Gender Differences with Anticoagulation Discontinuation

Pharmacology Watch

In this issue:
Some women with DVT may stop warfarin after six months; Vytorin and cancer; preventing recurrent stroke; and FDA news.

When is it safe to stop anticoagulation after an unprovoked venous thromboembolism? A new study suggests that women with minimal risk factors may safely stop anticoagulation after 6 months of therapy, although the same may not be true for men. Canadian researchers randomized 646 patients with a first, unprovoked major venous thromboembolism and followed them for 4 years. Data were collected for 69 potential predictors of recurrent venous thromboembolism while patients were taking oral anticoagulants and a multi-variable analysis of predictor variables was performed. Men had a 13.7% annual risk of recurrence after discontinuing oral anticoagulation and there was no combination of clinical predictors that could identify a low-risk subgroup of men. In women, 52% had zero or one of the following risk factors: hyperpigmentation, edema or redness of either leg, d-dimer ≥ 250 mcg/L while taking warfarin, body mass index ≥ 30 kg/m2, or age ≥ 65 years. These women had an annual risk of recurrent thromboembolism of 1.6% (95% CI, 0.3% to 4.6%). Women who had two or more of these risk factors had an annual risk of 14.1%. The authors conclude that women with zero or one risk factor may safely discontinue oral anticoagulant therapy after 6 months of therapy following their first unprovoked venous thromboembolism; however, this conclusion does not apply to men (CMAJ 2008;179:417-426). An accompanying editorial points out that patients with the first episode of unprovoked venous thromboembolism have a high rate of recurrence if they stop anticoagulation therapy — about 10% in the first year. Current guidelines from the American College of Chest Physicians recommend lifetime therapy for patients with a first episode of proximal deep venous thrombosis or pulmonary embolism provided that good anticoagulant monitoring is achievable and indefinite treatment is consistent with patient preferences. This study identifies a large group of women who may safely stop anticoagulation after 6 months although the authors do recommend further validation (CMAJ 2008;179:401-402).

FDA Announces Vytorin Investigation

The news keeps getting worse for Merck/Schering-Plough, the distributor of Vytorin®: The FDA has announced that it will investigate a report from the SEAS trial (Simvastatin and Ezetimibe in Aortic Stenosis) of the possible association between the use of Vytorin and increased incidence of cancer. The SEAS trial was designed to see if Vytorin, a combination of simvastatin and ezetimibe, would reduce cardiovascular events in patients with aortic stenosis. In a July press release, the company reported on preliminary data which showed that the trial did not show benefit for the primary endpoint of aortic-valve related major cardiovascular events, but did show that a larger percent of subjects treated with Vytorin were diagnosed with, and died from, all types of cancer compared to placebo during the 5-year study. There was improvement in the secondary endpoint of ischemic events (15.7% vs 20%) but no benefit in other secondary endpoints. The number of cancers was 105 (11.1%) in the Vytorin group vs 70 (7.5%) in the control group (P = 0.01), and the number of cancer deaths was 39 (4.1%) in the Vytorin group vs 23 (2.5%) in the control group (HR 1.67; 95% CI, 1.00 to 2.79; P = 0.05). The FDA is also looking at interim data from two large ongoing trials of Vytorin, the Study of Heart and Renal Protection (SHARP) and the Improved Reduction in High-Risk Subjects Presenting with Acute Coronary Syndrome (IMPROVE-IT) which, so far, have not shown an increased risk of cancer associated with Vytorin. The SHARP trial should be completed in 2010, while the IMPROVE-IT trial should be finished in 2012. Initial data from the SEAS trial were presented in the recent news conference; full results were published at (DOI: 10.1056/NEJMao0804602) on Sept. 2, 2008. The FDA says its investigation will take at least 6 months from the date of publication.

PRoFESS Trial Shows No Stroke Benefit

The recently published PRoFESS trial failed to show benefit of two strategies for preventing recurrent strokes. In the first arm of the study, the angiotensin-receptor blocker (ARB) telmisartan was compared to placebo in more than 20,000 patients with ischemic stroke. Patients were randomized to telmisartan 80 mg daily or placebo and followed for a mean follow-up of 2.5 years. Mean blood pressure was 3.8/2.0 mmHg lower in the telmisartan group; however, there was no difference in the rate of recurrent stroke (8.7% telmisartan vs 9.2% placebo [HR 0.95; 95% CI, 0.87 to 1.01; P = 0.11). The rate of new onset diabetes was 1.7% in the treatment group and 2.1% in the placebo group (P = 0.10). The authors conclude that therapy with telmisartan initiated soon after an ischemic stroke did not significantly lower the rate of recurrent stroke, diabetes, or major cardiovascular events. The second wing of the study compared aspirin plus 200 mg of extended release dipyridamole (Persantine®) twice daily vs clopidogrel (Plavix®) 75 mg daily in the same patient group. After a mean of 2.5 years of follow-up recurrent stroke occurred in 9% of patients receiving aspirin and dipyridamole and 8.8% of patients receiving clopidogrel (HR 1.01; 95% CI, 0.92 to 1.11). The secondary outcomes of stroke, myocardial infarction, or death from vascular causes occurred in 13.1% of both groups. The authors conclude that there is no evidence that either of the two treatments was superior to the other in the prevention of recurrent stroke (N Engl J Med, published on-line at, Aug. 27, 2008).

FDA Actions

The FDA has issued a warning regarding the use of simvastatin in patients who are taking amiodarone. More than 20 mg of simvastatin plus amiodarone puts patient at higher risk for rhabdomyolysis since amiodarone inhibits CYP 3A4, one of the enzymes that metabolizes simvastatin. The simvastatin labeling has contained a warning regarding concomitant use with amiodarone since 2002; however, the FDA continues to receive reports of rhabdomyolysis associated with use of the two drugs. Physicians are also urged to tell their patients to report any unexplained muscle pain, tenderness, or weakness while taking the drugs. Other risks for rhabdomyolysis associated with statins include advanced age, uncontrolled hypothyroidism, and renal impairment.

There should be plenty of flu vaccine this fall. The FDA has announced the approval of six manufactures including GlaxoSmithKline, ID Biomedical, MedImmune, Novartis, Sanofi Pasteur, and CSL Limited. The vaccine will again be a trivalent vaccine comprised of two influenza A viruses and one influenza B virus. All three strains are new this year, an unusual occurrence as usually only one or two strains are updated each year.

The FDA issued an alert in October 2007 regarding exenatide (Byetta®) and the risk of acute pancreatitis. Since then, 6 more cases of hemorrhagic or necrotizing pancreatitis have been reported to the FDA associated with use of the drug, including two deaths. Exenatide is an injectable incretin mimetic used to treat type 2 diabetes. The FDA is recommending that exenatide should be stopped immediately if pancreatitis is suspected. Currently there is no patient profile which would predict increased risk of pancreatitis. Amylin Pharmaceuticals, the manufacture of exenatide, is working with the FDA on new labeling regarding the risk of hemorrhagic or necrotizing pancreatitis.

This supplement was written by William T. Elliott, MD, FACP, Chair, Formulary Committee, Kaiser Permanente, California Division; Assistant Clinical Professor of Medicine, University of California-San Francisco. In order to reveal any potential bias in this publication, we disclose that Dr. Elliott reports no consultant, stockholder, speaker's bureau, research, or other financial relationships with companies having ties to this field of study. Questions and comments, call: (404) 262-5468. E-mail: