Rivaroxaban compared with warfarin in patients with atrial fibrillation and previous stroke or transient ischaemic attack: a subgroup analysis of ROCKET AF

Summary

Background

In ROCKET AF, rivaroxaban was non-inferior to adjusted-dose warfarin in preventing stroke or systemic embolism among patients with atrial fibrillation (AF). We aimed to investigate whether the efficacy and safety of rivaroxaban compared with warfarin is consistent among the subgroups of patients with and without previous stroke or transient ischaemic attack (TIA).

Methods

In ROCKET AF, patients with AF who were at increased risk of stroke were randomly assigned (1:1) in a double-blind manner to rivaroxaban 20 mg daily or adjusted dose warfarin (international normalised ratio 2·0–3·0). Patients and investigators were masked to treatment allocation. Between Dec 18, 2006, and June 17, 2009, 14 264 patients from 1178 centres in 45 countries were randomly assigned. The primary endpoint was the composite of stroke or non-CNS systemic embolism. In this substudy we assessed the interaction of the treatment effects of rivaroxaban and warfarin among patients with and without previous stroke or TIA. Efficacy analyses were by intention to treat and safety analyses were done in the on-treatment population. ROCKET AF is registered with ClinicalTrials.gov, number NCT00403767.

Findings

7468 (52%) patients had a previous stroke (n=4907) or TIA (n=2561) and 6796 (48%) had no previous stroke or TIA. The number of events per 100 person-years for the primary endpoint in patients treated with rivaroxaban compared with warfarin was consistent among patients with previous stroke or TIA (2·79% rivaroxaban vs 2·96% warfarin; hazard ratio [HR] 0·94, 95% CI 0·77–1·16) and those without (1·44% vs 1·88%; 0·77, 0·58–1·01; interaction p=0·23). The number of major and non-major clinically relevant bleeding events per 100 person-years in patients treated with rivaroxaban compared with warfarin was consistent among patients with previous stroke or TIA (13·31% rivaroxaban vs 13·87% warfarin; HR 0·96, 95% CI 0·87–1·07) and those without (16·69% vs 15·19%; 1·10, 0·99–1·21; interaction p=0·08).

Interpretation

There was no evidence that the relative efficacy and safety of rivaroxaban compared with warfarin was different between patients who had a previous stroke or TIA and those who had no previous stroke or TIA. These results support the use of rivaroxaban as an alternative to warfarin for prevention of recurrent as well as initial stroke in patients with AF.

Funding

Johnson and Johnson Pharmaceutical Research and Development and Bayer HealthCare.

Introduction

A history of transient ischaemic attack (TIA) or ischaemic stroke is a major risk factor for stroke in patients with non-valvular atrial fibrillation (AF), conferring a 2·5 times increased risk,¹ and is also a risk factor for bleeding with oral anticoagulation.² Two randomised trials have examined the benefits and risks of oral anticoagulation with warfarin for secondary stroke prevention in 485 patients with AF and previous stroke or TIA.3, 4, 5 The results were consistent with those in patients without previous stroke or TIA:⁶ warfarin reduced recurrent stroke by two-thirds (odds ratio [OR] 0·36, 95% CI 0·22–0·58) and increased major extracranial haemorrhage (4·32, 1·55–12·10) compared with no warfarin.3, 4, 5

Rivaroxaban, an oral direct factor Xa inhibitor, given at a dose of 20 mg once daily, was non-inferior to adjusted-dose warfarin (target international normalised ratio [INR] 2·0–3·0) in the prevention of stroke and systemic embolism among patients with non-valvular AF who were at moderate-to-high risk of stroke (mean CHADS₂ score [a measure of the risk of stroke, in which congestive heart failure, hypertension, age 75 years or older, and diabetes mellitus are each assigned 1 point and previous stroke or TIA is assigned 2 points] 3·5 [SD 0·9]) in the Rivaroxaban Once-daily, oral, direct Factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF).7, 8 In this prespecified subgroup analysis, we aimed to establish whether the efficacy and safety of rivaroxaban compared with warfarin among patients with previous TIA or ischaemic stroke was consistent with results among patients without previous stroke or TIA and the entire study population. Our rationale was that treatment effects might differ between patients with and those without previous stroke or TIA, because the risk of primary efficacy and safety outcomes differs between these groups.1, 2