HISTORICAL CONTROLS FOR MORTALITY: R.I.P

Purpose: Authors of observational studies frequently compare their results to previously published reports.  Mortality is a commonly utilized hard endpoint, and the observational study frequently demonstrates improved survival compared to the selected historical control population.  In this study, we sought to determine the variability in mortality rates in published clinical trials of cardiovascular interventions.

Method: After identifying large cardiovascular clinical trials which provided long term follow up and mortality rates, we calculated age and gender adjusted mortality hazard ratios in 621 clinical trial populations utilizing a competing risk model.  We then identified median and 25^th and 75^th percentile of the mortality hazard ratios for 9 common cardiovascular disease states.

Result: On average, patients in clinical trials evaluating stable coronary artery disease (N=165 studies) had mortality that was similar to that of the population as a whole (HR = 0.95), but the inter quartile range (IQR) was 0.76-1.22.  More profound differences in IQR were found for acute myocardial infarction (N =102) (HR = 2.98, IQR 1.78-4.08) and primary prevention studies (N = 66) (HR = 0.60, IQR 0.38-0.82).  There was at least a 20% difference between the first quartile and the median value for the hazard ratio for all categories studied.  In addition, between 1990 and 2010, there is a 65% reduction in mortality rates for both heart failure (N = 110) and acute myocardial infarction.  If a clinically significant difference in mortality is considered to be 20% or more, the observed variation in mortality hazard ratios here is so great that one can always find a control population to provide a favorable comparison.  The further back in time one searches, the easier it is to find a “suitable” control population.  

Conclusion: Variability in age and gender adjusted mortality hazard ratios, even for similar populations, is profound.  Contemporaneously obtained controls are necessary to be valid comparators.  Ultimately, the use of historical controls should find its place in history and rest in peace.