Risks of anticoagulation in patients with chronic kidney disease and atrial fibrillation: More than just bleeding?

Abstract

Individuals with kidney disease and their healthcare providers can be excused for having a lovehate relationship with anticoagulation. Chronic kidney disease (CKD) heightens the risk of conditions that normally require anticoagulation (deep venous thrombosis, atrial fibrillation), but it also greatly increases the risk of anticoagulationrelated complications, most notably major bleeding.1 This complicates the assessment of the risk/benefit ratio for initiating anticoagulation in individuals with CKD—particularly those with endstage kidney disease and atrial fibrillation, for whom there is weak evidence supporting a clinical benefit from anticoagulation but a clear signal for excess risk of death and major bleeding.2 As a result, current recommendations for initiating anticoagulation in patients with endstage kidney disease and atrial fibrillation at high risk for thromboembolism are equivocal,3 with most guidelines leaving it up to clinical judgement (and many clinicians in turn deciding to forego anticoagulation4). There is much stronger evidence for a net clinical benefit of anticoagulation in CKD patients not yet on dialysis who have atrial fibrillation and are at high risk for thromboembolism,5-7 supporting the use of anticoagulation in these patients despite their excess risk of major bleeding. The findings of Posch and colleagues in Research and Practice in Thrombosis and Haemostasis suggest that estimating the net clinical benefit of anticoagulation with vitamin K antagonists may require consideration of risks beyond just bleeding—specifically, potentially deleterious longterm effects on kidney function.8 Using data from the IMS Disease Analyzer Germany study—a longitudinal health record database from ~1300 primary care physicians in Germany—Posch and colleagues identified 37 476 individuals with stage 3 or 4 CKD and atrial fibrillation (captured via ICD10 codes) between January 1, 2009 and August 31, 2015. After excluding individuals diagnosed with atrial fibrillation or CKD prior to January 1, 2008; missing at least one followup eGFR measurement or having implausible eGFR values; having a prescription for a directacting oral anticoagulant (inhibiting factor Xa or thrombin); or missing baseline data to calculate the CHA2DS2VASc score, a total of 14 432 individuals were included in the final analytic sample. Of this group, 7409 had a prescription for a vitamin K antagonist as compared to 7023 who did not. The baseline characteristics of the two groups were fairly comparable except for age (median 78 years for those treated with vitamin K antagonists vs 79 for those who were not), sex (45% female in the vitamin K antagonist group vs 52% in the comparison group), and concurrent use of aspirin (21% in the vitamin K antagonist group vs 44% in the comparison group) at baseline. Importantly, there were no significant differences in median eGFR at baseline (48 mL/min/1.73 m2 in the vitamin K antagonist group vs 47 mL/min/1.73 m2 in the comparison group). In a linear mixed effect model that adjusted for baseline differences in age and CHA2DS2VASc score, individuals exposed to vitamin K antagonists had a greater mean annualized eGFR decline than those not exposed to vitamin K antagonists (mean difference 0.29 mL/min/1.73 m2/year, 95% CI 0.06, 0.53). The results were similar in propensity score adjusted analyses which used inverseprobabilityoftreatment weights to try to account for differences in baseline characteristics of the two groups (confounding by indication), and when using a 30% decline in eGFR as an alternate outcome (adjusted hazard ratio compared vitamin K antagonist exposure vs nonexposure, 1.20, 95% CI 1.11, 1.30). The results of this study support the findings from a posthoc analysis of the Randomized Evaluation of Long Term Anticoagulation Therapy trial that showed a faster decline in mean eGFR in individuals with atrial fibrillation randomized to warfarin as compared to dabigatran.9 Reasons for these findings are unclear. Posch and colleagues speculate that vitamin K antagonism may accelerate the development of vascular calcification in the kidney, leading to faster decline in eGFR.8 There is reasonable experimental data to support such speculation,10 though data directly linking exposure to vitamin