Recurrent Ischemic Stroke and CV Outcomes in Patients With Atrial Fibrillation With Ischemic Stroke Despite DOAC Therapy

In this article, the authors reported on the results of a population-based cohort study concerning the risks of recurrent stroke and cardiovascular outcomes in patients with atrial fibrillation (AF) who had suffered an incident ischemic stroke despite the regular use of direct oral anticoagulants (DOACs). The study included 3759 patients. The authors reported that, during follow-up, 463 patients (12.3%) experienced a recurrent ischemic stroke and 932 (24.8%) had major cardiovascular events (MACE). In DOAC failure patients, switching to a vitamin K antagonist was associated with a higher risk of both recurrent cerebrovascular and cardiovascular outcomes, while the switch from an original DOAC to another DOAC may not have led to a significant benefit in reducing the risk of recurrent ischemic stroke. However, according to the authors, a benefit may have been exhibited if they had broadened the outcomes to MACE since a higher incidence of cardiovascular events may have been noted in stroke patients with AF.

But, considering the net composite outcome (any ischemic stroke, MACE, intracerebral hemorrhage, subarachnoid hemorrhage, and death), there was no net clinical benefit observed in favor of changing the DOAC. The results of this study appear to be in line with those from previous studies. It would have been beneficial if the authors had investigated for 1) any possible interaction between DOACs and other drugs, 2) whether the dose of DOAC had been appropriate, 3) the independent predictors of outcome events, and 4) the pathogenesis of the new event.

Regarding the independent predictors of outcome events, in the RENO study, the CHA₂DS₂-VASc score after the index event was reported to be significantly associated with the risk of ischemic recurrence. Specifically, within the CHA₂DS₂-VASc score, the risk factors mainly associated with recurrence in patients on DOACs, were elderly age, male sex, previous stroke, diabetes mellitus, and congestive heart failure, most of which are nonmodifiable risk factors, suggesting that the recurrent event could have been due to the persistence of a stroke risk in those patient subgroups who are known to be at a high risk for unfavorable outcomes.¹

Another important point: it would have been equally interesting to know the pathogenesis of each new event. Concerning the possibility of alternative etiologies, initially, non-cardioembolic causes should be ruled-out (eg, intracranial or extracranial atherosclerosis and small-vessel disease) as generally a benefit can be gained from alternative therapeutic strategies. In fact, the RENO study reported that about 30% of the patients who suffered cerebrovascular events while on DOACs were classified as having strokes due to causes other than cardioembolism. However, in the RENO-EXTEND study, of the 920 included patients who had had a cardioembolic stroke as their index event, 401 had their type of DOAC changed after the index event whereas 351 did not. Of the patients who had their DOAC types changed, 34 (8.6%) had an ischemic outcome event compared with 27 (7.7%) of those who had not undergone a change to a different DOAC (P = .7).² These RENO-EXTEND results suggested that changing the DOAC type, also in patients who had a stroke while on DOAC therapy, may not have led to a greater benefit. Given this, the RENO-EXTEND authors suggested continuing the original DOAC after a cardioembolic event while on DOACs. However, in this scenario, one must seriously consider the possibility of changing the type of DOAC, with the principal aim of increasing compliance.

Further randomized clinical trials are warranted to both respond to these important clinical needs and also to explore for other novel approaches, which might include left atrial appendage occlusion, factor XIa inhibitors, and carotid filter placement.

References 

1. Paciaroni M, Agnelli G, Caso V et al. Causes and Risk Factors of Cerebral Ischemic Events in Patients With Atrial Fibrillation Treated With Non–Vitamin K Antagonist Oral Anticoagulants for Stroke Prevention. Stroke. 2019;50(8):2168-2174. https://www.ahajournals.org/doi/10.1161/STROKEAHA.119.025350
2. Paciaroni M, Caso V, Agnelli G et al. Recurrent Ischemic Stroke and Bleeding in Patients With Atrial Fibrillation Who Suffered an Acute Stroke While on Treatment With Nonvitamin K Antagonist Oral Anticoagulants: The RENO-EXTEND Study. 2022;53(8):2620-2627. https://www.ahajournals.org/doi/10.1161/STROKEAHA.121.038239