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Apixaban to Prevent Recurrence After Cryptogenic Stroke in Patients With Atrial Cardiopathy: The ARCADIA Randomized Clinical Trial

Hooman Kamel et al. JAMA. .

Abstract

Importance: Atrial cardiopathy is associated with stroke in the absence of clinically apparent atrial fibrillation. It is unknown whether anticoagulation, which has proven benefit in atrial fibrillation, prevents stroke in patients with atrial cardiopathy and no atrial fibrillation.

Objective: To compare anticoagulation vs antiplatelet therapy for secondary stroke prevention in patients with cryptogenic stroke and evidence of atrial cardiopathy.

Design, setting, and participants: Multicenter, double-blind, phase 3 randomized clinical trial of 1015 participants with cryptogenic stroke and evidence of atrial cardiopathy, defined as P-wave terminal force greater than 5000 μV × ms in electrocardiogram lead V1, serum N-terminal pro-B-type natriuretic peptide level greater than 250 pg/mL, or left atrial diameter index of 3 cm/m2 or greater on echocardiogram. Participants had no evidence of atrial fibrillation at the time of randomization. Enrollment and follow-up occurred from February 1, 2018, through February 28, 2023, at 185 sites in the National Institutes of Health StrokeNet and the Canadian Stroke Consortium.

Interventions: Apixaban, 5 mg or 2.5 mg, twice daily (n = 507) vs aspirin, 81 mg, once daily (n = 508).

Main outcomes and measures: The primary efficacy outcome in a time-to-event analysis was recurrent stroke. All participants, including those diagnosed with atrial fibrillation after randomization, were analyzed according to the groups to which they were randomized. The primary safety outcomes were symptomatic intracranial hemorrhage and other major hemorrhage.

Results: With 1015 of the target 1100 participants enrolled and mean follow-up of 1.8 years, the trial was stopped for futility after a planned interim analysis. The mean (SD) age of participants was 68.0 (11.0) years, 54.3% were female, and 87.5% completed the full duration of follow-up. Recurrent stroke occurred in 40 patients in the apixaban group (annualized rate, 4.4%) and 40 patients in the aspirin group (annualized rate, 4.4%) (hazard ratio, 1.00 [95% CI, 0.64-1.55]). Symptomatic intracranial hemorrhage occurred in 0 patients taking apixaban and 7 patients taking aspirin (annualized rate, 1.1%). Other major hemorrhages occurred in 5 patients taking apixaban (annualized rate, 0.7%) and 5 patients taking aspirin (annualized rate, 0.8%) (hazard ratio, 1.02 [95% CI, 0.29-3.52]).

Conclusions and relevance: In patients with cryptogenic stroke and evidence of atrial cardiopathy without atrial fibrillation, apixaban did not significantly reduce recurrent stroke risk compared with aspirin.

Trial registration: ClinicalTrials.gov Identifier: NCT03192215.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Kamel reported serving as Deputy Editor for JAMA Neurology, on clinical trial steering or executive committees for Medtronic and Janssen, and on clinical trial end point adjudication committees for AstraZeneca, Novo Nordisk, and Boehringer Ingelheim and having personal or household ownership interests in TETMedical, Spectrum Plastics Group, and Burke Porter Group. Dr Longstreth reported receiving grants from National Institutes of Health (NIH)–National Institute of Neurological Disorders and Stroke (NINDS) during the conduct of the study. Dr Tirschwell reported receiving grants from NIH/NINDS during the conduct of the study. Dr Kronmal reported receiving grants from the University of Washington during the conduct of the study. Dr Broderick reported receiving grants from NINDS during the conduct of the study; study medication and associated financial support for NINDS-funded FASTEST from Novo Nordisk, monies to department of neurology for work on executive committee of the TIMELESS Trial and consulting work from Roche-Genentech, monies to department of neurology for consulting work from Basking Biosciences, monies to department of neurology for consulting work from Brainsgate, and personal fees from Kroger Prescription Plans Inc’s Pharmacy &Therapeutics Committee outside the submitted work. Dr Plummer reported receiving grants from the NIH during the conduct of the study. Dr Pauls reported receiving grants from the NIH during the conduct of the study. Dr Cassarly reported receiving grants from the NIH during the conduct of the study and honoraria for NIH data and safety monitoring board and NIH study section participation. Dr Healey reported receiving grants from Bristol Myers Squibb (BMS)/Pfizer, Boston Scientific, and Medtronic and personal fees from Servier, and Bayer outside the submitted work. Dr Sharma reported receiving grants from the NIH during the conduct of the study and grants from BMS, Janssen, and Bayer outside the submitted work. Dr Krishnaiah reported receiving funds from NIH StrokeNet for patient randomization during the conduct of the study. Dr Kasner reported receiving grants from Bayer, Daichi Sankyo, Medtronic, BMS, and Genentech outside the submitted work. Dr Elkind reported receiving nonfinancial support from BMS-Pfizer Alliance for Eliquis (study drug in kind for the ARCADIA trial) and grants from Roche (ancillary support for the ARCADIA trial) during the conduct of the study and honoraria from Atria Academy for Science and Medicine and royalties from UpToDate outside the submitted work; Dr Elkind is employed by the American Heart Association. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Enrollment, Treatment Allocation, and Analysis in the ARCADIA Trial
ARCADIA indicates Atrial Cardiopathy and Antithrombotic Drugs in Prevention After Cryptogenic Stroke. aAtrial cardiopathy was defined as at least 1 of the following biomarkers: P-wave terminal force in electrocardiogram lead V1 >5000 μV × ms, serum N-terminal pro-B-type natriuretic peptide level >250 pg/mL, or left atrial diameter index ≥3 cm/m2 on echocardiogram. bEligible participants were randomly assigned in a 1:1 ratio to apixaban or aspirin using a central randomization system and a method that controlled the treatment imbalance within each StrokeNet Regional Coordinating Center. One patient was incorrectly randomized despite not meeting the atrial cardiopathy biomarker criteria.
Figure 2.
Figure 2.. Cumulative Rates of the Primary Efficacy Outcome of Recurrent Stroke, Stratified by Treatment Group
Recurrent stroke included stroke of ischemic, hemorrhagic, or unknown type. The mean (SD) follow-up period in both groups was 1.8 (1.3) years.
Figure 3.
Figure 3.. Analysis of Treatment Effect on the Primary Efficacy Outcome Across Subgroups
The primary efficacy outcome was recurrent stroke, which included stroke of ischemic, hemorrhagic, or unknown type. All subgroup analyses were prespecified. NT-proBNP indicates N-terminal pro-B-type natriuretic peptide and PTFV1, P-wave terminal force in lead V1. No statistically significant interactions were found at a Bonferroni-corrected P value threshold of .007, including when modeling the atrial cardiopathy biomarkers as continuous variables (P values for interaction: .68 [NT-proBNP], .35 [PTFV1], and .11 [left atrial diameter index] for treatment).
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