From the Cardiology Division, University of Bergen, Central Hospital in Rogaland, Stavanger, Norway, and the Department of Cardiology, University of Oslo, Rikshospitalet, Oslo, Norway
Angiotensin-converting enzyme (ACE) inhibitors increase survival and decrease morbidity in patients with acute myocardial infarction (MI) and symptoms of heart failure or left ventricular dysfunction.1 Selective, angiotensin type-1 receptor antagonism is a different approach to renin-angiotensin system inhibition. The Optimal Trial in Myocardial Infarction with the Angiotensin II Antagonist Losartan (OPTIMAAL) was a double-blind, randomized, multicenter, parallel-group, captopril-controlled study. The principal hypothesis was that losartan would be either superior, or at least not inferior, to captopril in reducing all-cause mortality in patients at high risk following acute MI.
A description of both the design and organization of the trial, the recruitment details, and the total study population at baseline have been published.2,3 The OPTIMAAL trial results were presented at the European Society of Cardiology meeting in September 2002 and subsequently published in the Lancet.4 Patients (N = 5,477) aged 50 years or older (mean [± SD], 67.4 [9.8] years), with confirmed acute MI and heart failure during the acute phase or a new Q-wave anterior infarction or reinfarction, were enrolled from 329 centers in seven European countries. Patients were assigned randomly to blinded treatment and titrated to a target dose of losartan, 50 mg once daily, or captopril, 50 mg three times daily, as tolerated.
Inclusion criteria were as follows: patients with an acute MI and signs or symptoms of heart failure during the acute phase. Patients with an acute MI and an ejection fraction less than 35% or a left ventricular end-diastolic dimension greater than 65 mm and a new Q-wave anterior wall acute MI or any reinfarction with previous pathological Q-waves in the anterior wall were also eligible. Patients were entered into the trial within 10 days of symptom onset. The study was designed to continue until a minimum of 937 patients reached the primary end point of all-cause mortality, which would detect a relative difference of at least 20% between treatment groups with 95% power.
A total of 5,477 patients were randomly assigned and all were included in the final analyses (figure 1). A total of 946 deaths (all-cause mortality) were reported during the follow-up of 14,866 patient-years. One patient was lost to follow-up. Table 1 shows the comparison of baseline characteristics for the entire study population and according to treatment group. Table 2 presents the end-point results (prespecified). The average follow-up was 2.7 (0.9) years from randomization through death or study termination. Figure 1 is a Kaplan-Meier curve for the primary end point (all-cause mortality).
The trial showed a strong but nonsignificant trend in favor of captopril in the primary end point of all-cause mortality. A single prespecified end point, cardiovascular death (a subgroup of the primary end point), did reach significance in favor of captopril (P = .035). The incidence rates of the other clinically important outcomes—reinfarction, need for revascularization, stroke, first all-cause hospitalizations, or all hospitalizations (figure 2)—were nearly identical between the groups, however. Losartan was significantly better tolerated, with fewer patients discontinuing study medication (P < .001).
An important post hoc observation was derived from study of the Kaplan-Meier curves. Two differing patterns were observed with regard to the treatment effect between losartan and captopril during the acute and chronic phases of the 40-month follow-up period. Almost the entire difference in mortality developed during the first 210 days of therapy post-MI. This time point corresponded to the maximal separation of the survival curves and also identified the time when one half of the deaths had occurred. In the first 210 days, the relative risk (RR) between groups was 1.24 (l.04—1.50) favoring captopril; subsequent to day 210, the relative risk was 1.02 (0.86–1.22). Of the 484 deaths during the final 33 months of follow-up, 243 occurred on losartan and 241 occurred on captopril. The pattern of morbidity and mortality suggests an early postacute MI remodeling phase and a stable, mild chronic heart failure phase.
Tolerability was strongly in losartan’s favor when both all-cause discontinuation and adverse experiences were evaluated. Fewer patients on losartan discontinued study medication for any reason (458 [17%] versus 624 [23%]; RR, 0.70 [0.62—0.79];
P < .001). Discontinuation due to adverse experience was also substantially less in the losartan patients (202 [7%] versus 387 [14%]; RR, 0.50 [0.42—0.59]; P < .001; figure 3).
ACE inhibitor treatment following acute MI has improved morbidity and mortality in the selected, postacute MI population with evidence of left ventricular systolic dysfunction with and without clinical heart failure.5 Therapy has been demonstrated to decrease the incidence of heart failure,6 lessen infarct expansion, and decrease the rate of reinfarction.7 Studies with short-term ACE inhibitor therapy in unselected patients with acute MI demonstrated a fairly small but significant outcome benefit compared with that demonstrated in selected high-risk patients placed on long-term therapy. The comprehensive experience with ACE inhibitors prevents use of placebo in clinical trials involving high-risk patients following acute MI.
