A comprehensive analysis of the effects of rivaroxaban on stroke or transient ischaemic attack in patients with heart failure, coronary artery disease, and sinus rhythm: the COMMANDER HF trial

Abstract

Aims: Stroke is often a devastating event among patients with heart failure with reduced ejection (HFrEF). In COMMANDER HF, rivaroxaban 2.5 mg b.i.d. did not reduce the composite of first occurrence of death, stroke, or myocardial infarction compared with placebo in patients with HFrEF, coronary artery disease (CAD), and sinus rhythm. We now examine the incidence, timing, type, severity, and predictors of stroke or a transient ischaemic attack (TIA), and seek to establish the net clinical benefit of treatment with low-dose rivaroxaban.

Methods and results: In this double-blind, randomized trial, 5022 patients who had HFrEF(≤40%), elevated natriuretic peptides, CAD, and who were in sinus rhythm were treated with rivaroxaban 2.5 mg b.i.d. or placebo in addition to antiplatelet therapy, after an episode of worsening HF. The primary neurological outcome for this post hoc analysis was time to first event of any stroke or TIA. Over a median follow-up of 20.5 (25th-75th percentiles 20.0-20.9) months, 150 all-cause stroke (127) or TIA (23) events occurred (ischaemic stroke in 82% and haemorrhagic stroke in 11% of stroke events). Overall, 47.5% of first-time strokes were either disabling (16.5%) or fatal (31%). Prior stroke, low body mass index, geographic region, and the CHA2DS2-VASc score were predictors of stroke/TIA. Rivaroxaban significantly reduced the primary neurological endpoint of all-cause stroke or TIA compared with placebo by 32% (1.29 events vs. 1.90 events per 100 patient-years), adjusted for the time from index HF event to randomization and stratified by geographic region (adjusted hazard ratio 0.68, 95% confidence interval 0.49-0.94), with a number needed to treat of 164 patients per year to prevent one stroke/TIA event. The principal safety endpoint of fatal bleeding or bleeding into a critical space, occurred at a similar rate on rivaroxaban and placebo (0.44 events vs. 0.55 events per 100 patient-years).

Conclusions: Patients with HFrEF and CAD are at risk for stroke or TIA in the period following an episode of worsening heart failure in the absence of atrial fibrillation. Most strokes are of ischaemic origin and nearly half are either disabling or fatal. Rivaroxaban at a dose of 2.5 mg b.i.d. reduced rates of stroke or TIA compared with placebo in this population.

Trial registration: COMMANDER HF (A Study to Assess the Effectiveness and Safety of Rivaroxaban in Reducing the Risk of Death, Myocardial Infarction, or Stroke in Participants with Heart Failure and Coronary Artery Disease Following an Episode of Decompensated Heart Failure); ClinicalTrials.gov NCT01877915.

Keywords: Heart failure; Oral anticoagulation; Stroke; Thrombotic; Transient ischaemic attack.

Figure 1

Temporal pattern of risk of stroke/transient ischaemic attack after an episode of worsening chronic heart failure with reduced ejection in the placebo arm of COMMANDER HF. The total duration of time was calculated by adding the time from worsening heart failure episode to randomization to the time from randomization to stroke/transient ischaemic attack. The incremental incidence rate (red bars)) and its 95% confidence intervals (grey lines) for each time segment were derived using the bootstrap method (10 000 resamples). Kaplan–Meier cumulative risk estimates over the first 12 months after an episode of worsening heart failure are displayed in blue.

Figure 2

Distribution of COMMANDER HF participants and observed stroke or transient ischaemic attack rates by CHA₂DS₂-VASc score. * Given strong treatment effect of rivaroxaban vs. placebo on stroke/transient ischaemic attack, Cox proportional hazards models for risk prediction were performed in the placebo group alone.

Take home figure

Time to first occurrence of stroke or transient ischaemic attack. Cox proportional hazards models were adjusted for all covariates presented in Table 2. Analyses were performed in the intention-to-treat cohort including all randomized unique subjects who have a signed valid informed consent. CI, confidence interval; HR, hazard ratio; TIA, transient ischaemic attack.