In patients with a recent TIA or non-disabling stroke and intracranial artery stenosis of 50 to 99%, does medical treatment with warfarin improve mortality and decrease risk for further cerebrovascular events compared with aspirin?
Among patients with a recent TIA or stroke and 50-99% intracranial arterial stenosis, warfarin increased the rate of adverse events including death and did not improve efficacy compared to aspirin.
Since the widespread adoption of CT and MR angiography for acute stroke management leading to more frequent detection of intracranial atherosclerosis, the best management of symptomatic intracranial artery stenosis for secondary stroke prevention needed to be addressed. The clinical equipoise stemmed from the fact that prior to the WASID trial, several retrospective papers suggested a possible benefit of warfarin over aspirin for the stroke prevention in this population but the WARSS trial (2001) suggested aspirin and warfarin were equivalent in the context of non-cardioembolic strokes. In fact, a survey of neurologists prior to the WASID trial showed clinicians at the time were equally divided between those who preferred warfarin and those who preferred antiplatelet agents in this context.
The Warfarin-Aspirin Symptomatic Intracranial Disease (WASID) trial enrolled patients with TIA or stroke attributed to intracranial arterial stenosis of 50-99%. Patients were randomized to warfarin with goal INR 2-3 or aspirin 1300 mg/d, and followed for the primary endpoint of ischemic stroke, intracranial hemorrhage, or non-stroke CV death. At nearly 2 years of median follow-up, the study was discontinued because of excess toxicity with warfarin including death (9.7% with warfarin versus 4.3% with aspirin), major hemorrhage (8.3% versus 3.2%), and MI (7.3% versus 2.9%).
WASID provided convincing evidence for the use of aspirin over warfarin for this patient population. In the subsequent SAMMPRIS trial (2015), the medical therapy arm using dual antiplatelet agents had lower rates of repeat strokes and TIAs compared with the aspirin arm in WASID, leading to current recommendation for dual antiplatelet therapy for 90 days following strokes attributed to intracranial atherosclerosis.
AHA/ASA Guidelines for the Prevention of Stroke in Patients With Stroke and Transient Ischemic Attack (2014, adapted)
- For patients with recent stroke or TIA (within 30 days) attributable to severe stenosis (70%–99%) of a major intracranial artery, the addition of clopidogrel 75 mg/d to aspirin for 90 days might be reasonable (Class IIb; Level of Evidence B).
- For patients with stroke or TIA attributable to 50% to 99% stenosis of a major intracranial artery, the data are insufficient to make a recommendation regarding the usefulness of clopidogrel alone, the combination of aspirin and dipyridamole, or cilostazol alone (Class IIb; Level of Evidence C).
- For patients with a stroke or TIA attributable to 50% to 99% stenosis of a major intracranial artery, maintenance of systolic BP below 140 mmHg and high-intensity statin therapy are recommended (Class I; Level of Evidence B).
- For patients with a stroke or TIA attributable to moderate stenosis (50%–69%) of a major intracranial artery, angioplasty or stenting is not recommended given the low rate of stroke on medical management and the inherent periprocedural risk of endovascular treatment (Class III; Level of Evidence B).
- For patients with stroke or TIA attributable to severe stenosis (70%–99%) of a major intracranial artery, stenting with the Wingspan stent system is not recommended as an initial treatment, even for patients who were taking an antithrombotic agent at the time of the stroke or TIA (Class III; Level of Evidence B).
- For patients with stroke or TIA attributable to severe stenosis (70%–99%) of a major intracranial artery, the usefulness of angioplasty alone or placement of stents other than the Wingspan stent is unknown and is considered investigational (Class IIb; Level of Evidence C).
- For patients with severe stenosis (70%–99%) of a major intracranial artery and recurrent TIA or stroke after institution of aspirin and clopidogrel therapy, achievement of systolic BP <140 mmHg, and high-intensity statin therapy, the usefulness of angioplasty alone or placement of a Wingspan stent or other stents is unknown and is considered investigational (Class IIb; Level of Evidence C).
