Effects of losartan and captopril on mortality and morbidity in high-risk patients after acute myocardial infarction - OPTIMAAL
Randomized trial comparing losartan to captopril in patients after acute myocardial infarction
Losartan administration would be superior or noninferior to captopril at decreasing the risk of all-cause mortality in high-risk patients after acute myocardial infarction
Patients Screened: 20573
Patients Enrolled: 5477
NYHA Class: I-IV
Mean Follow Up: 14,866 patient years. Mean 2.7+/-0.9 years.
Mean Patient Age: >50 years. Mean 67+/-9.8 years
Mean Ejection Fraction: <35% (14%)
1) Enrolled within 10 days of presentation AND 2) Acute myocardial infarction and signs or symptoms of heart failure (rales, S3, treatment with diuretics or vasodilators, persistent sinus tachycardia, or radiographic evidence of heart failure) OR 3) Acute myocardial infarction and ejection fraction <35% or left ventricular end diastolic dimension >65 OR 4) New Q-wave anterior wall myocardial infarction OR 5) Reinfarction with previous pathological Q-waves in the anterior wall
At the time of randomization: 1) Supine systolic arterial blood pressure of less than 100 mm Hg at the time of randomization 2) Current receipt of ACE inhibitor or angiotensin II receptor antagonist 3) Unstable angina 4) Stenotic valvular heart disease 5) Hemodynamically significant arrhythmia 6) Planned coronary revascularization
1) Sudden cardiac death or resuscitated cardiac death 2) Fatal or nonfatal myocardial infarction 3) Fatal or nonfatal stroke 4) Rate of hospital admission 5) NYHA functional class
Losartan (target dose 50 mg orally each day) v. Captopril (target dose 50 mg orally three times each day)
Aspirin (>70%), Beta-blocker (>60%), Statin (>60%), diuretic (40%)
There was no significant difference in the primary endpoint of all-cause mortality (18.2% losartan vs. 16.4% captopril; p=0.069 [RR 1.13 95% CI 0.99-1.28]). Likewise there were no significant differences in all prespecified endpoints except cardiovascular death (15.3% losartan vs. 13.3% captopril;p=0.032 [RR 1.17 95% CI 1.01-1.34]). The confidence interval boundary (>1.10) showed that losartan did not fulfill criteria for noninferiority. There was no significant increase in mortality in either group when stratified by beta-blocker use. Modest improvements in NYHA functional class over time were observed but no significant differences existed. Losartan was better tolerated than captopril with 17% discontinuing losartan for any reason vs. 23% discontinuing captopril; p<0.0001).
This trial did not demonstrate superiority or noninferiority for losartan compared to captopril. ACE inhibitors therefore remain first line therapy in high-risk patients after acute myocardial infarction. Losartan may be considered in such patients intolerant of ACE inhibitors. As the investigators note, because noninferiority criteria were not met, losartan is not conclusively better than placebo, but also these data also do not prove that losartan is no better than placebo. An interaction between losartan or captopril and beta-blockers was not seen in this trial. There is suggestion from the RENAAL and LIFE trials that higher doses of losartan may be more beneficial. Studies using higher doses of angiotensin II receptor antagonists or a combination of angiotensin II receptor antagonist and an ACE inhibitor in patients after acute myocardial infarction are soon to be released. These studies will help determine if higher doses of angiotensin II receptor antagonists or combination therapy will lead to improved outcomes when compared to ACE inhibitor monotherapy. In addition, few patients with preexisting heart failure were enrolled in this trial and further study of this population is warranted.
Presented by K. Dickstein at the Annual Meeting of the European Society of Cardiology, September 1, 2002. Published online in The Lancet, September 1, 2002.
Keywords: Losartan, Angiotensin Receptor Antagonists, Diuretics, Anterior Wall Myocardial Infarction, Captopril, Vasodilator Agents, Research Personnel, Tachycardia, Sinus, Heart Failure, Respiratory Sounds, Confidence Intervals
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