Objective: To emulate three target trials: single treatment vs. no treatment, joint treatment vs. no treatment, and head-to-head comparison of two treatments, we explain how to estimate the observational analogs of intention-to-treat and per-protocol effects, using hazard ratios and survival curves. For per-protocol effects, we describe two methods for adherence adjustment via inverse-probability weighting.
Study design and setting: Prospective observational study using electronic medical records of individuals aged 55-84 with coronary heart disease from >500 practices in the United Kingdom between 2000 and 2010.
Results: The intention-to-treat mortality hazard ratio (95% confidence interval) was 0.90 (0.84, 0.97) for statins vs. no treatment, 0.88 (0.73, 1.06) for statins plus antihypertensives vs. no treatment, and 0.91 (0.77, 1.06) for atorvastatin vs. simvastatin. When censoring nonadherent person-times, the per-protocol mortality hazard ratio was 0.74 (0.64, 0.85) for statins vs. no treatment, 0.55 (0.35, 0.87) for statins plus antihypertensives vs. no treatment, and 1.13 (0.88, 1.45) for atorvastatin vs. simvastatin. We estimated per-protocol hazard ratios for a 5-year treatment using different dose-response marginal structural models and standardized survival curves for each target trial using intention-to-treat and per-protocol analyses.
Conclusion: When randomized trials are not available or feasible, observational analyses can emulate a variety of target trials.
Keywords: Comparative effectiveness; Confounding; Electronic health records; Medication adherence; Secondary prevention; Survival analysis.
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