focus on the total health care system delay may optimize triage of patients with STEMI and may be the key to further improving survival of these patients,” the researchers wrote.

The study was supported by grants from the Helga and Peter Komings Foundation in Denmark and the Health Research Fund of Central Denmark Region. The funders had no role in the design of the study or the preparation of the manuscript. One of the researchers reported receiving an unrestricted grant from Falck EMS, Denmark, for research unrelated to the current study. None of the other researchers reported financial disclosures.

Subject Codes:
top_stories; cardiology; emergency_trauma;


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August 17, 2010   04:00 PM EDT

By Sharon Worcester
Elsevier Global Medical News
Breaking News

The use of implantable gentamicin-impregnated collagen sponges did not reduce the sternal wound infection rate following cardiac surgery in a prospective, randomized, controlled trial of 1,502 patients who were at high risk of infection because of diabetes and/or obesity.

Dr. Elliott Bennett-Guerrero of Duke University in Durham, N.C., and his colleagues reported their findings Aug. 18 in JAMA.

The findings directly contradicted those of a 2005 Swedish study, which found that the sponges reduced surgical wound infections by 53%, and which served as strong preliminary data for the current trial (Ann. Thoracic. Surg. 2005;79:153-62).

The sponges are approved in 54 countries, and the current phase III study was designed to “confirm these promising data and support regulatory approval in the United States.” However, the overall wound infection rates at 90 days were statistically similar at 8.4% and 8.7%, respectively, in patients who received standard care plus surgical site implantation of two of the topical antibiotic sponges, and in patients who received standard care with no additional intervention, researchers found. There were 753 patients in the sponge group and 749 in the standard care group,

Like the overall wound infection rates, the superficial and deep sternal wound infection rates were also similar in the treatment and control groups, at 6.5% and 6.1%, and 1.9% and 2.5%, respectively. Additionally, no differences were seen between the treatment and control groups in regard to the rehospitalization rate for sternal wound infection (3.1% and 3.2%, respectively), or in ASEPSIS score (mean, 1.9 and. 2.0, respectively) the investigators found (JAMA 2010;304:755-62).

The ASEPSIS score is a measure of additional treatment, presence of serous discharge, erythema, purulent exudates, separation of the deep tissues, isolation of bacteria, and duration of inpatient stay. Points are assigned for each variable and the scale has a minimum score of 0, with no theoretical maximum, the investigators explained.

Patients in the single-blind study were enrolled at 48 U.S. centers between Dec. 21, 2007, and March 11, 2009. Those randomized to the treatment group underwent insertion of two sponges with a total gentamicin dose of 260 mg, which was the same dose used in the Swedish study. Both groups received standardized care with prophylactic systemic antibiotics and rigid sternal fixation, with the treatment group also undergoing implantation with the sponges.

The groups were balanced regarding baseline characteristics, including age, weight, diabetes, and smoking history, and also in regard to perioperative variables.

As for why the antibiotic sponges failed to reduce infection rates in this study as they did in the Swedish study, the investigators suggested that important quality control measures used in their study – but not in the Swedish study – might be to blame. They cited measures including on-site monitoring and source data verification, central adjudication of outcomes by an independent blinded committee, and the inclusion of a large number of hospitals (48 in the U.S. study, compared with 2 in the Swedish study).

The researchers also wrote that ethnic and regional differences, such as varying distribution of bacterial pathogens between countries, could also explain the differing outcomes. For example, no cases of methicillin-resistant Staphylococcus aureus occurred in the Swedish trial, but in the U.S. study 6.3% of patients had MRSA growth from sternal wound infection, which may not be sensitive to gentamicin.

“Thus, variations in the distribution of bacterial pathogens among countries could affect efficacy in a trial of infection prevention such as the present one,” they said, also noting that the findings underscore the importance of large validation trials, as “positive single-center trials are often not confirmed in larger multicenter trials.”

The U.S. study was sponsored by Innocoll Technologies Ltd., the maker of the gentamicin-collagen sponges, and Dr. Bennett-Guerrero reported that he is in discussions with Excited States LLC regarding a consulting agreement to advise on a clinical trial involving surgical wound infection prevention. Another author on the study, Dr. T. Bruce Ferguson Jr., reported receiving honoraria from Innocoll Technologies Ltd. for serving on a steering committee.

Subject Codes:
infectious; top_stories; diabetes; new_drugs; dermatology; endocrinology; cardiology; surgery;


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August 17, 2010   04:00 PM EDT

By Cathy Dombrowski
“The Pink Sheet”

Three years after it first threatened to end approval for midodrine, the Food and Drug Administration on Aug. 16 sent Shire and generic manufacturers of the drug a letter that sets the withdrawal process in motion.

Prompting the action is failure by Shire or generic sponsors – Apotex Inc., Impax Laboratories Inc., Mylan Inc., Sandoz Inc., and Upsher-Smith Laboratories – to submit studies verifying the orphan drug’s clinical benefit in treating symptomatic orthostatic hypotension.

Midodrine received accelerated approval as ProAmatine in 1996 based on the surrogate end point of increase in 1-minute standing systolic blood pressure. The approval was made under Subpart H, an FDA regulation that allows for “accelerated approval of new drugs for serious or life-threatening illness.”

Original license holder Roberts Pharmaceutical Corp. agreed to conduct the postapproval confirmatory studies, but 14 years later, they remain uncompleted. The 1996 approval letter estimated the time for completion at 3-4 years, depending on rate of enrollment. Shire acquired ProAmatine when the U.K. firm merged with Roberts in 1999.

The Aug. 16 letter details the FDA’s proposal to withdraw approval for midodrine and gives Shire 15 days to request a hearing on the proposal, and generic firms 30 days to submit comments.

This is the first time the FDA has issued such a notice. It is not, however, the first time a Subpart H drug has been withdrawn. Pfizer voluntarily decided to pull Mylotarg (gemtuzumab) for myeloid leukemia off the market after the confirmatory trial was halted early because of a high death rate; the drug had been approved for 10 years.

Earlier attempts to prod midodrine manufacturers into conducting additional studies proved unsuccessful. The FDA held a meeting with sponsors in March 2007 to advise them of the need to resolve the question of midodrine’s efficacy by conducting further studies, and followed up with an Aug. 7, 2007, letter warning of possible withdrawal.

The following year, in response to questions, the agency told the firms that labeling changes from new studies would be eligible for 3 years of exclusivity and, in August 2009, it sent a letter requiring the studies.

Shire has little incentive to conduct new trials since the entry of generics in 2003 cut into ProAmatine sales, but the disease area does seem to be an attractive – if challenging – one for orphan drug developers. The FDA says about 100,000 patients in the United States filled prescriptions for midodrine in 2009.

Chelsea Therapeutics Inc. is developing Northera (droxidopa) in neurogenic orthostatic hypotension, but late last year modified the primary end point and decided to enroll additional patients to increase the power of phase III study 301. Further investigation is needed following study 302’s failure to achieve statistical significance of. Top-line data from study 301 is expected in September.

Elsevier Global Medical News and “The Pink Sheet” are published by Elsevier.

Subject Codes:
top_stories; new_drugs; general_primary; cardiology;


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August 17, 2010   03:02 PM EDT

By Denise Napoli
Elsevier Global Medical News
Breaking News

Women who drink more than two drinks per week are significantly more likely to develop psoriasis than are women who abstain from alcohol.

Moreover, when stratified by type of alcohol consumed, it is full-calorie, non-light beer – not wine, liquor, or light beer – that appears to raise the risk for the skin condition, according to a study of over 82,000 women published online Aug. 16 in the Archives of Dermatology.

Dr. Abrar A. Qureshi, director of the Translational Research Resource Center in the department of dermatology at Brigham and Women’s Hospital, Boston, looked at 116,430 female registered nurses from the Nurses’ Health Study II (an ongoing longitudinal study begun in 1989).

The nurses were asked about whether they had ever had a diagnosis of psoriasis between 1991 and 2005, with 1991 being the first year in the study in which alcohol intake data patterns were assessed. Weekly drinking was also assessed in 1995, 1999, and 2003 (doi:10.1001/archdermatol.2010.204).

Overall, among the 47,614 women who responded to the survey and reported consuming alcohol, the mean age was 36 years. It was the same for the 35,058 abstainers who responded.

The only differences between the cohorts were that the abstainers had a slightly higher body mass index (BMI) and were less physically active; drinkers were more likely to smoke or have ever smoked.

Dr. Qureshi and his colleagues found that with adjustment for age only, there was a 1.89 relative risk of developing psoriasis among patients who reported drinking more than 2.3 drinks per week (95% confidence interval, 1.29-2.77).

When adjusted for age, smoking, BMI, dietary folate, and physical exercise, the risk dropped, but only slightly, to 1.72 (95% CI, 1.15-2.57).

Furthermore, when stratified by type of alcohol, having five or more glasses of non-light beer per week was the only beverage to be significantly associated with incident psoriasis, after the multivariate adjustment (RR 1.76; 95% CI 1.15-2.69). Five or more glasses of light beer, white wine, or red wine were not significantly associated with psoriasis, nor were two or more glasses per week of liquor.

Finally, the authors analyzed alcohol intake and confirmed psoriasis according to the Psoriasis Screening Tool questionnaire, a one-page, self-administered, seven-question survey sent to all study participants who reported prior psoriasis diagnosis.

Among this subgroup of confirmed cases, after the same multivariate adjustment used in the earlier analysis, the relative risk associated with any alcohol intake above 2.3 drinks per week was even more pronounced – 2.54 (95% CI, 1.57-4.10), and for 5 or more non-light beer drinks per week, it was 2.29 (95% CI, 1.36-3.85).

The authors postulated that beer’s gluten content could be the culprit, since gluten has been tied to psoriasis in prior studies, and beer is one of the few nondistilled alcoholic beverages to use a starch source for fermentation – barley, most commonly. However, light beer also is made with grain and therefore contains gluten, albeit lower amounts.

One major limitation of the study, according to Dr. Qureshi, is the retrospective recall of psoriasis onset, which might have led to misclassification of some psoriasis incidents. Additionally, the researchers wrote, “This well-educated female cohort provides high-quality data with little loss to follow-up but does not represent a random sample of U.S. women,” nor of alcohol consumption rates.

Nevertheless, they added, “the biological effects of alcohol intake on psoriasis should be similar.”

Dr. Qureshi disclosed serving as a consultant to pharmaceutical makers Amgen and Genentech; the study was funded by grants from the National Institutes of Health/National Cancer Institute.

Subject Codes:
top_stories; dermatology; general_primary; womans_health;


http://www.imng.com


August 16, 2010   04:00 PM EDT

A recent study shows that women who drink full-calorie, non-light beer have a greater risk of developing psoriasis. (Photo courtesy Len Rizzi /National Cancer Institute)

By Sharon Worcester
Elsevier Global Medical News
Breaking News

The need for diabetes medication therapy is eliminated in the majority of obese type 2 diabetes patients who undergo bariatric surgery, findings from a retrospective time-series study of 2,235 patients suggest.

At 6 months after bariatric surgery, 75% of patients were off their diabetes medication, and at 1 and 2 years after surgery, 81% and 85%, respectively, were off their diabetes medication, Dr. Martin A. Makary and his colleagues at Johns Hopkins University, Baltimore, reported in the August issue of Archives of Surgery.

The effects were seen across all six classes of diabetes medication, with the greatest reductions in use occurring in patients taking metformin. About 53% of patients used metformin 3 months prior to surgery, and only 8% used metformin 1 year after surgery, the investigators found (Arch. Surg. 2010;145:726-31).

Factors independently associated with elimination of diabetes medication were younger age (odds ratios of 2.93 for those aged 18-34 years, 2.20 for those aged 35-44 years, and 1.76 for those aged 45-54 years, relative to those aged 55-64 years), male sex (OR 1.27), and Roux-en-Y gastric bypass procedure (OR 1.63 relative to gastric banding and other restrictive procedures).

Factors associated with reduced likelihood of discontinuing diabetes medication after surgery were the use of multiple diabetes medications preoperatively (OR 5.59 and 2.24 for those using one and two medications, respectively, and relative to using three or more medications), and the presence of diabetes complications (OR 1.45).

Patients in the study included adults from seven Blue Cross/Blue Shield health plans who underwent bariatric surgery between Jan. 1, 2002, and Dec. 31, 2005.

