Importance of phenotypes and sex for heart failure therapy implementation and outcomes

Background Given that heart failure (HF) is a disease with a major negative impact on both quality of life (QoL) and prognosis, early and accurate diagnosis and the use of effective treatments are crucial. Affecting 2-3% of Europe's population and about 60 million people worldwide, HF represents an important challenge not only for individuals but also for society, as recurrent hospitalizations are costly. There is a long-standing need for better implementation of guideline-directed medical therapy (GDMT) for HF with reduced ejection fraction (HFrEF), as well as further knowledge-building regarding the treatment of all HF phenotypes, including HF with mildly reduced EF (HFmrEF) and HF with preserved EF (HFpEF). Methods and results Study I: In patients with stable HFpEF, we evaluated the prognostic impact of Framingham criteria for heart failure (FC-HF) by assessing 438 ambulatory HFpEF patients at 4-8 weeks after an acute HF episode in the prospective KaRen study. We examined associations between four descriptive models of HFpEF and the composite endpoint of all-cause mortality and HF hospitalization within 18 months. The models consisted of FC-HF alone, FC-HF + natriuretic peptides (NPs), and FC-HF + NPs + echocardiographic criteria from the European Society of Cardiology (ESC) guidelines or the PARAGON trial respectively. Of 399 patients with FC data, 27% met the FC-HF mandatory in all models, and residual FC-HF in stable state was associated with increased risk of the endpoint in unadjusted analysis, strengthened by the addition of NPs and echo-parameters. No model independently predicted the endpoint but not having FC-HF at stable state follow up was associated with better prognosis. Study II: HF management in Sweden remains suboptimal despite evidence-based guidelines. To address this, a comprehensive HF program was formed and implemented 2012-2017 in the Stockholm County by a standardized care pathway centralized at five hospital-based HF clinics. Data from 2012-2017 included referrals and visits, HF hospitalizations per million inhabitants, dispensed medications post-admission, and adjusted 1-year all-cause mortality or HF readmission. Annual HF clinic visits increased 3.4-fold (3,372 to 11,527). Prescriptions of HF drugs rose significantly, especially among readmitted patients. Hospital admissions for HF decreased by 16% in total, by 13% among new-onset HF patients, and by 20% when previously known HF (p < 0.0001). Combined 1-year mortality or HF readmission was 48% (17,124/35,880) and improved annually (HR 0.98 [0.97-0.99], p < 0.001). Study III: In the prospective single-centre CABG (coronary artery bypass graft) PREFERS (preserved and reduced ejection fraction epidemiological regional study) we performed a thorough multimodal evaluation of elective CABG patients before and one year after surgery and collected long-term outcome data. By this a platform for further studies on the different HF phenotypes, several on cellular levels with material from heart muscle biopsies, was formed. 136 patients were classified by LV function into preserved EF (pEF), reduced EF (rEF), or normal, using echocardiography and NT-proBNP. At baseline, 45% had LV dysfunction (25% pEF, 20% rEF). At 1-year, pEF and rEF showed some improvement, while the normal group exhibited small but significant worsening diastolic function (E/é), NT-proBNP, and eGFR with unclear clinical significance. During a median 2.9-year follow-up, 5.8% died and 5.8% were hospitalized for HF. Study IV: Trends in GDMT use and outcomes after HF hospitalisation in Stockholm County were assessed with respect to sex and age during and after a HF care management program (study II) was launched. In 2012-2021 a total 57330 patient-years of follow up showed increased implementation of GDMT across all age groups and irrespective of sex. HF hospitalisations or all-cause death declined by in total 34% in women and 29% in men. Conclusions Underdiagnosing and undertreatment remain major challenges in the care for HF patients, despite existing evidence-based treatment options. A comprehensive HF care management project which aimed at improving both early detection of HF and adherence to recommended treatment, was associated with increased implementation of GDMT and a decrease in rehospitalisations and all-cause mortality. Importantly the increased adherence to GDMT was seen across age groups and regardless of sex, emphasizing the importance of equity in health care with an individually tailored approach. In individualizing HF care, prognostic tools for planning of interventions and follow-up are valuable. In a cohort of ambulatory HFpEF patients with a resent HF event, the prevalence of residual FC-HF tended to be associated with worse outcomes of HF rehospitalisation and mortality. Adding echocardiographic and biomarker criteria further strengthened this association, highlighting the possible role in clinical risk assessment. In our study of elective CABG patients with or without previous HF diagnosis LV dysfunction was common preoperatively and small deteriorations regarding diastolic function were found among those with normal LV function before CABG. Although probably not clinically significant they raise questions concerning long-term effects of cardiac surgery and how to best individualize follow up. List of scientific papers I. Prognostic impact of Framingham heart failure criteria in heart failure with preserved ejection fraction. Ulrika Löfström, Camilla Hage, Gianluigi Savarese, Erwan Donal, Jean-Claude Daubert4, Lars H. Lund and Cecilia Linde. ESC Heart Failure, 2019; 6: 830-839. https://doi.org/10.1002/ehf2.12458 II. Reorganization of heart failure management and improved outcome - the 4D HF Project. Matan D, Löfstrom U, Corovic Cabrera C, Eriksson B, Ekström M, Hage C, Ljunggren G, Lyngå P, Wallén H, Knudsen Malmqvist K, Linde C, Persson H. Scand Cardiovasc J. 2021 Feb;55(1):1-8. https://doi.org/10.1080/14017431.2020.1820075 III. Baseline characteristics and 1-year outcome by left ventricular function in the CABG PREFERS. Löfström U, Linde C, Eriksson MJ, Maret E, Corbascio M, Ekström M, Lyngå P, Wallén H, Persson B, Persson H, Hage C. Eur Heart J Open. 2025 Mar 5;5(2): oeaf014. https://doi.org/10.1093/ehjopen/oeaf014 IV. Temporal evaluation of heart failure treatment and outcome with regard to sex and age. Löfström U, Ljunggren G, Hage C, Persson H, Linde C. [Manuscript]