WARSS

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Mohr J, et al. "A Comparison of Warfarin and Aspirin for the Prevention of Recurrent Ischemic Stroke". The New England Journal of Medicine. 2001. 345(20):1444-1451.
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Clinical Question

In patients with a prior non-embolic ischemic stroke, is warfarin superior to ASA for secondary prevention?

Bottom Line

There was no significant differences between patients receiving ASA (325 MG) vs. warfarin (INR 1.4-2.8) in rates of recurrent ischemic strokes, death or major hemorrhage.

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, anti-coagulation for ischemic stroke prevention from a central embolic cause should also be considered for patients with an LV mural thrombus or anterior apical akinesis/dyskinesis following MI, severe cardiomyopathy, a mechanical LVAD, rhematic mitral valve disease and those with prosthetic heart valves.[2]

The role of anti-coagulation in those with non-embolic strokes is an area in evolution. The WARSS trial is one of the early high impact trials to suggest no benefit for secondary stroke prevention using anti-coagulation compared to anti-platelet therapy. Due to the increased convenience, practically, this has meant anti-platelet therapy for most patients who fall within this category. More recently,WASID which looked at warfarin compared to ASA in those with intra-cranial atherosclerosis showed increased mortality with warfarin use without benefits to ischemic stroke prevention.

Post-hoc subgroup analysis from the WARSS trial suggests that perhaps there is some benefit with anti-coagulation in patients with cryptogenic strokes with a National Institutes of Health stroke scale [NIHSS] score ≤5, posterior circulation infarcts sparing the brainstem and no prior history of hypertension. Because of this, there is an ongoing trial investigating the utility of anti-coagulation with dabigatran vs. ASA in patients with a TIA or cryptogenic stroke (NIHSS score <9 AND DWI lesion volume <25ml) within 48 hours of symptom onset.[3]

Design

  • Multicenter, prospective cohort study
  • N=2206
    • ASA= 1103, 21 lost to follow up
    • Warfarin= 1103, 12 lost to follow up
  • Setting: 48 centers in the United States
  • Enrollment: June 1993-June 2000
  • Follow-up: 2 years
  • Primary outcomes; Death and recurrent ischemic strokes

Population

Inclusion Criteria

  • 30-85 years old
  • No contra-indications for warfarin or antiplatelets
  • Had an ischemic stroke within the previous 30 days

Exclusion Criteria

  • Abnormal Base-line INR (>1.4)
  • Stroke atrributed to a procedure, high-grade carotid stenosis, or an inferred cardioembolic source (e.g. atrial fibrillation)
  • Inability to provide written consent

Baseline Characteristics

Given for Warfarin group, characteristic for other similar due to successful randomization

  • Age (yr): 63.3±11.2
  • Female sex no. (%): 447 (40.5)
  • Race or ethnic group no.(%):
    • White: 627 (56.8)
    • Black: 338 (30.6)
    • Hispanic: 105 (9.5)
    • Other: 33 (3.0)
  • Education no (%):
    • High school or less: 805 (73.0)
    • After high school: 287 (26.0)
    • Unknown: 11 (1.0)
  • Hypertension no. (%):
    • Yes: 746 (67.6)
    • No: 343 (31.1)
    • Unknown: 14 (1.3)
  • Diabetes mellitus no.(%):
    • Yes: 367 (33.3)
    • No: 733 (66.5)
    • Unknown: 3 (0.3)
  • Any cardiac disease no. (%) defined as MI, CHF, AF, angina, arrhythmia, or valvular heart disease:
    • Yes: 250 (22.7)
    • No: 822 (74.5)
    • Unknown: 31 (2.8)
  • History of transient ischemic attack, amaurosis fugax, or stroke — no. (%):
    • Yes: 321 (29.1)
    • No: 731 (66.3)
    • Unknown: 51 (4.6)
  • Current smoking no. (%):
    • Yes: 306 (27.7)
    • No: 792 (71.8)
    • Unknown: 5 (0.5)
  • Heavy alcohol intake (»4 drinks/day) no. (%):
    • Yes: 40 (3.6)
    • No: 1060 (96.1)
    • Unknown: 3 (0.3)
  • Duration of symptoms no. (%):
    • «24 hr, with clinically relevant infarct on CT or MRI: 74 (6.7)
    • >24 hr, with clinically relevant infarct on CT or MRI: 729 (66.1)
    • >24 hr, without clinically relevant infarct on CT or MRI: 300 (27.2)
  • Presumed cause of prior stroke no. (%):
    • Cryptogenic: 281 (25.5)
    • Small-vessel or lacunar: 612 (55.5)
    • Large-artery, severe stenosis or occlusion: 144 (13.1)
    • Other determined cause: 30 (2.7)
    • Conflicting mechanism: 36 (3.3)
  • Lesion found on brain imaging no. (%):
    • Superficial, cortical, or cerebellar: 143 (13.0)
    • Large deep (basal ganglia and other): 77 (7.0)
    • Superficial and deep combined: 126 (11.4)
    • Small deep: 315 (28.6)
    • Brain stem: 110 (10.0)
    • No primary lesion visible on scan: 304 (27.6)
    • Unknown: 28 (2.5)

Interventions

  • Stratified randomization to one of two groups:
    • ASA 325 MG PO daily (and placebo) with sham INR blood work
    • Warfarin 2MG daily (and placebo) then dose adjusted to achieve INR with range of 1.4 to 2.8

Outcomes

All outcomes presented as warfarin vs. ASA

Primary Outcomes

  • 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)
  • Recurrent ischemic stroke or death (model including interaction of treatment assignment and interruption of treatment): 196/1103 176/1103

Secondary Outcomes

  • No difference in time to primary outcome in ASA 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

  1. 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.
  2. 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.
  3. https://clinicaltrials.gov/ct2/show/NCT02295826