Sex-Related Differences in Long-term Outcomes across the Spectrum of Ejection Fraction in Heart Failure Patients

Background Recently, patients with supra-normal left ventricular ejection fraction (snLVEF) are reported to have high risk of adverse outcomes, especially in women. We sought to evaluate sex-related differences in the association between LVEF and long-term outcomes in heart failure (HF) patients. Methods The multicenter WET-HF Registry enrolled all patients hospitalized for acute decompensated HF (ADHF). We analyzed 3,943 patients (age 77 years; 59.8% male) registered from 2006 to 2017. According to LVEF the patients were divided into the 3 groups: HF with reduced EF (HFrEF), mildly reduced EF (HFmrEF) and preserved EF (HFpEF). The primary endpoint was defined as the composite of cardiac death and ADHF rehospitalization after discharge. Results Implementation of guideline-directed medical therapy (GDMT) such as renin-angiotensin-system inhibitor (RASi), β-blocker and their combination at discharge was significantly lower in women than men in HFmrEF. Lower prescription of RASi + β-blocker combination in female HFmrEF was noted even after adjustment for covariates (p=0.007). There were no such sex-related differences in HFrEF. Female sex was associated with higher incidence of the primary endpoint and ADHF rehospitalization after adjustment for covariates exclusively in HFmrEF. Restricted cubic spline analysis demonstrated a U-shaped relationship between LVEF and the hazard ratio of the primary endpoint in women, but such relationship was not observed in men ( p for interaction=0.037). Conclusions In women, not only lower LVEF but also snLVEF were associated with worse long-term outcomes. Additionally, sex-related differences in the GDMT implementation for HFmrEF highlight the need for sex-specific guidelines to optimize HF management. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement Grant-in-Aid for Young Scientists [Japan Society for the Promotion of Science KAKENHI, #18K15860 (Y.S.), #23K15168 (Y.S.)], a Grant-in-Aid for Scientific Research © [#23591062 (T.Y.), #26461088 (T.Y.), #16K09469 (Y.N.), #16H05215 (S.K.), #17K09526 (T.K.), #18K08056 (T.Y.), #20K08408 (T.K.), #20H03915 (S.K.)], a Health Labour Sciences Research Grant [#14528506 (S.K.)], the Sakakibara Clinical Research Grant for the Promotion of Sciences [T.Y. 2012-2020], the Japan Agency for Medical Research and Development [201439013C (S.K.)], and the Grant-in-Aid for Clinical Research from the Japanese Circulation Society [Y.S. 2019]. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The institutional review boards of Keio University Hospital (20090176), Kyorin University (605), Saitama Medical University (15-071), Sakakibara Heart Institute (11-021), St. Luke?s International Hospital (17-R074), Saiseikai Central Hospital (28-55), and National Hospital Organization Tokyo Medical Center (R20-172) I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes WET-HF registry * BMI : body mass index GDMT : guideline-directed medical therapy HF : heart failure HFrEF : heart failure with reduced ejection fraction HFmrEF : heart failure with mildly reduced ejection fraction HFpEF : heart failure with preserved ejection fraction MRA : mineralocorticoid receptor antagonists RASi : renin-angiotensin-system inhibitors snLVEF : supra-normal left ventricular ejection fraction VHD : valvular heart disease WET-HF Registry : West Tokyo Heart Failure Registry