Elsevier

American Heart Journal

Volume 198, April 2018, Pages 169-177
American Heart Journal

Clinical Investigation
Efficacy and safety of dabigatran compared with warfarin in patients with atrial fibrillation in relation to renal function over time—A RE-LY trial analysis

https://doi.org/10.1016/j.ahj.2017.10.015Get rights and content

Abstract

Background

Renal function may decline over time, and the efficacy and safety of dabigatran in atrial fibrillation (AF) in relation to renal function changes are unknown.

Methods

The RE-LY trial randomized 18,113 patients with AF to 2 doses of dabigatran or warfarin for stroke prevention. Serial creatinine measurements were available in 16,988 patients. The relations between treatment, outcomes, and renal function (Cockcroft-Gault) were investigated using Cox-regression (1) with renal function as a time-dependent covariate and (2) according to worsening renal function (WRF) during follow-up, predefined as a decline in estimated glomerular filtration rate >20% from baseline.

Results

During a median follow-up of 1.8 years, 4,106 (24.2%) participants were observed to have WRF, and 12,882 (75.8%) had stable renal function. The risks of all-cause mortality and major bleeding were higher in patients with WRF versus those with stable renal function (hazard ratio [95% CI]: 2.17 [1.81-2.59] and 1.43 [1.19-1.71], respectively; both P < .0005). The efficacy and safety of dabigatran versus warfarin were similar irrespective of renal function changes over time (interaction P values ≥ .13 in both models). Dabigatran 110 mg showed a greater relative risk reduction of major bleeding in patients with normal renal function (estimated glomerular filtration rate >80 mL/min) during follow-up (interaction P = .026).

Conclusions

In AF, WRF was associated with a higher risk of death and major bleeding. The efficacy and safety profile of dabigatran compared with warfarin was similar irrespective of renal function changes over time. Dabigatran 110 mg showed a greater relative risk reduction of major bleeding in patients with normal renal function during follow-up.

Section snippets

Study population

The RE-LY trial was a prospective, multicenter, randomized study comparing 2 blinded doses of dabigatran with open-label warfarin for stroke prevention in patients with AF and at least 1 risk factor for stroke.10., 12. All patients provided written informed consent, and approval by appropriate ethics committees were obtained at all sites. A total of 18,113 patients were randomized (1:1:1) to fixed doses, regardless of renal function, of dabigatran 110 or 150 mg twice daily or warfarin (target

Demographics and clinical characteristics in relation to renal function

During follow-up, a total of 4,106 (24.2%) patients had WRF (eGFR decline more than 20%), whereas a total of 12,882 (75.8%) had stable renal function (no WRF), of which 3297 (19.4% of total) were observed to have sustained good renal function (eGFR consistently >80 mL/min). Demographics and clinical characteristics in relation to WRF or stable (no WRF) renal function, and for patients with sustained good renal function according to 2 different cutoffs (>80 and >95 mL/min, respectively) are

Discussion

The present post hoc analysis showed that among patients with AF and at least 1 risk factor for stroke, approximately a quarter of the patients had a worsening of renal function during follow-up of up to 3 years. A WRF was associated with increased risk of all-cause mortality and major bleeding. Irrespective of changes of renal function over time, both dosages of dabigatran demonstrated an efficacy consistent with the overall result of the RE-LY study showing superiority for dabigatran 150 mg

Conclusions

In patients with AF on oral anticoagulation, WRF was associated with a higher risk of death and major bleeding. The advantageous efficacy and safety profile of dabigatran compared with warfarin was consistent with the overall result of the RE-LY study irrespective of renal function changes over time. In addition, dabigatran was associated with a greater relative risk reduction of major bleeding relative to warfarin in patients with normal renal function over time.

Disclosure statements

Dr Hijazi: lecture fees from Boehringer Ingelheim, Roche, Bristol-Myers Squibb, and Pfizer; consulting fees from Merck Sharp & Dohme, Roche, Bristol-Myers Squibb, and Pfizer.

Dr Hohnloser: consulting fees from Sanofi Aventis, Cardiome, Bristol-Myers Squibb, Boehringer Ingelheim, Johnson & Johnson, and Pfizer; research grants from Sanofi Aventis and St Jude Medical; lecture fees from Sanofi Aventis, St Jude Medical, Pfizer, Bristol-Myers Squibb, Medtronic, and Boehringer Ingelheim.

Dr Oldgren:

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