Apixaban Reduces Recurrent Stroke in Patients Without High-Risk Hypertension

Refining Antithrombotic Selection in Cryptogenic Stroke

Managing cryptogenic stroke remains a significant clinical challenge, as approximately 20% to 30% of ischemic events lack a definitive source despite extensive diagnostic workups [1]. While many of these cases are classified as embolic stroke of undetermined source, a meta-analysis of four randomized trials involving 13,970 patients found that direct oral anticoagulants did not reduce the risk of recurrent stroke compared to antiplatelet therapy (relative risk 0.95; 95% confidence interval, 0.83 to 1.08) [2]. This lack of benefit persists even in patients with multi-territory infarctions, defined as acute ischemia in two or more vascular distributions, where apixaban showed no advantage over aspirin (hazard ratio 1.0; 95% confidence interval, 0.62 to 1.71) despite these patients having a 2.5-fold higher risk of recurrence [3]. The clinical difficulty lies in the heterogeneous nature of these patients, where occult cardioembolic sources often overlap with hypertensive small vessel disease. A new exploratory analysis of 945 patients now examines how specific hypertensive phenotypes, such as high-risk hypertension (defined as systolic blood pressure of 160 mmHg or higher, left ventricular hypertrophy, or both), might explain these previous trial failures and guide more personalized treatment strategies [4, 5].

Defining the High-Risk Hypertensive Phenotype

The researchers conducted an exploratory analysis of the Apixaban to Prevent Recurrence After Cryptogenic Stroke in Patients With Atrial Cardiopathy (ARCADIA) randomized clinical trial to investigate how hypertensive phenotypes influence treatment efficacy. This specific analysis took place between April and August 2025, utilizing data from the original multicenter trial that was conducted from February 2018 to February 2023. The primary study spanned 185 sites across North America, providing a broad clinical foundation for evaluating secondary stroke prevention strategies. By focusing on the interaction between hypertension and antithrombotic response, the authors sought to determine if the presence of hypertensive arteriopathy, which refers to disease of the small arterial vessels caused by chronic high blood pressure, masked the potential benefits of anticoagulation in previous embolic stroke trials. The analytic cohort consisted of 945 patients with a recent cryptogenic stroke and atrial cardiopathy, a condition characterized by structural or functional changes in the left atrium that increase thromboembolic risk. This group was a subset derived from the 1015 patients originally randomized in the ARCADIA trial. To ensure the integrity of the data, the researchers excluded 70 patients who were missing essential blood pressure or echocardiography measurements. The final group of 945 participants had a mean age of 68.0 years (standard deviation of 10.8 years) and was majority female, with 513 patients (54.3%) represented. This population was then stratified based on the presence of hypertension with high-risk features, a clinical designation defined as having a systolic blood pressure of 160 mm Hg or higher at the time of enrollment, evidence of left ventricular hypertrophy (thickening of the heart's main pumping chamber) on echocardiography, or both. Within this cohort, 351 patients (37.1%) met the criteria for hypertension with high-risk features, while the remaining 594 patients did not. By isolating these two groups, the study aimed to differentiate between patients whose strokes were likely cardioembolic and those whose events may have been driven by underlying hypertensive small vessel disease. This distinction is critical for practicing clinicians, as the presence of severe hypertension or cardiac structural changes often serves as a marker for a different underlying stroke mechanism that may not respond to apixaban in the same manner as traditional embolic sources.

