Apixaban for treatment of embolic stroke of undetermined source (ATTICUS) randomized trial – update of patient characteristics and study timeline after interim analysis

Abstract

Background Secondary prevention after embolic stroke of undetermined source (ESUS) has not yet been established. ESUS is associated with high risk of recurrent ischemic stroke and clinically silent ischemic lesions. Secondary prevention with aspirin is the current standard therapy in ESUS patients, despite high prevalence of occult atrial fibrillation (AF). Purpose To determine whether the direct oral factor Xa inhibitor apixaban, started within 28 days after index stroke, is superior to aspirin in preventing new ischemic lesions in subjects with remote cardiac monitoring. Primary endpoint was detection of new ischemic lesions in flair and diffusion-weighted (DWI) MR imaging at 12 months follow-up. Methods The study enrolled ESUS patients with risk profile for cardiac thromboembolism (i.e., left atrium (LA) size >45 mm, spontaneous echo contrast in LA appendage, LA appendage flow velocity ≤0.2 cm/s, atrial high rate episodes, CHA2DS2-Vasc score ≥4, patent foramen ovale). Patients were randomized 1:1 into the aspirin and apixaban arms. Study drug was initiated within 3–28 days after minor/moderate stroke and 14–28 days after major stroke. MRI (Flair/DWI) was conducted within 7 days of AF detection by remote cardiac monitors and at 12 months. ClinicalTrials.gov Identifier: NCT02427126. Funding: The trial is supported by BMS-Pfizer Alliance. Results Enrollment was stopped after interims analysis (including 200 patients) due to futility. Overall, 373 patients were screened with 353 being enrolled (178 and 175 in apixaban and ASA arms, respectively). So far, 130 (73.0%) and 120 (68.6%) subjects from apixaban and ASA arms, respectively, completed the study. 2% death, 1.7% withdrawal, and 1.7% were lost to follow-up. 3.9% did not completed the study for other reasons. Mean age of the ATTICUS population was 68.5 years with 51% males. 80% of the subjects suffered from hypertension. Mean systolic blood pressure at enrollment was 132 mmHg, BMI was 27.7, and CHA2DS-VASc-Score was 4.9. So far, adverse events (AE) occurred in 63% of the subjects, 30% was documented as severe. 6.8% cases of recurrent ischemic stroke and no case of hemorrhagic stroke were reported. Only 1 case of severe bleeding was reported in the aspirin arm. Newly detected AF was reported in 80 patients (23%), 42 occurring in the aspirin arm. As required by protocol, latter were immediately switched from aspirin to apixaban. Due to ongoing data clearing, numbers and % will change until presentation. Conclusions In contrast to the recently published NAVIGATE and RESPECT ESUS trials, patients enrolled in ATTICUS need to exhibit additional AF predicting factors. Furthermore, mandatory cardiac remote monitoring will help to elucidate the impact of AF and the effects of early oral anticoagulation with apixaban compared to antiplatelet therapy with aspirin on the incidence of new ischemic lesions after ESUS. Preliminary data will be presented and discussed in the context of current literature. FUNDunding Acknowledgement Type of funding sources: Private company. Main funding source(s): The trial is supported by BMS-Pfizer Alliance.

European Stroke Organisation (ESO) guideline on screening for subclinical atrial fibrillation after stroke or transient ischaemic attack of undetermined origin

“…Nevertheless, final details are still lacking at the time of writing this guideline. 133 Another study, ARCADIA (AtRial Cardiopathy and Antithrombotic Drugs In Prevention After Cryptogenic Stroke, NCT03192215) is now randomising ESUS patients with atrial cardiomyopathy (P-wave terminal force >5000 µV × ms in ECG lead V 1 , serum NT-proBNP > 250 pg/mL and LA diameter index ⩾3 cm/m 2 on echocardiogram) for treatment with apixaban or aspirin. The primary efficacy outcome is recurrent stroke and primary safety outcomes are symptomatic intracranial haemorrhage or non-intracranial major haemorrhages.…”

Evaluating Rates of Recurrent Ischemic Stroke Among Young Adults With Embolic Stroke of Undetermined Source

“…To date, 23% of the study patients have developed AF during follow-up. 19 Hence, further assessment of predictors of AF in the ESUS population is warranted and is the basis for the ongoing randomized clinical trial ARCADIA (NCT03192215).…”

“…A secondary analysis of the NAVIGATE ESUS trial showed that left atrial diameter and premature atrial contraction frequency predicted subsequent clinical AF. The ATTICUS study, which stopped after the interim analysis owing to futility, looked at an ESUS population with a high risk profile for cardiac thromboembolism (ie, left atrium larger than 45 mm, spontaneous echo contrast in left atrium appendage, left atrium appendage flow velocity 0.2 cm/s or greater, atrial high-rate episodes, CHA2DS2-Vasc [congestive heart failure, hypertension, age 75 years and older, diabetes, stroke or transient ischemic attack, vascular disease, age 65-74 years, and sex category] score 4 or greater, and PFO). To date, 23% of the study patients have developed AF during follow-up .…”

“…The ATTICUS study, which stopped after the interim analysis owing to futility, looked at an ESUS population with a high risk profile for cardiac thromboembolism (ie, left atrium larger than 45 mm, spontaneous echo contrast in left atrium appendage, left atrium appendage flow velocity 0.2 cm/s or greater, atrial high-rate episodes, CHA2DS2-Vasc [congestive heart failure, hypertension, age 75 years and older, diabetes, stroke or transient ischemic attack, vascular disease, age 65-74 years, and sex category] score 4 or greater, and PFO). To date, 23% of the study patients have developed AF during follow-up . Hence, further assessment of predictors of AF in the ESUS population is warranted and is the basis for the ongoing randomized clinical trial ARCADIA (NCT03192215).…”

Atrial cardiopathy is associated with cerebral microbleeds in ischemic stroke patients

“…there are currently no guidelines for anti-coagulation use for ischemic stroke patients who are found to have atrial cardiopathy ( 37 , 38 ). The AtRial Cardiopathy and Antithrombotic Drugs In Prevention After Cryptogenic Stroke (ARCADIA) trial ( 8 ) and the Apixaban for Treatment of Embolic Stroke of Undetermined Source (ATTICUS) trial ( 39 , 40 ) are specifically randomizing patients with biomarker driven atrial cardiopathy (though different criteria than our study) to anticoagulation vs. antiplatelet therapy and may help answer some of these questions. Atrial cardiopathy may increase subclinical risk of embolic stroke, and with the addition of the findings of this study that risk may be marked by CMB ( 41 ).…”