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Aims: We tested the hypothesis that candesartan improves outcomes in heart failure (HF) with mid-range ejection fraction [HFmrEF; ejection fraction (EF) 40-49%].Methods and Results: In 7598 patients enrolled in the CHARM Programme (HF across the spectrum of EF), we assessed characteristics, outcomes and treatment effect of candesartan according to EF. Patients with HFmrEF (n = 1322, 17%) were similar to those with HF with reduced EF (HFrEF; n = 4323, 57%) with respect to some characteristics, and intermediate between HFrEF and HF with preserved EF (HFpEF; n = 1953, 26%) with respect to others. Over a mean follow-up of 2.9 years, the incidence rates for the primary outcome of cardiovascular death or HF hospitalization were 15.9, 8.5 and 8.9 per 100 patient-years in HFrEF, HFmrEF and HFpEF. In adjusted analyses, the rates of the primary outcome declined with increasing EF up to 50%. For treatment effect, the incidence rates for the primary outcome for candesartan vs. placebo were 14.4 vs. 17.5 per 100 patient-years in HFrEF [hazard ratio (HR) 0.82, 95% confidence interval (CI) 0.75-0.91; P < 0.001], 7.4 vs. 9.7 per 100 patient-years in HFmrEF (HR 0.76, 95% CI 0.61-0.96; P = 0.02), and 8.6 vs. 9.1 per 100 patient-years in HFpEF (HR 0.95, 95% CI 0.79-1.14; P = 0.57). For recurrent HF hospitalization, the incidence rate ratios were 0.68 in HFrEF (95% CI 0.58-0.80; P < 0.001), 0.48 in HFmrEF (95% CI 0.33-0.70; P < 0.001), and 0.78 in HFpEF (95% CI 0.59-1.03; P = 0.08). With EF as a continuous spline variable, candesartan significantly reduced the primary outcome until EF well over 50% and recurrent HF hospitalizations until EF well over 60%.Conclusion: Candesartan improved outcomes in HFmrEF to a similar degree as in HFrEF. ClinicalTrials.gov: CHARM Alternative NCT00634400, CHARM Added NCT00634309, CHARM Preserved NCT00634712. [ABSTRACT FROM AUTHOR]

Aims: In heart failure with preserved ejection fraction (HFpEF), regional heterogeneity of clinical phenotypes is increasingly recognized, with coronary microvascular dysfunction (CMD) potentially being a common shared feature. We sought to determine the regional differences in clinical characteristics and prevalence of CMD in HFpEF., Methods and Results: We analysed clinical characteristics and CMD in 202 patients with stable HFpEF (left ventricular ejection fraction ≥40%) in Finland, Singapore, Sweden, and United States in the multicentre PROMIS-HFpEF study. Patients with unrevascularized macrovascular coronary artery disease were excluded. CMD was assessed using Doppler echocardiography and defined as coronary flow reserve (adenosine-induced vs. resting flow) < 2.5. Patients from Singapore had the lowest body mass index yet highest prevalence of hypertension, dyslipidaemia, and diabetes; patients from Finland and Sweden were oldest, with the most atrial fibrillation, chronic kidney disease, and high smoking rates; and those from United States were youngest and most obese. The prevalence of CMD was 88% in Finland, 80% in Singapore, 77% in Sweden, and 59% in the United States; however, non-significant after adjustment for age, sex, N-terminal pro-brain natriuretic peptide, smoking, left atrial reservoir strain, and atrial fibrillation. Associations between CMD and clinical characteristics did not differ based on region (interaction analysis)., Conclusions: Despite regional differences in clinical characteristics, CMD was present in the majority of patients with HFpEF across different regions of the world with the lowest prevalence in the United States. This difference was explained by differences in patient characteristics. CMD could be a common therapeutic target across regions., (© 2023 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: There are few contemporary data on outcomes, costs, and treatment