- For patients with severe stenosis (70%–99%) of a major intracranial artery and actively progressing symptoms after institution of aspirin and clopidogrel therapy, the usefulness of angioplasty alone or placement of a Wingspan stent or other stent is unknown and is considered investigational
- Multicenter, double-blind, randomized controlled trial
- N=569 patients with TIA or stroke
- Aspirin (n=280)
- Warfarin (n=289)
- Setting: 59 centers in North America
- Enrollment: 1999-2003
- Mean follow-up: 36 months
- Analysis: Intention-to-treat
- Primary outcome: ischemic stroke, brain hemorrhage, or non-stroke CV death
- TIA or non-severe stroke within 90 days prior to randomization (including day 90)
- Modified Rankin score of < 3. Able to walk without assistance of another person, they can walk with a cane or walker.
- High grade stenosis (50%-99%) of a major intracranial artery (carotid artery, MCA stem (M1), vertebral artery, and basilar artery) documented by conventional angiography within 90 days prior to randomization (including day 90)
- TIA or stroke is attributed to high grade intracranial stenosis
- Age > 40 years
- Patient is able to follow an outpatient protocol (requiring monthly blood tests and clinic visits every four months for the duration of the study) and is available by telephone
- Patient understands the purpose and requirements of the study, can make him/herself understood, and has provided informed consent.
- Extracranial carotid stenosis (> 50%) ipsilateral to stenosis of the intracranial carotid artery or MCA (ie. tandem stenoses, either of which could have caused patients symptoms)
- Isolated stenosis of the anterior cerebral artery, posterior cerebral artery, MCA division, or a distal branch of the MCA
- Intracranial or extracranial arterial dissection, Moya Moya disease, vasculitis, radiation induced vasculopathy, fibromuscular dysplasia
- The presence of any of the following unequivocal cardiac sources of embolism: chronic or paroxysmal atrial fibrillation, mitral stenosis, mechanical valve, endocarditis, intracardiac clot or vegetation, myocardial infarction within three months, dilated cardiomyopathy, left atrial spontaneous echo contrast
- A contraindication to the use of either warfarin or aspirin (e.g. active peptic ulcer disease, active bleeding diathesis, platelets < 100,000, hematocrit < 30, clotting factor abnormality that increases the risk of bleeding, alcohol or substance abuse, severe gait instability, cerebral hemorrhage, systemic hemorrhage within the past year, severe liver impairment (SGOT > 3 X normal, cirrhosis), allergy to aspirin or warfarin, uncontrolled severe hypertension (systolic pressure > 180 mm Hg or diastolic pressure > 115 mm Hg), positive stool guaiac that is not attributable to hemorrhoids, creatinine > 3.0
- Indication for intravenous heparin beyond randomization
- A severe neurological deficit that renders the patient incapable of living independently
- Dementia or psychiatric problem that prevents the patient from following an outpatient program reliably
- Co-morbid conditions that may limit survival to less than 5 years
- Pregnancy or female in age range of childbearing potential who is not using contraception
- Enrollment in another study that would conflict with the current study
Given for the ASA group (n=280)
- Mean age — yr 62.8±11.3
- Male sex — no. (%) 168/280 (60.0)
- Race — no. (%)
- Black 83/280 (29.6)
- White 162/280 (57.9)
- Other 35/280 (12.5)
- History of hypertension — no. (%) 230/280 (82.1)