Overall, surgery was safe. The in-hospital mortality rate was 0.3%, and readmission rates were 7.5% within 30 days and 21% in 1 year, which is comparable to rates previously reported in the literature, the investigators said.

Dr. Makary and his colleagues used administrative claims data to assess use of diabetes medications and annualized health care costs at specified time intervals before and after surgery.

The improvements in health, as evidenced by the reduction or elimination of diabetes medication, were associated with a reduction in health-related costs; compared with the $6,376 annual cost observed in the 2 years prior to surgery, total annual health care costs per person increased by 9.7% ($616) in the first postoperative year, but they decreased by 34% ($2,179) in year 2, and by 71% ($4,498) in year 3. The median cost of surgery and related hospitalization was $29,959.

“We believe that the reduction in overall annual health care costs realized represents the improved health associated with successful therapy for obesity and type 2 diabetes,” they said. The findings corroborate those from previous reports from single institutions, and from recent studies showing that surgery resulted in greater likelihood of remission of type 2 diabetes than did conventional diabetes management, they noted.

“We found an improved long-term mortality rate in the bariatric surgery group, compared with the nonsurgical group (9% vs. 28%). Furthermore, the resolution of type 2 diabetes was sustained at 1 and 2 years after surgery,” they said. “Because weight loss following bariatric surgery has been observed to be sustained for decades, we believe that the protective effect against complications of diabetes is also likely to be long-term.”

Health care providers should consider discussing bariatric surgery with obese patients with type 2 diabetes, and health insurers – both private and public – should pay for bariatric surgery for appropriate candidates, they concluded.

Additional research is needed to evaluate the effects of bariatric surgery on preventing acute and chronic diseases, as well as on common operations, maternal and neonatal outcomes, and long-term health outcomes, they said.

The investigators reported having no financial disclosures.

Subject Codes:
top_stories; gastroenterology; diabetes; general_primary; endocrinology; surgery;


http://www.imng.com


August 16, 2010   04:00 PM EDT

Martin Makary

By Denise Napoli
Elsevier Global Medical News
Breaking News

Roughly 20% of 12- to 19-year-olds in the United States have some form of hearing loss, up from 15% of adolescents surveyed between 1988 and 1994, a study published Aug. 18 in JAMA has shown.

That represents a significant 31% jump that is likely underestimated, according to Dr. Josef Shargorodsky of the Brigham and Women’s Hospital in Boston and his associates.

Dr. Shargorodsky, who is also of the Massachusetts Eye and Ear Infirmary, Boston, and his associates looked at data from the National Health and Nutrition Examination Survey (NHANES) 2005-2006 and compared them with data from NHANES III, conducted between 1988 and 1994. Both surveys provide nationally representative data on U.S. civilians aged 12-19 years, and both surveys included audiometry testing of both high- and low-frequency hearing (JAMA 2010;304:772-8).

A total of 2,928 NHANES III participants who had full data from a complete audiometry exam were included for analysis in the more recent study; there were 1,771 participants from NHANES 2005-2006 who had complete data. There were no differences between the groups in terms of age, race, sex, or poverty-income ratio, although NHANES III participants were more likely to have had a history of three or more ear infections.

Dr. Shargorodsky and his associates found that among NHANES III participants, surveyed between 1988 and 1994, the prevalence of any hearing loss greater than 15 dB among 12- to 19-year-olds was 15%. By the 2005-2006 survey, in contrast, that number had jumped to 20%, representing roughly 6.5 million individuals.

The increases persisted when the data were stratified by type of hearing loss. For example, 11% of NHANES III participants had unilateral hearing loss; by 2005-2006, that number had jumped to 14%. The same increase was repeated when looking only at bilateral hearing loss, with a prevalence of 4% during NHANES III and 5.5% in 2005-2006.

The investigators also found that high-frequency hearing loss (13% in 1988-1994, vs. 16% in 2005-2006) was more prevalent than low-frequency loss (6% in 1988-1994, vs. 9% in 2005-2006) in both time periods. However, only the change in high-frequency loss was significant.

Even more significant – and more troubling – was the increased prevalence of mild or worse hearing loss (25 dB or greater) in the 2005-2006 survey (as opposed to “slight” hearing loss of between 15 and 25 dB). That figure jumped from 3.5% to 5% – or more than 1 in 20 adolescents.

Dr. Shargorodsky and his associates pointed out some limitations to their study. For one, they wrote, “children whose hearing aids could not be removed, who could not tolerate earphones, or who had cochlear implants were not tested,” although this likely contributed to underestimation of hearing loss, if anything. Additionally, the study’s cross-sectional design could not assess causality.

“Interval factors between surveys, such as vaccination against Haemophilus influenzae and Streptococcus pneumoniae, as well as greater awareness of music-induced hearing loss, may have led to the expectation of no change or a reduction in the prevalence of hearing loss, but this was not observed,” the researchers said.

They offered no explanation for the increase, although they suggested that the effects of noise exposure on hearing loss deserve further study.

Dr. Shargorodsky and his associates reported having no disclosures relevant to this study, which was funded by the Massachusetts Eye and Ear Infirmary Foundation and the Vanderbilt University.

Subject Codes:
top_stories; orl; pediatrics; general_primary;


http://www.imng.com


August 16, 2010   04:00 PM EDT

By Sharon Worcester
Elsevier Global Medical News
Breaking News

The earlier an advanced biologic therapy is initiated in a patient with a diabetic foot ulcer, the sooner the wound is likely to heal, with first use of engineered skin resulting in the fastest healing, findings from a large retrospective cohort study suggest.

First use of an advanced biologic therapy occurred at a mean of 28 days in 2,517 patients who presented with a diabetic neuropathic foot ulcer between Jan. 1, 2001, and Dec. 31, 2004, and who were treated with at least one such therapy. Healing occurred at a median of 100 days, Dr. Robert S. Kirsner of the University of Miami and his colleagues reported in the August issues of Archives of Dermatology.

The advanced biologic therapies reviewed in this study included bi-layered living skin substitute (Apligraf), recombinant human platelet–derived growth factor (becaplermin [Regranex]), and platelet releasate (Procuren). Human fibroblast–derived dermal substitute (Dermagraft) was not commercially available at the start of the study and therefore was not included.

A total of 1,892 patients (75%) were treated with recombinant growth factor, 446 (18%) were treated with bi-layered living cell therapy, 125 (5%) were treated with platelet releasate, and 54 (2%) were treated with platelet releasate or recombinant growth factor followed by bi-layered living cell therapy.

Healing was faster in those who received engineered skin as the first advanced biologic therapy used (median of 84 days vs. 101 days for recombinant growth factor therapy and 108 days for platelet releasate, after researchers adjusted for confounding factors). In addition, healing was 31.2% more likely than when topical recombinant growth factor was used first, and 40% more likely than when platelet releasate was used first, the investigators found. The differences were statistically significant (Arch. Dermatol. 2010;146:857-62).

However, the median time to use of engineered skin was 6 weeks, compared with 4 weeks for platelet releasate and 3 weeks for recombinant growth factor, and 25% of wounds treated with engineered skin were not treated until after 24 weeks, the investigators said.

The delay in using engineered skin vs. the other biologic treatments might be related to cost concerns, they suggested, but they also noted that several studies have found that use of advanced biologic therapies reduced costs.

Longer time to healing after the first advanced biologic therapy was used was significantly associated with larger wound area, more severe wound grade, longer duration prior to first visit, and longer time from first visit to use of advanced biologic therapy. These associations were present across all treatment groups, the investigators said.

The findings are important because diabetic foot ulcers are a major complication of diabetes, affecting up to 15% of diabetic patients during their lifetime and accounting for 20% of all diabetes-related hospital admissions in the United States. Faster foot healing can reduce the incidence of amputation in diabetic patients, the investigators said.

Although the findings underscore the importance of appropriate treatment for the management of chronic diabetic foot ulcers, this study focused on usage patterns with advanced biologic therapies and did not compare outcomes with these therapies and with standard therapy. Because of this and other limitations of the study—including its retrospective nature and the lack of detail on wound history and therapy for some patients—the results “should not be used in isolation when making decisions regarding when to use adjuvant therapy in combination with standard care,” the investigators wrote.

Nonetheless, proper treatment is critical, and delays in providing that treatment will lengthen time to healing, they concluded.

This study was supported in part by Organogenesis, makers of Apligraf. Coauthor Laure Stasik reported that she was employed by Diversified Clinical Services during the study but is now employed by Organogenesis.

Subject Codes:
top_stories; diabetes; new_drugs; dermatology; general_primary; endocrinology;


http://www.imng.com


August 16, 2010   04:00 PM EDT

By Sharon Worcester
Elsevier Global Medical News
Breaking News

The risk profiles for individuals who develop single vs. multiple basal cell carcinoma lesions differ, according to findings from the Rotterdam Study.

Of the 10,820 eligible members of the two cohorts used for the large, Dutch, population-based study, 361 (3%) were diagnosed with a single initial basal cell carcinoma (BCC) lesion, and 163 (1.5%) were diagnosed with subsequent BCC lesions during the study period.

After adjusting for numerous factors such as sex, age, hair and eye color, tendency to develop sunburn, smoking history, body mass index, and educational level, factors found to be significantly associated with developing a first BCC lesion were age (odds ratios of 1.39 and 1.01 for those aged 65-74 years and for those aged 75 years and older, respectively, vs. those younger than age 65 years), and red hair color (OR of 1.98 for red vs. brown or black hair), Dr. Ville Kiiski and colleagues at Erasmus Medical Center, Rotterdam, the Netherlands, reported in the August issue of Archives of Dermatology.

After adjusting for age at index lesion, sex, hair color, eye color, all ultraviolet-related factors, smoking history, and alcohol consumption, the factors found to be associated with a significantly increased risk of developing multiple lesions were lesion location on an upper extremity (hazard ratio 1.49), age younger than 65 years (HRs of 0.58 and 0.65 for those aged 75 years and older and for those aged 65 to 74 years, respectively, vs. those younger than age 65 years), hair color (HR of 1.43 for red vs. brown/black hair), and education level (HR of 1.42 for high vs. low education level), the investigators found (Arch. Dermatol. 2010;146:848-55).

This last finding “may be explained by the probability that people with higher levels of education (which correlates strongly with socioeconomic status) have different lifestyles,” such as more frequent exposure to ultraviolet rays for intermittent periods, they said. Also, people of higher socioeconomic status generally may be expected to live longer and, thus have more time to acquire lesions.

Patients were adults aged 55 years or older from the two Rotterdam Study cohorts, including one studied in 1990, and one studied in 1999. Participants were followed for a mean of 9.5 years.

The findings – particularly regarding increased risk among younger patients and red-heads – largely support those of previous studies, although in the current study men were not shown to be at significantly increased risk of developing a first lesion, which contrasts with findings from some prior studies, the investigators noted.

The differences in risk factor profiles for those who develop single vs. multiple BCC lesions, as seen in the current study, may suggest that phenotypic characteristics of patients are less important for determining risk once “cumulative environmental-genetic interaction has surpassed a certain threshold and resulted in a lesion,” Dr. Ville Kiiski and colleagues wrote.

“The clinical relevance of this finding is that physicians’ risk assessment efforts should differentiate between patients at risk for a first lesion and those who have a history of BCC,” they said, noting that those with the identified risk factors for multiple lesions may require a more stringent follow-up regimen.

That’s not to say, however, that other BCC patients do not require follow-up. ��In this sample of the general population, more than 30% of the patients with BCC developed subsequent skin cancer, emphasizing the need for annual follow-up for several years,” Dr. Ville Kiiski and colleagues stressed.

Given that more than 1 million people are diagnosed with BCC in the United States each year, and given the strain that is put on limited specialized care by the need for follow-up of the large group of patients with BCCs, additional research is needed to better identify those at risk of developing multiple lesions, they concluded.

The investigators reported no financial disclosures relevant to their study.

Subject Codes:
top_stories; OncologyEX; dermatology;


http://www.imng.com


August 16, 2010   04:00 PM EDT

By Elizabeth Mechcatie
Elsevier Global Medical News

Ulipristal acetate, an emergency contraceptive that is effective for up to 5 days after unprotected intercourse, has been approved by the Food and Drug Administration.

The FDA announced the approval on August 13, less than 2 months after the FDA’s Reproductive Health Drugs Advisory Committee unanimously agreed that the selective progesterone receptor modulator was an effective emergency contraceptive with an acceptable safety profile, when used within 5 days of unprotected intercourse or a known or suspected contraceptive failure, which are the approved indication. The indication also includes the statement that ulipristal “is not intended for routine use as a contraceptive.”