following a hospitalization for heart failure (hHF) in epidemiologically representative cohorts., Objectives: This study sought to describe rehospitalizations, hospitalization costs, use of guideline-directed medical therapy (GDMT) (renin-angiotensin system inhibitors, sacubitril/valsartan, beta-blockers, mineralocorticoid receptor antagonists, and sodium-glucose cotransporter-2 inhibitors), and mortality after hHF., Methods: EVOLUTION HF (Utilization of Dapagliflozin and Other Guideline Directed Medical Therapies in Heart Failure Patients: A Multinational Observational Study Based on Secondary Data) is an observational, longitudinal cohort study using data from electronic health records or claims data sources in Japan, Sweden, the United Kingdom, and the United States. Adults with a first hHF discharge between 2018 and 2022 were included. The 1-year event rates per 100 patient-years (ERs) for death and rehospitalizations (with a primary diagnosis of heart failure (HF), chronic kidney disease [CKD], myocardial infarction, stroke, or peripheral artery disease) were calculated. Hospital health care costs were cumulatively summarized. Cumulative GDMT use was assessed using Kaplan-Meier estimates., Results: Of 263,525 patients, 28% died within the first year post-hHF (ER: 28.4 [95% CI: 27.0-29.9]). Rehospitalizations were mainly driven by HF (ER: 13.6 [95% CI: 9.8-17.4]) and CKD (ER: 4.5 [95% CI: 3.6-5.3]), whereas the ERs for myocardial infarction, stroke, and peripheral artery disease were lower. Health care costs were predominantly driven by HF and CKD. Between 2020 and 2022, use of renin-angiotensin system inhibitors, sacubitril/valsartan, beta-blockers, and mineralocorticoid receptor antagonists changed little, whereas uptake of sodium-glucose cotransporter-2 inhibitors increased 2- to 7-fold., Conclusions: Incident post-hHF rehospitalization risks and costs were high, and GDMT use changed little in the year following discharge, highlighting the need to consider earlier and greater implementation of GDMT to manage risks and reduce costs., Competing Interests: Funding Support and Author Disclosures EVOLUTION HF is funded by AstraZeneca. Dr Cleland was supported by a British Heart Foundation Centre of Research Excellence (grant number RE/18/6/34217). Dr Bozkurt has received consulting, advisory or research support from Abbott Vascular, Amgen, AstraZeneca, Baxter Healthcare Corporation, Boehringer Ingelheim, Bristol Myers Squibb, Cardurion, Liva Nova, Relypsa, Renovacor, Roche, Sanofi, scPharmaceuticals, and Vifor. Dr Savarese has received grants from AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Merck, Novartis, Pharmacosmos, and Vifor; and personal fees from AstraZeneca, Cytokinetics, Edwards Lifesciences, Medtronic, Novartis, Pharmacosmos, Roche, Laboratoires Servier, and Vifor. Drs Adamsson Eryd, Bodegård, Khordoc, and Zhang are employees of AstraZeneca. Dr Cleland has received grants and/or personal fees from Abbott Laboratories, Amgen, AstraZeneca, Bayer, Biopeutics, Boehringer Ingelheim, Bristol Myer Squibb, Idorsia, Johnson & Johnson, Medtronic, MyoKardia, NI Medical, Novartis, Pharmacosmos, Pharma Nord, Respicardia, Laboratoires Servier, Torrent Pharmaceuticals, Vifor, and VisCardia. Dr Thuresson is an employee of Statisticon, which has received funding from AstraZeneca. Dr Vardeny has received personal or institutional research support from AstraZeneca. Dr Lund has received grant support, lecture fees, and/or consulting fees from Abbott Laboratories, Alleviant, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Edwards Lifesciences, Lexicon Pharmaceuticals, Medscape, Merck Sharp & Dohme, MyoKardia, Novartis, OrionPharma, Pharmacosmos, Sanofi, and Vifor. Dr Kishi has reported that he has no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Guidelines recommend early initiation of multiple