Thromboembolic and Hemorrhagic Outcomes in the Direct Oral Anticoagulant Trials Across the Spectrum of Kidney Function

Abstract

Chronic kidney disease is a common comorbidity among patients taking direct-acting oral anticoagulants (DOACs). Herein, we evaluate the influence of kidney function on stroke or systemic embolism (SEE), hemorrhage, and composite end points (stroke/SEE/hemorrhage/death and stroke/SEE/death) among patients on DOACs and warfarin. Baseline kidney function was categorized as glomerular filtration rate (GFR) ≥ 60 (reference), 45-59, and < 45mL/min/1.73 m 2 for participants in the Randomized Evaluation of Long-Term Anticoagulant Therapy (RE-LY) (n = 18,049), Apixaban for Reduction in Stroke and Other Thromboembolic Events (ARISTOTLE) (n = 18,187), and The Effective Anticoagulation with Factor Xa Next Generation in AF (ENGAGE AF) (n = 20,798) trials. Incidence of events was compared across GFR categories. Hazard ratios for events were estimated using Cox regression using intention-to-treat analysis adjusting for known predictors. A large proportion of participants had GFR < 60 (25-29% had 45 ≤ GFR < 60 and 9.5-12.6% with GFR < 45). Compared with patients with GFR ≥ 60, warfarin users across the trials with GFR ≥ 45-59 and GFR < 45 had a higher incidence of hemorrhage (P values < 0.0001) and warfarin users in the ARISTOTLE and ENGAGE trials had higher incidence of stroke/SEE (P values ≤ 0.05). Compared with patients with GFR ≥ 60, dabigatran users with GFR ≥ 45-59 and GFR < 45 had a higher incidence of stroke/SEE (P ≤ 0.02), hemorrhage (P < 0.001), and both composite end points (P < 0.0001). Compared with patients with GFR ≥ 60, apixaban and edoxaban users with GFR ≥ 45-59 and GFR < 45 had a higher incidence of hemorrhage (P values ≤ 0.05) and composite end points (P values ≤ 0.05). After adjustment, compared with patients with GFR ≥ 60, warfarin users with GFR < 60 in the ARISTOTLE and RE-LY trials had a higher risk of hemorrhage (P < 0.05), as did dabigatran (P < 0.001) and edoxaban (P ≤ 0.005) users, while apixaban users did not exhibit an increased risk (P = 0.08 GFR ≥ 45-59; P = 0.71 GFR < 45). Kidney function significantly influences the safety and efficacy of oral anticoagulants.

Pharmacogenetics of Bleeding and Thromboembolic Events in Direct Oral Anticoagulant Users

“…Furthermore, due to the limited sample size, we may have missed finding the effect of some of the potential confounders. For example, the results reflected the anticipated effect of the renal function, 47 but statistical significance was not achieved. Furthermore, we could not apply stratified analysis by dividing the bleeding events into minor and major bleedings as has been done in larger studies with warfarin users 48 …”

Rapid Detection of Apixaban by a ROTEM-Based Approach and Reversibility with Andexanet Alfa or DOAC-Stop

“…In the pivotal Aristotle trial, the annual rate of major bleeding was 2%, 8 9 10 but higher in patients with comorbidities such as chronic kidney disease. 11 In practice-based health care outside large randomized controlled trials complications are, however, usually more common. Thus, in a “real-world” study of a U.S. population, major bleedings on apixaban were almost 5% per year 12 and even higher, close to 8%, in a Korean population.…”

Personalizing Direct Oral Anticoagulant Therapy for a Diverse Population: Role of Race, Kidney Function, Drug Interactions, and Pharmacogenetics

“…Of all the patientspecific factors known to influence DOAC concentrations, clearance, and efficacy and safety, kidney function demonstrates the most impact for the individual patient and the population of DOAC users. 67,68…”

“…Although most studies have used CrCl to estimate and classify kidney function, a recent analysis 67 examined AF trial data using estimated glomerular filtration rate (eGFR) to assess the influence of kidney function on the efficacy and safety end points. A large proportion of participants had GFR < 60, (25–29% had GFR ≥ 45 to < 60 and 9.5–12.6% had GFR < 45).…”