WARSS
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Clinical Question
In patients with a recent non-embolic ischemic stroke, is warfarin superior to aspirin for secondary prevention?
Bottom Line
Among patients with non-embolic ischemic stroke, there was no significant differences between patients receiving aspirin (325 mg/d) vs. warfarin (goal INR 1.4-2.8) in rates of recurrent ischemic strokes, death, or major hemorrhage. Minor hemorrhage was more common in patients receiving warfarin.
Major Points
The use of warfarin in primary and secondary prevention of ischemic stroke in patients with central embolic etiologies has been well studied. Atrial fibrillation is by far the most common etiology in this category and pooled evidence suggests that adjusted-dose warfarin leads to a relative risk reduction of 68% (95% CI, 50 to 79) and an absolute risk from an annual stroke rate of 4.5% for controls to 1.4%.[1] Outside of atrial fibrillation, anticoagulation for ischemic stroke prevention from a central embolic cause is also considered for patients with an LV mural thrombus, anterior apical akinesis/dyskinesis following MI, and other etiologies.[2] The role of anticoagulation in those with non-embolic ischemic stroke had been uncertain.
WARSS (Warfarin–Aspirin Recurrent Stroke Study) was an early study demonstrating no benefit to anticoagulation over aspirin in secondary stroke prevention. Over 2,000 adults with recent ischemic, non-cardioembolic stroke were randomized to aspirin 325 mg/d or warfarin with an INR goal of 2-3, and matching placebo was provided to each group. The primary endpoint was death from any cause or recurrent ischemic stroke, and primary safety outcomes were major hemorrhage and minor hemorrhage which were adjudicated in a blinded manner. There was no difference between aspirin and warfarin in the rate of the primary endpoint (HR 1.13; P=0.25) or major hemorrhage (1.49 versus 2.22 per 100 patient-years; P=0.10). Minor hemorrhages were more common with warfarin (12.9 vs. 20.8 per 100 patient-years; P<0.001).
Due to the increased convenience and safety of aspirin and equal efficacy to warfarin, practically this has meant that patients with non-cardioembolic ischemic stroke are treated with aspirin rather than anticoagulation. More recently, WASID compared warfarin to aspirin in those with intracranial atherosclerosis and demonstrated increased mortality with warfarin use.
Post-hoc subgroup analysis from WARSS suggests a possible benefit of anticoagulation in patients with cryptogenic strokes with a (NIHSS) score ≤5, posterior circulation infarcts sparing the brainstem, and no prior history of hypertension. This group was studied in DATAS-2, which evaluated dabigatran versus aspirin in patients with TIA or cryptogenic stroke, and found no difference in hemorrhagic transformation; the study was not powered to evaluate difference in recurrent stroke.
Design
- Multicenter, prospective cohort study
- N=2206 patients with non-cardioembolic ischemic stroke
- Aspirin (n=1103)
- Warfarin (n=1103)
- Setting: 48 US centers
- Enrollment: 1993-2000
- Follow-up: 2 years
- Primary outcomes: Death or recurrent ischemic stroke
Population
Inclusion Criteria
- Age 30-85 years
- No contraindications to antithrombotic therapy
- Ischemic stroke within prior 30 days
Exclusion Criteria
- Baseline INR >1.4
- Stroke atrributed to a procedure, high-grade carotid stenosis, or an inferred cardioembolic source (eg, atrial fibrillation)
- Inability to provide written consent
Baseline Characteristics
From the warfarin group.
- Age: 63.3±11.2 years
- Female sex: 40.5%
- Race or ethnic group
- White: 56.8%
- Black: 30.6%
- Hispanic: 9.5%
- Other: 3.0%
- Education:
- High school or less: 73%
- After high school: 26%
- Unknown: 1%
- HTN 67%, DM 33%, cardiac disease 23%, history of TIA/stroke 29%
- Current smoking 28%, heavy alcohol use 3.6%
- Duration of symptoms:
- ≤24 hr, with clinically relevant infarct on CT or MRI: 6.7%
- >24 hr, with clinically relevant infarct on CT or MRI: 66.1%
- >24 hr, without clinically relevant infarct on CT or MRI: 27.2%
- Presumed cause of prior stroke:
- Cryptogenic: 25.5%
- Small-vessel or lacunar: 55.5%
- Large-artery, severe stenosis or occlusion: 13.1%
- Other determined cause: 2.7%
- Conflicting mechanism: 3.3%
- Lesion found on brain imaging:
- Superficial, cortical, or cerebellar: 13.0%
- Large deep (basal ganglia and other): 7.0%
- Superficial and deep combined: 11.4%
- Small deep: 28.6%
- Brain stem: 10.0%
- No primary lesion visible on scan: 27.6%
- Unknown: 2.5%
Interventions
- Stratified randomization to one of two groups:
- Aspirin 325 mg/d (and placebo) with sham INR blood work
- Warfarin (and placebo) dose adjusted to achieve INR with range of 1.4 to 2.8
Outcomes
Outcomes presented as warfarin vs. aspirin.
Primary Outcomes
- Recurrent ischemic stroke or death (model including interaction of treatment assignment and interruption of treatment): 196/1103 176/1103
- Probability of recurrent ischemic stroke or death at two years: 17.8 vs. 16.0 (HR 1.13, 95% CI 0.92–1.38, p=0.25)
- Probability of recurrent ischemic stroke or death or major hemorrhage at two years: 20.0 vs. 17.8 (HR 1.15, 95% CI 0.95–1.39, p=0.16)
- Probability of recurrent ischemic stroke or death, with data from patients lost to follow-up censored at two years: 17.6 vs. 15.9 (HR 1.13, 95% CI 0.92–1.39, p=0.24)
Secondary Outcomes
- No difference in time to primary outcome in aspirin vs. warfarin (information presented as Kaplan Meyer curves in manuscript)
Subgroup Analysis
- Subgroup analysis based on sex, race and cause of prior strokes did not reveal significant effects on primary end point
Adverse Events
- Death related to hemorrhage: 47/1103 (4.3%) vs. 53/1103 (4.8%) (HR=0.88, 95% CI 0.58–1.32, p=0.61)
- Major hemorrhage (intra-cranial, intra-spinal or transfusion requirement): 44/1103 (2.2%) vs. 30/1103 (1.5%) (HR=1.48, 95% CI 0.93–2.44, p=0.10)
- Minor hemorrhage: 413/1103 (20.8%) 259/1103 (12.9%) (HR=1.61, 95% CI 1.38–1.89, p<0.001)
Criticisms
- Mean daily INR for patients in WARSS taking warfarin was 2.1 (median, 1.9) given the target range of 1.4 to 2.8 compared to current recommended INR ranges of 2-3 for adjusted-dose warfarin therapy for most AF patients and 2.5-3.5 for patients with a mechanical mitral valves which likely carries higher bleeding risks.
Funding
- National Institute of Neurological Disorders and Stroke
- Medications and placebos were supplied by Dupont Pharmaceuticals and Bayer
Further Reading
- ↑ Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation. Analysis of pooled data from five randomized controlled trials. Arch. Intern. Med. 1994. 154:1449-57.
- ↑ Kernan WN et al. Guidelines for the prevention of stroke in patients with stroke and transient ischemic attack: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2014. 45:2160-236.