Factors associated with major bleeding events: insights from the ROCKET AF trial (rivaroxaban once-daily oral direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and embolism trial in atrial fibrillation)

Abstract

Objectives: This study sought to report additional safety results from the ROCKET AF (Rivaroxaban Once-daily oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation).

Background: The ROCKET AF trial demonstrated similar risks of stroke/systemic embolism and major/nonmajor clinically relevant bleeding (principal safety endpoint) with rivaroxaban and warfarin.

Methods: The risk of the principal safety and component bleeding endpoints with rivaroxaban versus warfarin were compared, and factors associated with major bleeding were examined in a multivariable model.

Results: The principal safety endpoint was similar in the rivaroxaban and warfarin groups (14.9 vs. 14.5 events/100 patient-years; hazard ratio: 1.03; 95% confidence interval: 0.96 to 1.11). Major bleeding risk increased with age, but there were no differences between treatments in each age category (<65, 65 to 74, ≥75 years; pinteraction = 0.59). Compared with those without (n = 13,455), patients with a major bleed (n = 781) were more likely to be older, current/prior smokers, have prior gastrointestinal (GI) bleeding, mild anemia, and a lower calculated creatinine clearance and less likely to be female or have a prior stroke/transient ischemic attack. Increasing age, baseline diastolic blood pressure (DBP) ≥90 mm Hg, history of chronic obstructive pulmonary disease or GI bleeding, prior acetylsalicylic acid use, and anemia were independently associated with major bleeding risk; female sex and DBP <90 mm Hg were associated with a decreased risk.

Conclusions: Rivaroxaban and warfarin had similar risk for major/nonmajor clinically relevant bleeding. Age, sex, DBP, prior GI bleeding, prior acetylsalicylic acid use, and anemia were associated with the risk of major bleeding. (An Efficacy and Safety Study of Rivaroxaban With Warfarin for the Prevention of Stroke and Non-Central Nervous System Systemic Embolism in Patients With Non-Valvular Atrial Fibrillation: NCT00403767).

Keywords: anticoagulants; atrial fibrillation; hemorrhage.

Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Figures

Figure 1. Major Bleeding by Treatment

Kaplan-Meier curves for major bleeding for the treatment groups. HR = hazard ratio.

Figure 2. Major Bleeding in Key Subgroups

On-treatment (safety population) major bleeding in key subgroups according to patient baseline characteristics. AF = atrial fibrillation; ASA = acetylsalicylic acid; BMI = body mass index; CHADS = congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, prior stroke, transient ischemic attack (TIA), or non–central nervous system thromboembolism (doubled); CI = confidence interval; CNS = central nervous system; CrCl = creatinine clearance; TIA = transient ischemic attack; VKA = vitamin K antagonists.

Figure 3. Blood Pressure at Randomization and Major Bleeding

Univariate relationship between systolic (SBP) and diastolic (DBP) blood pressure at randomization and major bleeding (at 2 years). Solid lines are predicted probabilities of major bleeding at 2 years; dashed lines are 95% confidence intervals. p values for linearity test in both figures >0.0001. SBP (2 linear segments, <135, ≥135): chi-square: 16.53, p = 0.0003, c-index: 0.5326; DBP (2 linear segments, <90, ≥90): chi-square: 51.71, p < 0.0001, c-index: 0.5678.