Ulipristal will be available in the fourth quarter of this year, according to Laboratoire HRA Pharma, the French manufacturer of the drug. In the United States, ulipristal will be distributed by Watson Pharma Inc., and will be marketed under the trade name ella. It has been available in Europe since May 2009, where it is marketed as ellaOne.

Ulipristal will be available by prescription only, unlike levonorgestrel-based emergency contraceptives (Plan B or Next Choice), which are recommended for use for up to 72 hours after unprotected intercourse or contraceptive failure. In the United States, the levonorgestrel-based drug is available without a prescription to women aged 18 years and older.

The recommended dose of ulipristal is one 30-mg tablet taken as soon as possible within 120 hours (5 days) after unprotected intercourse or a known or suspected contraceptive failure, with or without food. The drug can be taken at any time during the menstrual cycle. A repeat dose should be considered if a woman vomits within 3 hours of taking the pill, according to the label.

The indication does not include a specific age group, which was one of the main areas of controversy that surrounded the approval of previous emergency contraceptives. In the ulipristal label approved by the FDA, the pediatric-use section states that the safety and efficacy of ulipristal have been established in women of reproductive age, and that “safety and efficacy are expected to be the same for postpubertal adolescents less than 18 years and for users 18 years and older.”

Approval was based on the results of two phase III studies of women aged 18 years and older (in the United States) or aged 16 years and older (in the United States and Europe). In both studies, women received 30 mg of ulipristal within 48-120 hours of unprotected intercourse, which resulted in a pregnancy rate that was significantly lower than the expected pregnancy rate.

In the first study, conducted in the United States, the pregnancy rate was 2.10%, which was significantly lower than the expected pregnancy rate of 5.53%. In the second study, conducted in the United States and Europe, the pregnancy rate among women who took ulipristal was 1.78%, compared with the expected rate of 5.54%; the pregnancy rate among those who took the levonorgestrel emergency contraceptive was 2.59%.

Ulipristal was less effective in women with a high body mass index (greater than 30 kg/m²).

The most common side effects in the trials included headache, nausea, abdominal pain, dysmenorrhea, fatigue, and dizziness, which are similar to the side effects associated with the levonorgestrel emergency contraceptive, according to the FDA statement.

Abortion opponents have described ulipristal, which is similar to mifepristone, as an abortion drug. But the label states that the “likely primary mechanism of action of ulipristal acetate for emergency contraception” is inhibiting or delaying ovulation by postponing follicular rupture when taken immediately before a woman ovulates. The statement adds: “However, alterations to the endometrium that may affect implantation may also contribute to efficacy.”

Mifepristone, which is also a selective progesterone receptor modulator, is approved for use with misoprostol, for medical abortion.

The drug’s label is available at http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/022474s000lbl.pdf.

Subject Codes:
top_stories; pediatrics; general_primary; endocrinology; womans_health; emergency_trauma;


http://www.imng.com


August 16, 2010   02:19 PM EDT

By Michele G. Sullivan
Elsevier Global Medical News
Breaking News

Clinicians who prescribe low-dose glucocorticoid therapy probably do not need to expand their monitoring of potential adverse events beyond the current standards of care, with a few exceptions, a European League Against Rheumatism task force has determined.

But investigators in clinical trials of low-dose glucocorticoid therapies should expand their detection and reporting of any adverse events (AEs) associated with the drug, because the paucity of existing data made it nearly impossible for the group to create any practical side-effect monitoring guidelines.

The EULAR task force charged with creating the document found that only 31 of 348 published studies on low-dose glucocorticoid (GC) treatment contained adequate information on adverse events. The results were so limited that the group could not create an evidence-based guideline, relying instead solely on consensus to make its recommendations.

The lack of data on three potentially serious AEs was most concerning, Dr. M.C. van der Goes and colleagues wrote in the Aug. 6 online edition of Annals of the Rheumatologic Diseases (Ann. Rheum. Dis. 2010 Aug. 6 [doi:10.1136/ard.2009.124958]).

“This exercise has shown that evidence on occurrence is scarce for several adverse events, such as ischemic cardiovascular disease, adrenal insufficiency, and skin atrophy,” wrote Dr. van der Goes of University Medical Center Utrecht (the Netherlands) and coauthors. “We want to emphasize the need for more evidence on these three AEs in particular and want to stimulate identifying at least one of these three items in future clinical trials on GCs with duration of at least 1 year.”

After reviewing the extant literature, the task force agreed that there is no need for clinicians to expand their AE monitoring beyond standard of care for patients taking up to 10 mg of prednisone or the equivalent daily, with the exception of adding observation of ankle edema, osteoporosis monitoring, fasting blood glucose levels, and glaucoma risk factors. They also specified that:

– Observing patients for ankle edema, along with the usual monitoring of blood pressure and symptoms of ischemic cardiovascular disease, is sufficient to detect any cardiovascular AEs.

– Questioning patients about gastrointestinal complaints is sufficient for monitoring GI AEs.

– Obtaining fasting blood glucose levels and regular weight measurements is sufficient to monitor for endocrine AEs.

– Following local guidelines for dual-energy x-ray absorptiometry and radiographs of the spine and questioning patients about fractures is sufficient to monitor for musculoskeletal AEs.

– Querying patients about ophthalmic risk factors, family history, myopia, and diabetes, along with an ophthalmologic exam if necessary, is sufficient to monitor for ophthalmologic AEs.

However, the authors wrote, the designers of low-dose GC clinical trials need to quickly ramp up their AE reporting. Additional testing at baseline, during, and at the end of trials should include tests for lipids, electrolytes, hypertension, infections, psychological symptoms, endocrine and metabolic markers, dermatologic occurrences (skin atrophy, acne, hirsutism or alopecia, and bruising), osteoporosis markers, symptoms of osteonecrosis, cataracts, and glaucoma.

“In future clinical trials with GCs, there should be extra interest and awareness in not only performing this monitoring, but also in reporting the results,” the task force wrote. “The results should be reported in a standardized way, even if no problem or increased occurrence of an AE has been found. This would enable future meta-analyses on GC-related AEs.”

Results should be reported as means both for the group and on an individual level, with specific patient numbers, the group emphasized.

“In clinical trials, for most AEs, monitoring is recommended at least at baseline and end for maximal feasibility and because data on the time to develop an AE are lacking. ... With relatively few efforts, a large body of data on occurrence of GC-related AEs can be created,” they concluded.

The task force was appointed and funded by EULAR. None of the authors reported any potential financial conflicts.

Subject Codes:
top_stories; general_primary; rheumatology;


http://www.imng.com


August 13, 2010   07:39 PM EDT

By Heidi Splete
Elsevier Global Medical News
Breaking News

A clinical trial of the weight-loss drug rimonabant that included more than 18,000 patients was terminated because of concerns about suicide risk and other psychiatric side effects. The results were published online Aug. 12 in the Lancet.

Rimonabant is designed to promote weight loss by blocking the endocannabinoid receptor, which has been shown to reduce appetite and improve metabolic risk factors, including HDL cholesterol, triglycerides, blood glucose, and fasting insulin, wrote Dr. Eric J. Topol of Scripps Translational Science Institute in La Jolla, Calif., and his colleagues.

To assess the impact of rimonabant on cardiovascular events, researchers designed the Comprehensive Rimonabant Evaluation Study of Cardiovascular Endpoints and Outcomes (CRESCENDO) trial. Between Dec. 22, 2005, and July 29, 2008, this double-blind, placebo-controlled trial enrolled 9,381 adults who were randomized to receive a 20-mg rimonabant tablet daily, and 9,314 adults who were randomized to a placebo. Average age was 64 years; 64% of each group was male. The average waist circumference was 112 cm (about 44 inches) in both groups (Lancet 2010;376:517-23).

When CRESCENDO was discontinued after an average of 14 months’ follow-up, significantly more patients in the rimonabant group compared with the placebo group developed gastrointestinal side effects (33% vs. 22%), neuropsychiatric side effects (32% vs. 21%), and serious psychiatric side effects (2.5% vs. 1.3%). In addition, four patients in the rimonabant group and one patient in the placebo group committed suicide during the study period.

“Because of rimonabant’s actions on the CNS, screening questions about neurological and psychiatric symptoms were asked at baseline, 1 month, 3 months, and then every 3 months for the duration of the trial, and a neurological examination was to be done at baseline,” the researchers said. Patients who showed symptoms were referred to a neurologist or mental health specialist.

The study’s primary end point – a composite of cardiovascular death, myocardial infarction, or stroke – occurred in 4% of patients in each group (364 events in the rimonabant group and 375 in the placebo group).

“In this setting, the performance of a long-term trial for an expanded cardiovascular indication was affected by the track record of the drug in clinical practice that was marketed for weight loss,” the researchers noted.

In an accompanying editorial, Dr. S. Matthijs Boekholdt and Dr. Ron J.G. Peters of the Academic Medical Center in Amsterdam noted that postmarketing registries of patients using the drug showed an increased risk of suicide, and that the European Medicines Agency’s decision to stop marketing authorization was appropriate. Although the study results suggested that endocannabinoid blockers could help manage obesity, concerns about side effects led the European Medicines Agency to stop the marketing authorization for rimonabant in Europe in 2008. The Food and Drug Administration denied approval of the drug in the United States in 2007.

Had the study been completed, a significant improvement in cardiovascular outcomes could have outweighed some side effects. “However, any mortality associated with cardiovascular preventive therapy is generally viewed as unacceptable,” Dr. Boekholdt and Dr. Peters wrote. “Focus should now return to motivating patients to control their caloric intake and increase physical activity” (Lancet 2010;376:489-90).

The study was sponsored by Sanofi-Aventis, the developer of rimonabant, and the primary study authors disclosed receiving research support, consulting fees, and/or honoraria from Sanofi-Aventis. Neither Dr. Boekholdt nor Dr. Peters had any financial conflicts to disclose.

Subject Codes:
top_stories; mental_health; diabetes; general_primary; endocrinology; cardiology;


http://www.imng.com


August 12, 2010   06:30 PM EDT

By Elizabeth Mechcatie
Elsevier Global Medical News
Breaking News

The antiepileptic drug lamotrigine has been associated with aseptic meningitis in children and adults treated with the drug, most of whom required hospitalization, the Food and Drug Administration announced August 12.

The FDA is advising clinicians who suspect a patient on lamotrigine may have aseptic meningitis to evaluate the patient for other possible causes and treat as indicated, but to discontinue the drug “if no other clear cause of meningitis is identified.” Lamotrigine, marketed as Lamictal by GlaxoSmithKline, is approved for treating seizures and bipolar disorder

In a statement, Dr. Russell Katz, director of the division of neurology products at the FDA, described aseptic meningitis as “a rare but serious side effect of Lamictal use.”

From December 1994, when lamotrigine was approved, through November 2009, 40 cases of aseptic meningitis in pediatric and adult patients taking the drug were reported to the FDA, with symptoms starting within one to 42 days of treatment initiation (mean of 16 days). Of the 40 affected individuals, 35 had to be hospitalized for treatment. In most cases, symptoms resolved after treatment was stopped. In 15 cases, however, symptoms returned within 30 minutes to 24 hours (mean of 5 hours) of restarting the drug and were “often more severe,” the statement said.

All 40 patients with aseptic meningitis experienced headache, fever, nausea, vomiting, nuchal rigidity, rash, photophobia, and myalgias. The one reported fatality was not thought to be related to aseptic meningitis. In 25 cases, cerebrospinal fluid analyses were available and showed mild to moderate pleocytosis, normal glucose levels, and mild to moderate increase in protein. In most cases, white blood cell count differentials showed a predominance of neutrophils, but in about one-third of the cases, a predominance of lymphocytes was reported.

In some of the cases, patients had systemic lupus erythematosus or another autoimmune disease, and some patients had a new onset of signs and symptoms of other organ involvement, which “may suggest” that some of the meningitis cases “were part of a hypersensitivity or generalized drug reaction,” according to the statement.

The information on aseptic meningitis is being added to the lamotrigine prescribing information and patient medication guide.

Subject Codes:
top_stories; pediatrics; general_primary; neurology;


http://www.imng.com


August 12, 2010   03:00 PM EDT

By Elizabeth Mechcatie
Elsevier Global Medical News
Breaking News

SILVER SPRING, Md. (EGMN) – In a unanimous vote, a federal advisory panel on Aug. 11 agreed that the antiepileptic drug ezogabine had been shown to be effective as adjunctive therapy for partial onset seizures, but recommended that treated patients be closely monitored for the development of urinary retention.

