Novel oral anticoagulants in secondary prevention of stroke

In patients with atrial fibrillation (AF) oral anticoagulation with vitamin-K antagonists (warfarin, phenprocoumon) is effective both for primary and secondary stroke prevention yielding a 60–70% relative reduction in stroke risk compared with placebo, as well as a mortality reduction of 26 percent. Vitamin-K antagonists have a number of well documented shortcomings. Recently the results of randomised trials for three new oral anticoagulants that do not exhibit the limitations of vitamin-K antagonists have been published. These include direct factor Xa inhibitors (rivaroxaban and apixaban) and a direct thrombin inhibitor (dabigatran). The studies (RE-LY, ROCKET-AF, ARISTOTLE, AVERROES) provide promising results for the new agents, including higher efficacy and a significantly lower incidence of intracranial bleeds compared with warfarin or aspirin. The new drugs show similar results in secondary as well as in primary stroke prevention in patients with AF. Apixaban was demonstrated to be clearly superior to aspirin and had the same rate of major bleeding complications. Meta-analyses show that the novel anticoagulants are superior to warfarin for the reduction of stroke, major bleeding and intracranial bleeds. New anticoagulants add to the therapeutic options for patients with AF, and offer a number of advantages over warfarin, for both the clinician and patient, including a favorable bleeding profile and convenience of use. Aspirin is no longer an option in secondary stroke prevention in patients with atrial fibrillation. Consideration of these new anticoagulants will improve clinical decision making.

Introduction

Patients with atrial fibrillation (AF) are at a high risk of stroke. Stroke risk is even greater if AF patients have already suffered a transient ischemic attack (TIA) or an ischemic stroke [1]. Oral anticoagulation with adjusted-dose vitamin-K antagonists, e.g. warfarin, is effective for the prevention of stroke in AF patients [2]. Treatment with warfarin has many limitations including a narrow therapeutic window, interaction with food and many drugs, and the need for regular coagulation monitoring. Novel anticoagulants (NOACs) like apixaban, dabigatran or rivaroxaban are given in a fixed-oral daily dose irrespective of age, gender or body weight, do not require coagulation monitoring, have no interaction with food, and only few interactions with other drugs. The NOACs were compared with warfarin in patients with AF in three trials (ARISTOTLE, RE-LY and ROCKET-AF) [3], [4], [5] whereas the AVERROES trial studied AF patients not suitable for treatment with warfarin and compared apixaban with aspirin [6]. All four studies had subgroups of patients with prior TIA or ischemic stroke. The results for these subgroups are summarised and analysed here. The primary endpoint was stroke or systemic embolism in all trials. Stroke included ischemic stroke (which needs to be prevented) and cerebral hemorrhage (a complication of anticoagulation) [7], [8], [9], [10].

As shown in Table 1, patients with prior TIA or ischemic stroke in the four randomised trials had a very similar risk profile. They were on average 71 years old, had a high rate of hypertension and diabetes and a high CHADS₂ score. Between 30 and 40% of the patients were treated with aspirin at baseline.

Fig. 1 shows that in the ARISTOTLE trial the rate of stroke or systemic embolism was significantly higher in patients with prior stroke or TIA (i.e. secondary prevention) compared to patients without prior stroke or TIA (primary prevention; HR 2.52, 95% CI 2.09–3.04). The rate of stroke or systemic embolism in the subgroup of patients with previous stroke or TIA was 2.46 per 100 patient years of follow-up in the apixaban group and 3.24 in the warfarin group (hazard ratio [HR] 0.76, 95% CI 0.56–1.03) [11]. The absolute reduction in the rate of stroke and systemic embolism with apixaban vs warfarin was 0.77 per 100 patient years of follow-up (95% CI –0.08 to 1.63) in patients with and 0.22 (−0.03 to 0.47) in those without previous stroke or TIA (Fig. 1). Numerically all other vascular events shown in Table 2 were also less frequent with apixaban compared to warfarin.

In the AVERROES trial in patients with previous stroke or TIA, ten events of stroke or systemic embolism occurred in the apixaban group (2.39%/year) compared with 33 in the aspirin group (9.16%/year; HR 0.29, 95% CI 0.15–0.60) (Table 2) [12]. In those without previous stroke or TIA the rate of stroke and systemic embolism was lower (1.68%/year for apixaban, 3.06%/year for aspirin) (Fig. 2). Numerically all other vascular events shown in Table 2 were also less frequent on apixaban compared to aspirin.

In the RE-LY trial, within the subgroup of patients with previous stroke or transient ischemic attack, stroke or systemic embolism occurred in 65 patients (2.78%/year year) on warfarin compared with 55 (2.32%/year) on 110 mg dabigatran (relative risk RR 0.84, 95% CI 0.58–1.20) and 51 (2.07%/year) on 150 mg dabigatran (RR 0.75, 0.52–1.08) (Table 2). The rate of stroke was higher in patients with prior TIA or stroke compared to patients without (Fig. 3). The relative effects of both doses of dabigatran compared with warfarin were not significantly different between patients with previous stroke or transient ischemic attack and those without for any of the outcomes.

Fig. 4 shows that in ROCKET-AF the number of events per 100 person-years for the primary endpoint (stroke and systemic embolism) 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 0.7–1.16) and those without (1.44% vs 1.88%; HR 0.77, 0.58–1.01; interaction p = 0·23).

For the other vascular endpoints, no differences between NOACs and warfarin were observed. The Kaplan–Maier curves in Fig. 1, Fig. 2, Fig. 3, Fig. 4 clearly show the higher risk of stroke and systemic embolism in patients who already had a TIA or stroke compared to those in primary prevention. However, the relative effects of each of the novel anticoagulants compared with warfarin were consistent among patients with and without prior stroke or TIA (i.e. there was no significant interaction). Fig. 3 and the data in Table 2 indicate that in secondary stroke prevention both doses of dabigatran are equally effective.