A systematic review and meta-analysis found that nonfatal myocardial infarction (MI) was not an appropriate surrogate for all-cause or cardiovascular (CV) mortality in studies of treatments for patients with coronary artery disease (CAD). The study findings were published in JAMA Internal Medicine.

Researchers from Washington University School of Medicine in the United States searched publication databases through December 2020 for randomized clinical trials of interventions for the treatment of CAD. The study authors chose to limit their search to only include those published after 2000 in The New England Journal of Medicine, The Lancet, or JAMA. A total of 144 studies met the inclusion criteria. Surrogacy was defined as an R2 of 0.8.

The trials were of pharmacological agents (n=117), interventional therapies (n=17), lifestyle interventions (n=7), and imaging strategies (n=3) with the goal of mixed primary/secondary prevention (n=57), secondary prevention (n=46), primary prevention (n=24), and revascularization (n=17). Follow-up ranged between 2.0-3.9 years in 66 trials, 4.0-5.9 years in 57 trials, and 6.0 years or more in 21 trials.

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Being randomized to receive a treatment intervention reduced nonfatal MI (odds ratio [OR], 0.87; 95% CI, 0.85-0.90; P <.001; I2, 58%) as well as all-cause mortality (OR, 0.95; 95% CI, 0.93-0.97; P <.001; I2, 53%).

Comparing the 2 endpoints, the treatment effect on nonfatal MI failed to predict all-cause mortality (R2, 0.02; 95% CI, 0.00-0.08).

Stratified by study subject, nonfatal MI did not meet the threshold for surrogacy for studies of primary prevention (R2, 0.01; 95% CI, 0.001-0.26), secondary prevention (R2, 0.03; 95% CI, 0.00-0.20), mixed prevention (R2, 0.001; 95% CI, 0.00-0.08), or revascularization (R2, 0.21; 95% CI, 0.002-0.50).

There was no evidence for surrogacy among studies with a 2.0-3.9-year follow-up (R2, 0.004; 95% CI, 0.00-0.08), 4.0-5.9-year follow-up (R2, 0.06; 95% CI, 0.001-0.16), or 6.0-years-or-more follow-up (R2, 0.47; 95% CI, 0.12-0.81).

Stratified by year, there was no evidence for surrogacy among studies published between 2000-2009 (R2, 0.02; 95% CI, 0.00-0.17) or after 2010 (R2, 0.01; 95% CI, 0.00-0.09).

This study may have been limited by the definition of surrogacy, which was higher than previous studies (R2, 0.80 vs 0.65).

There was a lack of evidence from randomized clinical trials to suggest that nonfatal MI and all-cause mortality were equivalent outcomes among the CAD population.

“Thus, interventions that reduce nonfatal MI cannot be assumed to reduce mortality,” the study authors said. “Inclusion of nonfatal MI as an end point in [randomized clinical trials] may still be justified based on its association with impaired quality of life and increased use of health care resources, but not based on its surrogacy for mortality.”


O’Fee K, Deych E, Ciani O, Brown DL. 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. JAMA Intern Med. Published online October 25, 2021. doi:10.1001/jamainternmed.2021.5726