ACE Inhibitors vs. Angiotensin II Blockers: Is the War Over?

abstracts & commentary

Synopsis: The current use of ACE inhibitors in patients with left ventricular dysfunction or heart failure irrespective of the proximity to the myocardial infarction is indicated.

Sources: Pitt B, et al. Lancet 2000;355:1582-1587;Flather MD, et al. Lancet 2000;355:1575-1581.

Two important reports in the may 6, 2000, issue of Lancet provide considerable information regarding the role of angiotensin II in patients with left ventricular (LV) systolic dysfunction. ELITE I reported the unexpected observation that elderly patients randomized to captopril or losartan appeared to derive a major benefit from the angiotensin II receptor blocker (ARB), with a striking reduction in sudden death (Pitt B, et al. Lancet 1997;349:747-752). Although the primary end point in ELITE I was the serum creatinine response to therapy, several secondary end points suggested benefit from losartan, particularly in overall mortality of 46% and a reduction in sudden death of 64%. To the credit of the ELITE I investigators, ELITE II was rapidly planned and carried out to confirm or refute the surprising results of ELITE I. No other data have shown a benefit of ARB over angiotensin-converting enzyme inhibitor (ACEI). Several major ARB vs. ACEI ongoing trials involving 30,000 subjects (VALHeFT, CHARM, VALIANT, and OPTIMAAL) will ultimately resolve this issue.

ELITE II is an international trial that enrolled 3100 subjects older than 60 with class II-IV heart failure and an ejection fraction (EF) of less than or equal to 40%. These patients could not tolerate ACEI or were ACEI naive, and were randomized to losartan 50 mg daily or captopril 50 mg. t.i.d. Randomization was stratified based on concurrent beta blocker use. Median follow-up was 1.5 years. The primary end point was all-cause mortality; a variety of second end points included a composite of sudden cardiac death or resuscitated cardiac arrest. The results were completely neutral, although trends favored captopril for many end points and subgroups. Thus, all-cause mortality, sudden death, and hospital admissions were no different between captopril and losartan, nor was the time to these events. There was no decrease of sudden death or resuscitated cardiac arrest with the ARB. The effect of captopril was more robust in patients who were on a beta blocker than losartan plus a beta blocker. Side effects were greater with captopril, with more individuals stopping treatment on ACEI than ARB. Heart failure was noted during the short study duration in approximately 25% of each cohort. Pitt and colleagues and Flather and associates conclude "clinicians should prescribe an ACE inhibitor for the initial treatment of patients with heart failure and systolic left ventricular dysfunction." They further state that "It still remains to be established whether ARBS are a fully acceptable substitute for ACE inhibitors in heart failure."

In the same issue of Lancet, there is a comprehensive analysis of the major ACEI postinfarction trials, including SAVE, SOLVD, TRACE, and AIRE. The methodology used is believed to be superior to a classic meta-analysis, in that individual patient data were used from all studies. SAVE, AIRE, and TRACE data were combined and compared to SOLVD; all five trials were also assessed in the aggregate (almost 13,000 subjects). The results of this analysis are not surprising and confirm the individual trial conclusions, current practice guidelines, and the general view that ACE inhibitors are beneficial following myocardial infarction (MI). The mean age was 60, with 75-80% males. Mean ejection fraction (EF) was 32% in the SAVE, AIRE, and TRACE cohorts, and 27% in SOLVD. Twenty-five percent of the post-MI patients were on a beta blocker and 18% in the earlier SOLVD trial. Aspirin use was 75% in the combined trials and less than 50% in SOLVD. Mean treatment duration in SAVE, AIRE, and TRACE was 31 months. Mortality was substantially reduced by 26% with the four ACEI trials compared to placebo, with significant curve separation beginning at six weeks. The results of SOLVD were similar. The composite analysis for all five trials demonstrated a 23% reduction in death, with mortality curves continuing to separate for four years or more. Readmission for heart failure was reduced by 25% with the ACE inhibitors.

