Pharmacology Watch

Apixaban is Heating Up the Anticoagulation Market

In this issue: Apixaban could soon join the anticoagulation market; Chinese herbs for flu; chronic medication and discontinuation after hospitalization; and FDA actions.

Apixaban trial results look promising

There is soon to be a third player in the anticoagulation wars. Apixaban, an oral factor Xa inhibitor, will likely soon join dabigatran and rivaroxaban as alternatives to warfarin for preventing stroke in patients with atrial fibrillation (AF). Dabigatran, a direct thrombin inhibitor, was approved for this indication last year and rivaroxaban, also a factor Xa inhibitor, is likely to be approved in early September. (Rivaroxaban was previously approved for DVT prevention in patients undergoing orthopedic surgery.) Apixaban also looks very promising based on results of the ARISTOTLE trial, which was published online in the New England Journal of Medicine on August 28. ARISTOTLE enrolled 18,201 patients with AF and at least one additional risk factor for stroke. Patients were randomly assigned to apixaban 5 mg twice daily or warfarin with a target INR of 2-3. ARISTOTLE was designed as a noninferiority study with a primary outcome of ischemic or hemorrhagic stroke, or systemic embolism. After median follow-up of 1.8 years, the rate of the primary outcome was 1.27% per year in the apixaban group vs 1.60% in the warfarin group (hazard ratio [HR] 0.79; 95% confidence interval [CI] 0.66 to 0.95; P < 0.0014 noninferiority; P = 0.01 for superiority). The rate of major bleeding was 30% less with apixaban and the rate of death from any cause was 3.52% with apixaban and 3.94% with warfarin (P = 0.047). The rate of hemorrhagic stroke in the apixaban group was about half that in the warfarin group (0.24% per year vs 0.47% per year, P < 0.001) and the rate of all other strokes was 0.97% with apixaban vs 1.05% with warfarin (P = 0.42). The authors conclude that in patients with AF, apixaban was superior to warfarin in preventing stroke or systemic embolism, caused less bleeding, and resulted in lower mortality (N Engl J Med published online August 28, 2011). An excellent accompanying editorial discusses the seminal studies that compared the three new anticoagulants to warfarin for stroke prevention in patients with AF: RE-LY — dabigatran; ROCKET AF — rivaroxaban; and ARISTOTLE — apixaban. All three showed that the new drugs were significantly better than warfarin at reducing hemorrhagic stroke and all were at least as effective as warfarin at preventing ischemic stroke. All three drugs were also associated with a significantly lower rate of serious bleeding compared to warfarin. Apixaban was the only drug that showed a significant reduction in overall mortality, although both dabigatran and rivaroxaban showed trends in that direction. ROCKET AF has been criticized because the warfarin comparator group had a time in therapeutic range of only 55% compared to 64% in the RE-LY trial and 62% in ARISTOTLE; however, patients in the ROCKET AF study were at higher risk for stroke than in the other two studies. The bottom line is that all three drugs are effective in preventing stroke in patients with nonvalvular AF and seem to be safer than warfarin as well. The new drugs do not require any laboratory monitoring, which is convenient for patients and also lowers the overall cost of care (although all three drugs will be priced significantly higher than generic warfarin). Rivaroxaban has the advantage of a once daily dose vs the other two drugs, which must be dosed twice daily. None of the three drugs can be quickly reversed in the event of major bleeding or need for surgery. Apixaban is not yet approved in this country but when it is, it is likely that the competition between these three agents will be fierce, and for many purchasers of health care it may come down to cost.

Chinese herbs for flu treatment

For the flu season this year, you might consider Chinese herbs instead of antivirals based on the results of a study from China published in the Annals of Internal Medicine. More than 400 adults age 15-59 years with confirmed H1N1 influenza were randomized to oseltamivir 75 mg twice daily or a combination of 12 Chinese herbal medicines called maxingshigan-yinqiaosan 200 mL four times a day, a combination of oseltamivir plus maxingshigan-yinqiaosan, or placebo for 5 days. The primary outcome was time-to-fever resolution and the secondary outcomes included symptom scores and viral shedding. Both oseltamivir and maxingshigan-yinqiaosan, as well as the combination, resulted in significant reductions in the estimated median time-to-fever resolution compared to the control group (median time-to-fever resolution — no treatment 26 hours; oseltamivir 20 hours; maxingshigan-yinqiaosan 16 hours; combination 15 hours; all statistically significant at P < 0.001). Side effects were similar in all groups. The authors conclude that oseltamivir and maxingshigan-yinqiaosan, alone or in combination with each other, reduce time-to-fever resolution in patients with H1N1 influenza. They go so far as to suggest that maxingshigan-yinqiaosan may be used as an alternative treatment for H1N1 infections (Ann Int Med published online August 26, 2011). It may be difficult to obtain maxingshigan-yinqiaosan since it contains ephedra (which is not available in this country) and the authors could not determine if the benefits of maxingshigan-yinqiaosan were due to an antiviral effect or merely an antipyretic effect.

Chronic medications and hospitalization

Your patients' chronic medications may be inadvertently discontinued after hospitalization according to a population-based cohort study of almost 400,000 patients published recently in the Journal of the American Medical Association. Researchers from Canada reviewed the records of residents age 66 or older who were on statins, antiplatelet/anticoagulant agents, levothyroxine, respiratory inhalers, or gastric acid suppressing drugs on a chronic basis. When compared to nonhospitalized patients, patients admitted to the hospital — especially the ICU — were more likely to have their chronic medications discontinued. Discontinuation rates ranged from a low for levothyroxine of 12.3% discontinuation for hospitalizations vs 11% for controls, to antiplatelet/anticoagulant agents which were discontinued at a rate of 19.4% for hospitalizations vs 11.8% for controls. The discontinuation rates were even higher for patients who were admitted to the ICU. The authors conclude that patients admitted to the hospital are at relatively high risk for potential unintentional discontinuation of chronic medications (JAMA 2011;306:840-847). This study points out the importance of medication reconciliation at all post-hospital visits and may validate the role of computerized medical records, especially with regard to medication lists.

FDA actions

The FDA has approved a new fixed-dose combination pill for HIV-infected patients. Emticitabibine/rilpirivine/tenfovir DF is approved as a once-a-day pill for treatment of HIV-1 infection in treatment-naïve patients. This is the second triple combination anti-HIV agent approved and differs from the previous agent (Atripla) in that it contains the NNRTI rilpirivine rather than efavirenz. The new combination will be marketed as Complera.

The FDA has approved brentuximab vedotin to treat Hodgkin lymphoma (HL) and systemic anaplastic large cell lymphoma. The drug is approved for HL patients who have progressed after autologous stem cell transplant or after prior chemotherapy regimens and cannot receive a transplant. This represents the first the drug to treat HL since 1977. Brentuximab will be marketed as Adcetris.

The FDA has approved vemurafenib for the treatment of metastatic and unresectable melanoma, specifically in patients whose tumors have the BRAF V600E mutation. The approval was accompanied by a companion diagnostic test that will determine if a patient's melanoma cells have that mutation (about half of the patients with late stage melanomas). Only patients with the BRAF V600E mutation will respond to the drug since it targets the mutated protein that regulates cell growth. Vemurafenib is marketed by Genentech as Zelboraf.

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: