Pharmacology Watch

FDA Approves Apixaban for Patients with Nonvalvular AF

In this issue: Apixaban approval; new dental clinical practice guideline; apixaban for VTE; aspirin resistance; tamoxifen treatment; and FDA actions.

Apixaban superior to warfarin in trial

The FDA has approved apixaban — the long-awaited third novel oral anticoagulant (NOAC) — for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation (AF). The drug follows dabigatran (Pradaxa) and rivaroxaban (Xarelto) for this indication, which has been traditionally treated with warfarin. The safety and efficacy of apixaban was demonstrated in the 18,000 patient ARISTOTLE trial, which showed that in patients with nonvalvular AF, apixaban was superior to warfarin in preventing stroke and systemic embolism, caused less bleeding, and resulted in lower mortality than warfarin. The FDA will likely allow the manufacturers of apixaban to market the drug as "superior to warfarin." Apixaban is dosed twice a day, similar to dabigatran; rivaroxaban is dosed once a day. Apixaban and rivaroxaban are factor Xa inhibitors, while dabigatran is a direct thrombin inhibitor. No head-to-head studies have been done among the three NOACs, which are expected to compete aggressively for this lucrative market that is worth billions of dollars in sales. All three lack a reversal agent, which could potentially increase the risk of serious bleeding. Apixaban is marketed as Eliquis by Bristol-Myers Squibb and Pfizer.

New dental prophylaxis guideline

The American Academy of Orthopedic Surgeons (AAOS) and the American Dental Association (ADA) have jointly published a clinical practice guideline regarding dental prophylaxis in patients with orthopedic implants. The recommendations, which are based on very limited evidence, state that, "the practitioner might consider discontinuing the practice of routinely prescribing prophylactic antibiotics for patients with hip and knee prosthetic joint implants undergoing dental procedures." The guideline further states that they are unable to recommend for or against topical oral antibiotics in patients with implants, but they do recommend that patients with joint implants should "maintain appropriate oral hygiene," even though there is no evidence regarding this recommendation. This guideline does little to settle the debate between orthopedic surgeons, who often recommend lifetime dental prophylaxis, and infectious disease specialists who generally recommend against dental prophylaxis after 1 year. This rather weakly worded guideline is probably not the guidance most primary care physicians were hoping for, since they are generally responsible for prescribing prophylactic antibiotics and are responsible for possible adverse effects. The full guideline is available at

Length of treatment for VTE

How long should we treat patients with venous thromboembolism (VTE)? VTE includes deep-vein thrombosis and pulmonary embolism. Current guidelines recommend 3-6 months of anticoagulation for unprovoked VTE — usually low-molecular weight heparin followed by warfarin. A new study suggests that an additional year of the factor Xa inhibitor apixaban (recently approved for stroke prevention in nonvalvular atrial fibrillation, see page 1) may be beneficial for these patients. In an industry-sponsored study, patients with VTE who had completed 6-12 months of anticoagulation therapy were randomized to an additional 12 months of apixaban (2.5 or 5 mg twice a day) or placebo. Nearly 2500 patients were included in the intention-to-treat analysis. Recurrent VTE or death from VTE occurred in 73 of 829 patients randomized to placebo (8.8%) compared to 14 of 840 patients on 2.5 mg of apixaban (1.7%) and 14 of 813 patients on 5 mg of apixaban (1.7%; P < 0.001 for both comparisons). The rates of major bleeding were 0.5% in the placebo group and 0.2% and 0.1% in the apixaban 2.5 mg and 5 mg groups, respectively. The rate of death from any cause was 1.7% in the placebo group and 0.8% and 0.5% in the apixaban 2.5 mg and 5 mg groups, respectively. The authors conclude that extended anticoagulation with apixaban at either a treatment dose (5 mg bid) or thromboprophylactic doses (2.5 mg bid) reduced the risk of recurrent VTE without increasing the rate of major bleeding (N Engl J Med published online Dec. 8, 2012. doi: 10.1056/NEJMoa1207541). In this study, the majority of patients were younger than age 75 without other comorbities such as low body weight or renal impairment. It is also unknown if the results of this study are applicable to other approved anticoagulants such as rivaroxaban.

Aspirin resistance and enteric coating

Could "aspirin resistance" be due to enteric coating? The concept of aspirin resistance is very controversial with some experts suggesting that it does not exist. A new study suggests that enteric coating of aspirin may be partially responsible for "pseudoresistance." Researchers recruited 400 healthy volunteers who were then screened for their response to a single, oral dose of 325 mg immediate-release or enteric-coated aspirin. Variable absorption caused nearly half of those taking enteric-coated aspirin to have apparent resistance (49%), while this was not seen in any of the subjects taking immediate-release aspirin. On re-exposure, all of those with variable absorption responded to aspirin. The authors conclude that the study failed to identify a single case of true aspirin resistance, but pseudoresistance, reflecting delayed and reduced drug absorption, complicates enteric-coated but not immediate-release aspirin (Circulation published online Dec. 4, 2012. doi: 10.1161/CIRCULATIONAHA.112.117283). This study seems to contradict the concept that up to 40% of the population is "aspirin resistant." There is a suggestion that the concept of aspirin resistance has been touted by the manufacturers of expensive brand-name aspirin substitutes. This study may question the wisdom of the routine use of enteric-coated aspirin, especially given that enteric coating has very little benefit with regard to gastrointestinal protection.

Is 10 years of tamoxifen better?

Ten years of tamoxifen may be better than the standard 5 years for women with estrogen receptor (ER)-positive breast cancer, according to a new study from the United Kingdom. Researchers randomized about 6800 ER-positive women with early breast cancer who had completed 5 years of adjuvant tamoxifen to another 5 years of treatment or stopping therapy. There were 617 recurrences in the 3428 women who took tamoxifen for 10 years vs 711 in 3418 women who stopped at 5 years (P = 0.002). There was also a lower death rate (331 vs 397, P = 0.01) and reduced overall mortality (639 vs 722, P = 0.01) in the 10-year group. There were higher rates of endometrial cancer (relative risk [RR] 1.74, 95% confidence interval [CI], 1.30-2.34) and pulmonary embolism (RR 1.87; CI, 1.13-3.07) in the 10-year group, but no higher rate of stroke and a lower risk of ischemic heart disease (RR 0.76; CI, 0.60-0.95). The authors suggest that 10 years of tamoxifen in ER-positive patients can approximately halve breast cancer mortality during the second decade after diagnosis (Lancet published online Dec. 5, 2012. 61963-1).

FDA actions

The FDA has approved pasireotide diaspartate injection for the treatment of Cushing's disease in patients who are not candidates for surgery or for whom surgery has not worked. The drug is considered an orphan drug. The safety and efficacy were evaluated in a trial of 162 patients with Cushing's disease who were randomized to one of two doses of the drug. About 20% of participants had normal urine cortisol levels within 6 months. Side effects included increased blood sugar levels and liver injury. The drug is administered subcutaneously twice a day. It is marketed by Novartis as Signifor. In February 2012, the FDA approved mifepristone (Korlym) for the treatment of Cushing's syndrome.

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: