The superior yield of the new Strategy of Enoxaparin, Revascularization, and Glycoprotein IIb/IIIa Inhibitors (SYNERGY) trial was presented by Dr. Kenneth Mahaffey and colleagues. The objectives of the study were to assess the use of enoxaparin in high-risk acute coronary syndrome patients and determine its safety in the cardiac catheterization laboratory. Two of the following 3 inclusion criteria had to be met to enter the study: age older than 60 years; ECG ST changes; or positive biomarkers. Of the > 10,000 patients entered, 45% met all 3 criteria. The primary end point was all-cause death and myocardial infarction at 30 days. The patients entered were randomized to enoxaparin vs unfractionated heparin (UHep). Almost all of the patients underwent cardiac catheterization (90%), 60% were also on clopidogrel, and 50% were given IIb/IIIa agents. The incidence of the primary end point was 14% and not different between the 2 treatments. Death occurred in 3% and MI in 12%; neither were significantly different in the 2 groups. Major bleeding was higher in the enoxaparin group (9.1 vs 7.6%; P = .008). There was no difference in other cardiac catheterization adverse events, and there were no major subgroup findings. Mahaffey et al concluded that in high-risk early invasive strategy acute coronary syndrome patients there was no difference in the efficacy of enoxaparin vs Uhep, but major bleeding was more frequent on enoxaparin.
Comment by Michael H. Crawford, MD
Mahaffey et al pointed out that there are several limitations to the study that temper the conclusions. First, patients who were given one of the study drugs prior to randomization but did have their drug switched per the protocol were not excluded. Whether this switching of drugs produced adverse effects is unknown, as is whether any effects favored one group over another. Of interest, the ESSENCE trial, which showed benefit of enoxaparin over Uhep, didn’t allow prerandomization treatment with the study drugs. However, this was also a lower-risk group in which such a stipulation was easier to uphold. Second, Mahaffey et al did not control postrandomization management, which resulted in a noteworthy incidence of crossovers. This was especially the case in patients who underwent revascularization after randomization, since many were switched from enoxaparin to Uhep. Third, the excess bleeding was mainly seen in the patients undergoing revascularization where the exact level of enoxaparin’s effect may be more difficult to determine and may be added to if Uhep is also given. Despite these caveats, this study is not good news for enoxaparin. It will be interpreted that the invasive cardiologists and surgeons’ reluctance to use this drug is well founded. The presenters emphasized that a special noninferiority analysis showed no inferiority of enoxaparin vs Uhep, but this seems like blowing smoke. What it does mean is that if there are reasons to use enoxaparin instead of Uhep, the results should be the same overall. However, in those patients undergoing revascularization, there is going to persist unease about the bleeding risks of an agent that has a prolonged duration of action and no good way of determining its level of effectiveness at any one time. Since determining who is going to need revascularization early may not always be easy, this is going to put a damper on the use of this agent in higher-risk patients more likely to undergo revascularization.
The Warfarin and Antiplatelet Trial in Chronic Heart Failure (WATCH) was presented by Barry Massie, MD, from San Francisco. This was a VA cooperative study that tested the hypotheses: 1) Warfarin is superior to antiplatelet drugs; and 2) Aspirin has adverse effects in patients on angiotensin-converting enzyme inhibitors (ACEI) in heart failure patients. Inclusion criteria included NYHA class II-IV heart failure, left ventricular ejection fraction < 35%, and baseline ACEI therapy. Exclusions included high bleeding risk, atrial fibrillation, and unstable patients. The patients were randomized to 3 groups: warfarin to an INR of 2.5-3.0, aspirin 162 mg/d, and clopidogrel 75 mg/d. Follow-up was for 2-5 years. The primary end point was all-cause mortality, myocardial infarction, and stroke. Secondary end points included the above plus hospitalization for heart failure, unstable angina, and peripheral emboli. There were also safety and economic analyses. Enrollment was 40% of expected so the primary and secondary end points were combined to increase the power of the study. In January 2002 the trial was stopped because of low enrollment, not the results of the study. In all, 1587 patients were enrolled and followed for a mean of 23 months. ACEI use was 88%, and angiotensin receptor blocker use was 11% (99% combined). Beta-blockers were used in 70%. Mean INR was 2.6, with only 31% in the target 2.5-3.0 range, but 70% in the 2.0-3.5 range. There was an overall 93% adherence to the prescribed drug therapy. Three-quarters of the patients had ischemic cardiomyopathy, 56% were class II-IV, and mean EF was 24%.
For the primary end point, there was no statistically significant difference between aspirin and warfarin, but there was a trend for fewer strokes on warfarin. Heart failure admissions were increased on aspirin (P < .001).
The number of hospitalizations/100 patent-years was reduced 31% on warfarin vs aspirin. There were no differences in the primary end point between aspirin and clopidogrel, but there was a trend for more hospitalizations on aspirin. Bleeding complications were increased on warfarin. The investigators concluded that warfarin use in heart failure patients with systolic dysfunction is no better than antiplatelet therapy for preventing death and adverse cardiovascular events including emboli.
However, as compared to clopidogrel and warfarin therapy, aspirin increased hospitalizations for heart failure.
Comment by Michael H. Crawford, MD
Despite the fact that this is the largest trial of anticoagulants in heart failure to date, it was underpowered to detect differences in the treatments concerning the primary end point. Power was estimated at 40-60% depending on which end point was examined. Consequently, there is no mandate for warfarin in heart failure patients due to systolic dysfunction, unless other indications are present. Definitive answers will have to await the WARCEF trial, which is ongoing. The only finding of statistical significance in this study was the increase in hospitalizations for heart failure in the aspirin group.
This finding is consistent with other studies, which have suggested a negative interaction between aspirin and ACEI. However, the investigators cautioned that this is a secondary end point in an underpowered trial and has to be viewed with some skepticism. On the other hand, in the question-and-answer period after the presentation, Dr. Massie stated that he has changed his practice in 3 ways based upon these results: 1) He no longer uses aspirin in nonischemic cardiomyopathy; 2) He stops aspirin if the patient has refractory heart failure; and 3) He does not use aspirin if they have other indications for either warfarin or plavix.
Dr. Crawford, Professor of Medicine, Associate Chief of Cardiology for Clinical Programs, University of California San Francisco, is Editor of Clinical Cardiology Alert.