Efficacy of dabigatran in stroke prevention maintained irrespective of renal function

Hijazi Z, Hohnloser SH, Oldgren J et al.
Circulation. 2013 Dec 9. [Epub ahead of print]

Background

Impaired renal function is associated with an increased prevalence of atrial fibrillation (AF) [1-3], as well as an increased risk of thromboembolic events in patients with non-valvular AF[4-7]. According to guidelines, AF patients should be treated with oral anticoagulants, due to risk of stroke [8]. Since impaired renal function brings about an increased risk of major bleeding [9], oral anticoagulation therapies may be underused in AF populations.
Dabigatran is a novel direct thrombin inhibitor with approximately 80% renal elimination [10]. In the Randomised Evaluation of Long-Term Anticoagulant Therapy (RELY) trial, over 18000 patients with AF were randomised to two different doses (110 mg and 150 mg bid) or dabigatran etexilate or warfarin [11]. Dabigatran 150 mg twice a day was associated with a lower risk of stroke and systemic embolism (SE), with a similar risk of bleeding. Dabigatran 110 mg twice daily had a similar risk of stroke and SE and a lower risk of bleeding. This article describes a prespecified analysis of the efficacy and safety of dabigatran compared to warfarin with respect to renal function. Glomerular filtration rate (GFR) was estimated with three different equations; Cockcroft-Gault, the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI), and according to cystatin C.

Main results

• Patients who had eGFR>80 ml/min according to the Cockcroft-Gault equation, had an annual stroke or SE rate of 0.88% as compared to 1.59% in patients with eGFR 50-80 ml/min, and 2.16% in patients with eGFR<50 ml/min. A similar dose-response relationship was seen for the secondary outcome of all-cause mortality (2.25%, 3.67% and 7.13% respectively).
  Using the other GFR estimations gave similar associations between decreased kidney function and increased incidence of CV events.
• No significant heterogeneity was seen between subgroups defined by renal function, with regard to stroke and SE rates in the different treatment groups, nor for ischemic stroke rates and all-cause mortality.
• Based on the Cockcroft-Gault equation, patients with eGFR>80 ml/min had annual major bleeding rates of 1.98%, and patients with eGFR 50-80 ml/min had 3.30%, as compared to 5.48% with eGFR<50 ml/min. Intracranial bleeding also increased  substantially with worsening renal function (0.20%, 0.51% and 0.69%).
• Dabigatran 110 mg was associated with fewer major bleedings across the entire range of renal function, based on Cockcroft-Gault eGFR groups.
  Using Cockcroft-Gault estimation of eGFR, dabigatran 150 mg did not differ from warfarin with respect to major bleeds. Using CKD-EPI, significantly fewer major bleedings occurred in patients with eGFR > 80 ml/min (HR: 0.59, 95%CI: 0.41-0.84) on dabigatran 150 mg as compared to warfarin.
• With respect to a composite consisting of stroke, SE, pulmonary embolism, myocardial infarction, death or major bleeding events, decreased renal function was associated with an increase of CV events, based on all three methods of GFR estimation.
• Only when using the newer and more accurate CKD-EPI GFR estimation method, a significant interaction was seen for renal function with a significantly greater relative reduction in net clinical benefit outcomes with dabigatran 150 mg vs. warfarin in patients with eGFR>80 ml/min (HR: 0.71, 95%CI: 0.56-0.90, P(interaction): 0.0371).

Conclusion

Decreased renal functions is associated with increased incidence of CV events. The efficacy of dabigatran 110 mg and 150 mg relative to warfarin in the prevention of stroke or SE in AF was consistent with the overall trials, across the range of renal function.
With respect to major bleedings, renal function did not affect the relative safety of dabigatran as compared to warfarin. However, when the newer CKD-EPI equation was used to estimate eGFR, a greater relative reduction of major bleeding risk was seen for both doses of dabigatran when eGFR>80 ml/min.

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