Is inadequate risk stratification diluting hazard ratio estimates in randomized clinical trials?

Clin Trials. 2024 Feb 2:17407745231222448. doi: 10.1177/17407745231222448. Online ahead of print.ABSTRACTIn randomized clinical trials, analyses of time-to-event data without risk stratification, or with stratification based on pre-selected factors revealed at the end of the trial to be at most weakly associated with risk, are quite common. We caution that such analyses are likely delivering hazard ratio estimates that unwittingly dilute the evidence of benefit for the test relative to the control treatment. To make our case, first, we use a hypothetical scenario to contrast risk-unstratified and risk-stratified hazard ratios. Thereafter, we draw attention to the previously published 5-step stratified testing and amalgamation routine (5-STAR) approach in which a pre-specified treatment-blinded algorithm is applied to survival times from the trial to partition patients into well-separated risk strata using baseline covariates determined to be jointly strongly prognostic for event risk. After treatment unblinding, a treatment comparison is done within each risk stratum and stratum-level results are averaged for overall inference. For illustration, we use 5-STAR to reanalyze data for the primary and key secondary time-to-event endpoints from three published cardiovascular outcomes trials. The results show that the 5-STAR estimate is typically smaller (i.e. more in favor of 5-STAR the test treatment) than the originally reported (traditional) estimate. This is not surprising beca...
Source: Clinical Trials - Category: Research Authors: Source Type: research