At a meeting the Food and Drug Administration’s Peripheral and Central Nervous System Drugs Advisory Committee also voted 11 to 0, with 2 abstentions, that they agreed that the risk of urinary retention could be mitigated by monitoring patients, pointing out the importance of educating clinicians in how to properly evaluate patients for changes in urinary symptoms. But none of the panel members thought that the urologic or other safety issues associated with ezogabine should preclude the approval of the drug for the proposed indication, as an adjunctive treatment of patients aged 18 and older with partial onset seizures with or without secondary generalization.

The panel was not asked to vote specifically on whether to recommend approval. The recommended starting dose is 300 mg per day, increasing at weekly intervals by a maximum of 150 mg/day, to a maximum dose ranging from 600 mg to 1,200 mg per day (daily dose is divided into three divided doses per day).

If approved, ezogabine would be the first neuronal potassium channel opener for treating epilepsy, according to the manufacturer, Valeant Pharmaceuticals Inc. Neuronal potassium channels “play a major role in the control of neuronal excitability,” according to the company’s background materials.

The three pivotal trials were international, randomized, 24-26 week studies comparing ezogabine (600 mg/day, 900 mg/day and/or 1200 mg/day, in three divided doses) to placebo, as add-on therapy, in about 1,200 patients, aged 16-75 years (their mean age was 35-38 years), who experienced at least four seizures over a 28-day period, with or without secondary generalization, despite treatment with one to three AEDs. (About 800 patients were on ezogabine and 75% were on two or more AEDs.)

In the studies, the primary end point – the percent reduction from baseline in partial seizure frequency over 28 days – was significantly greater among those on ezogabine, compared with placebo. Reductions in the frequency of seizures ranged from 35% to 44% among those on the 1,200 mg dose, 29%-40% among those on 900 mg/day, and 23%-28% among those on the 600 mg dose, compared with 13%-18% among those on placebo.

As with other AEDs, central nervous system-related side effects were the most common adverse events in the pivotal trials, and included dizziness and somnolence; they were generally related to dose, affected patients early in treatment and were the most common cause of discontinuation of the drug. Discontinuation rates in the study were high, which the company attributed to the forced titration design of the study.

Urinary effects, which were observed in animal studies and are attributed to the drug’s inhibition of the contractility of bladder smooth muscle, were more common among treated patients. In the phase III studies, voiding dysfunction and urinary retention were reported in 5% of patients on all doses, compared with 3% of those on placebo, but there was no association with urinary tract infections, according to the company. Among the 1,365 patients who received the drug in phase II/III trials, there were four cases of urinary retention that required catheterization in treated patients, (compared with 1 patient on placebo) in phase II/III studies, all resolved once treatment stopped, except for one patient who required intermittent catheterization.

Other adverse events that were more common in treated patients included hallucinations and psychosis, and abnormal liver function tests, which were infrequent. There was a slight, transient QT prolonging effect of the drug seen in healthy volunteers titrated to 1,200 mg/day, but there was no clinical evidence of QT prolongation in clinical studies.

Valeant plans to study real-world safety in a prospective postmarketing study in the United States and has proposed a risk management plan to address the potential risks of the drug, which includes instructions to clinicians to “consider the potential effects in the bladder when deciding for whom the drug is appropriate” and a medication guide for patients explaining the potential risks associated with treatment, including how to recognize signs of urinary retention.

The FDA is expected to make a decision on approval by Aug. 30.

If approved, Valeant plans to market ezogabine as Potiga. The FDA usually follows the recommendations of its advisory panels. Panel members have been cleared of potential conflicts of interest by the FDA prior to the meeting, but occasionally, the FDA grants a waiver to a panelist with a conflict of interest.

Subject Codes:
top_stories; new_drugs; neurology;


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August 11, 2010   07:58 PM EDT

By Mary Ann Moon
Elsevier Global Medical News
Breaking News

Transplantation of donor bone marrow or umbilical cord blood partially corrected the collagen deficiency in five of seven children with recessive dystrophic epidermolysis bullosa who underwent the experimental therapy, greatly ameliorating their severe symptoms by improving their skin and mucosal integrity, according to a recent report in the Aug. 12 issue of the New England Journal of Medicine.

In the phase II clinical trial, six of the patients were alive at 130-799 days after the procedure; their rates of recovery and ultimate outcomes varied. Two showed rapid and dramatic clinical improvement in wound healing and mucocutaneous blistering, two showed marked improvement, and one showed slow, modest improvement. Another patient had a recurrence of blistering after 2 months of substantial improvement, said Dr. John E. Wagner of the University of Minnesota Health Center, Minneapolis, and his associates.

One of the patients who responded to the transplantation died from opportunistic infections on day 183. And one of the patients died before bone marrow infusion could be performed, from complications of the conditioning immunomyeloablative chemotherapy.

Epidermolysis bullosa (EB) refers to a group of inherited skin diseases characterized by painful erosions and blisters on skin and mucosal membranes, induced by mild trauma. Recessive dystrophic EB is one of the most severe forms of the disease, present at birth and often eventually resulting in esophageal strictures, mutilating scars, local and systemic infections, joint contractures, fusion of fingers and toes, and aggressive squamous-cell carcinomas. Median survival is only 30 years.

EB is caused by loss-of-function mutations in the gene that encodes for collagen type VII (C7). The mutations cause a severe decrease in the expression of C7, “a collagen localized at the dermal-epidermal junction” that contributes to the formation of “anchoring fibrils that tether the epidermal basement membrane to the dermal matrix,” noted the investigators. When C7 is not expressed properly, these fibrils fail to form properly, “and epidermal-dermal adherence is lost beneath the lamina densa of the basement membrane,” Dr. Wagner and his colleagues explained.

“To date, the care of patients with recessive dystrophic EB has been palliative and restricted to the treatment of individual wounds,” they added.

The investigators explored whether bone marrow or cord blood transplantation might correct the collagen mutations systemically in a murine model. When that proved successful, they undertook the clinical trial in the seven pediatric patients (aged 15 months to 14.5 years). All had extensive cutaneous disease and four had severe mucosal disease requiring esophageal dilation and placement of a gastrostomy tube for nutritional support. Five patients had severe mitten deformities, four required wheelchairs, two had renal impairment, and four had severe iron-deficiency anemia.

One patient died before transplantation from hemorrhagic cardiomyopathy “that was probably due to cyclophosphamide cardiotoxicity,” and a second had to delay transplantation until different complications from the conditioning chemotherapy resolved. At transplantation, five patients received unfiltered marrow stem cells from a human leukocyte antigen – identical but healthy sibling, and one of these five also received umbilical cord blood from the same donor. A sixth patient received umbilical cord blood from an unrelated donor.

All six patients showed improved wound healing and decreased mucocutaneous blistering within the first 100 days, with three showing marked improvement within 30 days. The percentage of affected body surface area was reduced significantly in three patients, as assessed by clinician and parent reports and by documented reductions in the need for bandages.

Four patients were able to discontinue all immunosuppressive therapy and the fifth has tolerated tapering of cyclosporine, according to the investigators.

Skin biopsy specimens showed increases in C7 immunoreactivity at the dermal-epidermal junction after transplantation in all six patients. Testing with an anti-C7 antibody showed an increase in C7 expression over time in five of the six.

At baseline, electron micrographs had shown “a complete absence of mature anchoring fibrils.” After transplantation, five of the six patients showed “scanty, wispy structures under the lamina densa,” which could represent rudimentary anchoring fibrils or fragmented elastic fibrils. More study is needed to further characterize these structures. None of the micrographs showed the morphologic hallmarks of normal anchoring fibrils, the investigators reported (N. Engl. J. Med. 2010;363:629-39).

“Unexpectedly, we detected substantial proportions of donor cells in the skin and mucosa after treatment; these proportions varied over time and with the location of the biopsy site,” they wrote.

Although the precise identity and function of these donor cells has yet to be determined, “we favor the possibility that these healthy donor cells residing in the skin secrete C7 and that the secreted C7 is subsequently incorporated into the lamina densa at the dermal-epidermal junction,” Dr. Wagner and his colleagues noted,

“Substantial efforts are under way to understand the physiology of the apparent clinical response after bone marrow transplantation and to identify the stem-cell population responsible for this effect,” they wrote.

Until this trial was performed, it was not known whether patients with preexisting mucocutaneous disease could tolerate the conditioning regimens used to prepare for allogeneic bone marrow transplantation. In particular, mucositis was feared because it is a common side effect even in patients without mucocutaneous disease. “The unique skin and mucosal membrane defects of this disease pose a particular challenge to any bone marrow transplantation program,” the investigators added.

Yet only one of the six patients developed severe cutaneous toxicity. All patients developed mucositis, but the condition responded to therapy. “Notably, no patient had uncontrolled cellulitis, despite pretransplantation bacterial or fungal skin colonization,” they noted.

Other adverse events included transient hyperbilirubinemia (four patients) and renal insufficiency requiring 3 days of hemodialysis (two patients). No patient developed acute or chronic graft-vs.-host disease.

“Clearly, much remains to be learned regarding the mechanism of the apparent functional correction as well as the long-term risks and benefits of this therapeutic approach, including the risk of squamous-cell carcinoma, which may occur after chemotherapy or as a result of incomplete correction of the underlying disease,” Dr. Wagner and his colleagues noted.

“Already, we and others are considering modifications to enhance safety, such as coinfusion of mesenchymal stromal cells or the use of reduced-dose conditioning before bone marrow transplantation,” they added.

This study was supported by the University of Minnesota Academic Health Center; the National institutes of Health; the Ministry of Health, Labor, and Welfare of Japan; the Ministry of Education, Culture, Sports, Science, and Technology of Japan; the Epidermolysis Bullosa (Liao Family) Research Fund; the Sarah Rose Mooreland EB Fund; and the Children’s Cancer Research Fund. One of Dr. Wagner’s associates reported previous ties to Johnson & Johnson, Procter & Gamble, Novartis, Astellas, and Allergan.

Despite the still unresolved clinical and scientific issues with this experimental therapy, the systemic approach to this genetic skin disease “represents a leap forward,” wrote Dr. Leena Bruckner-Tuderman in an accompanying editorial (N. Engl. J. Med. 2010;363:680-2).

The study by Dr. Wagner and his colleagues “gives cautious hope that effective therapy of recessive dystrophic EB and other genetic skin diseases may one day be available,” noted Dr. Bruckner-Tuderman, is in the department of dermatology at the University of Freiburg (Germany) Medical Center.

Future research should focus on the extent and duration of the therapeutic effects, particularly on whether higher C7 levels in the skin and improvements in mucocutaneous integrity can be sustained over the long term. In addition, more objective methods to assess treatment response are needed, as parental and clinical observation can be “quite subjective.”

Dr. Wagner and his colleagues demonstrated that some patients with mucocutaneous fragility can tolerate the conditioning regimen and other procedures and medications needed for bone marrow transplantation. But they also showed that some cannot, and that the life-threatening adverse effects must be weighed carefully against potential benefits.

In their report, the investigators did not specifically address the issue of subject age in this clinical trial. Although some may consider it questionable to test an experimental treatment in children, it was important in this instance to conduct the test among patients in optimal clinical condition.

In recessive dystrophic EB, the severe secondary symptoms accrue with time, so it is reasonable to perform the transplantation as early as possible, “with the aim of preventing severe scarring, deformities, and also, ultimately squamous-cell carcinomas.”

She reported no financial disclosures.

Subject Codes:
top_stories; dermatology; pediatrics; general_primary;


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August 11, 2010   05:00 PM EDT

Elsevier Global Medical News
Breaking News

The article “U.S. CDC Committee Recommends Against Using CSL Biotherapies Flu Vaccine in Children Under 8” (published August 5, 2010) described imprecisely a committee recommendation. The story should have read: “The Advisory Committee on Immunization Practices voted on Aug. 5 to recommend that a seasonal influenza vaccine manufactured by CSL Biotherapies for the U.S. market not be used in children between the ages of 6 months and 8 years.”

Subject Codes:
infectious; top_stories; orl; pediatrics; allergy; pulmonology; emergency_trauma;


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August 10, 2010   01:11 PM EDT

By Heidi Splete
Elsevier Global Medical News
Breaking News

The pandemic caused by the 2009 H1N1 influenza virus is over, according to a statement issued Aug. 10 by Dr. Margaret Chan, director-general of the World Health Organization.

