Randomized controlled trial of oral captopril, of oral isosorbide mononitrate and of intravenous magnesium sulphate started early in acute myocardial infarction: safety and haemodynamic effects

Abstract

The purpose of this randomized controlled study was to assess the haemodynamic effects, safety and tolerability in acute myocardial infarction (AMI) of one month of oral captopril, one month of oral isosorbide mononitrate and 24 h of intravenous magnesium. It was carried out in four United Kingdom and six Polish hospitals in consecutive phases: oral captopril vs oral mononitrate vs placebo were compared among 400 patients in a 'three-way' study; and then oral captopril vs placebo and oral mononitrate vs placebo were compared among 474 patients in '2 x 2' and '2 x 2 x 2' factorial studies (with 208 patients in the latter study also randomized between intravenous magnesium and open control). The factorial studies differed from the three-way study in that one group of patients was allocated both oral captopril and oral mononitrate, a higher maintenance dose of captopril was used (following the same initial dose), and once daily controlled-release mononitrate was used. In the three-way study, the mean of the lowest systolic blood pressures recorded during the first 4 h after randomization were (mmHg +/- standard error): 104 +/- 2 captopril vs 105 +/- 1 mononitrate vs 112 +/- 2 placebo (P < 0.001 for captopril or for mononitrate vs placebo), and in the factorial studies were 105 +/- 1 captopril vs 110 +/- 1 placebo (P < 0.01) and 106 +/- 1 mononitrate vs 108 +/- 1 placebo (NS). There was an excess of hypotension recorded among patients allocated active treatment (captopril > mononitrate > placebo) and there was a small, but significant, excess of cardiogenic shock with captopril compared with control in the factorial study. However, in these studies, neither captopril nor mononitrate were associated with any overall increase in the incidence of hypotension considered severe enough to lead to treatment being stopped. No other serious complications were observed, and compliance with study tablets at hospital discharge was not significantly different between the active and placebo groups. Patients allocated magnesium in the 2 x 2 x 2 factorial study had a slightly lower mean systolic blood pressure just after the initial 15 min bolus injection (126 +/- 2 magnesium vs 134 +/- 3 control; P < 0.05) but there were no significant differences during the subsequent 24 h maintenance infusion period. Apart from some facial flushing, magnesium did not appear to be associated with any complications.(ABSTRACT TRUNCATED AT 400 WORDS)

Treatment of Hypertension in the Prevention and Management of Ischemic Heart Disease

“…123 Early intravenous ␤-blockade was also supported in the ISIS-1 trial and by a meta-analysis of 30 trials in nearly 30 000 patients. 124, 125 The recent publication of the COMMIT (ClOpidogrel and Metoprolol in Myocardial Infarction Trial)/Chinese Cardiac Study (CCS)-2 provided additional insight into ␤-blocker strategies. 126 The investigators randomized 45 852 acute MI patients to intravenous then oral ␤-blockers at presentation versus placebo and assessed the coprimary outcomes of (1) the composite of death, reinfarction, or cardiac arrest and (2) death due to any cause.…”

“…119,120,129 This effect of early (within 24 hours) ACE inhibitor therapy is particularly pronounced in higher-risk patients: those with anterior or particularly large infarcts, previous infarction, HF, depressed LV ejection fraction (LVEF), and tachycardia. 95,118,125 Angiotensin Receptor Blockers ARBs are a useful alternative to ACE inhibitors. The VALIANT trial 89 randomized patients with LV dysfunction and/or HF within 10 days after acute MI to additional therapy with valsartan, captopril, or both and monitored them for Ϸ2 years.…”

Newer Pharmaceutical Agents for STEMI Interventions

“…In the Magnesium in Coronaries (MAGIC) and The Fourth International Study of Infarct Survival (ISIS-4) trials, IV magnesium showed no benefit compared with placebo in patients with STEMI. 49,50 The 2004 American College of Cardiology Foundation/American Heart Association guidelines recommended that IV magnesium should not be used routinely, except for those with documented magnesium deficiency and in patients with polymorphic ventricular tachycardia.…”

Factorial Designs in Clinical Trials

“…The Fourth International Study of Infarct Survival (ISIS-4) was a 2 × 2 × 2 factorial trial assessing the efficacy of oral captopril, oral mononitrate, and intravenous magnesium sulfate in 58 050 patients with suspected myocardial infarction [12,17]. No significant interactions among the treatments were observed and each main effect comparison was based …”