Apixaban 5mg Twice Daily and Clinical Outcomes in Patients With Atrial Fibrillation and Advanced Age, Low Body Weight, or High Creatinine
A Secondary Analysis of a Randomized Clinical Trial

Alexander JH, Andersson U, Lopes RD, et al, for the ARISTOTLE Investigators
JAMA Cardiol 2016; published online ahead of print

Background

In patients with atrium fibrillation (AF), reduced doses of oral anticoagulation are recommended for those with increased predicted exposure and a related increased risk of bleeding. However, reduced doses of NOACs are more frequently used in AF patients than expected [1,2].

In the ARISTOTLE trial (Apixaban forReduction of Stroke and Other Thromboembolic
Complications in Atrial Fibrillation trial), apixaban 5 mg twice daily versus warfarin was studied in AF patients. A reduced dose of apixaban (2.5 mg twice daily) was used in patients with 2 or more of the following dose-reduction criteria: age ≥ 80 years; weight ≤ 60 kg; creatinine levels ≥ 1.5 mg/dL [3,4].  

In this secondary analysis of the ARISTOTLE study it was assessed whether the effects of apixaban 5 mg twice daily on stroke or systemic embolism and bleeding – compared to warfarin - varied among patients with 1 or no dose-reduction criterion. Moreover, the frequency of dose reduction and the safety of the 5 mg twice daily dose of apixaban compared with warfarin were assessed across the range of individual dose-reduction criteria.

Main results

• In the ARISTOTLE trial, 95.4% of patients were randomised to receive apixaban 5 mg twice daily or warfarin. Of these, 76.9% had no dose-reduction criteria and 22.8% had only 1 dose-reduction criterion. Out of the patients with only 1 dose-reduction criterion, 41.3% were ≥ 80 years old, 36.0% weighed ≤ 60 kg, and 22.8% had creatinine levels ≥ 1.5 mg/dL.
• Compared with patients with no dose-reduction criterion, patients with 1 dose-reduction criterion had higher rates of stroke or systemic embolism (HR: 1.47; 95% CI: 1.20-1.81), ischemic stroke (HR: 1.54; 95% CI: 1.21-1.96), major bleeding (HR: 1.89; 95% CI: 1.62-2.20), intracranial haemorrhage (HR: 1.72; 95% CI: 1.23-2.39), all-cause death (HR: 2.01; 95% CI: 1.78-2.28) or CV death (HR: 1.88; 95% CI: 1.58-2.23).
• However, comparing warfarin to apixaban 5 mg twice daily showed consistently less major bleeding among patients with 1 and no dose-reduction criterion (P for interaction = 0.71). Similar results were seen for each dose-reduction criterion.
• Furthermore, there was no evidence of statistical heterogeneity in the effect of apixaban versus warfarin on stroke or systemic embolism (P for interaction = 0.36), ischemic stroke (P for interaction = 0.14), intracranial haemorrhage (P for interaction = 0.26), all-cause death (P for interaction = 0.054) or CV death (P for interaction = 0.26).
• Across the range of age, weight, creatinine level and creatinine clearance, apixaban was consistently associated with a numerically lower risk of major bleeding than warfarin.

Conclusion

AF patients with advanced age, or low body weight, or renal dysfunction have a higher risk of stroke or systemic embolism and major bleeding. Although patients with at least two of these criteria received dose-reduction, patients with only one criterion received the standard apixaban dose of 5 mg twice daily. These analysis showed that patients with one criterion have similar benefit of the 5 mg twice daily dose of apixaban – compared to warfarin - as patients without these criteria, with respect to stroke or systemic embolism and bleeding. Therefore, the 5 mg twice daily dose of apixaban should be the preferred dose of apixaban for these patients, in contrast to 2.5 mg twice daily.

Find this article online at JAMA Cardiol

References

1. Connolly SJ, Ezekowitz MD, Yusuf S, et al; RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361(12):1139-1151.
2. Giugliano RP, Ruff CT, Braunwald E, et al; ENGAGE AF-TIMI 48 Investigators. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2013;369(22):2093-2104.
3. Granger CB, Alexander JH, McMurray JJ, et al; ARISTOTLE Committees and Investigators. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365(11):981-992.
4. Frost CE, Song Y, Shenker A, et al. Effects of age and sex on the single-dose pharmacokinetics and pharmacodynamics of apixaban. Clin Pharmacokinet. 2015;54(6):651-662.