Efficacy and Safety of Apixaban Compared With Warfarin in Patients With Atrial Fibrillation in Relation to Renal Function Over Time
Insights From the ARISTOTLE Randomized Clinical Trial

Hijazi Z, Hohnloser SH, Andersson U, et al.
JAMA Cardiol. 2016;1(4):451-460

Background

Oral anticoagulation is essential to reduce risk of stroke in patients with atrial fibrillation (AF). The risk of thromboembolic and bleeding complications is higher in AF patients with renal impairment [1-4]. Treatment with edoxaban, an oral factor Xa inhibitor, was associated with decreased efficacy in AF patients with creatinine clearance > 95 mL/min [5,6].
Although the ARISTOTLE trial showed that apixaban, compared with warfarin, was associated with favourable efficacy and safety in AF patients with impaired renal function at randomisation, it is not clear whether this benefit is sustained over time, given the natural decline of renal function with age [7,8].
In this study, the efficacy and safety of apixaban versus warfarin was evaluated in relation to changes of renal function over time in 16 869 AF patients who participated in the ARISTOTLE study.

Main results

• At 12 months, median eGFR decline was 1.02 mL/min (IQR: -6.72 to 4.52 mL/min), with 13.6% of patients showing eGFR decline>20%. Worsening renal function was most strongly associated with older age, low haematocrit, presence of heart failure, vascular disease, and diabetes.
• No clinically relevant difference was seen in the change in renal function over time between the groups randomised to apixaban vs warfarin.
• Compared with patients with stable eGFR ≥ 80mL/min, patients with stable eGFR ≤ 50 mL/min had double annual rates of ischemic or unspecified strokes (1.44% vs 0.69%), 3-fold higher annual rates of all-cause mortality (6.64% vs 2.14%) and similarly higher annual rates of major bleeding (3.81% vs 1.34%).
• In patients with worsening renal function (eGFR deterioration >20%), annual rate of stroke or systemic embolism (HR: 1.53; 95% CI: 1.17-2.01), major bleeding (HR: 1.56; 95% CI: 1.27-1.93), and mortality (HR: 2.31; 95% CI: 1.98-2.68) was consistently higher compared with patients with stable renal function during follow-up, irrespective of the baseline renal function.
• In participants randomised to apixaban compared with warfarin with worsening renal function over time, relative risk of major bleeding (HR: 0.76; 95% CI: 0.54-1.07; P = 0.73) and stroke or systemic embolism (HR: 0.80; 95% CI: 0.51-1.24; P = 0.86) was lower, independently of changes in renal function during the study. No reduced risk was seen for ischemic or unspecified stroke (HR: 0.88; 95% CI: 0.52-1.48; P = 0.94).

Conclusion

In AF patients on oral anticoagulation, worsening renal function was most strongly associated with older age, low haematocrit, presence of heart failure, vascular disease, and diabetes. Worsening renal function was associated with a higher risk of subsequent cardiovascular events. Treatment with apixaban compared with warfarin had no effect on renal function and the advantages in efficacy and safety of apixaban compared with warfarin were similar among patients with normal, poor, or worsening renal function.

Find this article online at JAMA Cardiol

References

1. Fox KA, Piccini JP,Wojdyla D, et al. Prevention of stroke and systemic embolism with rivaroxaban compared with warfarin in patients with non-valvular atrial fibrillation and moderate renal impairment. Eur Heart J. 2011;32(19):2387-2394.
2. Go AS, Fang MC, Udaltsova N, et al; ATRIA Study Investigators. Impact of proteinuria and glomerular filtration rate on risk of thromboembolism in atrial fibrillation: the anticoagulation and risk factors in atrial fibrillation (ATRIA) study. Circulation. 2009;119(10):1363-1369.
3. Hijazi Z, Hohnloser SH, Oldgren J, et al. Efficacy and safety of dabigatran compared with warfarin in relation to baseline renal function in patients with atrial fibrillation: a RE-LY (Randomized Evaluation of Long-term Anticoagulation Therapy) trial analysis. Circulation. 2014;129(9):961-970.
4. Hohnloser SH, Hijazi Z, Thomas L, et al. Efficacy of apixaban when compared with warfarin in relation to renal function in patients with atrial fibrillation: insights from the ARISTOTLE trial. Eur Heart J. 2012;33(22):2821-2830.
5. 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.
6. Ruff CT, Giugliano RP, Antman EM, et al. Evaluation of the novel factor Xa inhibitor edoxaban compared with warfarin in patients with atrial fibrillation: design and rationale for the Effective aNticoaGulation with factor xA next GEneration in Atrial Fibrillation-Thrombolysis InMyocardial Infarction study 48 (ENGAGE AF-TIMI 48). Am Heart J. 2010;160(4):635-641.
7. Heidbuchel H, Verhamme P, Alings M, et al. EHRA practical guide on the use of new oral anticoagulants in patients with non-valvular atrial fibrillation: executive summary. Eur Heart J. 2013; 34(27):2094-2106.
8. 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.