Combining heart failure hospitalization with all-cause mortality as a composite end point increased the overall event rate by 64% to 134% compared to mortality alone, varying by trial duration.
Meta-Analysis
Does combining heart failure hospitalization with all-cause mortality yield a consistently predictable increase in event rate across heart failure RCTs compared with mortality alone?
Combining HF hospitalization with all-cause mortality increases overall event rates in HF trials by 64% to 134%, with longer-duration trials showing a more predictable increase.
Effect estimate: 64% to 134% relative increase
Randomized clinical trials (RCTs) are a cornerstone of evidence-based medicine. Their design, implementation, and interpretation are sometimes subject to flaws and errors. To achieve statistical significance and economically feasible RCTs, the use of composite end points in heart failure (HF) trials has become more common. We analyzed the incremental value of combining HF hospitalizations with all-cause mortality in trials of chronic HF that enrolled >1000 placebo patients and had a mean follow-up >9 months. We tested the assumption that, compared with mortality, combining HF hospitalization with all-cause death would yield a consistently predictable increase in event rate across HF RCTs. Average placebo arm duration of follow-up was determined, and standardized placebo event rates per 100 patient-years were estimated. Twelve major HF RCTs were included in this analysis. There was a substantial relative increase in the event rate ranging from 64% to 134% when a composite end point was used. This increase was not related to disease severity as described by annual mortality rate. The relative contribution of combining HF hospitalization with all-cause mortality was, however, influenced by the duration of the trial. Combining HF hospitalization with all-cause mortality increases the overall event rate in HF clinical trials; the relative increase varies widely and is unrelated to disease severity. Longer-duration trials have a more predictable increase in events than short RCTs. Trial duration must be considered when composite end points are used during the design and interpretation of HF RCTs.
Skali et al. (2006) conducted a meta-analysis in chronic heart failure. Composite end point (HF hospitalization and all-cause mortality) vs. All-cause mortality alone was evaluated on Relative increase in event rate (64% to 134% relative increase). Combining heart failure hospitalization with all-cause mortality as a composite end point increased the overall event rate by 64% to 134% compared to mortality alone, varying by trial duration.