Pharmacology Watch

Rivaroxaban Now Approved for Stroke Prevention

In this issue: New indication for rivaroxaban; new study on warfarin testing; medications causing adverse drug events; niacin as an add-on therapy; and FDA actions.

Rivaroxaban for atrial fibrillation patients

Rivaroxaban (Xarelto), Janssen Pharmaceutical's once-a-day oral Xa inhibitor, has been approved for reducing the risk of stroke in patients with atrial fibrillation. The drug was previously approved for prophylaxis of deep vein thrombosis in patients undergoing hip or knee replacement. Rivaroxaban is the second "non-warfarin" oral anticoagulant to be approved for this indication after the direct thrombin inhibitor dabigatran (Pradaxa). The approval was based on the ROCKET AF trial, a double-blind, randomized, noninferiority comparative trial with warfarin, which showed a rate of stroke or systemic embolism of 2.1% per year for rivaroxaban and 2.4% per year for warfarin. The study looked at 14,000 patients over 700 days of follow-up. Rates of major and non-major bleeding were the same with the two drugs, although the rate of intracranial hemorrhage was lower for rivaroxaban while the rate of GI bleeding was lower with warfarin. ROCKET AF showed noninferiority of rivaroxaban vs warfarin but not superiority (N Engl J Med 2011;365:883-891). The approval sets up a major marketing showdown between Janssen and Boehringer Ingelheim, the manufacturer of dabigatran, for this multibillion dollar market. Meanwhile, Pfizer and Bristol-Myers Squibb are jointly developing a third drug — apixaban, also a factor Xa inhibitor — which is undergoing an "accelerated review" by the FDA with approval likely in March 2012. All three drugs have the potential disadvantage of the lack of an antidote, a problem that seems to be plaguing dabigatran with more than 250 fatal bleeding episodes reported worldwide since the drug was approved in 2010. A recent report suggests that prothrombin complex concentrate may be an effective reversal agent for rivaroxaban but not dabigatran (Circulation 2011;124:1573-1579).

Warfarin testing every 12 weeks?

One of the major disadvantages of warfarin over the newer anticoagulants is the need for frequent prothrombin time monitoring and dose adjustment. Most guidelines recommend a maximum interval of 4 weeks between testing. A new study suggests that stable patients may be safely tested at 12-week intervals. A total of 226 patients who were on a stable dose of warfarin for at least 6 months were assigned to testing every 4 weeks, while the other half had blood tests done every 4 weeks, but sham INRs within the target range were reported for two of the three 4-week periods. The percentage of time in the therapeutic range was 74.1% in the 4-week group compared with 71.6% in the 12-week group (noninferiority P = 0.020 for a 7.5% point margin). Patients in the 12-week group had fewer dose changes and secondary outcomes, including major bleeding, thromboembolism, and death that were no different between the two groups. The authors conclude that assessment of warfarin dosing every 12 weeks seems to be safe and noninferior to assessment every 4 weeks, although they recommend further study (Ann Intern Med 2011;155:653-659). This study is important given the marked cost differential between warfarin and dabigatran or rivaroxaban. Some patients, especially if they pay for their own medications, may opt to remain on warfarin if they are on a stable dose, especially if they only require testing four times a year.

Adverse drug events in the elderly

Although low cost, warfarin remains one of the most dangerous medications in common usage. In fact, hospitalizations for adverse events in the elderly are much more likely to be caused by commonly used medications, such as warfarin, rather than medications classified as high risk in the elderly, according to a new study from the CDC. Researchers used a national database of adverse drug events from 2007-2009 to estimate the frequency and rates of hospitalization after emergency department visits for adverse events in older adults to assess the risk of specific medications causing this hospitalization. It is estimated that adverse drug events led to nearly 100,000 hospitalizations during the 2-year period with nearly half among adults 80 years of age or older. Nearly two-thirds of the hospitalizations were due to unintentional overdoses. Four medications or medication classes were implicated alone or in combination in 67% of hospitalizations including warfarin (33.3%), insulins (13.9%), oral antiplatelet agents (13.3%), and oral hypoglycemic agents (10.7%). High-risk medications were implicated in only 1.2% of hospitalizations. The authors suggest that efforts to promote the safe management of antithrombotic and antidiabetic agents have the potential to substantially reduce harm to our older patients (N Engl J Med 2011;365:2002-2012). This study points out that we may be spending too much effort in managing "high-risk" medications in the elderly, while warfarin alone is responsible for a third of medication-related hospitalizations.

Is it time to retire niacin?

An editorial published online in the New England Journal of Medicine asks, "Niacin at 56 Years of Age — Time for an Early Retirement?" Retirement may be the logical next step after publication of the AIM-HIGH trial, the National Heart Lung and Blood Institute's trial comparing niacin plus intensive statin therapy with intensive statin therapy alone in patients with established cardiovascular disease. The study was halted early when it was found that the addition of 1500-2000 mg of niacin per day to simvastatin, despite significantly raising HDL levels an average of 7 points, had no effect on the primary endpoint, which was a composite of the rate of death from coronary artery disease, nonfatal myocardial infarction, ischemic stroke, hospitalization for acute coronary syndrome, or symptom-driven coronary or cerebral revascularization (primary endpoint 16.4% niacin group, 16.2% placebo group; P = 0.79) (N Engl J Med published online November 15, 2011). The accompanying editorial suggests there is lack of evidence to support niacin as an add-on therapy in patients with cardiovascular disease who have well-controlled LDL cholesterol levels. Additionally, long-acting niacin is relatively expensive and frequently causes flushing — two additional factors that argue against continued use of the drug except, perhaps, in patients who are intolerant of statins (N Engl J Med published online November 15, 2011).

FDA actions

The news isn't much better for fenofibrate. The FDA has issued a safety communication for the cholesterol lowering medication stating that the drug may not lower the risk of major cardiovascular events based on data from the ACCORD Lipid trial. ACCORD (similar in design to AIM-HIGH) evaluated the efficacy and safety of fenofibrate plus simvastatin vs simvastatin alone in patients with type 2 diabetes. There was no significant difference in the risk of experiencing a major adverse cardiac event between the two groups, and women may have even experienced an increase in the risk for major adverse cardiac events with combination therapy vs simvastatin alone. The FDA is requiring the manufacturer of Trilipix brand fenofibric acid to conduct a clinical trial to evaluate the cardiovascular effects of the drug in patients at high risk for cardiovascular disease who are already taking statins (

The FDA has approved a new formulation of zolpidem for treatment of insomnia in patients who wake up in the middle of the night and have difficulty returning to sleep. Zolpidem, originally marketed as Ambien and now available as a generic, is a short-acting hypnotic. The new product is a lower dose sublingual formulation that comes in a 1.75 mg dosage recommended for women and 3.5 mg for men. The lower dose for women is recommended because women clear the drug more slowly than men. It can be used if the patient has at least 4 hours of bedtime remaining. Zolpidem sublingual is marketed by Transcept Pharmaceuticals as Intermezzo.

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) 262-5404. E-mail: