Rivaroxaban: EINSTEIN at ASH and another rock on the road to approval 1

The presentation of the EINSTEIN-Extension trial of rivaroxaban for VTE at the American Society of Hematology meeting in New Orleans on Tuesday was overshadowed by the drug’s developer’s disclosure of a new rock on rivaroxaban’s road to FDA approval.

The company developing rivaroxaban, Bayer, said in a press release that it would not respond to an FDA Complete Response Letter this year, as it had previously stated, but would instead “communicate an updated filing strategy in its Annual Press Conference on February 28, 2010,” according to a Bayer press release.
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RE-COVER at ASH: Dabigatran equals warfarin for VTE treatment Reply

Dabigatran (Pradaxa) is as effective as warfarin for the treatment of VTE, according to results of the RE-COVER study presented today at the American Society of Hematology meeting today and published online in the New England Journal of Medicine.

Sam Schulman and colleagues randomized 2539 patients with acute VTE to warfarin or dabigatran (150 mg twice daily) for 6 months. Patients were initially treated with heparin for 5 to 11 days. At 6 months the incidence of recurrent VTE was 2.2% (27 patients) in the warfarin group versus 2.4% (30 patients) in the dabigatran group, a difference which fell within the prespecified margin for noninferiority (p<0.0001). Major bleeding occurred in 20 dabigatran-treated patients and 24 warfarin-treated patients. There were no significant differences in mortality, ACS, or liver function test abnormalities.

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Industry, academic researchers, and clinical trials: the slippery slope Reply

Ed Silverman’s venerable Pharmalot blog recently posted a useful summary of some of the conflict of interest problems that come up when physicians enroll their patients in clinical trials. The basis for the article was a 62-page paper from the  Center for Health & Pharmaceutical Law & Policy at the Seton Hall Law School.

But what really caught our eye was a detailed comment at the bottom of the post by “Pharmavet,” who is, apparently, a pharmaceutical executive with extensive experience in the clinical trials arena. You should read his entire comment, filled with insights gained from years of daily battle in the trenches, but here are a few highlights:
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BMJ: risk of VTE after surgery is higher and lasts longer than expected Reply

The risk of VTE after surgery is higher and lasts longer than expected, according to an article in the BMJ by Valerie Beral and colleagues on behalf of the Million Women Study collaborators. Using data from nearly 1 million women admitted to the hospital in the UK and nearly a quarter of a million admissions for surgery, the study found that women who had surgery were 70 times more likely to have VTE than women not having surgery. For outpatient procedures the risk was increased 10 times.
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BMJ: Large observational study finds excess CV risk with sulphonylureas, but benign outcomes with TZDs Reply

In recent years the debate over the proper use  and relative benefits of diabetes drugs has been unceasing. The significance of the controversy has been elevated due to the rising tide of diabetes and the commercial importance of many of these drugs. Now a new and very large observational study from the UK may help shed light on the real world impact of these drugs, but the more difficult decisions relating to these drugs surely will not be settled by studies of this nature.
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Roche’s taspoglutide beats sitagliptin in phase III trial 2

Two phase III trials with taspoglutide have met their primary endpoint, according to an announcement by Roche. Taspoglutide is under development by Roche as a once-weekly GLP-1 inhibitor for use in type 2 diabetics.

In the T-emerge 4 trial, taspoglutide was superior to sitagliptin in reducing HbA1c levels in 636 patients who had failed to reach treatment targets with metformin. The trial also included a placebo arm, but the press release did not give results for this part of the trial. (CardioBrief has asked Roche for clarification about this point.)
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JAMA: It’s hard to beat Framingham; beware the meta-analysis Reply

Don’t believe the hype about new risk factors, or other attempts to modify the Framingham Risk Score (FRS). That’s the message of Ioanna Tzoulaki, George Liberopoulos, and John Ioannidis in a JAMA review article assessing claims of improvements to the FRS. The same issue contains a commentary by Charles Hennekens and David DeMets warning against the dangers of small trials, meta-analyses, and subgroup analyses.
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Circulation: exercise may help slow aging process by protecting telomeres 1

Intensive exercise protects against telomere shortening, according to an intriguing new study appearing in Circulation. German researchers studied young professional runners, middle-aged athletes, and age-matched controls who did not exercise regularly.

“The most significant finding of this study is that physical exercise of the professional athletes leads to activation of the important enzyme telomerase and stabilizes the telomere,” said Ulrich Laufs, the study’s lead author from Saarland University in Homburg, Germany, in an AHA press release.
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Dronedarone (Multaq) gains EU approval for atrial fibrillation Reply

Sanofi-aventis announced today that dronedarone (Multaq) received approval for the indication of atrial fibrillation in the European Union. Dronedarone was approved in the US last July. (Click here for our previous coverage of dronedarone.)