guideline-directed medical therapies (GDMTs) to reduce mortality/rehospitalization in patients with heart failure and reduced ejection fraction. Understanding GDMT use is critical to improving clinical practice., Objectives: This study sought to describe GDMT use in Japan, Sweden, and the United States in contemporary real-world settings., Methods: EVOLUTION HF (Utilization of Dapagliflozin and Other Guideline Directed Medical Therapies in Heart Failure Patients: A Multinational Observational Study Based on Secondary Data) is an observational cohort study using routine-care databases. Patients initiating any GDMT within 12 months of a hospitalization for heart failure (hHF) discharge were included. Dapagliflozin (the only sodium-glucose cotransporter-2 inhibitor approved at study onset), sacubitril/valsartan, angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), beta-blockers, and mineralocorticoid receptor antagonists (MRAs) were considered separately. Doses and discontinuation were assessed in the 12 months following initiation. Target dose was defined as ≥100% of the guideline-recommended dose., Results: Overall, 266,589 patients were included. Mean times from hHF to GDMT initiation were longer for novel GDMTs (dapagliflozin or sacubitril/valsartan) than for other GDMTs: 39 and 44 vs 12 to 13 days (Japan), 44 and 33 vs 22 to 31 days (Sweden), and 33 and 19 vs 18 to 24 days (United States). Pooled across countries, proportions of patients who discontinued therapy (not including switches from ACE inhibitor or ARB to sacubitril/valsartan) within 12 months were 23.5% (dapagliflozin), 26.4% (sacubitril/valsartan), 38.4% (ACE inhibitors), 33.4% (ARBs), 25.2% (beta-blockers), and 42.2% (MRAs). Corresponding target dose achievements were 75.7%, 28.2%, 20.1%, 6.7%, 7.2%, and 5.1%, respectively., Conclusions: Initiation of novel GDMTs is delayed compared with other GDMTs. Few patients received target doses of GDMTs requiring uptitration. Persistence was higher for dapagliflozin than other GDMTs., Competing Interests: Funding Support and Author Disclosures EVOLUTION HF is funded by AstraZeneca. Dr Savarese has received grants from AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Merck, Novartis, Pharmacosmos, and Vifor; and personal fees from AstraZeneca, Cytokinetics, Medtronic, Pharmacosmos, Roche, Servier, and Vifor. Dr Vardeny has received personal or institutional research support from AstraZeneca. Drs Adamsson Eryd and Bodegård are employees of AstraZeneca. Dr Lund has received grant support, lecture fees, and consulting fees from AstraZeneca. Dr Thuresson is an employee of Statisticon, which has received funding from AstraZeneca. Dr Bozkurt has received consulting fees from Amgen, AstraZeneca, Bristol Myers Squibb, scPharmaceuticals, Baxter, Sanofi, Relypsa, Vifor, Roche, and Boehringer Ingelheim; has served on the steering committees of Relypsa and Renovacor; has served on a Clinical Event Committee for Abbott Pharmaceuticals; and has served on the Data Safety Monitoring Board for LivaNova Pharmaceuticals. Dr Kishi has reported that he has no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Aims: To assess the proportion of patients with heart failure and reduced ejection fraction (HFrEF) who are eligible for sacubitril/valsartan (LCZ696) based on the European Medicines Agency/Food and Drug Administration (EMA/FDA) label, the PARADIGM-HF trial and the 2016 ESC guidelines, and the association between eligibility and outcomes., Methods and Results: Outpatients with HFrEF in the ESC-EORP-HFA Long-Term Heart Failure (HF-LT) Registry between March 2011 and November 2013 were considered. Criteria for LCZ696 based on EMA/FDA label, PARADIGM-HF and ESC guidelines were applied. Of 5443 patients, 2197 and 2373 had complete information for trial and guideline eligibility assessment, and 84%, 12% and 