Disclosures: The study authors and del Rosario report no relevant financial disclosures. Please see the Editor’s Note for all other authors’ relevant financial disclosures.
October 28, 2021
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Nonfatal MI poor surrogate for mortality in trials of patients with CAD

Disclosures: The study authors and del Rosario report no relevant financial disclosures. Please see the Editor’s Note for all other authors’ relevant financial disclosures.
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In a meta-analysis of randomized trials that included patients with CAD, nonfatal MI was not an adequate surrogate for all-cause or CV mortality, researchers reported.

Kevin O’Fee, MD, internal medicine resident at Washington University School of Medicine in St. Louis, and colleagues conducted a meta-analysis of 144 randomized trials testing interventions to treat or prevent CAD covering 1,211,897 patients to determine whether nonfatal MI can be used as a surrogate for all-cause or CV mortality in patients with or at high risk for CAD.

Middle aged white man having heart attack
Source: Adobe Stock

The researchers assessed trial-level correlations between nonfatal MI and all-cause or CV mortality and set the criterion of surrogacy at an R2 of 0.8.

According to the researchers, nonfatal MI did not meet the criterion for surrogacy for all-cause mortality (R2 = 0.02; 95% CI, 0-0.08) or CV mortality (R2 = 0.11; 95% CI, 0.02-0.27).

O’Fee and colleagues also found nonfatal MI did not meet the criterion for surrogacy for all-cause mortality in the following cohorts:

  • trials in primary prevention (R2 = 0.01; 95% CI, 0.001-0.26);
  • trials in secondary prevention (R2 = 0.03; 95% CI, 0-0.2);
  • trials in mixed primary and secondary prevention populations (R2 = 0.001; 95% CI, 0-0.08);
  • revascularization trials (R2 = 0.21; 95% CI, 0.002-0.5);
  • trials enrolling patients before 2000 (R2 = 0.22; 95% CI, 0.08-0.36);
  • trials enrolling patients from 2000 to 2009 (R2 = 0.02; 95% CI, 0-0.17);
  • trials enrolling patients in 2010 and later (R2 = 0.01; 95% CI, 0-0.09);
  • trials with 2 to 3.9 years of follow-up (R2 = 0.004; 95% CI, 0-0.8);
  • trials with 4 to 5.9 years of follow-up (R2 = 0.06; 95% CI, 0.001-0.16); and
  • trials with 6 or more years of follow-up (R2 = 0.3; 95% CI, 0.01-0.55).

Potential explanations include more sensitive biomarkers and improvements in treatments, competing risks of non-CV death and the diversity of causes of MI, O’Fee and colleagues wrote.

In a related Editor’s Note, Mithi del Rosario, MD, internal medicine resident at the University of California, San Francisco, and editorial fellow at JAMA Internal Medicine, and colleagues wrote: “While it is biologically plausible for nonfatal MI to predict mortality, there is little evidence to show that it actually does. This study raises important questions on the appropriateness of nonfatal MI as a clinical trial endpoint, with specific emphasis on methodologic concerns and an inability to predict mortality.”

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