Saran, Rajiv

Background: Patients with atrial fibrillation and severely decreased kidney function were excluded from the pivotal non–vitamin K antagonist oral anticoagulants (NOAC) trials, thereby raising questions about comparative safety and effectiveness in patients with reduced kidney function. The study aimed to compare oral anticoagulants across the range of kidney function in patients with atrial fibrillation. Methods and Results: Using a US administrative claims database with linked laboratory data, 34 569 new users of oral anticoagulants with atrial fibrillation and estimated glomerular filtration rate ≥15 mL/(min·1.73 m 2 ) were identified between October 1, 2010 to November 29, 2017. The proportion of patients using NOACs declined with decreasing kidney function—73.5%, 69.6%, 65.4%, 59.5%, and 45.0% of the patients were prescribed a NOAC in estimated glomerular filtration rate ≥90, 60 to 90, 45 to 60, 30 to 45, 15 to 30 mL/min per 1.73 m 2 groups, respectively. Stabilized inverse probability of treatment weighting was used to balance 4 treatment groups (apixaban, dabigatran, rivaroxaban, and warfarin) on 66 baseline characteristics. In comparison to warfarin, apixaban was associated with a lower risk of stroke (hazard ratio [HR], 0.57 [0.43–0.75]; P <0.001), major bleeding (HR, 0.51 [0.44–0.61]; P <0.001), and mortality (HR, 0.68 [0.56–0.83]; P <0.001); dabigatran was associated with a similar risk of stroke but a lower risk of major bleeding (HR, 0.57 [0.43–0.75]; P <0.001) and mortality (HR, 0.68 [0.48-0.98]; P =0.04); rivaroxaban was associated with a lower risk of stroke (HR, 0.69 [0.51–0.94]; P =0.02), major bleeding (HR, 0.84 [0.72–0.99]; P =0.04), and mortality (HR, 0.73 [0.58–0.91]; P =0.006). There was no significant interaction between treatment and estimated glomerular filtration rate categories for any outcome. When comparing one NOAC to another NOAC, there was no significant difference in mortality, but some differences existed for stroke or major bleeding. No relationship between treatments and falsification end points was found, suggesting no evidence for substantial residual confounding. Conclusions: Relative to warfarin, NOACs are used less frequently as kidney function declines. However, NOACs appears to have similar or better comparative effectiveness and safety across the range of kidney function.

Background: Stroke prevention using warfarin is challenging in AF patients with CKD, due to high bleeding risk and difficulties in the INR control. NOACs provide alternative options, but all have greater degrees of renal clearance. This study aimed to compare the outcomes of apixaban, dabigatran, rivaroxaban, and warfarin across the range of kidney function in patients with AF. Methods: Using a US administrative database including private insurance or Medicare Advantage patients with linked claims and laboratory data, we identified 34,569 new users of oral anticoagulants with AF and eGFR ≥15 between 10/1/2010-11/29/2017. Stabilized IPTW balanced four treatment groups on 66 baseline characteristics. The primary outcomes included stroke, major bleeding, and mortality. Weighted Cox proportional hazards models compared treatments in the overall population and in each eGFR subgroup, with mortality as a competing risk for stroke and major bleeding. Results: The proportion of patients using warfarin increased as the kidney function declined - 26.5%, 30.4%, 34.6%, 40.5%, and 55.0% of patients were prescribed warfarin in eGFR ≥90, 60-90, 45-60, 30-45, 15-30 groups, respectively. In comparison to warfarin, apixaban was associated with a lower risk of stroke, major bleeding, and mortality; dabigatran was associated with a similar risk of stroke, and a lower risk of major bleeding and mortality; rivaroxaban was associated with a lower risk of stroke, major bleeding, and mortality (Figure). When comparing one NOAC to another NOAC, apixaban and dabigatran were associated with a lower risk of major bleeding than rivaroxaban (HR 0.61 [0.51-0.73], p<0.001 for apixaban versus rivaroxaban; HR 0.67 [0.50-0.90], p=0.007 for dabigatran versus rivaroxaban); dabigatran was associated with a higher risk of stroke than apixaban (HR 1.65 [1.11-2.46], p=0.01); there was no difference in mortality. There was no significant interaction between treatment and eGFR categories for any outcome, but the number of patients with low eGFR was small. Conclusions: In practice, relative to warfarin, NOACs are progressively less commonly used with increasing degree of renal dysfunction. However, each NOAC was consistently associated with at least equivalent effectiveness and safety compared with warfarin across the range of kidney function.

Background: Patients with end-stage kidney disease (ESKD) on dialysis were excluded from clinical trials of direct oral anticoagulants for atrial fibrillation (AF). Recent data have raised concerns regarding the safety of dabigatran and rivaroxaban, but apixaban has not been evaluated despite current labeling supporting its use in this population. The goal of this study was to determine patterns of apixaban use and its associated outcomes in dialysis-dependent patients with ESKD and AF. Methods: We performed a retrospective cohort study of Medicare beneficiaries included in the United States Renal Data System (October 2010 to December 2015). Eligible patients were those with ESKD and AF undergoing dialysis who initiated treatment with an oral anticoagulant. Because of the small number of dabigatran and rivaroxaban users, outcomes were only assessed in patients treated with apixaban or warfarin. Apixaban and warfarin patients were matched (1:3) based on prognostic score. Differences between groups in survival free of stroke or systemic embolism, major bleeding, gastrointestinal bleeding, intracranial bleeding, and death were assessed using Kaplan–Meier analyses. Hazard ratios (HRs) and 95% CIs were derived from Cox regression analyses. Results: The study population consisted of 25 523 patients (45.7% women; 68.2±11.9 years of age), including 2351 patients on apixaban and 23 172 patients on warfarin. An annual increase in apixaban prescriptions was observed after its marketing approval at the end of 2012, such that 26.6% of new anticoagulant prescriptions in 2015 were for apixaban. In matched cohorts, there was no difference in the risks of stroke/systemic embolism between apixaban and warfarin (HR, 0.88; 95% CI, 0.69–1.12; P =0.29), but apixaban was associated with a significantly lower risk of major bleeding (HR, 0.72; 95% CI, 0.59–0.87; P <0.001). In sensitivity analyses, standard-dose apixaban (5 mg twice a day; n=1034) was associated with significantly lower risks of stroke/systemic embolism and death as compared with either reduced-dose apixaban (2.5 mg twice a day; n=1317; HR, 0.61; 95% CI, 0.37–0.98; P =0.04 for stroke/systemic embolism; HR, 0.64; 95% CI, 0.45–0.92; P =0.01 for death) or warfarin (HR, 0.64; 95% CI, 0.42–0.97; P =0.04 for stroke/systemic embolism; HR, 0.63; 95% CI, 0.46–0.85; P =0.003 for death). Conclusions: Among patients with ESKD and AF on dialysis, apixaban use may be associated with a lower risk of major bleeding compared with warfarin, with a standard 5 mg twice a day dose also associated with reductions in thromboembolic and mortality risk.