Purpose: Comparative effectiveness research requires analysis of large datasets to determine optimal therapy for subsets of patients. There has been a marked increase in publication of cardiovascular clinical trials over the past 20 years. With this increase in reports, there has also been an increase in the use of composite primary endpoints. There is, however, little data on how frequently results of major adverse cardiovascular events (MACE) diverge from that of the primary composite endpoint.
Method: To determine how frequently results diverged, we evaluated all major cardiovascular clinical trials with extended mortality follow up published in JAMA, NEJM and the Lancet since 1986. Data was collected on the primary endpoint studied, demographics of the study population, and the principal components of MACE: the number of deaths, cardiovascular deaths, myocardial infarction, and stroke that occurred with the treatment and control in each study. Hazard ratios and confidence intervals were calculated for each of these components.
Result: There are 385 studies included: death and composite endpoint were reported in all, CV mortality in 275, MI rate in 249 and stroke incidence in 182. There were 111 (28%) studies that had a statistically significantly positive primary endpoint, 50 (20%) studies had a significant reduction in MI, 48 (12%) had a reduction in death, 35 (13%) had a reduction in CV death, and 35 (19%) had reduction in stroke. Few reported studies had a statistically significant increase in events with treatment. There were 235 studies (61%) that had at least 1 MACE with an HR>1. Of the 111 positive studies, 34 (31%) had at least one MACE with an HR>1. Of the 23 studies that were stopped early due to efficacy, 4 had at least 1 MACE with an HR>1. Only 42 of the 111 positive studies reported all 4 components of MACE.
Conclusion: MACE in cardiovascular clinical trials commonly have HR that diverge. This occurs even when studies have statistically significantly positive results or are discontinued early for efficacy. These results demonstrate the necessity of collecting and reporting all appropriate major adverse events. Publication of this data is necessary to best judge the risks and benefits of the interventions studied in clinical trials.
See more of: The 34th Annual Meeting of the Society for Medical Decision Making