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• W2000537889 abstract "In recent years there has been an enormous impetus toward practicing medicine based on clinical trial evidence. In no field has there been more success in this effort than in cardiology, where mega-trials have become commonplace. Substantial strides have been made in deploying treatments for which large population benefits have been documented in such areas as acute coronary syndromes and heart failure. As these advances mount, it becomes increasingly tempting to seek guidance for all medical judgments from results of existing clinical trials. However, as important as it is to identify what we know from clinical trial results, it is equally important to recognize what we don't know. Based on the review by Park1 in this issue of Congestive Heart Failure, it is clear that existing trials fail to resolve whether the impact of aspirin on clinical outcomes in patients with heart failure is positive, neutral, or negative. We may draw a single lesson from any conclusive clinical trial result: that if we administer the precise intervention studied to a population identical to that enrolled, receiving the identical concomitant treatments, we will most likely see the same overall impact on the primary end point investigated. Recognizing this point should cause us to resist drawing conclusions regarding aspirin use in patients with heart failure—even those with concomitant coronary artery disease—from data supporting its benefit in populations with ischemic or vascular syndromes. To do so would require the assumptions that differences in population and in concomitant medications between those in existing aspirin trials and our patients with heart failure are insufficient to alter the conclusions drawn. Based on the review by Park, such assumptions are far from warranted. The role for aspirin in preventing cardiovascular events in select populations is compelling. In meta-analyses2 and in individual clinical trials,3-6 antiplatelet treatment, particularly aspirin, has been shown to reduce the incidence of morbid and fatal cardiovascular events, particularly among patients with prior acute coronary syndromes. In drawing upon these results to derive management conclusions for patients with heart failure, two key questions must be answered: 1) are there reasons to believe that these results might not apply in the presence of heart failure? and 2) are there reasons to believe that other medications routinely used in heart failure—particularly angiotensin-converting enzyme (ACE) inhibitors—might render aspirin less effective, neutral, or even detrimental? The answers to both of these questions appear to be yes, based on both physiologic and clinical trial evidence. These answers do not lead to the conclusion that aspirin is detrimental or even that it doesn't provide benefit—just that we don't know. Aspirin is a nonsteroidal anti-inflammatory agent, inhibiting the synthesis of both vasodilatory and vasoconstrictor prostaglandins. In low doses there is a preponderance of irreversible inhibition of thromboxane production by platelets, with less effect on production by endothelial cells of prostacyclin and other vasodilatory and antiproliferative prostaglandins. However, as Park points out, Davie et al.7 demonstrated that 75 mg of aspirin inhibited the vasodilatory effect of intra-arterial arachidonic acid in patients with heart failure. Other nonsteroidal anti-inflammatory agents raise blood pressure, lower glomerular filtration pressure, and induce fluid retention, effects that have evoked strong warnings against their use in patients with heart failure. Although such effects with low-dose aspirin are likely minimal, their presence and potential impact on outcomes during long-term administration, particularly among patients receiving ACE inhibitors, have not been investigated. The safety and efficacy of aspirin in patients with heart failure and coronary artery disease cannot be extrapolated from existing clinical trial evidence. Cleland et al.8 summarized results from five trials in which aspirin was started more than 1 month following myocar-dial infarction (MI) and from patients within two studies—the Aspirin Myocardial Infarction Study (AMIS)9 and the second Persantine-Aspirin Reinfarction Study (PARIS-II)10—with symptoms of heart failure following MI. In both cases, there was no support for the benefit of long-term aspirin administration. As Park indicates, physiologic investigations and heart failure clinical trials both yield conflicting evidence regarding the interaction between aspirin and ACE inhibitors. One likely source of interaction is inhibition by aspirin of bradykinin-mediated synthesis of vasoactive prostaglandins, since extensive experimental evidence supports a contribution of bradykinin potentiation to ACE inhibitor benefits. However, there is a second potential source of clinical interaction: overlapping, nonadditive benefits of aspirin and ACE inhibition. There is clear evidence that ACE inhibitors prevent clinical syndromes associated with arterial thrombosis.11-13 These benefits are likely mediated by ACE inhibitor effects on the arterial wall, including an antithrombotic and/or prothrombolytic effect.14 It is possible that the added benefit of aspirin in preventing intra-arterial thrombosis is reduced in the presence of ACE inhibitors. We found a strong negative interaction between baseline antiplatelet agent use and ACE inhibitor benefit in the combined Studies of Left Ventricular Dysfunction (SOLVD) trial.15 Patients receiving antiplatelet agents (overwhelmingly aspirin) at baseline had no demonstrable benefit on the primary end point of all-cause mortality. Conversely, an apparent benefit from baseline aspirin use, after correction for other variables, appeared to reside exclusively among patients randomized to placebo, as opposed to enalapril. The absolute event rates yielded no evidence for harm from the combination, only the absence of additive benefit. Our findings have been replicated in some ACE inhibitor trials16 but not others.13, 17 Notably, there was no adverse interaction between prerandomization aspirin use and ACE inhibitor benefit in the Survival and Ventricular Enlargement (SAVE) trial.13 Differences in this regard between SOLVD and SAVE may result from differences in stability of aspirin use within the population. In SAVE, with enrollment occurring between 3 and 16 days following acute MI, it is likely that aspirin was initiated in many patients following randomization. In SOLVD, antiplatelet drug treatment was likely to have been more stable. These analyses suffer a number of limitations, including their post hoc nature, complexities of correction for associated variables, and a paucity of information regarding aspirin dose. Beyond the role of antiplatelet agents, recommendations for warfarin use in patients with heart failure and sinus rhythm similarly remain controversial, and the impact of warfarin use on the added benefits of aspirin in this population is unknown. In another post hoc analysis of SOLVD,18 we found significantly better survival, after correction for other variables, in patients receiving warfarin at baseline. It seems likely, though untested, that concomitant warfarin use would further shift the balance away from a role for aspirin in patients with heart failure. So where are we? Conclusive recommendations regarding antiplatelet and anticoagulant drug use in heart failure will have to await results of prospective randomized trials. While we await these results, we must continue to practice medicine. We must avoid forcing the square peg of existing aspirin trials into the round hole of the contemporary population with heart failure receiving ACE inhibitors. Current guideline recommendations offer little help—post-MI guidelines avoid the issue of patients with heart failure, and heart failure guidelines state merely that the role of aspirin and ACE inhibitors must each be evaluated, “based on their own merits.”19 Park concludes that recommendations regarding aspirin use should differ between patients with and without “severe heart failure”. In the absence of a clear signal from existing clinical trial data supporting aspirin benefit in patients with heart failure, and given the potential for an interaction between ACE inhibitors and aspirin, it is appropriate that physiologic insights should help to guide our practice. The benefits of aspirin are most likely conferred by the agent's anti-platelet effect, and this action may be delivered—perhaps more effectively—through non-prostaglandin-mediated pathways. Avoidance of aspirin should be considered in patients with heart failure receiving ACE inhibitors, and, in the absence of contraindication, use of either warfarin (based on existing cohort data) or clopidogrel should be considered as an alternative. A more conclusive recommendation will likely follow results of ongoing clinical investigation, notably the Warfarin and Antiplatelet Therapy in Chronic Heart Failure (WATCH) trial." @default.
• W2000537889 created "2016-06-24" @default.
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• W2000537889 date "2003-07-01" @default.
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• W2000537889 title "Aspirin and Heart Failure: Square Evidence Meets a Round Patient" @default.
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