The Emergency Committee of the WHO declared the end of the H1N1 pandemic after reviewing the most recent global influenza data, including reports from countries that are now in the midst of flu season.

The H1N1 virus has not gone away, but the absence of out-of-season flu outbreaks and the current disease intensity levels have changed significantly from a year ago and now resemble seasonal influenza, Dr. Chan said in her statement. Many countries are reporting a mix of flu viruses, compared with the domination of the 2009 H1N1 virus at this time last year, she said.

“Continued vigilance is extremely important, and WHO has issued advice on recommended surveillance, vaccination, and clinical management during the post-pandemic period,” Dr. Chan said.

The 2010-2011 flu vaccine has been formulated to protect against the 2009 H1N1 virus, an H3N1 virus, and an influenza B virus, according to the Centers for Disease Control and Prevention.

Subject Codes:
infectious; top_stories; orl; dermatology; pediatrics; H1N1; general_primary; womans_health; allergy; rheumatology; emergency_trauma; gerontology;


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August 10, 2010   01:14 PM EDT

By Robert Finn
Elsevier Global Medical News
Breaking News

A prospective observational study that began following more than 50,000 California teachers in 1995 has confirmed reports linking hormone replacement therapy to breast cancer, but suggests obesity may offer some protection.

Data from 56,867 women enrolled in the California Teachers Study indicate that women who used estrogen therapy for at least 15 years had a 19% increase in the risk of breast cancer, and women who used combined estrogen-progestin therapy had an 83% increase in breast cancer risk.

The increase in risk was confined to tumors that were positive for both estrogen and progesterone receptors, wrote Tanmei Saxena of the University of Southern California, Los Angeles, and her coauthors. It was also more pronounced in women with low body mass index (BMI).

Ms. Saxena is an M.D./Ph.D. student at USC’s Keck School of Medicine. The study is published in the September issue of the journal Cancer Epidemiology, Biomarkers and Prevention.

“These findings, taken in context of the larger literature on this topic, continue to underscore the need to personalize risk-benefit discussions for women contemplating the use of [hormone therapy],” wrote the investigators (Cancer Epidemiol. Biomarkers Prev. 2010;19:OF1-13).

The California Teachers Study is a prospective cohort study of 133,479 women who were enrolled in 1995. For the purposes of this study, the investigators excluded women who were not California residents, who had a previous or unknown history of breast cancer, who were older than 80 years at baseline, who were premenopausal or of unknown menopausal status, or who had an unknown history of hormone therapy.

Of the remaining 56,867 perimenopausal and postmenopausal teachers, 2,857 women (5%) were diagnosed with pathologically confirmed invasive breast cancer through December 2006, after a mean follow-up of 9.8 years. The average age at diagnosis was 67.1 years.

In a multivariate analysis, the investigators adjusted for race/ethnicity, first-degree family history of breast cancer, BMI, smoking history, alcohol consumption during the year prior to baseline, mammographic screening over the prior 2 years, parity and age at first full-term pregnancy, age at menarche, age at menopause, and history of breast biopsy.

Compared with women who never used any hormone therapy, those who did had a statistically significant 40% increase in the risk of breast cancer. The increase in risk was 19% for women who reported at least 15 years of estrogen-alone therapy, and 83% in women who reported at least 15 years of combined estrogen-progestin therapy.

Current use of hormonal therapy was associated with higher risk than past use. The greatest increase in risk – 69% – was among women who were using estrogen-progestin therapy currently and had never used any other formulation. The investigators noted that duration of use tended to be shorter among former users.

The longer the women used hormone therapy, the greater the risk. The increase associated with duration of use was statistically significant for all forms of hormone therapy. For example, women using estrogen-progestin therapy for less than 2 years at baseline had a 12% increase in the risk of breast cancer, compared with women who never used hormone therapy. The increase in risk was 42% for those using estrogen-progestin therapy for 3-5 years, 50% at 6-9 years, 67% at 10-14 years, 79% at 15-19 years, and 92% at 20 years or more.

Among current users of hormonal therapy, the association with breast cancer risk was statistically significant only for tumors that were both estrogen receptor–positive and progesterone receptor–positive, with increased risks of 33% in women who had 15 or more years of estrogen therapy and 84% in those who had been on estrogen and progestin for 15 years or more. The risks were even higher for women whose tumors were also HER2 positive, but the investigators suggested this might be a statistical fluke because of the small numbers involved. No association was seen between long duration of hormone use and triple-negative tumors.

BMI seemed to modify the risk associated with hormonal therapy, the investigators reported. Among women with a BMI of 25 or less, the relative risk of breast cancer was 2.1 in current long-term users of estrogen and progestin, compared with women who had never used hormone therapy (P less than .0001). In women with a BMI of 25-30, the relative risk was 1.9 in current long-term users of estrogen and progestin (P less than .0001). However, the effect was not statistically significant in women with a BMI higher than 30 (RR 1.2, P = .11).

The National Cancer Institute and the California Breast Cancer Research Fund sponsored the study. A coauthor disclosed serving as an expert witness for plaintiffs pursuing Prempro litigation.

Subject Codes:
top_stories; OncologyEX; general_primary; endocrinology; womans_health;


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August 10, 2010   01:00 PM EDT

By M. Alexander Otto
Elsevier Global Medical News
Breaking News

Vertebroplasty provided quicker, stronger, and more durable pain relief from acute, osteoporotic vertebral compression fractures than did conservative pain management, judging from the findings of a randomized, open-label trial published online by the Lancet Aug. 10.

“In a subgroup of patients with acute [fractures] and persistent pain, percutaneous vertebroplasty is effective and safe,” concluded Dr. Caroline Klazen, a radiologist at St. Elisabeth Hospital in Tilburg, the Netherlands, and her colleagues (Lancet 2010 Aug. 10 [doi:10.1016/S0140-6736(10)60954-3]).

Two previous studies found no benefit for vertebroplasty compared with bed rest, analgesics, and other conservative measures, but both trials included patients with fractures of up to a year old (N. Engl. J. Med. 2009; 361:557-68; N. Engl. J. Med.2009;361:569–79).

The Lancet study pitted vertebroplasty against conservative treatment within a mean of 5.6 weeks of fracture symptom onset; vertebroplasty patients experienced greater pain relief initially and throughout the trial’s yearlong follow-up.

“Apparently,” vertebroplasty shortly after a fracture “is more effective for pain relief” than vertebroplasty performed months afterward, Dr. Klazen and her colleagues wrote.

Recruited from the radiology departments of six hospitals in the Netherlands and Belgium, 101 patients were randomized to vertebroplasty and 101 to conservative measures. Patients were at least 50 years old, and 69% were female.

All of the patients had radiologically confirmed compression fractures at or below thoracic vertebrae 5 with bone edema on magnetic resonance imaging and a minimum height loss of 15%.

They also had tenderness at the fracture level; bone density T scores at or below –1; back pain for 6 weeks or less; and a pain score of at least 5 on a 10-point visual analog scale (VAS), with 10 being the worst pain.

In the vertebroplasty group, fractures were injected with a mean volume of 4.1 mL polymethylmetacrylate bone cement under fluoroscopic guidance.

At 1 month, those injected with the bone cement had a mean reduction of 5.2 VAS points from baseline (95% CI, 5.88-4.72), compared with a mean reduction of 2.7 points (95% CI, 3.22-1.98) in those treated conservatively.

At 1 year, vertebroplasty subjects had a mean reduction of 5.7 VAS points from baseline (95% CI, 6.22-4.98); conservatively treated patients had a mean reduction of 3.7 points (95% CI, 4.35-3.05).

Vertebroplasty patients used significantly less pain-relieving medication at day 1, week 1, and month 1, but the difference in drug use was not significant at later stages of follow-up.

The authors noted that the intervention was not blinded, and that “knowledge of the treatment assignment might have affected patient responses to questions or radiologist assessments.”

Computed tomographic scanning found that cement leaked out of 97 of the 134 vertebral bodies injected in the 101 vertebroplasty subjects. “Most leaks were discal or into segmental veins; none were into the spinal canal,” the authors noted.

Cement deposited in a segmental pulmonary artery in one patient, but all cement leaks remained asymptomatic.

In a commentary, orthopedic surgeons Dr. Douglas Wardlaw, of Woodend Hospital in Aberdeen, Scotland, and Dr. Jan Van Meirhaeghe, of St. Jan General Hospital in Brugge, Belgium, noted that the study “lends support to the large body of medical opinion that vertebroplasty has a part to play in the management of the pain of vertebral compression fractures” (Lancet 2010 Aug. 10 [doi:10.1016/S0140-6736(10)61162-2]).

But they noted “an unexplained significant difference at baseline” in quality of life and disability measurements between the two groups that suggests “the control group might have been generally healthier than the vertebroplasty group.”

Dr. Klazen and her colleagues attributed the differences to chance.

Dr. Wardlaw and Dr. Van Meirhaeghe also noted that in the two previous studies that found no benefit for vertebroplasty, the comparators were sham treatments, not conservative pain management.

In one of the trials, the sham included injecting bupivacaine, a long-acting local anesthetic, into fractures, which itself might have brought relief, they wrote.

By using conservative pain management as a comparator, Dr. Klazen and her colleagues noted, vertebroplasty was tested against “the reference treatment and thus provides the clinician with directly applicable information about how to best treat the patient.”

Dr. Klazen and her colleagues reported no conflicts of interest. Their study was funded by ZonMw, a Dutch organization for health care research and innovation, and Cook Medical, makers of the bone cement used in the trial. Dr. Wardlaw and Dr. Van Meirhaeghe reported receiving consulting fees and travel and accommodation expenses from Medtronic Spinal and Biologics Europa BVBA for their role in the FREE balloon kyphoplasty trial.

Subject Codes:
top_stories; orthopaedics; general_primary; endocrinology; pain; womans_health; rheumatology; surgery; gerontology;


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August 09, 2010   06:30 PM EDT

By Mary Ann Moon
Elsevier Global Medical News
Breaking News

Greater waist circumference was associated with a higher mortality risk independent of body mass index, according to a report in the August 9/23 issue of the Archives of Internal Medicine.

Waist circumference is positively associated with mortality risk within all categories of BMI – normal, overweight, and obese. In fact, the relationship between greater waist circumference and higher mortality is strongest among women with a normal BMI, said Eric J. Jacobs, Ph.D., and his associates in the epidemiology research program at the American Cancer Society, Atlanta.

The link between waist circumference and mortality has been reported in numerous studies, but this is the first study to examine that association within the standard categories of BMI, they noted (Arch. Intern. Med. 2010;170:1293-1301).

Dr. Jacobs and his colleagues used data from the Cancer Prevention Study II Nutrition Cohort, a large prospective study that obtained demographic, medical, and behavioral factors by self-administered questionnaire. They reviewed the findings on 48,500 men and 56,343 women aged 50 years and older in the 1990s who were followed through 2006. Almost all of the study subjects were white. The median baseline age was 67 years for women and 69 years for men.

The 14,647 deaths during follow-up included 5,410 cancer deaths, 4,942 cardiovascular deaths, 1,189 deaths resulting from respiratory disorders, and 3,106 deaths from all other causes.

Any waist circumference greater than the smallest sizes (less than 90 cm in men or less than 75 cm in women) was associated with higher mortality. The mortality risk rose linearly with increasing waist circumference both in men and women.

Waist circumference was positively related to mortality in all patients. For men, the relative risk of mortality rose 16% (with normal BMI), 18% (overweight), and 21% (obese) with every 10-cm increase in waist size. For women, the relative risks with every 10-cm increase were greater for those with normal BMIs: 25% (normal), 15% (overweight), and 13% (obese).

When analyzed by cause of death, the link between waist circumference and mortality was strongest with death from respiratory causes, followed by cardiovascular disease and then cancer, Dr. Jacobs and his associates reported.

The investigators found no significant interactions between BMI-adjusted waist circumference and diabetes, smoking, or follow-up time. In addition, the researchers saw no interaction between waist circumference and hormone therapy in women. Relative mortality risks associated with waist circumference appeared to be greater in men who were less physically active.

“Results from this large prospective study emphasize the importance of waist circumference as a risk factor for mortality in older adults, regardless of whether the BMI is categorized as normal, overweight, or obese. Our results suggest that, regardless of weight, avoiding gains in waist circumference may reduce risk of premature mortality,” the researchers said.