The approval comes with a contraindication for use in unstable patients with class III and IV heart failure, and a recommendation against its use in patients with LVEF below 35%.

Click here to read the press release from Sanofi-aventis…

NEJM: very low troponin T levels in stable CAD associated with death and HF, but not MI Reply

Using a new, highly sensitive assay for cardiac troponin T, investigators from the PEACE trial have been able to demonstrate that nearly all patients with stable CAD have detectable levels of troponin T, and that these levels may predict death and heart failure. Somewhat surprisingly, however, troponin T levels were not significantly associated with MI in the study. The results appear in a report in the New England Journal of Medicine by Torbjørn Omaland and other PEACE Trial investigators, led by Eugene Braunwald.
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Did Medicaid pay for all those Plavix ads on the news? Reply

Direct-to-consumer (DTC) advertising doesn’t increase drug usage but it does raise the cost of drugs, according to an article by Michael Law and colleagues in Archives of Internal Medicine.

Using Plavix (clopidogrel) as a case study, the researchers studied pharmacy data from Medicaid programs from 1999 through 2005. Plavix did not begin DTC advertising until 2001. The researchers found that DTC advertising did not appear to increase the amount of clopidogrel sold, but they did observe “a sudden and sustained increase in cost per unit” after DTC initiation.
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Vioxx: what did Merck know and when did it know it? 1

Merck may have been aware of the heightened cardiovascular risk of rofecoxib (Vioxx) years before it withdrew the drug from the market in 2004, according to an article appearing in the Archives of Internal Medicine.

Joseph Ross and colleagues analyzed data available to the manufacturer from 30 randomized trials and enrolling over 20,000 subjects. As early as December 2000, only a year and a half after the drug’s approval in May 1999, the data from the trials available at the time gave a strong cardiovascular safety signal (RR= 2.18, CI=0.93-5.81, p=0.07). The signal grew increasingly convincing, reaching significance (p=0.05) by June 2001 with a 35% increased risk of cardiovascular thromboembolic events or death. The signal continued to grow stronger: by September 2004 the use of rofecoxib was associated with a highly significant 43% elevated risk (RR=1.43, CI=1.16-1.76, p<0.001).
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FDA also announces safety review of sibutramine (Meridia) 1

Following a similar earlier communication today from the European Medicines Agency, the FDA late this afternoon announced an ongoing safety review of Meridia (sibutramine). The FDA announcement includes some details not contained in the EMEA communication.

According to the FDA announcement (see below), preliminary data from the SCOUT trial (Sibutramine Cardiovascular Morbidity/Mortality Outcomes in Overweight or Obese Subjects at Risk of a Cardiovascular Event) suggest that patients taking sibutramine may have a higher risk of cardiovascular events (heart attack, stroke, resuscitated cardiac arrest, or death) than patients taking placebo. The FDA reported that the rate of cardiovascular events was 11.4% in the sibutramine arm versus 10% in the placebo arm.
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EINSTEIN at ASH: rivaroxaban (Xarelto) prevents recurrent VTE, but bleeding may be a concern Reply

EINSTEIN-Extension, which will be presented as a late-breaking clinical trial at the American Society of Hematology meeting in New Orleans on December 8, demonstrates that rivaroxaban (Xarelto), the direct oral factor Xa inhibitor, is effective in the long-term prevention of recurrent venous thromboembolism. But a high bleeding rate may dampen enthusiasm for the new oral anticoagulant.

The trial randomized 1,197 patients who had already completed 6-12 months of anticoagulant treatment for a first acute episode of VTE to either rivaroxaban or placebo for an additional 6-12 months. Symptomatic recurrent VTE occurred in  42 (7.1%) of placebo patients and 8 (1.3%) of rivaroxaban patients, representing a highly significant 82% relative risk reduction. When therapy was stopped, after a mean duration of 190 days, there were 6 new events in each group in the following month.
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AHA: Ken Baughman dies after a traffic accident in Orlando 7

Ken Baughman, 63, has died as a result of a traffic accident on Monday in Orlando, FL. Baughman, the former head of the division of cardiology at Johns Hopkins, was the Director of the Advanced Heart Disease Program at Brigham & Women’s Hospital.
The Boston Globe reports that Baughman was hit by a car at 6 AM while jogging at the intersection of Sand Lake Road and Universal Boulevard in Orlando.

Here are statements from Baughman’s family, the president of Brigham and Women’s Hospital, and from the AHA:
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FDA issues public health advisory on interaction between clopidogrel and omeprazole 2

Updated: The FDA has issued a public health advisory to highlight updated safety information regarding an interaction between clopidogrel (Plavix) and omeprazole. The label change, which was made on Friday, was reported first by CardioBrief yesterday.

An FDA official explained that the label changes were based on data from a new study performed by the sponsor: Here are the study details as written in the new label:
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