Divergent Outcomes Based on Vascular Risk Profiles

The researchers compared the efficacy of apixaban, administered at either 5 mg or 2.5 mg twice daily, against aspirin at a dose of 81 mg once daily. The primary outcome measured was the occurrence of recurrent ischemic stroke or systemic embolism, which occurs when a blood clot travels from the heart to other parts of the body. Over a median follow-up period of 1.6 years, with an interquartile range of 0.7 to 3.0 years, a total of 67 patients in the analytic cohort experienced a recurrent ischemic stroke or systemic embolism. Statistical analysis revealed a significant interaction between the presence of hypertension with high-risk features and the effect of the assigned antithrombotic treatment, suggesting that the clinical profile of the patient fundamentally alters how they respond to these medications. In the subgroup of 594 patients who did not have high-risk hypertension, apixaban was associated with a significantly lower risk of recurrence compared to aspirin, yielding a hazard ratio (a measure of how often a particular event happens in one group compared to another) of 0.43 with a 95% confidence interval of 0.22 to 0.85. This reduction in risk translated to an annualized rate difference of -3.4% for those treated with apixaban. These data indicate that in the absence of severe hypertensive markers, anticoagulation provides a substantial protective benefit against recurrent embolic events in patients with atrial cardiopathy, effectively reducing the relative risk of recurrence by 57% compared to antiplatelet therapy. Conversely, among the 351 patients with high-risk hypertension, defined by severe systolic elevation or left ventricular hypertrophy, no significant association was observed between the type of antithrombotic therapy and the risk of recurrence. In this high-risk group, the hazard ratio for apixaban versus aspirin was 1.68 with a 95% confidence interval of 0.78 to 3.62, and the annualized rate difference was 2.4%. The lack of benefit for apixaban in this population suggests that the underlying stroke mechanism in these patients may be related to hypertensive small vessel disease rather than the thromboembolic pathways typically targeted by anticoagulants.

Clinical Implications for Embolic Stroke Classification

The researchers suggest that the inclusion of strokes due to hypertensive arteriopathy, a condition where chronic high blood pressure causes structural damage to small cerebral arteries, may explain the lack of benefit for anticoagulation observed in previous clinical trials of embolic stroke of undetermined source. In those earlier studies, the inability to distinguish between true embolic events and small vessel disease likely diluted the observed treatment effect of anticoagulants. By analyzing the 945 patients in the ARCADIA cohort, the authors demonstrated that the presence of high-risk hypertensive features, specifically a systolic blood pressure of 160 mm Hg or higher or left ventricular hypertrophy on echocardiography, identifies a population where the underlying stroke mechanism is less likely to be thromboembolic in nature. For the practicing clinician, these findings suggest that screening for advanced hypertensive end-organ damage can refine the selection of candidates for anticoagulation in the setting of cryptogenic stroke and atrial cardiopathy. In the 594 patients without these high-risk features, apixaban was associated with a significantly lower risk of recurrence compared to aspirin, with a hazard ratio of 0.43 and a 95% confidence interval of 0.22 to 0.85. Conversely, in the 351 patients with high-risk hypertension, the hazard ratio was 1.68 with a 95% confidence interval of 0.78 to 3.62, indicating no significant association between treatment type and outcome. This distinction addresses the persistent challenge of distinguishing between cardioembolic mechanisms and hypertensive small vessel disease. By identifying patients without markers of severe hypertensive arteriopathy, physicians may more accurately isolate those with true atrial cardiopathy who are most likely to benefit from factor Xa inhibition rather than antiplatelet therapy.

References

1. Chi K, Song J, Zarif TE, et al. Oral anticoagulants or antiplatelets for cryptogenic stroke: a systematic review and meta-analysis. European Heart Journal. 2024. doi:10.1093/eurheartj/ehae666.2309

2. Pirera E, D’Anna L, Raimondo DD, Tuttolomondo A. Direct Oral Anticoagulants Versus Aspirin for Stroke Prevention After Embolic Stroke of Undetermined Source: An Updated Meta-Analysis of Randomized Controlled Trials. Journal of Clinical Medicine. 2024. doi:10.3390/jcm13226730

3. Karunamuni N, Gologorsky R, Longstreth W, Tirschwell D, Elkind M, Kamel H. Abstract 136: Infarct Topography, Effect of Anticoagulation, and Recurrence after Cryptogenic Stroke: A Subgroup Analysis of the ARCADIA Trial. Stroke. 2025. doi:10.1161/str.56.suppl_1.136

4. Ridha M, Hailat R, Stanton R, et al. Hypertension With High-Risk Features in Cryptogenic Stroke: An Exploratory Analysis of the ARCADIA Randomized Clinical Trial.. JAMA neurology. 2026. doi:10.1001/jamaneurol.2026.0855

5. Ridha M, Hailat R, Stanton RJ, et al. Abstract A033: Potential Benefit of Apixaban Among Patients Without High-Risk Hypertension In Cryptogenic Stroke: A Secondary Analysis of the ARCADIA Trial. Stroke. 2026. doi:10.1161/str.57.suppl_1.a033