Assessment of Nonfatal Myocardial Infarction as a Surrogate for All-Cause and Cardiovascular Mortality in Treatment or Prevention of Coronary Artery Disease: A Meta-analysis of Randomized Clinical Trials

Abstract

Importance: Although nonfatal myocardial infarction (MI) is associated with an increased risk of mortality, evidence validating nonfatal MI as a surrogate end point for all-cause or cardiovascular (CV) mortality is lacking.

Objective: To examine whether nonfatal MI may be a surrogate for all-cause or CV mortality in patients with or at risk for coronary artery disease.

Data sources: In this meta-analysis, PubMed was searched from inception until December 31, 2020, for randomized clinical trials of interventions to treat or prevent coronary artery disease reporting mortality and nonfatal MI published in 3 leading journals.

Study selection: Randomized clinical trials including at least 1000 patients with 24 months of follow-up.

Data extraction and synthesis: Trial-level correlations between nonfatal MI and all-cause or CV mortality were assessed for surrogacy using the coefficient of determination (R2). The criterion for surrogacy was set at 0.8. Subgroup analyses based on study subject (primary prevention, secondary prevention, mixed primary and secondary prevention, and revascularization), era of trial (before 2000, 2000-2009, and 2010 and after), and follow-up duration (2.0-3.9, 4.0-5.9, and ≥6.0 years) were performed.

Main outcomes and measures: All-cause or CV mortality and nonfatal MI.

Results: A total of 144 articles randomizing 1 211 897 patients met the criteria for inclusion. Nonfatal MI did not meet the threshold for surrogacy for all-cause (R2 = 0.02; 95% CI, 0.00-0.08) or CV (R2 = 0.11; 95% CI, 0.02-0.27) mortality. Nonfatal MI was not a surrogate for all-cause mortality in primary (R2 = 0.01; 95% CI, 0.001-0.26), secondary (R2 = 0.03; 95% CI, 0.00-0.20), mixed primary and secondary prevention (R2 = 0.001; 95% CI, 0.00-0.08), or revascularization trials (R2 = 0.21; 95% CI, 0.002-0.50). For trials enrolling patients before 2000 (R2 = 0.22; 95% CI, 0.08-0.36), between 2000 and 2009 (R2 = 0.02; 95% CI, 0.00-0.17), and from 2010 and after (R2 = 0.01; 95% CI, 0.00-0.09), nonfatal MI was not a surrogate for all-cause mortality. Nonfatal MI was not a surrogate for all-cause mortality in randomized clinical trials with 2.0 to 3.9 (R2 = 0.004; 95% CI, 0.00-0.08), 4.0 to 5.9 (R2 = 0.06; 95% CI, 0.001-0.16), or 6.0 or more years of follow-up (R2 = 0.30; 95% CI, 0.01-0.55).

Conclusions and relevance: The findings of this meta-analysis do not appear to establish nonfatal MI as a surrogate for all-cause or CV mortality in randomized clinical trials of interventions to treat or prevent coronary artery disease.

Figure 1.. Preferred Reporting Items for Systematic Review and Meta-analysis Diagram

MI indicates myocardial infarction.

Figure 2.. Correlations of Treatment Effects on Nonfatal Myocardial Infarction (MI) and All-Cause or Cardiovascular Mortality

A, Overall analysis of 144 trials for the association between the logarithm of the odds ratio (log OR) for the surrogate end point of nonfatal MI and the true end point of all-cause mortality. B, Analysis of 112 trials for the association between the log OR for the surrogate end point of nonfatal MI and the true end point of cardiovascular mortality. C, Subgroup analysis of trials reporting hazard ratios (HRs) for the association between the log HR for the surrogate end point of nonfatal MI and the true end point of all-cause mortality. The dark blue area represents the 95% CI for the regression line (solid blue), light blue area represents the 95% prediction interval, and circle sizes are proportionate to the number of observations.

Figure 3.. Subgroup Analysis by Study Subject for the Association Between the Logarithm of the Odds Ratios (Log ORs) for the End Points

Surrogate end point of nonfatal myocardial infarction and the true end points of all-cause mortality primary prevention (A), mixed primary-secondary prevention (B), secondary prevention (C), and revascularization (D). The dark blue area represents the 95% CI for the regression line (solid blue), light blue area represents the 95% prediction interval, and circle size is proportionate to the number of observations.

Figure 4.. Subgroup Analysis by Era of Trial Enrollment for the Association Between the Logarithm of the Odds Ratios (OR) for End Points

Surrogate end point of myocardial infarction (MI) and true end point of all-cause mortality in trials with first patient enrolled before 2000 (A) from 2000 to 2009 (B), and in 2010 and after (C). The dark blue area area represents the 95% CI for the regression line (solid blue). Light blue area represents the 95% prediction interval. Circle size is proportionate to trial size.