Early ACEI-Aspirin Interaction in Acute Myocardial Infarction
Abstracts & Commentary
Synopsis: The effects of ACEI on all the clinical end points were not influenced by ASA and "the benefits of ASA and ACEI are approximately independent of each other, in which case the greater benefit will be obtained by using both treatments."
Sources: Latini R, et al. J Am Coll Cardiol 2000;35:1801-1807; Hall D. J Am Coll Cardiol 2000;35:1808-1812.
There is a lingering controversy regarding the question as to whether use of aspirin with angiotensin-converting enzyme inhibitor (ACEI) therapy attenuates the beneficial effects of the latter drugs in patients with heart failure. An unpublished analysis of the Studies of Left Ventricular Dysfunction (SOLVD) treatment and prevention trials suggested that use of aspirin is associated with a decreased benefit of enalapril in patients with symptomatic or asymptomatic left ventricular (LV) systolic dysfunction. Other data are suggestive that a negative interaction exists, but conclusive proof has yet to be established. Because the majority of heart failure patients have underlying coronary artery disease (CAD), this is a question of great importance, given the mandate to use both aspirin and an ACEI in patients with CAD and impaired LV function, respectively. Latini and colleagues pooled individual patient data from four trials using ACEI during the acute phase of acute myocardial infarction (MI), continued short-term for no more than six weeks to examine the issue of whether use of aspirin attenuated the benefits derived from ACEI in these studies. The concomitant primary analysis was the effect of ACEI on total mortality at 30 days; secondary end points included mortality within the first week and a variety of adverse clinical outcomes. The studies examined included CONSENSUS II, GISSI-3, ISIS-4, and Chinese Cardiac Study (CCS), with an aggregate of 96,712 subjects for whom adequate data were available. Of these, the vast majority (86,484) received antiplatelet therapy, almost always aspirin; just more than 10% did not receive aspirin. The latter individuals were slightly older, more women, and, importantly, had a greater likelihood of having early heart failure (26% vs 17%), and were less likely to have received thrombolytic therapy (40% vs 66%). Thus, nonaspirin users appeared to represent a higher risk group than the majority. Aspirin use at entry ranged from 75% to 94%, and averaged 89%. The primary end point of 30-day mortality in these trials favored ACEI, as previously published, by an absolute value of 0.5%, or 7.1% vs. 7.6%. Aspirin use did not significantly attenuate the effects of ACEI; the 30-day mortality was 6% in those taking ACEI and aspirin, and 10% in those who were on ACEI alone (P = NS). Early seven-day mortality was 7% with aspirin and 15% in the absence of aspirin use (P = NS). Analysis of clinical events indicated that ACEI increased the likelihood of hypotension and elevation of serum creatinine and decreased the incidence of nonfatal heart failure. Aspirin did not significantly affect these end points, nor did it alter the 30-day MI or stroke rate. Latini et al conclude that the effects of ACEI on all the clinical end points were not influenced by ASA, and that "the benefits of ASA and ACEI are approximately independent of each other, in which case the greater benefit will be obtained by using both treatments." Aspirin did not appear to modify the safety profile of early ACEI, although there was a greater proportion of renal dysfunction in patients taking both drugs. Latini et al state that guidelines suggesting a possible negative interaction between these two agents in acute MI patients should be reconsidered.
In an accompanying editorial, Hall of the German Heart Center in Munich outlines a cogent conflicting opinion. His lengthy editorial comment essentially refutes the argument that aspirin does not attenuate the efficacy of ACEI, as suggested by careful analysis of the heart failure literature. He emphasizes that in congestive heart failure, aspirin use does ameliorate the survival benefits of ACEI. He stresses that in the Latini et al meta-analysis, the individuals who did not receive aspirin had double the 30-day mortality, suggesting that there are clearly two different patient groups, with aspirin nonusers being significantly sicker. Hall notes that the reduction in heart failure in the four studies in the Latini et al analysis was 50% less in patients who received concomitant aspirin and ACEI (3.3% vs 8.8%). In the Consensus II trial, as noted by Latini et al, there was a trend toward a less favorable outcome in patients receiving enalapril and aspirin, which in the meta-analysis of Latini et al was neutralized by the more favorable outcomes with combined therapy in GISSI-3, ISIS-4, and the Chinese study. Hall discusses the various mechanisms of the interaction, emphasizing the role of aspirin and prostaglandins in helping understand the controversy.
