Patient-Reported Outcome Endpoint Emulation in Heart Failure External Control Arm Study (EMULATE-HF PRO-ECA Study)
Author(s)
Onyeka Illoh, OD, MPH1, Almut Winterstein, RPh, PhD, FISPE2, Zafar Zafari, MSc, PhD1, Javed Butler, MD, MPH, MBA3, Mathangi Gopalakrishnan, MPharm, PhD1, Susan dosReis, BSPharm, PhD, FISPE1.
1Department of Practice, Sciences, & Health Outcomes Research, University of Maryland School of Pharmacy, Baltimore, MD, USA, 2Department of Pharmaceutical Outcomes and Policy and Center for Drug Evaluation and Safety, College of Pharmacy, University of Florida, Gainesville, FL, USA, 3Baylor Scott and White Research Institute, Dallas, TX, USA.
1Department of Practice, Sciences, & Health Outcomes Research, University of Maryland School of Pharmacy, Baltimore, MD, USA, 2Department of Pharmaceutical Outcomes and Policy and Center for Drug Evaluation and Safety, College of Pharmacy, University of Florida, Gainesville, FL, USA, 3Baylor Scott and White Research Institute, Dallas, TX, USA.
OBJECTIVES: This study aims to use a target trial emulation approach to evaluate the utility and methodological challenges of external control arm (ECA) studies for analyzing patient-reported outcomes (PRO).
METHODS: We performed an emulation analysis of a PRO endpoint, as assessed in the EMPEROR-Reduced trial, using contemporaneous data from the EMPEROR-Preserved trial placebo arm as the external control. Adults with heart failure (HF) aged ≥18 years with ejection fraction >30% to < 55% and N-terminal-pro-brain natriuretic peptide ≥ 600 pg/ml on empagliflozin or placebo were eligible for inclusion. We adjusted for imbalance in the measured baseline covariates between treatment groups using propensity score methods. The outcome of change from baseline in the clinical summary score (CSS) of the Kansas City Cardiomyopathy Questionnaire (KCCQ) and 95% confidence interval (CI) at Week 52 was estimated using inverse probability of treatment weighting (IPTW)-adjusted mixed model for repeated measures. We conducted bias analysis to assess the sensitivity of the findings to an unmeasured confounder.
RESULTS: A total of 526 subjects on empagliflozin and 628 external control subjects were included in the study. After IPTW-adjustment, the change from baseline in the KCCQ-CSS at Week 52 comparing empagliflozin to the ECA was modest and did not meet statistical significance (0.49; 95% CI: -3.49, 4.48). The IPTW-adjusted effect estimate was generally consistent with the EMPEROR-Reduced trial result for the target subset population (0.54; 95% CI: -2.52, 3.59), leading to the same conclusion. Sensitivity analyses supported the robustness of the findings.
CONCLUSIONS: We successfully replicated the evaluation of a PRO endpoint in an ECA study. Challenges and lessons learned will be used to formulate requirements for relevant ECA data sources and propose best practices. Ensuring robust strategies for the collection, quality, validation, and analysis of PRO data in ECA studies is crucial for the interpretation of findings.
METHODS: We performed an emulation analysis of a PRO endpoint, as assessed in the EMPEROR-Reduced trial, using contemporaneous data from the EMPEROR-Preserved trial placebo arm as the external control. Adults with heart failure (HF) aged ≥18 years with ejection fraction >30% to < 55% and N-terminal-pro-brain natriuretic peptide ≥ 600 pg/ml on empagliflozin or placebo were eligible for inclusion. We adjusted for imbalance in the measured baseline covariates between treatment groups using propensity score methods. The outcome of change from baseline in the clinical summary score (CSS) of the Kansas City Cardiomyopathy Questionnaire (KCCQ) and 95% confidence interval (CI) at Week 52 was estimated using inverse probability of treatment weighting (IPTW)-adjusted mixed model for repeated measures. We conducted bias analysis to assess the sensitivity of the findings to an unmeasured confounder.
RESULTS: A total of 526 subjects on empagliflozin and 628 external control subjects were included in the study. After IPTW-adjustment, the change from baseline in the KCCQ-CSS at Week 52 comparing empagliflozin to the ECA was modest and did not meet statistical significance (0.49; 95% CI: -3.49, 4.48). The IPTW-adjusted effect estimate was generally consistent with the EMPEROR-Reduced trial result for the target subset population (0.54; 95% CI: -2.52, 3.59), leading to the same conclusion. Sensitivity analyses supported the robustness of the findings.
CONCLUSIONS: We successfully replicated the evaluation of a PRO endpoint in an ECA study. Challenges and lessons learned will be used to formulate requirements for relevant ECA data sources and propose best practices. Ensuring robust strategies for the collection, quality, validation, and analysis of PRO data in ECA studies is crucial for the interpretation of findings.
Conference/Value in Health Info
2025-05, ISPOR 2025, Montréal, Quebec, CA
Value in Health, Volume 28, Issue S1
Code
PT10
Topic
Methodological & Statistical Research
Topic Subcategory
Confounding, Selection Bias Correction, Causal Inference, PRO & Related Methods
Disease
No Additional Disease & Conditions/Specialized Treatment Areas, SDC: Cardiovascular Disorders (including MI, Stroke, Circulatory)