Design, Progress and Challenges of a Double-Blind Trial of Warfarin versus Aspirin for Symptomatic Intracranial Arterial Stenosis

Abstract

Background and Relevance: Atherosclerotic stenosis of the major intracranial arteries is an important cause of transient ischemic attack (TIA) or stroke. Of the 900,000 patients who suffer a TIA or stroke each year in the USA, intracranial stenosis is responsible for approximately 10%, i.e. 90,000 patients. There have been no prospective trials evaluating antithrombotic therapies for preventing recurrent vascular events in these patients. The main objective of this trial is to compare warfarin [International Normalized Ratio (INR) 2–3] with aspirin (1,300 mg/day) for preventing stroke (ischemic and hemorrhagic) and vascular death in patients presenting with TIA or stroke caused by stenosis of a major intracranial artery. Study Design: Prospective, randomized, double-blind, multicenter trial. The sample sizerequired will be 403 patients per group, based on stroke and vascular death rates of 33% per 3 years in the aspirin group vs. 22% per 3 years in the warfarin group, a p value of 0.05, power of 80%, a 24% rate of ‘withdrawal of therapy’, and a 1% rate of ‘lost to follow-up’. Conduct of Trial: Patients with TIA or nondisabling stroke caused by ≧50% stenosis of a major intracranial artery documented by catheter angiography are randomized to warfarin or aspirin. Patients are contacted monthly by phone and examined every 4 months until a common termination date. Mean follow-up in the study is expected to be 3 years. Conclusion: This study will determine whether warfarin or aspirin is superior for patients with symptomatic intracranial arterial stenosis. Furthermore, it will identify patients whose rate of ischemic stroke in the territory of the stenotic intracranial artery on best medical therapy is sufficiently high to justify a subsequent trial comparing intracranial angioplasty/stenting with best medical therapy in this subset of patients.

Sex Differences Do Not Exist in Outcomes among Stroke Patients with Intracranial Atherosclerosis in China: Subgroup Analysis from the Chinese Intracranial Atherosclerosis Study

“…The WASID study was a randomized clinical trial that had firm inclusion and exclusion criteria [19]. They included TIA or non-disabling stroke that occurred within 90 days before randomization, age of at least 40 years, and excluded tandem 50-99% stenosis of the extracranial carotid artery, a contraindication to aspirin or warfarin therapy, an indication for heparin administration after randomization.…”

Increased Risk of Cardiovascular Events in Stroke Patients Who had Not Undergone Evaluation for Coronary Artery Disease

“…Initial stroke severity was determined based on the National Institute of Health Stroke Scale (NIHSS). Cerebral atherosclerosis was defined as having at least ≥1 steno-occlusive lesion of >50% based on the North American Symptomatic Carotid Endarterectomy Trial (for extracranial arteries)15 or on the Warfarin vs. Aspirin for Symptomatic Intracranial Disease method (for intracranial arteries) 16. Framingham risk scores were calculated for each patient.…”

Infarct Patterns, Collaterals and Likely Causative Mechanisms of Stroke in Symptomatic Intracranial Atherosclerosis

“…Details of the design of WASID and the baseline characteristics of patients in the trial have been published previously (13, 14) . All 569 patients enrolled in WASID had a transient ischemic attack or nondisabling stroke within 90 days prior to enrollment that was attributable to angiographically verified 50% to 99% stenosis of a major intracranial artery (carotid, middle cerebral, vertebral or basilar).…”