Phased target trial design and meta-analysis in a head-to-head treatment comparison

• Background: For conditions with rare clinical outcomes, real-world treatment comparisons are challenging to design and prone to confounding.Objectives: To present a robust methodologic approach for rigorous and transparent assessment of rare outcomes using real-world data.Methods: We emulated a target trial using an active comparator, new-user design to compare dronedarone to sotalol for rhythm control in atrial fibrillation (AF) as both are recommended for similar patient phenotypes. Using one protocol, a pre-specified stepwise approach was implemented across 4 datasets (Optum CDM; IBM MarketScan; Veterans Affairs Electronic Health Records; Swedish National Patient Register). Meta-analysis was used to ensure sufficient capture of specific, rare primary outcomes (cardiovascular (CV) hospitalization and ventricular proarrhythmia) and to evaluate consistency of findings across patient populations. Steps 1–3 focused on cohort selection, propensity score matching (PSM), baseline equipoise and residual confounding assessment via negative control outcome analyses. In steps 4–6, outcomes in the individual cohorts were analyzed using an as-treated approach and Cox proportional hazards models. Step 7 included a heterogeneity assessment, meta-analysis using fixed effects models, and hypothesis testing using a hierarchical approach. In step 8, sensitivity analyses, including E-values and Inverse Probability of Censoring Weighting, were conducted to verify the robustness of findings.Results: In step 1, 35,467 sotalol and 27,955 dronedarone patients with AF who were antiarrhythmic drug-naive were identified across databases. In steps 2–3, 23,275 dronedarone patients were PS-matched to 23,275 sotalol patients. Baseline covariates were well-balanced and little-to-no residual confounding was observed via the negative control analyses. Individual HRs were estimated in steps 4–6, and, when no significant heterogeneity between databases was observed, hazard ratios (HRs) were pooled across datasets in step 7. For example, for CV hospitalization, dronedarone was superior to sotalol with no heterogeneity (HR: 0.91; 95% CI: 0.85, 0.97; Cochran Q p-value: 0.32). Eleven sensitivity analyses were conducted in step 8 and confirmed that findings were generally robust.Conclusions: An active comparator, new-user design using the target trial approach coupled with meta-analysis generated consistent findings across databases and countries using one protocol. Similar methods, including a pre-specified stepwise approach, negative control outcome, and tests for robustness should be considered for real-world studies where specific, rare outcomes need to be examined in a rigorous and transparent way.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Kardiologi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Cardiac and Cardiovascular Systems (hsv//eng)

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