Coronary disease & ACSRandomised controlled trial
Potential bias in efficacy estimates due to intercurrent treatment discontinuations
- Methodological review of randomized clinical trials and simulation study
- review of large antithrombotic randomized clinical trials (RCTs) published in The New England Journal of Medicine (2020-2025)
- simulations under three scenarios
- ICH E9(R1) framework
Authors' conclusion
Discontinuation is common, prognostically meaningful, and often oversimplified in analysis, threatening the validity of RCT findings. Explicitly addressing discontinuation as an intercurrent event within the estimand framework, along with stratified outcome curves, can improve interpretation and support more robust trial conclusions.
Study context
- Population
- Large antithrombotic RCTs published in The New England Journal of Medicine (2020–2025)
- Participants
- fourteen reviewed antithrombotic RCTs
- Comparison
- Treatment policy (intention-to-treat) and while-on-treatment strategies were compared within the ICH E9(R1) framework
Primary result
As reported in the abstract
Treatment discontinuation in reviewed trials · more than 6 months follow-up
- about one-third of patients discontinued treatment in trials with more than 6 months follow-up, with higher imbalance in open-label studies
- Over half of discontinuations were safety-related, yet timing and temporary interruptions were rarely reported
Further findings
Analytic handling of discontinuation
- Most reported both ITT and per-protocol (PP) analyses, with PP assuming non-informative censoring and yielding larger efficacy estimates
Simulations
- treatment policy and while-on-treatment strategies were biased when discontinuation was outcome-associated
- Simon-Makuch curves helped identify prognostic discontinuation differing by treatment arm
Original publication
Potential bias in efficacy estimates due to intercurrent treatment discontinuations. Eur Heart J Qual Care Clin Outcomes. Published 31 May 2026. doi:10.1093/ehjqcco/qcag084
Summarised from the published abstract; every number is checked against it