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. 2023 Jun;25(6):912-921.
doi: 10.1002/ejhf.2868. Epub 2023 May 18.

Sex differences in the generalizability of randomized clinical trials in heart failure with reduced ejection fraction

Megan Schroeder  1   2 , Yvonne Mei Fong Lim  3   4 , Gianluigi Savarese  2 , Kiliana Suzart-Woischnik  5 , Claire Baudier  6 , Tomasz Dyszynski  5 , Ilonca Vaartjes  3 , Marinus J C Eijkemans  3 , Alicia Uijl  2   7 , Ronald Herrera  5 , Eleni Vradi  8 , Jasper J Brugts  7 , Hans-Peter Brunner-La Rocca  9 , Vanessa Blanc-Guillemaud  9 , Sandra Waechter  10 , Fabrice Couvelard  9 , Benoit Tyl  9 , Samuel Fatoba  5 , Arno W Hoes  3 , Lars H Lund  2 , Christoph Gerlinger  11   12 , Folkert W Asselbergs  7   13 , Diederick E Grobbee  3   14 , Maureen Cronin  15 , Stefan Koudstaal  16
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Free article

Sex differences in the generalizability of randomized clinical trials in heart failure with reduced ejection fraction

Megan Schroeder et al. Eur J Heart Fail. 2023 Jun.
Free article

Abstract

Aims: In order to understand how sex differences impact the generalizability of randomized clinical trials (RCTs) in patients with heart failure (HF) and reduced ejection fraction (HFrEF), we sought to compare clinical characteristics and clinical outcomes between RCTs and HF observational registries stratified by sex.

Methods and results: Data from two HF registries and five HFrEF RCTs were used to create three subpopulations: one RCT population (n = 16 917; 21.7% females), registry patients eligible for RCT inclusion (n = 26 104; 31.8% females), and registry patients ineligible for RCT inclusion (n = 20 810; 30.2% females). Clinical endpoints included all-cause mortality, cardiovascular mortality, and first HF hospitalization at 1 year. Males and females were equally eligible for trial enrolment (56.9% of females and 55.1% of males in the registries). One-year mortality rates were 5.6%, 14.0%, and 28.6% for females and 6.9%, 10.7%, and 24.6% for males in the RCT, RCT-eligible, and RCT-ineligible groups, respectively. After adjusting for 11 HF prognostic variables, RCT females showed higher survival compared to RCT-eligible females (standardized mortality ratio [SMR] 0.72; 95% confidence interval [CI] 0.62-0.83), while RCT males showed higher adjusted mortality rates compared to RCT-eligible males (SMR 1.16; 95% CI 1.09-1.24). Similar results were also found for cardiovascular mortality (SMR 0.89; 95% CI 0.76-1.03 for females, SMR 1.43; 95% CI 1.33-1.53 for males).

Conclusion: Generalizability of HFrEF RCTs differed substantially between the sexes, with females having lower trial participation and female trial participants having lower mortality rates compared to similar females in the registries, while males had higher than expected cardiovascular mortality rates in RCTs compared to similar males in registries.

Keywords: Enrichment strategies; Females; Heart failure; Randomized clinical trial; Real-world evidence; Standardized mortality ratios.

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References

    1. Vogel B, Acevedo M, Appelman Y, Bairey Merz CN, Chieffo A, Figtree GA, et al. The Lancet women and cardiovascular disease Commission: reducing the global burden by 2030. Lancet. 2021;397:2385-438.
    1. Lam CSP, Arnott C, Beale AL, Chandramouli C, Hilfiker-Kleiner D, Kaye DM, et al. Sex differences in heart failure. Eur Heart J. 2019;40:3859-3868c.
    1. Beale AL, Meyer P, Marwick TH, Lam CSP, Kaye DM. Sex differences in cardiovascular pathophysiology: why women are overrepresented in heart failure with preserved ejection fraction. Circulation. 2018;138:198-205.
    1. Lainščak M, Milinković I, Polovina M, Crespo-Leiro MG, Lund LH, Anker SD, et al. Sex- and age-related differences in the management and outcomes of chronic heart failure: an analysis of patients from the ESC HFA EORP Heart Failure Long-Term Registry. Eur J Heart Fail. 2020;22:92-102.
    1. Lawson CA, Zaccardi F, Squire I, Ling S, Davies MJ, Lam CSP, et al. 20-year trends in cause-specific heart failure outcomes by sex, socioeconomic status, and place of diagnosis: a population-based study. Lancet Public Health. 2019;4:e406-20.

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