TY - JOUR
T1 - Sex differences in the generalizability of randomized clinical trials in heart failure with reduced ejection fraction
AU - Schroeder, Megan
AU - Lim, Yvonne Mei Fong
AU - Savarese, Gianluigi
AU - Suzart-Woischnik, Kiliana
AU - Baudier, Claire
AU - Dyszynski, Tomasz
AU - Vaartjes, Ilonca
AU - Eijkemans, Marinus J. C.
AU - Uijl, Alicia
AU - Herrera, Ronald
AU - Vradi, Eleni
AU - Brugts, Jasper J.
AU - Brunner-la Rocca, Hans-Peter
AU - Blanc-Guillemaud, Vanessa
AU - Waechter, Sandra
AU - Couvelard, Fabrice
AU - Tyl, Benoit
AU - Fatoba, Samuel
AU - Hoes, Arno W.
AU - Lund, Lars H.
AU - Gerlinger, Christoph
AU - Asselbergs, Folkert W.
AU - Grobbee, Diederick E.
AU - Cronin, Maureen
AU - Koudstaal, Stefan
N1 - Funding Information: This study is part of the BigData@Heart project and is funded by the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement number 116074. This Joint Undertaking receives support from the European Union's Horizon 2020 research and innovation programme and the European Federation of Pharmaceutical Industries and Associations. The funders had no role in the design, analysis, interpretation of data or writing of the manuscript. Publisher Copyright: © 2023 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.
PY - 2023/6
Y1 - 2023/6
N2 - 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.
AB - 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.
KW - Enrichment strategies
KW - Females
KW - Heart failure
KW - Randomized clinical trial
KW - Real-world evidence
KW - Standardized mortality ratios
UR - http://www.scopus.com/inward/record.url?scp=85159653557&partnerID=8YFLogxK
U2 - https://doi.org/10.1002/ejhf.2868
DO - https://doi.org/10.1002/ejhf.2868
M3 - Article
C2 - 37101398
SN - 1388-9842
VL - 25
SP - 912
EP - 921
JO - European journal of heart failure
JF - European journal of heart failure
IS - 6
ER -