Comment by Jonathan Abrams, MD
Both of these reports make points that are valid. There are, however, major differences in the databases being examined, and the clinician must be aware of this. Latini et al evaluate only the short-term, nonselective use of ACEI in acute MI, where the drugs are initiated as soon as possible after admission and continued for no more than 5-6 weeks. GISSI-3 and ISIS-4 confirmed that early nitrate administration produced only a trend for improved outcome, but that early ACEI administration did result in a modest 7% reduction in short-term mortality, as confirmed in the new meta-analysis. However, it is clear that the 10-12% of individuals in this assessment who did not receive aspirin had a number of clinical risk parameters, and the fact that aspirin itself was not administered may have also played somewhat of a negative role, in that this drug has been shown conclusively to improve morbidity and mortality in acute MI when administered upon admission. The meta-analysis data do not directly reflect subjects with congestive heart failure or LV systolic dysfunction. The strategy that ACEI should be given only to high-risk patients, as in Survival and Ventricular Enlargement (SAVE), AIRE, and Trandolapril Cardiac Evaluation (TRACE), is not addressed by Latini et al. The large majority of patients in the Latini et al analysis had relatively preserved LV function, as the ACEI was given to "all comers," irrespective of clinical status. The SOLVD data, as well as the detailed analysis of a variety of major heart failure trials by Hall, wave a red flag as to a negative interaction between the two drugs. For instance, several trials (such as AIRE and SAVE) found that the use of aspirin and ACEI demonstrated a lesser reduction in cardiovascular end point mortality; in CONSENSUS II and SOLVD there also appeared to be a somewhat worse outcome in those individuals receiving aspirin. In the Latini et al meta-analysis, at both seven-day and 30-day outcomes the nonuse of aspirin was favored.
How does one make sense out of these data? Two major clinical issues are critical to this discussion: 1) whether a study is long term, lasting several years; and 2) whether congestive heart failure or significant LV dysfunction was an enrollment marker for ACEI. Other data confirm that the use of nonsteroidal anti-inflammatory drugs increases the likelihood of congestive heart failure, and the use of aspirin, by interfering with prostaglandin synthesis through the cyclo-oxygenase pathway, may thus attenuate the effects of ACEI. It is difficult to recommend not using aspirin in individuals with CAD, irrespective of their LV systolic function. The HOPE trial showed that ramipril had a favorable effect in large numbers of individuals with preserved LV function and no heart failure who ordinarily might not receive an ACEI. This study should stimulate an increased use of these highly effective drugs in CAD patients, particularly those individuals with acute MI who have good LV function and no heart failure, as was the case in three of the four studies in the meta-analysis. Whether concomitant aspirin use with an ACE inhibitor in these short-term trials would ultimately have shown a greater disparity in outcomes between ACE with or without aspirin is not known. Other data emphasized by Hall suggest this might be the case. There was a trend in the Latini et al analysis favoring ACEI alone, although statistical significance was not achieved. This is important, as this is a large database.
In summary, I suggest that clinicians rethink the issue. In patients with acute MI or unstable angina who are on or will receive an ACEI, aspirin clearly appears to be safe and effective and does not appear to have an adverse effect on outcomes. However, in individuals with chronic LV dysfunction, particularly with symptomatic heart failure, the use of aspirin (or nonsteroidal anti-inflammatory drugs) must be carefully considered. In patients who have systolic heart failure, antiplatelet agents probably should be precluded. In individuals with CAD who are clinically stable with no history of heart failure, even with a depressed ejection fraction, one can go in either direction. This controversy will more than likely linger for years to come.
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