Abstract & Commentary
A number of clinical trials have been reported using warfarin alone or in combination with aspirin in patients with coronary artery disease. In the aggregate, they have been relatively inconclusive. Furthermore, contemporary guidelines have included anticoagulation as a class I indication for post-MI patients. Two recent studies, CARS (Lancet. 1997;350:389), and CHAMP (Circulation. 2002;105:557) were unable to demonstrate a benefit of the combination of aspirin and warfarin. WARIS II, the present trial, sought to conclusively resolve the issue of warfarin efficacy following MI. The trial was carried out in Norway in 20 institutions with enrollment beginning in 1994 and ceasing in 2000. All individuals had a mean 4-year period of active therapy.
The WARIS II study compared the effects of full-dose warfarin, aspirin alone, and an aspirin-warfarin combination but with a lower target INR on the primary end point of mortality, nonfatal reinfarction, or embolic stroke. The trial was stopped by design at a cumulative event rate of 17%. WARIS II was conducted on an intention-to- treat analysis. Each of the 3 groups consisted of 1200 patients who were evenly matched with respect to clinical features. Almost half were smokers and < 10% had diabetes; approximately 13% had a prior MI. The types of MI were both Q wave (58%) and non-Q (42%) infarctions. The warfarin alone group had a target INR of 2.8 -4.2; the mean INR throughout the study was 2.8. In the combined therapy group, target INR was 2.0-2.5, with a mean INR for the trial period of 2.2; one third of individuals in the warfarin alone group had a mean INR level below 2.8, and one fourth in the combination cohort had INR levels below 2.0. The combination group received aspirin 75 mg daily, and the aspirin alone cohort dose was 160 mg daily.
Results: Compared to aspirin alone, the combination therapy group had a 29% risk reduction in the primary end point (P = 0.001), and the warfarin alone patients had a 19% risk reduction (P = 0.03). Thus, both warfarin groups did better than aspirin alone. There was no statistical difference between the two warfarin cohorts. The benefits of warfarin resulted from a reduction in nonfatal MI and thromboembolic stroke; there was no survival difference. Total revascularizations were less in the 2 warfarin groups (NS). By the end of the study, approximately 35% of the patients had discontinued the warfarin for a variety of reasons. There was a significant increase in major and minor bleeding with the warfarin. Thus, minor bleeding in the 3 groups (aspirin, warfarin alone, combination) was 0.8%, 2.1%, and 2.7% per year; major bleeding was 0.17%, 0.7%, 0.6% per year, respectively.
The study concludes that in the post-MI patient, warfarin alone or in combination with low-dose aspirin is superior to aspirin alone. Overall event rates were lower than in prior studies, with an annual composite of 4.2% per year. The warfarin groups had approximately 4 times the major bleeding rate as the aspirin alone; 36% assigned to warfarin discontinued the drug. The overall risk reduction for reinfarction was 44% and 26% for the combined and warfarin only cohorts, respectively, vs aspirin; 38% for both warfarin groups vs aspirin for thrombotic stroke, and no difference in mortality (Hurlen, et al. N Engl J Med. 2002;347:969-974).
Comment by Jonathan Abrams, MD
These data may come as somewhat of a surprise to United States physicians, who have not been impressed with the argument that anticoagulation with warfarin should be a routine strategy in post-MI patients, who are already taking many other drugs. For instance, in the current American Heart Association GET WITH THE GUIDELINES program, the major pharmacologic interventions include aspirin, a beta blocker, an ACE inhibitor, and a statin. Hurlen and associates hypothesize that the reason older clinical trials with warfarin have not been convincing is related to the failure to achieve sustained therapeutic anticoagulation, as assessed by INR. This appears to have been done very well in the WARIS II study, although there was a substantial (one third) withdrawal rate in the warfarin patients (many for revascularization procedures). Clearly, bleeding was increased, as would be anticipated. Hurlen et al do not offer a balance sheet summary as to the advantages of decreasing recurrent MI and stroke vs major and minor bleeding. It is obvious that anticoagulation therapy cannot benefit all, in that there were many subjects who withdrew, and many patients who had bothersome or significant bleeding. Moreover, inadequate INR levels remained a significant problem, with 25-35% of the warfarin cohorts not achieving an optimal INR.
Should this study change our clinical practice? This is a question that may not be answerable by this study, but at the very least WARIS II should encourage physicians who wish to use anticoagulation to do so with the support of a well conducted randomized trial. There was a gradation of risk reduction with aspirin 160 mg per day being least protective, and the combination of aspirin 75 mg and moderate INR levels with warfarin had the best clinical results with respect to reduction of nonfatal MI and stroke. It is unclear why there was no mortality benefit; Hurlen et al suggested that this might be due to the protective effects of aspirin in the nonwarfarin cohort. The use of beta blockers and statins in the overall study was excellent. Although revascularization procedures were somewhat less in the warfarin groups, this did not achieve statistical significance. Nevertheless, one wonders if individuals who undergo a PCI during an infarction might be considered for a long-term anticoagulation. No data regarding LV function, atrial fibrillation, or high-risk status are provided. An analysis of ejection fraction and its possible relation to stroke as well as non fatal recurrent MI would be of interest. Finally, it is clear that anticoagulation with warfarin on a chronic basis should not be approached in a cavalier fashion. Warfarin patients must have access to a high quality and even obsessive anticoagulation clinic or program. In addition, the increasing use of clopidogrel in individuals who undergo PCI may alter the landscape, by providing additional antiplatelet action and reducing the benefits of warfarin. This study provides a rationale for the use of warfarin in the post-MI patient assuming low-dose aspirin is used and the INR levels are adequate (2.0-2.4) but not higher. Nevertheless, the WARIS II cohort of 3630 patients is not particularly large by contemporary standards, and the lack of a survival benefit dampens one’s enthusiasm for a routine post-MI warfarin approach. After many years of debate, it would appear that anticoagulation in the post-MI patient may become mainstream, at least in some individuals.
Dr. Abrams is Professor of Medicine Division of Cardiology University of New Mexico, Albuquerque.
A number of clinical trials have been reported using warfarin alone or in combination with aspirin in patients with coronary artery disease. In the aggregate, they have been relatively inconclusive.
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