Influence of Clinical Trials of Acute Coronary Syndrome Beyond the Primary Hypothesis: A Systematic Review

Conducting a clinical trial involves significant risks, time, and resources. The return on investment for these trials, measured by advancing health care and contributions to the scientific literature, is often uncertain.

To assess the long-term effects of major clinical trials of acute coronary syndromes contemporary to the Assessment of Pexelizumab in Acute Myocardial Infarction (APEX-AMI) trial, which did not achieve its primary objective.

The Cochrane Central Register of Controlled Trials database was screened for clinical trials of acute coronary syndromes (including unstable angina, ST-elevation myocardial infarction, and non-ST-elevation myocardial infarction) with more than 1000 participants and primary results published between January 1, 2005, and December 31, 2009, in Circulation, European Heart Journal, JAMA, Journal of the American College of Cardiology, The Lancet, and The New England Journal of Medicine. For identified trials, bibliographic information, citations, trial name, registration, inclusion diagnosis, intervention type, sample size, primary outcome result, sponsor information, and academic involvement were extracted. To identify secondary analyses, bibliographic information for citing articles, their citations, and their abstracts were extracted. Clinical practice guideline bibliographies for citations of trial publications were reviewed, and the class and level of evidence of resulting recommendations were extracted.

Of 784 records screened, 30 were primary publications of 25 clinical trials. Through December 31, 2018, these trials were cited a median of 497 times (interquartile range [IQR], 424-931 citations). Trials that did not achieve their primary objective had fewer primary citations (the number of times that each published journal article with the primary [main] results of a trial was cited) (median, 443 [IQR, 396-468] vs 868 [IQR, 645-1774] citations, P = .006). The frequency of secondary analyses peaked within 5 years of the primary trial at 643. Trials that did not achieve the primary objective had fewer secondary analyses (median, 15 [IQR, 5-31] vs 18 [IQR, 10-43] analyses, P = .44) that were not cited significantly less often (median, 484 [IQR, 191-1299] vs 1124 [IQR, 410-4283] citations, P = .16). All trials were cited by at least 1 clinical practice guideline.

This review found that trials that achieved the primary objective were frequently cited. Secondary research activity did not differ by primary result, and the primary trials and secondary analyses contributed to clinical practice recommendations. These data show the long-term importance of clinical trials regardless of primary outcome result.