The findings are important in light of the fact that current clinical guidelines do not address waist circumference in normal-weight patients and do not recommend weight loss for abdominally obese patients unless they have a high BMI, Dr. Jacobs and his associates noted.

The study was limited in that it included participants who were at least 50 years old, and it included very few nonwhite subjects. Thus, “results may not be generalizable to younger populations or those of other racial or ethnic backgrounds,” the authors noted.

No financial disclosures were reported.

Subject Codes:
top_stories; diabetes; general_primary; endocrinology; womans_health;


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August 09, 2010   04:00 PM EDT

Greater waist circumference is associated with higher mortality risk regardless of BMI. The association is strongest with death from respiratory causes, followed by cardiovascular disease, and then cancer. (Photo: Copyright Keith Frith/FOTOLIA)

By Mary Ann Moon
Elsevier Global Medical News
Breaking News

When plasma levels of beta-amyloid rise above normal and then decrease or stabilize in healthy elderly patients, it signals the onset of a rapid decline in several cognitive domains, according to a study published online Aug. 9 in the Archives of Neurology.

In most patients, that decline takes the form of Alzheimer’s disease. In the minority who don’t develop full-blown dementia, there is a marked cognitive decline that primarily affects memory rather than language or visuospatial domains, said Stephanie A. Cosentino, Ph.D., of the Taub Institute for Research in Alzheimer’s Disease and the Aging Brain, New York, and her associates.

Some previous studies have shown a correlation between elevated plasma beta-amyloid (Abeta) levels and the development of mild amnestic cognitive impairment or frank Alzheimer’s disease (AD) within a few years. However, other studies have found that decreasing, rather than elevated levels, correlate with these cognitive declines.

The findings of this study by Dr. Cosentino and her colleagues suggest that the timing of the plasma sampling and of the subjects’ disease stage may account for these discrepant results.

The investigators used data from a population-based study of aging to examine the link between plasma levels of the soluble oligomers Abeta-40 and -42 and cognitive changes. A total of 880 nondemented study participants provided one blood sample at baseline in 1999 and a second sample about 4.5 years later. They also underwent a battery of neuropsychological tests at approximately 18-month intervals.

During follow-up, 481 remained cognitively healthy, 329 developed cognitive or functional impairment but no dementia, and 70 developed AD. The cohort involved nearly equal percentages of Hispanics (37%), whites (31%), and African Americans (31%).

“Overall, high initial levels of plasma Abeta-40 and Abeta-42, and stable or decreasing Abeta-42 at follow-up, were associated with faster global cognitive decline regardless of dementia status,” Dr. Cosentino and her associates wrote (Arch. Neurol. 2010 Aug. 9 [doi:10.1001/archneurol.2010.189]).

Subjects whose initial Abeta-40 and Abeta-42 levels were in the top three quartiles had significantly faster cognitive decline than did those in the lowest quartile. Those with either decreasing or stable Abeta-42 levels at the second measurement had significantly faster cognitive decline than other subjects.

An elevated level of Abeta-42 at baseline predicted cognitive decline in memory, language, and visuospatial domains, with subjects in the highest quartile of beta-amyloid level consistently declining significantly faster than subjects in the lowest quartile.

However, in the subgroup of subjects who remained cognitively unimpaired, those with high baseline levels of Abeta-42 showed declines only in the memory domain.

The investigators suggested that these subjects may be in the early stages of AD but have not yet shown sufficient decline in nonmemory domains to meet the criteria for dementia. Alternatively, these subjects may remain free of dementia due to biological factors such as the ability to clear high levels of beta-amyloid or psychosocial factors such as the presence of cognitive reserve.

“Another interpretation of the association between plasma Abeta-42 and memory is that amyloid changes are an important factor in cognitive aging, independent of underlying AD. Stated differently, the observable change in both plasma Abeta and memory in this group could be a fundamentally different process than that involved in AD or might fall short of a critical threshold beyond which the full pathological presentation and clinical dementia syndrome of AD would unfold,” the investigators wrote.

Future studies must “determine more definitively the specificity of Abeta profiles for predicting dementia vs their significance for cognitive aging more generally. Comprehensive understanding of plasma Abeta across the cognitive spectrum and its relation to dementia will require collection of plasma Abeta at multiple times beginning in early to mid life, as well as validation against Abeta imaging and autopsy,” they added.

The study was funded by grants from the National Institutes of Health. The investigators had no relevant disclosures to report.

Subject Codes:
top_stories; general_primary; neurology; gerontology;


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August 09, 2010   04:00 PM EDT

Elsevier Global Medical News
Breaking News

The article “CDC Panel Recommends Against Using CSL Biotherapies Flu Vaccine in Children Under 8” (published Aug. 5) contained a error in the headline. The vaccine is indicated for children aged 6 months to 8 years, therefore the headline should have stated that the vaccine is for children under 9.

Subject Codes:
infectious; top_stories; orl; pediatrics; general_primary; allergy; emergency_trauma;


http://www.imng.com


August 05, 2010   09:00 PM EDT

By Calvin Godfrey
Elsevier Global Medical News
Breaking News

A pair of industry-funded multicenter studies has contributed to the growing call for infant vaccination against severe rotavirus gastroenteritis in the developing world.

The findings, published online Aug. 6 in the Lancet, come more than a year after the World Health Organization’s Strategic Advisory Group of Experts declared that rotavirus vaccines should be included in national immunization programs all over the world – particularly in countries with high diarrheal fatalities (Lancet 2010 Aug. 6 [doi:10.1016/S0140-6736(10)60755-6]).

Previous trials conducted in industrialized nations demonstrated rotavirus vaccine to be both safe and effective. However, far less clinical research has been conducted in low-income populations in Africa and Asia, where an estimated 85% of rotavirus fatalities occur (J. Infect. Dis. 2009;200:S1-S8).

The two new studies explored African and Asian infant populations in double-blind, placebo-controlled, multicenter randomized trials.

A comment accompanying the two studies called for long-term subsidies from wealthier countries to ensure effective use of the vaccination in places with the greatest need (Lancet 2010 Aug. 6 [doi:10.1016/S0140-6736(10)60896-3]).

“It is likely that diarrhea deaths in the poorest countries could be reduced by 25%, which will greatly help these [countries] achieve the target of Millennium Development Goal 4,” comment coauthor Dr. E. Anthony S. Nelson, of the pediatrics department at the Chinese University of Hong Kong, said in an interview.

In the first of the two studies, an international team led by K. Zaman, Ph.D., of the International Centre for Diarrhoeal Disease Research in Bangladesh, carried out its trials in rural Matlab, Bangladesh, and neighborhoods in and around the seaside city of Nha Trang, Vietnam.

A total of 2,036 infants aged 4-12 weeks were randomly assigned three 2-mL oral doses of Merck’s pentavalent rotavirus vaccine or placebo. There were no enrollment restrictions based on HIV status. The investigators said the infants showed no signs of preexisting gastrointestinal disorders when they began administering the dosages at roughly 6, 10, and 14 weeks of age.

Over the course of the next 2 years, Dr. Zaman and colleagues noted 38 cases of severe rotavirus gastroenteritis in the vaccinated group, compared with 71 in the placebo group. The investigators calculated the overall vaccine efficacy at 48%, which is lower than efficiencies observed in industrialized countries in Europe and the Americas.

Adverse events were relatively few. A total of 2.5% of the vaccinated subjects and 2.0% in the placebo group had at least one adverse event, and the investigators did not attribute any of those effects to the vaccine.

The second study, led by George E. Armah, Ph.D., of the University of Ghana, Accra, was conducted in Africa, where diarrheal disease remains the second biggest culprit in the continent’s 800,000 annual child deaths (Lancet 2007;369:91-2).

Dr. Armah and colleagues employed the same methodology on a larger population – 5,468 infants. HIV-positive cases were not excluded.

They conducted the multicenter trial in clinics located in rural Ghana and Kenya, as well as an urban center in Mali. During the 2-year follow-up, Dr. Armah and colleagues recorded 79 cases of severe rotavirus gastroenteritis in the vaccinated group, compared with 129 in the placebo group. Severe adverse events occurred in 1.5% of those vaccinated and 1.7% of those who received placebos.

The overall vaccine efficacy was calculated at 39.3%. “This protection was especially high through the first year of life (64.2% vaccine efficacy), when the disease burden, including mortality, is highest,” the investigators wrote (Lancet 2010 Aug. 6 [doi:10.1016/S0140-6736(10)60889-6]).

The authors of both studies endorsed the WHO’s call for the expansion of rotavirus vaccination.

Both teams, as well as a comment coauthor, stated some financial conflicts. Merck, the manufacturer of the oral vaccine used for both trials, helped design and oversee the studies with substantial input from the international nonprofit group PATH (Program for Appropriate Technology in Health). Merck employees and shareholders participated in the research process and helped fund the projects. Grant funding from GAVI (Global Alliance for Vaccines and Immunization) was contributed to the effort via PATH. Dr. Nelson has funding and other research relationships with Merck, Baxter, Intercell, GlaxoSmithKline, MedImmune, and Wyeth, including a phase III Rotarix vaccine study.

Subject Codes:
infectious; top_stories; new_drugs; pediatrics; pulmonology;


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August 05, 2010   06:30 PM EDT

By Robert Finn
Elsevier Global Medical News
Breaking News

The Advisory Committee on Immunization Practices voted on Aug. 5 to withdraw a seasonal influenza vaccine manufactured by CSL Biotherapies from the U.S. market for children between the ages of 6 months and 8 years.

The company’s trivalent influenza vaccine (TIV) sold under the trade name Afluria in the United States was associated with a large increase in the risk of fevers and febrile seizures in children in Australia and New Zealand. In April 2010, authorities in those two countries recommended that physicians suspend use of CSL’s influenza vaccines in children aged 5 years and under. In response, the company voluntarily withdrew its vaccine from markets in the southern hemisphere.

In the northern hemisphere, CSL’s influenza vaccines have been approved for use in Germany, the United Kingdom, and the United States. In June 2010, authorities in the United Kingdom recommended that physicians avoid using CSL’s influenza vaccine in children aged 5 years and under.

In making their recommendation, members of the Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices (ACIP) noted that there should be adequate supplies of seasonal influenza vaccine even in the absence of Afluria. Other manufacturers are expected to supply 145-150 million doses of the vaccine in the United States; the largest number of doses ever used in one flu season was 114 million.

During the course of the teleconference, representatives of Sanofi-Aventis, GlaxoSmithKline, Novartis, and MedImmune all said that they had adequate supplies of vaccine, and they were willing to increase production if necessary to compensate for the 6-12 million doses that CSL had been expected to provide.

According to the CDC’s medical epidemiologist Dr. Tim Uyeki, CSL’s vaccine was associated with a ninefold increase in the risk of febrile seizures, compared with other manufacturers’ vaccines in children aged 6 months through 4 years in Australia. The rate was nine per 1,000 doses in these children, compared with an expected rate of one per 1,000 doses. The rate of febrile seizures was especially high in children aged 3-4 years old given Fluvax Junior, one of CSL’s two versions of this year’s TIV. The rate in those children was 15 per 1,000 doses.

Febrile seizures occurred an average of 7.2 hours after the child received a dose of vaccine, with a range of 5.9-8.4 hours. Dr. Uyeki said that no explanation for the increased risk of fever and febrile seizures has been identified.

Although there was no apparent increase in febrile seizures in children aged 5-8 years, children in that age group did experience an increase in the incidence of fever. Sixteen percent of children in that age group experienced a fever following a dose of a CSL flu vaccine, compared with 9% of children receiving another manufacturer’s vaccine.

ACIP members voted to include children aged 5-8 years in their recommendation in order to increase the simplicity and consistency of the public health message. Other ACIP recommendations regarding flu vaccination in children, both for the seasonal TIV and for pandemic influenza A(H1N1), involve children age 6 months to 8 years, and most members believed it would be confusing to have this new recommendation cover children age 6 months to 5 years.

They did agree, however, that children aged 5-8 years could receive the CSL vaccine if they were at especially high risk from influenza and if no other vaccine was available.

Several committee members voiced concern about providers who may already have placed orders for the CSL vaccine. Since most vaccine from other manufacturers has already been allocated, they worried that it would be too late for some clinicians to change their orders. In response, a representative from the American Medical Association recommended that providers visit the AMA’s Influenza Vaccine Availability Tracking System (IVATS) at http://www.preventinfluenza.org/ivats. A spreadsheet at that site lists names and contact information for distributors who have vaccine available.

