¹Institute for Biostatistics, Hannover Medical School, Hannover, Germany

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Introduction: In an adequately designed randomised controlled trial for confirming the efficacy of a new drug in patients with chronic heart failure (CHF), mortality (all-cause or cardiovascular) should usually be the primary endpoint – either alone or as a part of a composite endpoint with outcomes related to worsening heart failure (WHF) [1]. Clinical symptoms or functional capacity are only acceptable as primary endpoint in specific scenarios. With more than one primary endpoint, a multiplicity adjustment strategy is required to control the study-wise type-1-error (T1E). In specific cases where two primary endpoints are defined, different multiplicity adjustment strategies can be applied from a statistical perspective. Traditionally, they were considered co-primary, i.e. the null hypotheses for both have to be rejected to conclude study success. Recently, the so-called dual primary endpoint concept has been proposed and applied in CHF trials. We aim to clarify differences between the two multiplicity concepts, and illustrate implications for the interpretation of trial success.

Methods: With co-primary endpoints, no adjustment of the significance level for testing each null hypothesis is needed, but the sample size usually needs to be increased to maintain the pre-defined power of the study. In contrast, with the dual primary endpoint concept, an (uneven) Bonferroni split of the T1E between the primary endpoints is foreseen. While the T1E is formally controlled, study success can be concluded as soon as the null hypothesis for one of the primary endpoints is rejected even if there is no benefit or a small detriment in the other primary outcome. This is obviously not in line with clinical interpretation of the overall trial outcome and regulatory decision-making [2]. The recently published SUMMIT trial defined dual primary endpoints as a composite of cardiovascular death or a WHF event and the change from baseline to 52 weeks in the Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS) [3]. Consequently, one could claim study success based on a benefit in KCCQ-CSS alone despite a (small) detriment in the composite primary endpoint, which is not in line with both the CHF and the multiplicity EMA guideline [1], [4]. To resolve this conflict, we propose to define them as co-primary by requiring superiority for KCCQ-CSS and non-inferiority with a pre-specified margin for the composite primary endpoint.

Results: The proposed co-primary endpoint concept of combining superiority and non-inferiority for respective primary endpoints can be implemented in two different ways: 1) Two-step procedure, where non-inferiority for both has to be shown first before demonstrating superiority for at least one or 2) Showing non-inferiority for one and superiority for the other (or vice versa) [2]. Both approaches allow flexible modelling of the minimum requirements for both primary endpoints by carefully choosing the respective non-inferiority and superiority limit.

Conclusion: The proposed approach only leads to a small increase in sample size but it solves the interpretability problem of dual primary endpoints by aligning the statistical conclusion with clinical interpretation of study success and regulatory decision-making.

The authors declare that they have no competing interests.

The authors declare that an ethics committee vote is not required.

Literatur

[1] European Medicines Agency Committee for Medicinal Products for Human Use. Guideline on clinical investigation of medicinal products for the treatment of chronic heart failure. 2017. Available from: https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-clinical-investigation-medicinal-products-treatment-chronic-heart-failure-revision-2_en.pdf
[2] Großhennig A, Thomas NH, Brannath W, Koch A. How to avoid concerns with the interpretation of two primary endpoints if significant superiority in one is sufficient for formal proof of efficacy. Pharmaceutical Statistics. 2023;22(5):836-845. DOI: 10.1002/pst.2314
[3] Packer M, Zile MR, Kramer CM, Baum SJ, Litwin SE, Menon V, et al. Tirzepatide for Heart Failure with Preserved Ejection Fraction and Obesity. The New England journal of medicine. 2025;392(5):427-437. DOI: 10.1056/NEJMoa2410027
[4] European Medicines Agency, Committee for proprietary medicinal products. Points to consider on multiplicity issues in clinical trials. 2002. Available from: https://www.ema.europa.eu/en/documents/scientific-guideline/points-consider-multiplicity-issues-clinical-trials_en.pdf