Of particular interest, recurrent MI was reduced in the post-MI ACE I trials from 13.2% in placebo controls to 10.8% in the ACEI groups, with a comparable decrease in SOLVD (11% in controls, 8.9% with enalapril). This translates to a 20% reduction in recurrent MI. For the composite end point of death, MI, and readmission for heart failure, the overall event rate of 41% in controls (approximately 10% per year) was reduced to 34% with ACE I (risk reduction of 28%). Stratification by EF demonstrated that the overall risk of death correlated with the degree of depression of EF; the benefit of ACE I was greater in the subjects with the lowest EF. There was no age or sex heterogeneity, and no benefit of ACEI related to baseline blood pressure or heart rate. Renal dysfunction occurred in 5.2% of the ACE inhibitor patients compared to 3.6% with placebo. Pitt et al and Flather et al stress that their prior overview of early post-MI treatment in short-term ACEI studies is complemented by the current analysis of long-term treatment of patients at considerably greater risk. The previous analysis (Circulation 1998;97:2202-2212) demonstrated a proportional reduction of mortality of only 7% at five weeks post-MI (P = 0.0004). ACEI benefit was seen in patients with preserved EF with respect to the recurrent MI in the present analysis.

Aspirin did not ameliorate the benefits of ACE inhibitors in this analysis. In patients receiving a beta blocker, there was an additive beneficial effect of ACE I. Pitt et al and Flather et al conclude that " current practice of use of ACE inhibitors in patients with left ventricular dysfunction or heart failure irrespective of the proximity to the myocardial infarction is indicated." They recommend use of these drugs for all patients post-acute MI, and especially in high-risk subjects.

Comment by Jonathan Abrams, MD

The ELITE II trial and the new analysis of the five major ACEI trials in patients with heart failure and/or LV dysfunction support a message that has been well received by clinicians, but not consistently implemented: Routine ACEI therapy is indicated post-MI or with LV dysfunction. The recently reported HOPE trial (Clinical Cardiology Alert 1999;18:89) strongly suggests that subjects with a prior MI and/or clinical vascular disease should be treated with an ACEI irrespective of LV function status. While I have long believed that only medium- to high-risk post-MI patients should be treated with an ACEI, the older analysis of short-term ACEI studies, HOPE, and the current meta-analysis clearly support the use of an ACEI in any patient who has had an MI, irrespective of LV function or no history of heart failure. High-risk patients, including individuals with even transient heart failure or with an EF less than 35%, are mandatory candidates for ACE inhibitors.

One important lesson from ELITE II and the combined analysis of the post-MI ACEI trials is clear. The results of a single, small clinical trial, particularly with outcomes that are unexpected, should be put into perspective and not taken as gospel. There is no obvious physiologic explanation why an adrenergic receptor binder (ARB) should reduce sudden death, as suggested by ELITE I. As the authors of ELITE II appropriately state, the results of ELITE I were more than likely due to the play of chance. In an accompanying editorial by Velasquez and Califf, it is stressed that assumptions are not enough for clinicians to accept the results of a single trial. They point out that while the number of individuals in ELITE I (~ 700) would have been considered a major clinical trial many years ago, this is no longer consistent with a contemporary evidence-based randomized, controlled trial that could influence clinical practice. Conversely, the HOPE trial, enrolling close to 10,000 individuals, with a long follow-up, may be sufficiently robust for physicians to change their practice, administering an ACE inhibitor to patients who previously were not considered appropriate for these drugs. We await with considerable interest the results of complementary trials to HOPE. The ACE inhibitors represent an extraordinary advance in contemporary cardiovascular medicine. Along with the statins and now the platelet IIb/IIIa antagonists, ACEIs have strongly influenced daily practice. Nevertheless, as Dr. Jay Cohn has stressed, patients with congestive heart failure and depressed LVEF continue to die in a relentless fashion even with ACE inhibition; thus, heart failure mortality remains high. For instance, in ELITE II, all-cause mortality at 18 months was approximately 16-17%. In the ACEI trials, mortality was 26% in placebo patients and 23% in the ACE inhibitor patients, which is more than than 5% per year, even with the best available treatment at high-quality centers. Clearly, new therapies for congestive heart failure with LV dysfunction are needed. The suggestion from ELITE II and the new meta-analysis that the combination of an ACE inhibitor and a beta blocker provides the most optimal outcomes for heart failure patients is of importance. As many reports have indicated, ACE inhibitors remain underused in heart failure, but there is an even larger problem with underuse of beta blockers. Stable patients, particularly class II-III, on an ACE inhibitor should also be treated with a beta blocker in order to slow the adverse consequences of LV remodeling and the increased burden of morbidity and mortality.