In related news, the CDC reported Aug. 4 that they’ve observed outbreaks of seasonal influenza A(H3N2) in two nonbordering counties in Iowa, along with sporadic cases of influenza 2009 H1N1 A and B in 11 other states.

The agency reminded physicians to consider influenza as a possible diagnosis in individuals with respiratory illnesses even though influenza is not often seen in the summer. Clinicians also were advised not to rely on the rapid influenza diagnostic test because of its moderate sensitivity and an increased chance of false positives during times when overall influenza prevalence is low.

While several members of ACIP disclosed that they had relationships with vaccine manufacturers, only members with no such conflicts of interest were permitted to vote.

Subject Codes:
infectious; top_stories; orl; pediatrics; allergy; pulmonology; emergency_trauma;


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August 05, 2010   02:49 PM EDT

By Mary Ann Moon
Elsevier Global Medical News
Breaking News

The use of antiepileptic drugs does not appear to raise the risk of suicide beyond the increased risk already associated with the underlying conditions for which patients take these medicines, according to a report in the Aug. 5 issue of the New England Journal of Medicine.

Antiepileptic drugs (AEDs) were associated with an increased risk of suicide attempts or completions among patients with depression and in the relatively small group of patients who were taking AEDs for indications other than epilepsy, depression, or bipolar disorder. However, this increase in risk likely was related to the underlying disorders, not to the use of AEDs per se, Dr. Alejandro Arana of Risk MR Pharmacovigilance Services, Zaragoza, Spain, and his associates reported.

These findings contradict those of a 2008 meta-analysis of placebo-controlled clinical trials that prompted the U.S. Food and Drug Administration to issue a safety warning on the risk of suicidality associated with AEDs. That meta-analysis was limited in that it included trials with relatively short treatment times (24 weeks) and short follow-up times. The analysis also did not use “systematic or standardized language to define suicidal ideation and behavior across clinical trials,” Dr. Arana and his colleagues noted.

The study population comprised 5,130,795 primary care patients in the United Kingdom whose anonymous demographic, medical, and prescription information was entered into a database between 1988 and 2008. The patients had a mean age of 34 years and were followed for a mean of 6.2 years. The researchers excluded patients with a family history of suicide or a personal history of suicide attempts, because both are major risk factors for a subsequent attempt and could confound the study results.

The drugs included in this analysis were carbamazepine, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, valproate, and zonisamide.

There were 66,925 patients with epilepsy. Of these, 16,120 had no concurrent depression or bipolar disorder and were not receiving AEDs.

Another 77,319 patients were taking AEDs but did not have epilepsy, depression, or bipolar disorder. The indications for which they were taking the drugs were unknown. However, pain-related diagnoses such as herpes zoster were documented in nearly 20% of this group, and it is likely that many others also were receiving antiepileptics for pain. Pain, especially chronic pain, is associated with an increased risk of suicide, the investigators noted.

A total of 8,212 patients attempted suicide, including 464 who completed suicide.

Epilepsy patients who used AEDs did not have a significantly higher rate of suicide events than did epilepsy patients who were not taking the drugs (48/100,000 person-years vs. 38/100,000 person-years, respectively). Similar results were observed when the investigators compared the rate of suicide events for patients with bipolar disorder who were or were not taking AEDs.

In contrast, the rate of suicide events for patients with depression alone was significantly higher in those who were taking AEDs than in those who were not (177/100,000 person-years vs. 129/100,000 person-years, respectively).

In a case-control study involving a large subgroup of the patients with a chronic disease or a history of alcohol abuse, a mental disorder, or use of lithium, antipsychotic drugs, or antidepressants, AED use was associated with a significantly greater odds of a suicide event than was nonuse.

“Although a causal role of antiepileptic drugs is possible, it is also possible that the use of antiepileptic drugs in these patients is a marker of severe depression or the presence of another condition that may be associated with an increased risk of suicide-related events,” Dr. Arana and his associates wrote (N. Engl. J. Med. 2010;363:542-51).

With a follow-up of 6 years as opposed to just weeks for the meta-analysis cited by the FDA, the investigators noted that their study was able to “dilute” the well-known confounding effect of a high rate of suicide events in the first weeks after a psychoactive medicine is initiated.

The study was supported by Sepracor. Several investigators have served as consultants for, and have received grants for unrelated projects from, UCB Pharma, Novartis, and/or Johnson and Johnson.

Subject Codes:
top_stories; mental_health; general_primary; neurology;


http://www.imng.com


August 04, 2010   05:00 PM EDT

By Alicia Ault
Elsevier Global Medical News
Breaking News

The Food and Drug Administration on Aug. 4 released warning letters it had sent to the owners of five laser vision correction centers that are not complying with agency rules that govern such facilities.

Under the FDA’s medical device regulations, the laser centers, which perform laser-assisted in situ keratomileusis (LASIK), are subject to certain requirements, including the reporting of adverse events.

The letters were sent in late April to five centers, some of which are part of national chains: the Lasik Vision Institute in Lake Worth, Fla.; the LASIK Vision Institute in Pittsburgh; the Saint Vincent Surgery Center in Erie, Pa.; the TLC Vision Corp.’s center in Plymouth Meeting, Pa.; and the LasikPlus Vision Center in Concord, Calif.

The agency said inspections in January had revealed that these centers were out of compliance with FDA rules.

It is not the first time the agency has issued such warnings to laser vision centers. In October 2009, it sent letters to 17 centers deemed to have inadequate adverse event reporting.

Also at that time, the FDA, the National Eye Institute, and the U.S. Department of Defense launched a 3-year study, the LASIK Quality of Life Collaboration Project, to determine the percentage of patients with significant quality of life problems after LASIK surgery and to identify the predictors of these problems, according to the agency.

Subject Codes:
top_stories; ophthalmology; general_primary;


http://www.imng.com


August 04, 2010   12:40 PM EDT

By Sharon Worcester
Elsevier Global Medical News
Breaking News

Daily B vitamin supplementation is no more effective than is placebo for reducing the incidence of major vascular events in patients who have had a recent stroke or transient ischemic attack, according to findings from the Vitamins to Prevent Stroke (VITATOPS) trial.

Among 8,164 patients enrolled in the multicenter, parallel, double-blind trial, major vascular events (nonfatal stroke, nonfatal myocardial infarction, or death from any vascular cause) occurred in 15% of patients randomized to B vitamin supplementation and in 17% randomized to placebo after a median follow-up period of 3.4 years. This translated into a nonsignificant relative risk of 0.91, Dr. Graeme J. Hankey of Royal Perth (Australia) Hospital and his colleagues from the VITATOPS Trial Study Group reported online August 4 in the Lancet Neurology.

When each type of vascular event was analyzed separately, B vitamin supplementation was not associated with a significant reduction in the relative risk for nonfatal or fatal stroke, nonfatal or fatal MI, or death from any cause. However, there was a slight, but statistically significant, reduction in the risk of death from vascular causes (relative risk, 0.86).

Dr. Hankey and his associates wrote that the findings suggest that B vitamins, while safe in post-stroke and post-TIA patients, should not be recommended to prevent recurrent stroke (Lancet Neurology 2010 Aug. 4 [doi:10.1016/S1474-4422(10)70187-3]).

Study participants were enrolled between Nov. 19, 1998, and Dec. 31, 2008, within 7 months of experiencing stroke or TIA and were randomized to receive placebo or 2 mg of folic acid, 25 mg of vitamin B6, and 0.5 mg of vitamin B12 daily in addition to usual medical care.

No unexpected adverse events occurred during follow-up, and no significant differences were seen between the treatment and placebo groups in regard to common adverse events, the investigators noted.

Although prior cross-sectional and observational epidemiologic studies have suggested that raised plasma concentrations of total homocysteine are associated with increased risk for major vascular events, and that B vitamin supplementation can lower total homocysteine – as it did in the current study – this did not translate to a reduced incidence of subsequent vascular events in the study, they said.

Fasting blood tests performed at the end of follow-up in 1,164 patients showed that the B vitamin group had 3.8 micromol/L lower homocysteine than in the placebo group (10.5 vs. 14.3 micromol/L). An analysis of a subset of 925 patients with fasting blood levels of homocysteine available from baseline and follow-up indicated that each 1.0 micromol/L decrease in total homocysteine was associated with only a nonstatistically significant 2% reduction in risk of the primary outcome.

The study is limited by incomplete adherence to trial drugs and by incomplete follow-up, as well as by a relatively short duration of follow-up, which “might not have been long enough to adequately identify or exclude any long-term effects of B vitamins,” the investigators noted.

To control for random error, the researchers added their data to those from other randomized controlled trials of homocysteine-lowering therapy in patients with or without preexisting cardiovascular disease. This “updated meta-analysis” also showed that B vitamins are not significantly more effective than placebo for reducing the risk of the composite outcome of stroke, myocardial infarction, or vascular death (RR, 0.99).

“A planned meta-analysis of individual data from all previous, and three ongoing, randomized controlled trials of B vitamins will provide more reliable estimates of the long-term effects of B vitamins in the prevention of stroke and other major vascular events among patients with stroke or transient ischemic attack, particularly when caused by symptomatic cerebral small vessel disease,” the investigators wrote. They noted that in a subgroup analysis, B vitamins were shown to possibly reduce the risk of stroke, myocardial infarction, or vascular death in patients with symptomatic small vessel disease of the brain causing lacunar infarction or intracerebral hemorrhage – a reduction that has also been suggested by other investigators who have reported that homocysteine is a risk factor for cerebral small vessel disease.

“If validated, this finding could explain any apparent differential effect of homocysteine lowering on small vessel ischemic stroke, compared with large artery ischemic stroke and myocardial infarction,” they said.

According to Dr. Peter Sandercock of the department of clinical neurosciences at Western General Hospital, Edinburgh, the VITATOPS trial indicated that there is still weak evidence for a small relative risk reduction in fatal or nonfatal stroke with B vitamin supplementation. This is one reason why B vitamins might still be potentially worthwhile in stroke and TIA patients. “A large global trial – preferably with a treatment regimen that results in a larger reduction in homocysteine concentrations – with several tens of thousands of patients would be required to confirm or refute such moderate effects,” he wrote (Lancet Neurology 2010 Aug. 4 [doi:10.1016/S1474-4422(10)70188-5]).

Indeed, there are numerous examples of treatments that required an accumulation of data from large, sufficiently powered trials along with meta-analyses of the data from those trials before the benefits of the treatments were appreciated. Examples include antiplatelet treatment with aspirin, cholesterol reduction with drugs, and tamoxifen for breast cancer. The jury is still out until other ongoing trials of homocysteine reduction and various meta-analyses are completed.

While “the VITATOPS trial does not provide sufficiently robust evidence to support a policy of giving B vitamin supplements for secondary prevention after transient ischaemic attack or minor stroke ... there is still a place for further trials of homocysteine-lowering treatment, especially if the intervention can achieve and sustain large reductions in homocysteine,” he wrote.

Dr. Hankey and some other authors of the study reported receiving payments and honoraria for various duties for companies that manufacture stroke therapies, including Johnson and Johnson, Sanofi-Aventis, and Schering Plough, Boehringer Ingelheim, and Pfizer. Dr. Sandercock reported that he has no conflicts of interest.

The study was funded by the Australia National Health and Medical Research Council, the U.K. Medical Research Council, the Singapore Biomedical Research Council, the Singapore National Medical Research Council, the Australia National Heart Foundation, the Royal Perth Hospital Medical Research Foundation, and the Health Department of Western Australia.

Subject Codes:
top_stories; neurology;


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August 03, 2010   06:30 PM EDT

By Robert Finn
Elsevier Global Medical News
Breaking News

A brief intervention in the emergency department resulted in modest reductions in violence and alcohol use, according to a randomized, controlled trial involving 726 adolescents.

The teenagers, all of whom reported violence and alcohol abuse during the past year, were randomized to receive either a brochure (the control condition) or a 35-minute intervention delivered via computer or by a therapist. Both interventions were targeted at alcohol use and violence and were based on motivational interviewing techniques and skills training. The interventions included a review of goals, tailored feedback, a decisional balance exercise, role plays, and referrals, wrote Maureen A. Walton, Ph.D., of the University of Michigan, Ann Arbor, and her colleagues (JAMA 2010;304:527-35).

