Pharmacology Update

Apixaban Tablets (Eliquis®)

By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD, Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente; and Assistant Professor of Medicine, University of California, San Francisco. Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA. Drs. Elliott and Chan report no financial relationships relevant to this field of study.

A second factor XA inhibitor (novel oral anticoagulant, NOAC), after rivaroxaban, has been approved for prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation (AF). Apixaban is marketed by Bristol-Myers Squibb and Pfizer as Eliquis.

Indications

Apixaban is indicated to reduce the risk of stroke and systemic embolism in patients with nonvalvular AF.1

Dosage

The recommended dose is 5 mg twice daily.1 For patients 80 years or older, weight 60 kg or less, with serum creatinine 1.5 mg/dL or higher, or concomitant administration of strong dual inhibitors of CYP3A4 and P-gp (e.g., itraconazole, clarithromycin, ritonavir), the dose is 2.5 mg twice daily. It may be taken with or without food.

Potential Advantages

Apixaban has been demonstrated to be superior to warfarin in preventing stroke and systemic embolism with a lower risk of bleeding in patients with nonvalvular AF.1,2

Potential Disadvantages

There is currently no antidote or reversal agent available for apixaban. Bleeding is the most common adverse event. The risk of bleeding is significant if taken concomitantly with antiplatelet drugs. This combination resulted in the termination of a trial of apixaban in patients with acute coronary syndrome on antiplatelet therapy.1,3

Comments

Apixaban’s efficacy for stroke prevention in AF was based on a multinational, double-blind, randomized, non-inferiority comparative trial to warfarin (ARISTOTLE).1,2 Patients (n = 18,201) with nonvalvular AF and one or more risk factors (e.g., diabetes, hypertension, prior stroke, or TIA) were randomized to apixaban 5 mg twice daily or dose-adjusted warfarin (target IRN range 2-3). The cohort had a median age of 70 years, 65% male, 90% with hypertension, and median CHADS2 score of 2.1 (30% higher than 3). The median duration of follow-up was 1.8 years. The primary efficacy outcome was stroke or systemic embolism and the secondary outcome was death from any cause. The primary safety outcome was major bleeding events. The secondary safety endpoint was a composite of major bleeding and clinically relevant nonmajor bleeding. Analysis was based on intention-to-treat. The efficacy of apixaban was superior to warfarin. The rate (%/yr) of stroke or systemic embolism was 1.27% for apixaban and 1.6% for warfarin (hazard ratio [HR], 0.79; 95% confidence interval [CI], 0.66-0.95). The difference was mainly attributed to hemorrhagic strokes. The rates of hemorrhagic stroke (0.24% vs 0.47%) and all-cause mortality (3.52% vs 3.94%) were statistically in favor of apixaban. The rates of major (2.23% vs 3.09%) and clinically nonmajor bleeding events (4.07% vs 6.01%) were also statistically in favor of apixaban. Apixaban was also more effective than aspirin in reducing risk of stroke and systemic embolism (1.62% vs 3.63%; HR, 0.45; 95% CI, 0.32 to 0.63) with similar risk of bleeding in patients who have failed or were unsuitable for a vitamin K antagonist.1,4,5 Apixaban has been found to be more effective than enoxaparin as thromboprophylaxis after hip and knee replacement.6,7 It was also recently reported to reduce recurrent venous thromboembolism when used as extended treatment in patients who completed 6-12 months of anticoagulation therapy for VTE,8 although it is not yet approved for either of these indications.

Clinical Implications

Apixaban is the third NOAC to be approved following dabigatran and rivaroxaban. Rivaroxaban was shown to be noninferior to warfarin, while both apixaban and dabigatran were found to be superior to warfarin. There are currently no direct comparative studies among the three drugs. It is difficult to compare across studies due to the differences in the study population and level of warfarin anticoagulation (% time in therapeutic range) among studies, although RELY (dabigatran) and ARISTOTLE (apixaban) are more reflective of “real world” AF patients.9 The results of a recently published indirect comparison analysis suggested similar efficacy among all three drugs for secondary prevention, and dabigatran may be more effective as primary prevention compared to apixaban but with higher risk of major bleeding and gastrointestinal bleeding.10 The wholesale acquisition cost for a 30-day supply of apixaban is $250.37, which is similar to dabigatran, and more than rivaroxaban ($231.60). Warfarin is $10-$45 for 30 days, not including cost for laboratory monitoring.

References

1. Eliquis Prescribing Information. Bristol-Myer-Squibb and Pfizer. December 2012.

2. Granger CB, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011;365:981-992.

3. Alexander JH, et al. Apixaban with antiplatelet therapy after acute coronary syndrome. N Engl J Med 2011;365:699-708.

4. Connolly SJ, et al. Apixaban in patients with atrial fibrillation. N Engl J Med 2011;364:806-817.

5. Flaker GC, et al. Bleeding during treatment with aspirin versus apixaban in patients with atrial fibrillation unsuitable for warfarin: Stroke 2012;43:3291-3297.

6. Lassen MR, et al. Apixaban versus enoxaparin for thromboprophylaxis after hip replacement. N Engl J Med 2010;363:2487-2498.

7. Lassen MR, et al. Apixaban versus enoxaparin for thromboprophylaxis after knee replacement (ADVANCE-2). Lancet 2010;375:807-815.

8. Agnelli G, et al. Apixaban for extended treatment of venous thromboembolism. N Engl J Med 2012; Dec. 8. [Epub ahead of print.]

9. Lee S, et al. BMJ Open 2012;2:Pii:e001768. doi:10.11/bmjopen-2012-001768.

10. Rasmussen LH, et al. Primary and secondary prevention with new oral anticoagulant drugs for stroke prevention in atrial fibrillation: Indirect comparison analysis. BMJ 2012;345:e7097.