ArticleContemporary clinical trials2020
Adherence-adjustment in placebo-controlled randomized trials: An application to the candesartan in heart failure randomized trial.
Article in Contemporary clinical trials, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
3 citing papers in PubMed, 15 citations in OpenAlex.
- Pain and treatment outcomes after initiating methadone vs buprenorphine among medicare patients with opioid use disorder and comorbid chronic pain: A target trial emulation.PLoS medicine · 2026Article
- Intention-to-treat analysis when only a baseline value is available.Contemporary clinical trials communications · 2020Article
- Adjusting for adherence in randomized trials when adherence is measured as a continuous variable: An application to the Lipid Research Clinics Coronary Primary Prevention Trial.Clinical trials (London, England) · 2020Article
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Authors and funding
5 authors at 3 institutions in 1 country.
Funding
Abstract
backgroundThe per-protocol effect provides important information in randomized trials with incomplete adherence. Yet, because valid estimation typically requires adjustment for prognostic factors that predict adherence, per-protocol effect estimates are often met with skepticism. In placebo-controlled trials, however, the validity of adjustment can be indirectly verified by demonstrating no association between adherence and the outcome among the placebo arm. Here, we describe a two-stage procedure in which we first adjust for time-varying adherence in the placebo arm and then use a similar procedure to estimate the per-protocol effect.
methodsWe use the Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM) randomized trial. First, we compare adherers versus non-adherers in the placebo arm, adjusting for pre- and post-randomization variables. Second, we use models validated in the placebo arm to estimate the per-protocol effect of adherence to candesartan versus placebo in the full trial.
findingsWe successfully estimated no association between adherence and mortality in the placebo arm; hazard ratio: 0.91 (95% CI: 0.51, 2.52). We then estimated the per-protocol effect under two sets of protocol-defined stopping criteria after adjustment for post-randomization confounders. The mortality hazard ratio estimates ranged from 0.91 to 0.93 for the per-protocol effect estimates, similar to the intention-to-treat effect estimates.
interpretationAdherence adjustment in the CHARM trial is feasible when appropriate assumptions about missing data and confounding are made. These assumptions cannot be verified but can be supported through the use of placebo-arm adherence assessment.
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