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  5. Potential bias in efficacy estimates due to intercurrent treatment discontinuations

Potential bias in efficacy estimates due to intercurrent treatment discontinuations

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File(s)
42217496.pdf (870.44 KB)
No Access Until
2027-09-16
Permanent Link(s)
https://hdl.handle.net/1813/128197
Collections
Department of Healthcare Policy & Research
Author
Redfors, Bjorn
Choi, Jacky
Gaudino, Mario
Reynolds, Harmony R.
Zhong, Judy
Abstract

BACKGROUND: Treatment discontinuation is a common intercurrent event in randomized clinical trials (RCTs) that can bias treatment effect estimates, yet it remains underrecognized and inconsistently addressed. Antithrombotic trials provide a relevant case, as bleeding-related discontinuation is common and more often occur in patients at increased risk also for ischemic events. METHODS: We reviewed large antithrombotic RCTs published in The New England Journal of Medicine (2020-2025) to assess reporting and analytic handling of treatment discontinuation. We also conducted simulations to examine how discontinuation patterns influence efficacy estimates under three scenarios: discontinuation only in the treatment arm, in both arms with similar patterns, and in both arms but outcome-associated only in the treatment arm. Treatment policy (intention-to-treat) and while-on-treatment strategies were compared within the ICH E9(R1) framework. RESULTS: Among fourteen reviewed antithrombotic RCTs, about one-third of patients discontinued treatment in trials with more than six 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. Most reported both ITT and per-protocol (PP) analyses, with PP assuming non-informative censoring and yielding larger efficacy estimates. In simulations, treatment policy and while-on-treatment strategies were biased when discontinuation was outcome-associated, while Simon-Makuch curves helped identify prognostic discontinuation differing by treatment arm. CONCLUSIONS: 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.

Journal / Series
European heart journal. Quality of care & clinical outcomes
Volume & Issue
12(6)
Date Issued
2026-09-16
Publisher
Oxford University Press
Keywords
WCM Library Coordinated Deposit
•
Humans
•
Randomized Controlled Trials as Topic
•
Bias
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Fibrinolytic Agents/therapeutic use
•
Treatment Outcome
•
Treatment Interruption
•
Antithrombotic drugs
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Clinical trial
•
Estimand
•
Intercurrent events
•
Treatment discontinuation
Related DOI
https://doi.org/10.1093/ehjqcco/qcag084
Previously Published as
Redfors B, Choi J, Gaudino M, Reynolds HR, Zhong J. Potential bias in efficacy estimates due to intercurrent treatment discontinuations. European heart journal. Quality of care & clinical outcomes. 2026;12(6):1011-1022. doi: 10.1093/ehjqcco/qcag084. PMID: 42217496.
Rights
Attribution-NonCommercial-NoDerivatives 4.0 International
Rights URI
https://creativecommons.org/licenses/by-nc-nd/4.0/
Type
article

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