The OPTIMAAL study compared the effect of treatment with losartan, 50 mg once daily, versus captopril, 50 mg three times daily, on morbidity and mortality in patients with evidence of heart failure or left ventricular dysfunction following acute MI. This study did not demonstrate either superiority or noninferiority of losartan in relation to captopril. Captopril demonstrated a nonsignificant but favorable difference in total mortality, but the incidence rates of reinfarction and all-cause hospitalization were almost identical between the two groups. Losartan was better tolerated and had fewer discontinuations due to adverse events.
It is essential to interpret the results of OPTIMAAL in light of the fact that losartan was compared with an effective, active drug at an adequate dose (captopril 150 mg). Captopril is indicated for the treatment of patients with chronic heart failure and following acute MI in most countries; it is off patent and is used widely. Since this study demonstrated neither superiority nor noninferiority of losartan relative to captopril, and considering the convincing evidence that exists for the use of ACE inhibitors in such patients, ACE inhibitors should remain the first-line therapy in patients following complicated acute MI. Losartan was better tolerated than captopril, however, and was associated with significantly fewer discontinuations due to adverse experience. Keeping patients on long-term therapy in everyday practice is a major problem for primary care physicians, and tolerability translates into improved compliance.
It should also be emphasized that there were a large number of important clinical outcomes with regard to morbid events that occur frequently in high-risk patients following acute MI: reinfarctions (n = 763), revascularizations (n = 1,672), strokes (n = 272), and hospitalizations (n = 9,183). Here the similarities between treatments are striking, even with the low dose of losartan. These findings suggest that an angiotensin II antagonist may be a reasonable alternative in such patients intolerant of ACE inhibitors. At the present time, however, these two modes of inhibiting the renin-angiotensin system cannot be considered equal for high-risk acute MI patients.
The critical question of the optimal dose of losartan is very important. Indeed, this question may yet be unresolved for ACE inhibitors.1 Most studies with losartan in heart failure employed a target dose of 50 mg, but doses from 5 mg to 150 mg in patients with heart failure resulted in a stepwise increase in plasma renin activity and angiotensin II levels, indicating greater negative feedback at the highest doses.8 The considerable event rate in the early post-Ml phase of the OPTIMAAL trial underlines the possible importance of rapid titration and adequate dosage, especially during the early remodeling phase. Indeed, evidence from post-MI studies with ACE inhibitors suggests that over half of the benefits of these agents in the first 30 days post-MI occur within the first week.1
The somewhat slow uptitration of the losartan dose in OPTIMAAL would have compounded any problems related to a suboptimal dose
of losartan as compared with adequate doses of captopril administered three times daily. Inadequate dosage combined with slow up-
titration would be consistent with the early separation of the mortality curves, the significantly greater increase in serum creatinine from baseline to 1 month with captopril
as compared with losartan (P < .001), and the greater first-dose blood-pressure—lowering effect of capto-pril as compared with losartan. Losartan resulted in fewer adverse experiences of hypotension during follow-up (13.2% versus 26.3%;
P = .002), also suggesting a difference in the pharmacodynamic effect of the two agents at the dosages used. An ongoing morbidity and mortality trial, Heart Failure Endpoint Evaluation with the Angiotensin II Antagonist Losartan (HEAAL),9 is comparing 50- and 150-mg doses of losartan in a heart failure population, and may provide some additional information on the issue of optimal dosage.
The Valsartan in Acute Myocardial Infarction Trial (VALIANT) was designed to test the potential superiority of valsartan compared with captopril and was well powered (95% power to detect a 15% difference) with 14,808 patients; its results were reported at the American Heart Association meeting in November 2003.10 It contained three arms, including an arm with the combination of an angiotensin II antagonist and an ACE inhibitor. The comparator was identical to that of OPTIMAAL (captopril 50 mg three times daily). VALIANT, however, tested a relatively large dose of the angiotensin II antagonist valsartan—160 mg twice daily in the stand-alone arm and 80 mg twice daily in the combination arm with captopril. The titration of these agents was performed as rapidly as the investigator deemed fit. VALIANT also contained a noninferiority hypothesis with a noninferiority margin similar to OPTIMAAL; an upper one-sided 95% boundary for the relative risk of valsartan relative to captopril was set to a prespecified clinically important difference between the therapies. The study convincingly achieved the noninferiority boundary and confirmed equivalence for the two treatments. Combination therapy did not confer any added benefit.10
There is convincing evidence for the use of ACE inhibitors in certain patients following acute MI. Since the OPTIMAAL trial did not demonstrate either superiority or noninferiority of losartan versus captopril, ACE inhibitors should remain the first-line therapy in patients following complicated acute MI. Losartan, however, was better tolerated than captopril and was associated with significantly fewer discontinuations due to adverse events. While the role of losartan in patients intolerant of ACE inhibition is not clearly defined, it may be reasonable to consider it in such patients. n
This study was supported by an unconditional grant from Merck Sharp & Dohme Research Laboratories, West Point, Pennsylvania.