On every violence-related measure, all three groups, including the control group, showed substantial declines from baseline at 3 months and again at 6 months. For example, at baseline 83% of the therapist group, 76% of the computer group, and 78% of the control group reported severe peer aggression during the past year. At 3 months the percentages reporting aggression were 48%, 54%, and 62%, respectively, and at 6 months they were 45%, 49%, and 49%.

Similarly, all three groups showed substantial declines in every alcohol-related measure at 3 months and additional declines in most alcohol-related measures at 6 months. For example, at baseline 53% of the therapist group, 49% of the computer group, and 54% of the control group reported binge drinking. At 3 months the percentages declined to 34%, 29%, and 35%, respectively, and at 6 months they were 33%, 33%, and 34%.

Included in the study were adolescents aged 14-18 years who were being seen in a level I trauma center for a variety of reasons. Excluded were teens experiencing suicidal ideation, abnormal vital signs, insufficient cognitive orientation, and several other conditions. Of 3,764 patients approached for screening, 446 refused and 2,509 did not meet inclusion criteria, the most important of which was reported alcohol use and reported violence within the past year. More than 100 others refused participation, leaving 726 to be randomized. A total of 626 completed the 6-month assessment.

Several of the between-group differences were statistically significant. Compared with those in the control group, teenagers in the therapist group were significantly less likely to report severe peer aggression, an experience of peer violence, or consequences of violence at 3 months. None of those differences were statistically significant at 6 months. At 6 months, but not at 3 months, those in the therapist group reported significantly fewer alcohol consequences than controls.

The investigators reported several encouraging results from a number-needed-to-treat analysis. For example, only eight at-risk adolescents would need to receive the therapist intervention to prevent severe peer aggression in one adolescent. Ten at-risk adolescents would need to receive the therapist intervention to prevent one from being victimized by a peer. And 17 adolescents would need to receive the therapist intervention to prevent alcohol consequences in 1 teen.

In an accompanying editorial, Dr. Richard Saitz and Dr. Timothy S. Naimi of Boston University criticized several aspects of the study. They noted that the study’s trial registration suggested that the investigators measured quite a few additional primary outcomes that they did not mention in their report, including drug use, injury, delinquency, and weapon carrying. The fact that they measured so many primary outcomes raises the concern of type I experimental error because of multiple comparisons.

In addition, they suggested that participants in face-to-face counseling might be less likely to report unsafe or undesirable behaviors at follow-up (JAMA 2010;304:575-7).

The study was supported by the National Institute on Alcohol Abuse and Alcoholism. The authors reported no financial conflicts. Dr. Saitz reported having been a consultant for online alcohol-related screening and brief intervention education projects supported by National Institutes of Health grants. He also has been compensated by Beth Israel Deaconess Hospital and the National Institute on Alcohol Abuse and Alcoholism for serving on data and safety monitoring boards. He has been or anticipates being compensated as a speaker or consultant on alcohol and drug topics by multiple government agencies, academic institutions, professional societies, and private companies. Dr. Naimi reported currently receiving NIH grant support.

Subject Codes:
top_stories; mental_health; pediatrics; emergency_trauma;


http://www.imng.com


August 03, 2010   04:00 PM EDT

Richard Saitz

By Robert Finn
Elsevier Global Medical News
Breaking News

An intervention intended to increase empowerment among Chinese female victims of intimate partner violence failed to decrease depression appreciably more than did usual community services, according to a randomized, controlled trial published Aug. 4 in JAMA.

Women in both the experimental and control groups achieved substantial reduction in depression scores, as measured by the Chinese version of the Beck Depression Inventory II (C-BDI-II). Mean scores of 38-39 placed the women in the “severe depression” category at baseline. At the end of the 12-week intervention, mean scores declined to 24-26 in both groups, corresponding to “moderate depression.” Six months later, mean scores declined to 16-18, corresponding to “mild depression” (JAMA 2010;304:536-43).

After the researchers adjusted for differences in baseline scores, Agnes Tiwari, Ph.D., of the University of Hong Kong, and her colleagues found a 2.7-point difference between the groups in C-BDI-II scores at the final follow-up. Although that difference achieved statistical significance, it did not achieve the 5-point difference needed for meaningful clinical significance.

The study involved 200 women, aged 18 years and older, who screened positive for intimate partner violence (IPV) at a community center in Hong Kong between 2007 and 2009. They were randomly assigned to experimental and control groups. Participants in the control group received usual community services, including childcare, health care, health promotion, and recreation.

Women in the experimental group received an intervention consisting of two components: empowerment and social support. The empowerment component, delivered by a research assistant in a 30-minute one-to-one interview, aimed to increase women’s safety through recognition of danger and use of a safety plan. They learned about the cycle of violence, facts and options, community resources, and legal interventions. The social support component consisted of 12 weekly telephone calls with a research assistant and 24-hour access to a hotline.

None of the women were lost to follow-up during the course of the 9-month study. A total of 88 of the 100 women in the experimental group received all 12 weeks of telephone support, and the remaining 12 all received 10 or 11 weeks, indicating a very high level of adherence to the experimental protocol.

While the differences in depression scores between the groups were not clinically meaningful, women in the experimental group were significantly more likely than were controls to say that the intervention was “useful to extremely useful” in improving their intimate relationships (94% vs. 82%) and in helping them resolve conflicts with their intimate partners (98% vs. 84%).

The study was supported by the Food and Health Bureau of the Hong Kong Government. The authors of the study and the editorial said they had no financial relationships to disclose.

Subject Codes:
top_stories; mental_health; general_primary; womans_health;


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August 03, 2010   04:00 PM EDT

By Mitchel L. Zoler
Elsevier Global Medical News
Breaking News

U.S. waistlines grew once again in 2009, with results from a national, annual telephone survey of more than 400,000 Americans showing that national obesity prevalence in adults reached a new high of 26.7%, up more than 1% from 2007, and by nearly 7% from 2000.

Nine states, all clustered in the South and southern Midwest, had statewide obesity prevalence rates of at least 30% in 2009, up from no states in 2000, and up from three states in 2005 and 2007.

The new data show “obesity continues to be a major public health problem. We need intensive, comprehensive and ongoing efforts to address obesity,” said Dr. Thomas R. Frieden, director of the Centers for Disease Control and Prevention in Atlanta. The CDC runs the annual Behavioral Risk Factor Surveillance System (BRFSS) survey that generated these data, and CDC researchers reported the findings (MMWR 2010;59 [Aug. 3]:1-5

“Over the past decades, obesity has risen faster than anyone could have imagined,” Dr. Frieden said at a press conference on Aug. 3 where he presented and discussed the new data.

The continued growth of obesity has substantial health and economic consequences. The CDC report noted that each obese person (body mass index of at least 30 kg/m²) accrued on average $1,429 increased cost annually for medical care, compared with those at normal weight. With the report estimating roughly 75 million obese American adults in 2009 – up by 2.4 million from 2007 – the total medical-cost price tag for adult, American obesity ran to beyond $150 billion per year.

The new report highlighted the need to intensify efforts already underway to reduce and prevent obesity in America. “Obesity is a complex problem that requires both personal and community action. We need to change our communities into places where healthy eating and active living are the easiest path,” said Dr. William Dietz, director of the CDC’s Division of Nutrition, Physical Activity, and Obesity.

As with tobacco, “we believe that changes in policy, environment, and systems are necessary to control and prevent the epidemic. There has been a broad cultural shift that has made high-calorie food more readily available and has reduced the opportunities for physical activity,” Dr. Dietz said at the press conference. He was optimistic that “there has never before been a greater convergence of energy and interest in the problem of obesity” as there now is in the United States.

“Obesity is a societal problem that will take a societal response,” Dr. Frieden said.

Dr. Dietz also noted that these findings derived from self-reports to the BRFSS are underestimates of true obesity prevalence because of the unreliability of self-reported height and weight data in telephone surveys.

The 2009 obesity rates varied substantially by several demographic factors. The highest prevalence rates occurred in Americans aged 50-59 and 60-69, with a 31% obesity rate in both age groups. Obesity prevalence only reached 20% in those aged 18-29, and 21% in those 70 or older.

Race or ethnicity also had a substantial impact, with African Americans having a 37% obesity prevalence, followed by a 31% rate in Hispanics and a 25% rate in white. Among African American women the obesity rate soared to 42%, compared with a 31% rate in African American men. Overall, however, gender had a modest effect, with a 27% obesity rate in all American men and a 26% rate in all women.

Education also tracked with obesity, with college graduates having an overall 21% rate, compared with a 29% rate among those with even some college-level education, and a 33% obesity rate in people who did not finish high school.

Geography also linked with major variations in obesity rates. The rate reached 28% in the South and Midwest, and 24% in the East and West. A state-by-state breakdown showed even wider variation. Nine states, all clustered in the south-central United States, had statewide obesity rates at or above 30%: Alabama, Arkansas, Kentucky, Louisiana, Mississippi, Missouri, Oklahoma, Tennessee, and West Virginia all fell into this group, with Mississippi topping the list with a statewide prevalence of 34.4%. At the other end of the spectrum, Colorado had the lowest prevalence rate, 18.6%. The only other part of the United States with a rate less than 20% was Washington, D.C. at 19.7%

The reasons that Colorado residents have had relative success warding off obesity remains unclear, Dr. Dietz said. The high altitude where many residents live may be a factor, as people expend more energy to breathe at higher altitudes. Also, the state has supported physical activity for many years by, for example, building biking and walking paths, and Colorado residents responded by developing a culture of activity, he said. Explanations of why Washington, D.C., residents also had a relatively low obesity rate are also unclear; one factor may be high reliance on public transit in the city.

Subject Codes:
top_stories; diabetes; pediatrics; general_primary; endocrinology; cardiology;


http://www.imng.com


August 03, 2010   03:09 PM EDT

Thomas R. Frieden

By Mary Ann Moon
Elsevier Global Medical News
Breaking News

A diet rich in certain foods such as nuts, fish and vegetables and low in high-fat dairy foods and red meat appears exert a preventative effect on the development of Alzheimer's disease, according to a study published online April 12 in the Archives of Neurology.

“Our findings provide support for further exploration of food-combination–based dietary behavior for the prevention of this important public health problem,” wrote Yian Gu, Ph.D., of the Taub Institute for Research in Alzheimer’s Disease and the Aging Brain at Columbia University, New York, and associates.

The researchers sought to assess food combinations rather than individual nutrients in relation to Alzheimer’s risk, so they studied dietary data obtained by food frequency questionnaires in two multiethnic cohorts: elderly subjects participating in the 1992 and the 1999 Washington Heights–Inwood Columbia Aging Project (WHICAP). Their study included 2,148 individuals who underwent serial batteries of neuropsychological tests, assessments of social and occupational function, and specific testing for cognitive deficits and dementia.

During an average follow-up of about 4 years, 253 of these subjects developed Alzheimer’s disease. Subjects were diagnosed for dementia using the criteria developed by the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer Disease and Related Disorders Association. Some of the patients may have had stroke in addition to Alzheimer’s.

The investigators calculated dietary patterns based on variations in the content of seven key nutrients that have been most consistently related to dementia risk in the literature. Only one dietary pattern was found to be strongly associated with AD prevention: a diet rich in omega-3 polyunsaturated fatty acids, omega-6 polyunsaturated fatty acids, vitamin E, and folate, and poor in saturated fatty acids and vitamin B12.

This pattern correlated with high intakes of salad dressing, nuts, fish, tomatoes, poultry, cruciferous and dark leafy green vegetables and low intakes of high-fat dairy foods, such as butter, red meats, and organ meats, Dr. Gu and colleagues said (Arch. Neurol. 2010 April 12 [doi:10.1001/archneurol.2010.84]).

The protective effect of such a diet did not change after the data were adjusted to account for age, level of education, ethnicity, and sex. Further analysis adjusting for smoking status, body mass index, caloric intake, comorbidities, and apolipoprotein E genotype only slightly attenuated the results.

Similarly, adding data on alcohol consumption and the use of nutritional supplements did not substantially change the association between this dietary pattern and lower risk of AD. In addition, the results were “essentially unchanged” when the analysis was repeated in the subgroup of subjects who developed AD without concomitant stroke.

The study was limited by the use of a single measurement of diet that did not capture long-term dietary habits.

This study was funded by the National Institute on Aging. No financial conflicts of interest were reported.

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


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May 02, 2013   04:00 PM EDT