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<p>Rigorous integration of external controls in large-scale cardiovascular prevention randomized controlled trials (RCTs) is under-explored. The Cocoa Supplement and Multivitamin Outcomes Study (COSMOS), a primary prevention RCT of cocoa extract supplementation, initially showed a statistically non-significant effect on total cardiovascular disease (CVD). We aimed to obtain more robust estimates of cocoa extract effects by integrating external control data from The VITamin D and OmegA-3 TriaL (VITAL), a similarly designed large-scale RCT. We analyzed 21,442 COSMOS participants (median 3.6-year follow-up) and used the VITAL omega-3 placebo arm as an external control. Outcomes included the original COSMOS primary CVD endpoint (a composite of myocardial infarction [MI], stroke, cardiovascular death, and coronary revascularization) and major adverse cardiovascular events (MACE; MI, stroke, and cardiovascular death). Two statistical approaches were used: a propensity score-based inverse probability weighting (IPW)-weighted Cox proportional hazard model and a doubly robust method to estimate 4-year risk ratios (RRs) and 95% confidence intervals (CIs) via bootstrapping. IPW-weighted VITAL-placebo data showed similar covariate distributions and 4-year event rates to COSMOS-placebo. While COSMOS data alone showed non-significant RRs (CVD: 0.91 [95% CI 0.79, 1.04]; MACE: 0.84 [0.70, 1.00]), incorporating VITAL-placebo showed protective effects of cocoa extract for cardiovascular endpoints ; RRs were 0.87 [0.76, 0.98] for CVD and 0.80 [0.68, 0.93] for MACE in Cox models; and those were 0.84 [0.74, 0.95] for CVD and 0.77 [0.67, 0.89] for MACE in the doubly robust method. E-values and sensitivity analyses indicated robustness. The present results suggest that original non-significant results of COSMOS could be due to type 2 error. While additional assumptions are needed, external control integration offers a feasible approach to strengthen interpretations of large-scale prevention trials.</p>

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Combining external placebo-arm data in a prevention trial: effects of cocoa extract supplementation on cardiovascular disease

  • 期刊论文

  • 发表日期：

    2026年5月18日

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  • Rikuta Hamaya,
  • Sidong Li,
  • Pamela M. Rist,
  • Aladdin H. Shadyab,
  • JoAnn E. Manson,
  • Howard D. Sesso

摘要

Rigorous integration of external controls in large-scale cardiovascular prevention randomized controlled trials (RCTs) is under-explored. The Cocoa Supplement and Multivitamin Outcomes Study (COSMOS), a primary prevention RCT of cocoa extract supplementation, initially showed a statistically non-significant effect on total cardiovascular disease (CVD). We aimed to obtain more robust estimates of cocoa extract effects by integrating external control data from The VITamin D and OmegA-3 TriaL (VITAL), a similarly designed large-scale RCT. We analyzed 21,442 COSMOS participants (median 3.6-year follow-up) and used the VITAL omega-3 placebo arm as an external control. Outcomes included the original COSMOS primary CVD endpoint (a composite of myocardial infarction [MI], stroke, cardiovascular death, and coronary revascularization) and major adverse cardiovascular events (MACE; MI, stroke, and cardiovascular death). Two statistical approaches were used: a propensity score-based inverse probability weighting (IPW)-weighted Cox proportional hazard model and a doubly robust method to estimate 4-year risk ratios (RRs) and 95% confidence intervals (CIs) via bootstrapping. IPW-weighted VITAL-placebo data showed similar covariate distributions and 4-year event rates to COSMOS-placebo. While COSMOS data alone showed non-significant RRs (CVD: 0.91 [95% CI 0.79, 1.04]; MACE: 0.84 [0.70, 1.00]), incorporating VITAL-placebo showed protective effects of cocoa extract for cardiovascular endpoints ; RRs were 0.87 [0.76, 0.98] for CVD and 0.80 [0.68, 0.93] for MACE in Cox models; and those were 0.84 [0.74, 0.95] for CVD and 0.77 [0.67, 0.89] for MACE in the doubly robust method. E-values and sensitivity analyses indicated robustness. The present results suggest that original non-significant results of COSMOS could be due to type 2 error. While additional assumptions are needed, external control integration offers a feasible approach to strengthen interpretations of large-scale prevention trials.