Author + information
- Freddy Del-Carpio Munoz, MD, MSc∗ (, )
- Xiaoxi Yao, PhD,
- Neena S. Abraham, MD, MSCE,
- M. Fernanda Bellolio, MD, MS,
- Alejandro A. Rabinstein, MD,
- Samuel J. Asirvatham, MD,
- Robert D. McBane, MD,
- Bernard J. Gersh, MB, ChB, DPhil, FRCP,
- Nilay D. Shah, PhD and
- Peter A. Noseworthy, MD
- ↵∗Division of Cardiovascular Diseases, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, Minnesota, 55905
The pivotal RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy) trial demonstrated that dabigatran (150 mg twice daily) was superior to warfarin in reducing thromboembolism with a similar risk of major bleeding (1). Because renal dysfunction increases the risk of thromboembolism and bleeding and dabigatran has significant renal clearance, establishing its comparative effectiveness versus warfarin across the range of renal function is critical in determining the optimal treatment for patients with atrial fibrillation (AF). Indeed, an interaction between renal function and major bleeding risk has been previously described (2,3), and another novel oral anticoagulant, edoxaban, has been associated with an increased risk of stroke compared with warfarin among patients with creatinine clearance >95 ml/min. The present report aims to evaluate the risks of thromboembolism and major bleeding associated with dabigatran and warfarin in relation to renal function.
We conducted a retrospective analysis of administrative claims from Optum Lab Data Warehouse and identified adult users of either dabigatran or warfarin for AF between 2008 and 2014. Baseline estimated glomerular filtration rate (GFR), calculated using the Modification of Diet in Renal Disease equation, was available for all included patients. We identified dabigatran-treated patients with AF and propensity-matched patients treated with warfarin in a 1:3 ratio. Propensity score matching with replacement was used to account for the differences in patients’ baseline characteristics. We used Poisson regression to compare outcomes across the range of renal function and tested the interaction between treatment effect and renal function. Outcomes included: 1) thromboembolism, including ischemic stroke, transient ischemic attack, or systemic embolism; and 2) major bleeding.
We included 17,015 patients in the study (5,469 dabigatran users and 11,546 warfarin users). The median age was 70 years (interquartile range [IQR]: 62 to 77 years) in the dabigatran cohort and 71 years (IQR: 63 to 79 years) in the warfarin cohort. The median CHA2DS2-VASc (congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, stroke/transient ischemic attack, vascular disease, age 65 to 74 years, sex category) score was 4 (IQR: 2 to 5) in the dabigatran cohort, and 4 (IQR: 3 to 5) in the warfarin cohort. The median of the HAS-BLED (hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile international normalized ratio, elderly, drugs/alcohol concomitantly) score was 2 (IQR: 2 to 3) in both cohorts. Dabigatran and warfarin users were closely balanced for all other baseline covariates and had similar length of follow-up, 0.68 and 0.69 year, respectively. The index GFR did not differ by treatment arm and was normal (GFR ≥90 ml/min/1.73 m2) for just under 20% of participants. One-half of participants had mild kidney disease (GFR 60 to 89 ml/min/1.73 m2), and nearly 30% had moderate kidney disease (stage 3, GFR 30 to 59 ml/min/1.73 m2). Severe kidney disease (GFR <30 ml/min/1.73 m2) was infrequent, occurring in approximately 2% of the sample. We found significant interaction between treatment and GFR for thromboembolism (p < 0.01), major bleeding (p < 0.001), and gastrointestinal bleeding (p < 0.001), but not for intracranial bleeding (p = 0.91). As seen in Figure 1, in patients with GFR ≥90 ml/min/1.73 m2, the incidence rate per 100 person-years was higher in dabigatran compared with warfarin for thromboembolism (1.26 vs. 0.41; incidence rate ratio [IRR]: 3.14; 95% confidence interval [CI]: 1.11 to 8.88; p < 0.05) and lower for major bleeding (0.64 vs. 2.28; IRR: 0.28; 95% CI: 0.10 to 0.81; p < 0.05). In patients with GFR 60 to 89 ml/min/1.73 m2, dabigatran was associated with a lower risk of major bleeding (1.09 vs. 2.78 per 100 person-years; IRR: 0.39; 95% CI: 0.25 to 0.62; p < 0.001) and a similar risk of thromboembolism (1.0 vs. 1.39 per 100 person-years). None of the dabigatran users with GFR <30 ml/min/1.73 m2 had a thromboembolic event compared with 2.95 events per 100 person-years in the warfarin group, but there was a higher rate of major bleeding on dabigatran compared with warfarin (19.23 vs. 5.37 per 100 person-years; p < 0.01).
In this large cohort of real-world patients with atrial fibrillation receiving oral anticoagulation, we demonstrate significant heterogeneity in treatment effects between dabigatran and warfarin across the range of baseline renal function. The risk-benefit ratio favored dabigatran for patients with mild or moderate renal impairment, but there was a higher risk of thromboembolism in subjects with normal renal function. The small number of subjects in the severe renal impairment group precludes a definitive conclusion. Further studies addressing the interaction of renal function and the safety and efficacy of dabigatran versus warfarin are needed to confirm our findings.
Please note: Dr. Gersh is a member of a data safety monitoring board for Mount Sinai St. Lukes, Boston Scientific Corporation, Teva Pharmaceutical Industries, St. Jude Medical Inc., Janssen Research & Development, Baxter Healthcare Corporation, Cardiovascular Research Foundation, and Thrombosis Research Institute; and he is a consultant for Janssen Scientific Affairs, Xenon Pharmaceuticals, Cipla Limited, and Armetheon Inc. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- American College of Cardiology Foundation