Association of Alternative Anticoagulation Strategies and Outcomes in Patients With Ischemic Stroke While Taking a Direct Oral Anticoagulant

Abstract

Background and Objectives:Ischemic stroke despite direct oral anticoagulant (DOAC) is increasingly common and portends high risk of subsequent ischemic stroke. Efficacy and safety of antithrombotic regimens following the condition are unclear. We aimed to compare the outcomes of patients with ischemic stroke despite DOAC with and without an alternative antithrombotic regimen, and determine the risk factors of recurrent ischemic stroke while on anticoagulation.Methods:In a population-based, propensity-score weighted, retrospective cohort study, we compared the clinical outcomes of DOAC-to-warfarin switch, DOAC-to-DOAC switch (DOACswitch) or addition of antiplatelet agents, with unchanged DOAC regimen (DOACsame) among non-valvular atrial fibrillation (NVAF) patients who developed the first ischemic stroke despite DOAC from 1stJanuary 2015 to 31stDecember 2020 in Hong Kong. Primary outcome was recurrent ischemic stroke. Secondary outcomes were intracranial hemorrhage, acute coronary syndrome and death. We performed competing risk regression analyses to compare the clinical endpoints, and determined the predictors of recurrent ischemic stroke in an unweighted multivariable logistic regression model.Results:During the 6-year study period, among 45,946 AF patients on DOAC as stroke prophylaxis, 2,908 patients developed ischemic stroke despite DOAC. 2,337 NVAF patients were included in the final analyses. Compared to DOACsame, warfarin (aHR 1.96, 95%CI 1.27-3.02, p=0.002) and DOACswitch(aHR 1.62, 95%CI 1.25-2.11, p-value <0.001) were associated with increased risk of recurrent ischemic stroke. In DOACsamegroup, adjunctive antiplatelet agent was not associated with reduced risk of recurrent ischemic stroke. Diabetes mellitus, concurrent cytochrome P450/P-glycoprotein (CYP/P-gp) modulators and large artery atherosclerotic disease (LAD) were predictors of recurrent ischemic stroke.Discussion:In NVAF patients with ischemic stroke despite DOAC, the increased risk of recurrent ischemic stroke with switching to warfarin called for caution against such practice, while the increased ischemic stroke with DOAC-to-DOAC switch demands further studies. Adjunctive antiplatelet agent did not appear to reduce ischemic stroke relapse. As diabetes mellitus, use of CYP/P-gp modulators and LAD were predictors of recurrent ischemic stroke, further investigations should evaluate if strict glycemic control, DOAC level monitoring and routine screening for carotid and intracranial atherosclerosis may reduce ischemic stroke recurrence in these patients.Classification of Evidence:This study provides Class II evidence that in patients with non-valvular atrial fibrillation suffering an ischemic stroke while being treated with a DOAC, continuing treatment with that DOAC is more effective at preventing recurrent ischemic stroke than switching to a different DOAC or to warfarin.

Author Response: Association of Alternative Anticoagulation Strategies and Outcomes in Patients With Ischemic Stroke While Taking a Direct Oral Anticoagulant

“…We sincerely thank Wolfe et al for the comments. The low rate of large artery atherosclerotic disease (LAD) in our atrial fibrillation (AF) cohort 1 echoed our other study that among ischemic strokes, the proportion of intracranial atherosclerotic disease declined from 23.3% to 8.8% from 2004 to 2018 in Hong Kong. 2 This difference may explain the disparity in LAD rates because the cohort of minor strokes/TIA quoted was recruited from 2011 to 2015.…”

Changing or Retaining Direct Oral Anticoagulant After Ischemic Stroke Despite Direct Oral Anticoagulant Treatment

“… 18 Regarding safety, all investigations showed that changing or retaining prestroke DOAC resulted in a comparable ICH risk. However, our study reported a relatively higher hazard ratio for ICH than the other 2 studies (ie, 1.49 versus 1.06 for Hong Kong and 1.03 for Taiwanese studies), 17 , 18 implying that a large‐scale investigation will be required for validation.…”

“…A Hong Kong study demonstrated that changing the prestroke DOAC to a different DOAC or warfarin increased the risk of recurrent IS. 17 Results from another Taiwanese study showed comparable recurrent stroke risk in patients who changed from a prestroke DOAC to another DOAC but increased IS risk in patients who changed from DOAC to warfarin. 18 Regarding safety, all investigations showed that changing or retaining prestroke DOAC resulted in a comparable ICH risk.…”

Atrial Fibrillation and Ischemic Stroke despite Oral Anticoagulation

“…Emerging evidence from prospective observational cohorts [12,15,16] and post hoc analysis of the pivotal RCT comparing DOACs with VKA in patients with AF [17] found patients with breakthrough strokes despite OAC to be at increased risk of further recurrence constituting a highly vulnerable patient population. The optimal prevention strategy to further reduce recurrence risk in such patients is still unknown [15,18,19]. Breakthrough strokes may be caused by competing, non-AF-related mechanisms (i.e., large or small vessel disease), which accounts for The latest European and American guidelines for management of AF recommend DOAC in preference to VKA for stroke prevention in selected AF patients (excluding patients with mechanical heart valves or moderate-to-severe mitral stenosis) with increased stroke risk [4,22].…”