Bleeding Risk of Direct Oral Anticoagulants in Patients With Heart Failure And Atrial Fibrillation

Abstract

Background: Patients with heart failure and atrial fibrillation are an important atrial fibrillation subgroup in which direct oral anticoagulants (DOACs) have not been adequately studied in real-world settings. Since DOACs rely on renal elimination and renal dysfunction is prevalent in patients with heart failure, their use may increase bleeding risk, negating some of their advantage over warfarin. Methods: We conducted a retrospective cohort study using linked Veterans Administration databases of patients with heart failure newly started on warfarin or DOACs for atrial fibrillation from October 2010 to August 2017 (23 635 warfarin, 25 823 DOAC). Outcomes included time to first bleeding, stroke, and death using Cox proportional hazards models with inverse probability of treatment weighting. Results: Total bleeding (hazard ratio, 0.62 [95% CI, 0.56–0.68]), major bleeding (hazard ratio, 0.49 [95% CI, 0.40–0.61]), and death (hazard ratio, 0.74 [95% CI, 0.71–0.78]) were lower with DOAC than warfarin, and with apixaban and dabigatran, but not rivaroxaban. Moderate/severe chronic kidney disease was common (48.7%); moderate chronic kidney disease was associated with increased bleeding with DOACs but not warfarin. However, death and bleeding remained lower with DOACs than warfarin across all renal function levels and clinical subgroups. A >20% transient/persistent decline in renal function occurred in 53% of DOAC-treated patients at some point during follow-up, would have required dose reduction in 10.5% of patients, and was associated with increased bleeding. Dose adjustments were made more often, and bleeding and death were lower in patients seen by pharmacists or anticoagulation clinics. There were significant between-site variations in DOAC dosing. Conclusions: DOACs overall, apixaban and dabigatran, but not rivaroxaban, were associated with less total bleeding and death than warfarin in patients with heart failure and atrial fibrillation at all levels of renal function. Renal function decline resulted in increased bleeding in patients with DOACs. DOAC dose adjustment was often indicated, associated with increased bleeding when not adjusted, emphasizing the need for closer monitoring in these patients.

Single-Dose Pharmacokinetics of Milvexian in Participants with Normal Renal Function and Participants with Moderate or Severe Renal Impairment

“…FXIa inhibitors have the potential to improve the benefit/risk profile of existing anticoagulants by reducing thrombus formation without causing an increase in bleeding [ 13 – 20 ]. There is additional unmet need for safer anticoagulants in renal impairment patients with concomitant cardiovascular disease as these patients have a higher intrinsic risk of bleeding [ 39 ], and this risk may further increase with currently available anticoagulants [ 36 – 38 ].…”

“…Patients with renal impairment are at heightened risk of bleeding when taking anticoagulant therapies [ 35 ]; however, it is unknown if this is purely due to increases in drug exposure, intrinsic features of this patient population, or a combination of both [ 36 – 38 ]. The increased risk of bleeding in patients with renal impairment has been observed even without anticoagulant therapies, with one study demonstrating a 1.5-fold increased risk of bleeding in patients with chronic kidney disease compared with those without chronic kidney disease [ 39 ].…”

Analysis of Adverse Events in the Treatment of Patients with Non-Valvular Atrial Fibrillation with Oral Anticoagulants: Data from the “ANTEY” Observational Study

“…In addition, it is well-known that patients with heart failure have a high prevalence of renal dysfunction [ 22 ]. Since all NOACs are renally eliminated to various degrees while warfarin is not, progressive renal function decline leads to an increased risk of bleeding in the treatment of NOAC [ 24 , 25 ]. However, in our study there was only one patient with renal dysfunction (according to the criteria of the HAS-BLED scale).…”

Risk of bleeding among individuals on direct acting oral anticoagulants: an academic medical center cohort study.

“…When analyzing the DOAC and NSAIDs drug exposure, our study showed higher rates than other observational studies but similar to the ARISTOTLE trial (8.2%). 9,26,39,43 We must consider that NSAIDs can be used almost worldwide as overthe-counter (OTC) medications. Given that OTC medication use is not well documented, thus the exposure can be underestimated.…”