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Canadian Journal of Cardiology

Are Factor Xa Inhibitors Efficacious for Ischemic Stroke Prevention in Patients Without Atrial Fibrillation? Evidence From Randomized Clinical Trials

Published:September 27, 2022DOI:https://doi.org/10.1016/j.cjca.2022.09.022

      Abstract

      Background

      Clinical trials provide conflicting evidence regarding oral factor Xa inhibitors for prevention of ischemic stroke in patients without a history of atrial fibrillation (AF).

      Methods

      We performed a critical appraisal of randomized clinical trials that tested oral factor Xa inhibitors in patients without AF that reported ischemic stroke.

      Results

      Considering the 11 trials that reported > 10 ischemic strokes during follow-up (97,578 participants, 1195 ischemic strokes), 1 tested apixaban (57 strokes), 1 betrixaban (52 strokes), and 9 rivaroxaban (1086 strokes). In 7 trials with placebo comparisons, numerically fewer ischemic strokes occurred among those assigned factor Xa inhibitors in 7 of 8 randomized comparisons (range of hazard ratios [HRs], 0.89-0.51), including statistically significant reductions in 2 trials that compared rivaroxaban 2.5 mg twice daily vs placebo on a background of aspirin in patients with cardiovascular disease, COMPASS (HR, 0.51; 95% confidence interval [CI], 0.38-0.68) and COMMANDER-HF (HR, 0.64; 95% CI, 0.43-0.95). Compared with aspirin in 4 trials, oral factor Xa inhibitors were associated with fewer ischemic strokes in 2, with statistically significant reduction in 1 (rivaroxaban 5 mg twice daily in COMPASS; HR, 0.69; 95% CI, 0.53-0.90). Major bleeding was increased by oral factor Xa inhibitors in all 7 placebo-controlled trials (HR range, 1.42-4.08), with statistically significant increases reported in 5 trials, and in all 4 aspirin-controlled trials (all statistically significant increases; HR range, 1.52-2.72).

      Conclusions

      Aggregate evidence on the basis of placebo comparisons from randomized trials supports the potential for oral factor Xa inhibitors to reduce ischemic stroke in patients without AF, but major bleeding is increased.

      Résumé

      Contexte

      Les données des essais cliniques se contredisent au sujet de l’utilisation d’inhibiteurs du facteur Xa administrés par voie orale dans la prévention des accidents vasculaires cérébraux (AVC) ischémiques chez les patients sans antécédents de fibrillation atriale (FA).

      Méthodologie

      Nous avons réalisé une évaluation critique d’essais cliniques à répartition aléatoire portant sur les inhibiteurs du facteur Xa chez des patients sans FA ayant subi un AVC ischémique.

      Résultats

      Nous avons étudié 11 essais pour lesquels plus de 10 AVC ischémiques ont été rapportés lors du suivi (pour un total de 97 578 participants et 1195 AVC ischémiques) : 1 essai sur l’apixaban (57 AVC), 1 essai sur le betrixaban (52 AVC) et 9 essais sur le rivaroxaban (1086 AVC). Dans 7 essais comparant le traitement actif avec un placebo, le nombre d’AVC ischémiques était moindre chez les patients traités par l’inhibiteur de facteur Xa dans 7 des 8 comparaisons après répartition aléatoire (étendue des rapports de risques instantanés [RRI] : 0,89 à 0,51). Les réductions étaient statistiquement significatives dans deux de ces essais, qui ont comparé la prise de rivaroxaban à 2,5 mg deux fois par jour à un placebo en plus d’un traitement de fond par aspirine chez des patients atteints de maladies cardiovasculaires, soit l’essai COMPASS (RRI : 0,51; intervalle de confiance [IC] à 95 % : 0,38 à 0,68) et l’essai COMMANDER-HF (RRI : 0,64; IC à 95 % : 0,43 à 0,95). Dans les 4 essais utilisant l’aspirine comme élément de comparaison, l’administration orale d’un inhibiteur du facteur Xa a été associée à un nombre moindre d’AVC ischémiques dans 2 essais, et la réduction était statistiquement significative dans 1 essai (le rivaroxaban à 5 mg deux fois par jour dans l’essai COMPASS; RRI : 0,69; IC à 95 % : 0,53 à 0,90). La fréquence des saignements majeurs a augmenté dans les groupes prenant un inhibiteur du facteur Xa par voie orale dans les 7 essais avec placebo (étendue du RRI : 1,42 à 4,08), l’augmentation étant statistiquement significative dans 5 essais sur 7, ainsi que dans les 4 essais avec l’aspirine comme élément de comparaison (augmentation statistiquement significative dans tous les essais; étendue du RRI : 1,52 à 2,72).

      Conclusions

      Les données agrégées des études randomisées et comparatives avec placebo militent en faveur des inhibiteurs du facteur Xa administrés par voie orale pour réduire les AVC ischémiques chez les patients sans FA; par contre, on note une augmentation de la fréquence des saignements majeurs.
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