- History of diabetes — no. (%) 101/279 (36.2)
- History of a lipid disorder — no. (%) 188/274 (68.6)
- Blood pressure — mm Hg
- Systolic 139.0±16.7
- Diastolic 76.6±10.3
- Glycosylated hemoglobin — % 7.8±2.5
- Cholesterol — mg/dl
- High-density lipoprotein 43.6±13.1
- Low-density lipoprotein 124.6±38.0
- Smoking status — no. (%)
- Never 96/280 (34.3)
- Previously 115/280 (41.1)
- Currently 69/280 (24.6)
- History of coronary artery disease — no. (%) 68/273 (24.9)
- History of ischemic stroke — no. (%) 58/271 (21.4)
- Qualifying event
- Stroke 164/280 (58.6)
- Transient ischemic attack 116/280 (41.4)
- Use of antithrombotic therapy at time of qualifying event — no. (%) 143/280 (51.1)
- Time from qualifying event to randomization — days 18.0±14.0
- Concomitant medications at randomization — no. (%)
- Statin 163/280 (58.2)
- Diuretic 64/280 (22.9)
- ACE inhibitor or angiotensin II receptor blocker 113/280 (40.4)
- Stenotic artery
- Internal carotid 55/271 (20.3)
- Middle cerebral 92/271 (33.9)
- Vertebral 53/271 (19.6)
- Basilar 55/271 (20.3)
- Multiple arteries 16/271 (5.9)
- Percent stenosis of affected artery 64.1±16.5
- <50 — no. (%) 34/276 (12.3)
- 50–69 — no. (%) 138/276 (50.0)
- 70–99 — no. (%) 103/276 (37.3)
- 100 — no. (%) 1/276 (0.4)
- Patients were randomized to either aspirin 1300 mg/day or warfarin (initiated at 5 mg daily), titrated to an International Normalized Ratio (INR) of 2 - 3.
Comparisons are ASA vs. Warfarin
- Ischemic stroke, brain hemorrhage, or death from non-stroke vascular causes
- 22% vs. 22% (HR=1.04; 0.73–1.48, P=0.83)
- Ischemic stroke or brain hemorrhage
- 21% vs. 18% (HR=1.20; 0.82–1.75, P=0.34)
- Ischemic stroke: 20% vs. 17% (HR=1.23; 0.84–1.80, P=0.29)
- Ischemic stroke in territory of stenotic artery: 15 vs. 12 (HR=1.26; 0.81–1.97, P=0.31)
- Disabling or fatal ischemic stroke: 9% vs. 6% (HR=1.46; 0.80–2.68, P=0.22)
- Ischemic stroke, MI, or death from vascular cause other than stroke: 24% vs. 25% (HR=0.98; 0.70–1.37, P=0.90)
Comparisons are aspirin vs. warfarin.
- Death no. (%): 12 (4.3) vs. 28 (9.7), HR=0.46 (95% CI: 0.23–0.90), P=0.02
- Death from vascular causes no. (%): 9 (3.2) vs. 17 (5.9), HR=0.56 (95% CI: 0.25–1.26), P=0.16
- Death from nonvascular causes: 3 (1.1) vs. 11 (3.8), HR:0.30 (95% CI: 0.08–1.07), P=0.05
- Major hemorrhage 9 (3.2) vs. 24 (8.3), HR=0.39 (95% CI: 0.18-0.84), P=0.01
- Myocardial infarction 7 (2.5) vs. 12 (4.2), HR:0.62 (95% CI: 0.24–1.58), P=0.31
- The dose of ASA used for this trial is 1300mg/day (able to be decreased down to minimum 325 MG per day if experiencing side effects), which is much higher than the typical dose used for secondary stroke prevention today (between 80-325 MG ASA).
- The National Institute of Neurological Disorders and Stroke, National Institutes of Health.
- Bristol-Myers Squibb (after the incorporation of DuPont Pharma) supplied the warfarin(Coumadin) and placebo warfarin tablets, and Bayer supplied the aspirin and placebo aspirin tablets for the trial; neither of these companies supplied direct funding for the trial.
- Chimowitz MI et al. The Warfarin-Aspirin Symptomatic Intracranial Disease Study. Neurology 1995. 45:1488-93.
- Thijs VN & Albers GW Symptomatic intracranial atherosclerosis: outcome of patients who fail antithrombotic therapy. Neurology 2000. 55:490-7.
- Mohr JP et al. A comparison of warfarin and aspirin for the prevention of recurrent ischemic stroke. N. Engl. J. Med. 2001. 345:1444-51.
- 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.