Overall Study Question
To determine whether warfarin is superior to ASA for secondary prevention of acute ischemic stroke in patients without atrial fibrillation. The study sample included 2,206 30-85 yr old (mean age 63 yrs) patients with an ischemic stroke (non-cardioembolic, non carotid artery source) during the previous 30 days and either severe, moderate, or no post-stroke disability (92% had minimal or no disability). Patients had no obvious contraindications to warfarin therapy. 68% had hypertension, 33% had diabetes, 28% had known cerebrovascular disease at the time of their index stroke. The primary outcome variable was death from any cause or recurrent ischemic stroke. The secondary outcome variable was major or minor hemorrhage. The study intervention was ASA 325mg once daily or Warfarin titrated to INR 1.4-2.8 (mean achieved 2.1, 70.7% within target range) for 2 years.
Are the Results of the Study Valid?
1. Was assignment of patients randomized?
2. Were all patients who entered the trial properly accounted for and attributed at its conclusion?
Yes. Primary endpoint status at 2 years was established for 98.5% of patients. Only 11 patients withdrew consent and only 22 were lost to follow-up. A total of 3 primary events occurred during the trial among the patients who were ultimately lost to follow up.
3. Were patients, their clinicians, and study personnel ‘blind’ to treatment?
Yes. A double-dummy design was used and double-blinding was maintained by using the same blood monitoring schedule in both groups. INR testing was done by a central laboratory for all patients. Site investigators were sent actual INR results for warfarin-treated patients and false INR results for ASA treated patients, so “warfarin” dosage adjustment was occurring in both groups to maintain the double-blind.
4. Were the groups similar at the start of the trial?
Yes. The two populations were similar for almost all reported baseline characteristics. Of possible significance, the warfarin arm had more diabetics and large artery strokes at baseline (~3% absolute difference for each).
5. Aside from the experimental intervention, were the groups treated equally?
Yes. Appropriate measures were taken to maintain blinding and all other study procedures were identical.
What were the Results?
1. How large was the treatment effect?
Death or recurrent stroke at 2 years was identified in 16% of ASA recipients and 17.8% of warfarin recipients (p=0.25). Recurrent ischemic stroke, death or major hemorrhage occurred in 17.8% of ASA patients and 20.0% of warfarin patients (NS). Major hemorrhages occurred in 1.5% of ASA and 2.2% of warfarin recipients (p=0.1). Minor hemorrhage was reported in 12.8%/year of ASA patients versus 20.8%/yr of warfarin patients (p<0.001). Finally, death due to hemorrhage was identified in 0.4%/yr of ASA patients versus 0.6%/yr of warfarin patients (NS). There were no significant differences among any of the subgroups reported (including location or severity of initial infarct).
2. How precise was the estimate of the treatment effect?
For the primary endpoint, the 95%CI for the hazard ratio (1.13) was 0.92 – 1.38. My calculation of the 95%CI for the absolute risk difference (1.81%, favouring ASA) is 3.12%. This means that the results are consistent with warfarin being superior to ASA by an absolute difference of 1.31% through to warfarin being inferior to ASA by as much as 4.93%. If one arbitrarily assumes a minimally clinically significant ARR difference of 2% (note: using the ASA event rate in this trial, this would be equivalent to as much as a 12.5% relative difference), it is possible that there is ASA is superior to warfarin, or there no difference between these two drugs. However, warfarin could not be superior to ASA. Conversely, If one sets the minimally clinically significant ARR difference at 5% (i.e. the difference the investigators powered this study to detect), the results are consistent with warfarin and ASA being equivalent. This trial was not set up to demonstrate equivalence of the two treatments, but rather to detect a 30% relative (4.8% absolute) difference in efficacy between them, favouring either treatment.
Will the Results Help Me in Caring for My Patients?
1. Can the results be applied to my patient care?
Yes. This trial was well conducted and the results were appropriately reported.
2. Were all clinically important outcomes considered?
Mostly. A potentially important endpoint not reported was the severity (i.e. the degree of subsequent disability) of the strokes which occurred during the trial. Recent evidence from Wilterdink et al indicates that ASA use at the time of a stroke can result in less severe stroke-related disability. (1) If there were a difference between ASA and warfarin with respect to this parameter, it would be of clinical importance.
3. Are the likely treatment benefits worth the potential harms and costs?
If readers accept that ASA and warfarin are equivalent based on this data (or conversely, that warfarin is potentially inferior), the currently accepted strategy of using ASA alone in this population should remain unchanged.
While this trial did not reveal improved outcomes among warfarin-treated patients, it nevertheless provides us with some clinically relevant information.
The finding is that warfarin may be considered an alternative to ASA in ASA-allergic patients for secondary stroke prevention is clinically relevant. Since warfarin would likely be contraindicated in patients with prior ASA-associated PUD/GI bleeding, this would not represent a suitable alternative in this circumstance. Another alternative to ASA would include clopidogrel. Generally, clopidogrel would be favoured over warfarin due to its ease of use and possibly lower cost when monitoring is considered. Thus, warfarin is likely still relegated to 3rd or 4th-line therapy (i.e. after ASA, clopidogrel, ASA plus dipyridamole, and possibly ticlopidine) in this population, just as it was before this trial, except that now data is available to support its use at all, whereas before none was available.
This study would also suggest that newly diagnosed stroke patients who are receiving warfarin for another indication (e.g. post-anterior MI thrombosis prophylaxis) may not require the addition of ASA to their drug regimen. Warfarin alone should be effective for stroke prophylaxis in this setting.
While the possibility that the finding that INR <2.0 was not as protective as INR >2.0 in this trial is intriguing, this must be allayed by the finding that no differences (or even a trend toward differences) were observed over the range of INR of 1.5 to >3.0.
Finally, this trial does not address the question of whether combination low-INR warfarin plus ASA is superior to either alone in this patient population. The SPIRIT trial showed increased major bleeding among patients treated with ASA plus higher intensity warfarin for the same indication. Regardless, any regimen involving adjusted-dose warfarin would likely be more monitoring-intensive and therefore more expensive than antiplatelet therapy alone.
Mohr JP, Thompson JL, Lazar RM, Levin B, Sacco RL, Furie KL, Kistler JP, Albers GW, Pettigrew LC, Adams HP Jr, Jackson CM, Pullicino P; Warfarin-Aspirin Recurrent Stroke Study Group. A comparison of warfarin and aspirin for the prevention of recurrent ischemic stroke. N Engl J Med 2001;345:1444-51.