An approach to explore for a sweet spot in randomized trials

J Clin Epidemiol. 2020 Apr:120:59-66. doi: 10.1016/j.jclinepi.2019.12.012. Epub 2019 Dec 23.

Abstract

Objective: The objective of the study was to demonstrate how a conventional randomized trial can be analyzed through a stratified or a matched approach to identify a potential sweet spot where observed differences might be accentuated in the mid range of disease severity.

Design and setting: We review a landmark randomized trial of heart failure patients that tested whether implantable defibrillators reduce mortality (n = 2,521).

Results: Overall, 22% (182/829) of the patients in the defibrillator group died compared with 29% (484/1,692) of patients in the control group. Proportional hazards analysis yielded a modest 25% survival benefit (hazard ratio = 0.75, 95% confidence interval: 0.63 to 0.89). Stratified analysis of the trial yielded a larger 52% survival benefit for those in the middle quintile of disease severity (hazard ratio = 0.48, 95% confidence interval: 0.29 to 0.79). In contrast, little of the survival benefit was explained by patients with the greatest disease severity (hazard ratio = 0.89, 95% confidence interval: 0.69 to 1.15). The discrepancy between crude and stratified analyses could be visualized by graphical displays and replicated with matched comparisons.

Conclusion: Our approach for analyzing a randomized trial could help identify a potential sweet spot of an accentuated treatment effect.

Keywords: Cardiac defibrillator; Clinical trials; Heterogeneous treatment effect; Patient diversity; Precision medicine; Sudden death.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Death, Sudden, Cardiac / epidemiology*
  • Death, Sudden, Cardiac / prevention & control*
  • Defibrillators, Implantable*
  • Female
  • Heart Failure / therapy*
  • Humans
  • Male
  • Middle Aged
  • Randomized Controlled Trials as Topic / methods*
  • Randomized Controlled Trials as Topic / statistics & numerical data*
  • Severity of Illness Index
  • Treatment Outcome

Grants and funding