12% met EMA/FDA label, PARADIGM-HF and guideline criteria, respectively. Absent PARADIGM-HF criteria were low natriuretic peptides (21%), hyperkalemia (4%), hypotension (7%) and sub-optimal pharmacotherapy (74%); absent Guidelines criteria were LVEF>35% (23%), insufficient NP levels (30%) and sub-optimal pharmacotherapy (82%); absent label criteria were absence of symptoms (New York Heart Association class I). When a daily requirement of ACEi/ARB ≥ 10 mg enalapril (instead of ≥ 20 mg) was used, eligibility rose from 12% to 28% based on both PARADIGM-HF and guidelines. One-year heart failure hospitalization was higher (12% and 17% vs. 12%) and all-cause mortality lower (5.3% and 6.5% vs. 7.7%) in registry eligible patients compared to the enalapril arm of PARADIGM-HF., Conclusions: Among outpatients with HFrEF in the ESC-EORP-HFA HF-LT Registry, 84% met label criteria, while only 12% and 28% met PARADIGM-HF and guideline criteria for LCZ696 if requiring ≥ 20 mg and ≥ 10 mg enalapril, respectively. Registry patients eligible for LCZ696 had greater heart failure hospitalization but lower mortality rates than the PARADIGM-HF enalapril group., (© 2019 The Authors. European Journal of Heart Failure © 2019 European Society of Cardiology.)

Background: Limited data exist describing impact of body mass index (BMI) on post‒left ventricular assist device (post-LVAD) outcomes. We sought to define the relationship between body mass index (BMI) and adverse events (AEs) after LVAD implantation by examining the ISHLT Mechanically Assisted Circulatory Support (IMACS) registry., Methods: Patients implanted with a contemporary continuous flow (CF)-LVAD were stratified into 4 groups using pre-operative BMI: underweight (UW; BMI ≤18.5 kg/m 2 ); non-obese (NO; BMI >18.5 to <30 kg/m 2 ); obese (OB; BMI ≥30 to <40 kg/m 2 ); and morbidly obese (MO; BMI ≥40 kg/m 2 ). Freedom from AEs was evaluated using the Kaplan-Meier method and risk factors for development of first AE were identified using multiphase parametric hazard modeling. AEs included infection, thromboembolic events, bleeding, device malfunction, and neurologic dysfunction., Results: Between 2013 and 2015, a total of 9,408 patients underwent implantation of a CF-LVAD, which consisted of 368 (4%) UW, 5,719 (61%) NO, 2,770 (29%) OB, and 444 (5%) MO patients. Survival among the 4 BMI cohorts was similar at 2years (70.8% to 75.8%, p = 0.24). MO patients were less likely to be free from a non‒VAD-related infection (p < 0.0001) or device-related infection (p = 0.0014) at 2years (50.3%, 70.7%) when compared with OB (58.3%, 78.7%), NO (65.2%, 81.4%), and UW (68.9%, 77.4%) patients. UW (81.5%) and NO (81.3%) patients were more likely to be free from device malfunction at 2years when compared with OB (78.3%) and MO (72.6%) (p = 0.0006). Thromboembolic events were rare and more common in the UW cohort (p = 0.026)., Conclusions: Although BMI was not correlated with 2-year mortality, an increased rate of infectious and device-related AEs was noted in OB and MO LVAD patients. In a group with few options for transplant, the event morbidity in obese patients can be expected to impact morbidity with longer support durations., (Copyright © 2018 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

The Heart Failure Survival Score (HFSS) and peak exercise oxygen consumption (VO2) predict survival in ambulatory patients with heart failure and are used for selection for cardiac transplantation. However, the populations tested have predominately been men. To investigate if peak VO2 and the HFSS predict prognosis in women, we derived HFSS and measured peak VO2 in 274 women referred for cardiac transplantation and in 278 men matched by referral year. Seven HFSS parameters were obtained, including presence of coronary artery disease, left ventricular ejection fraction, heart rate, mean arterial blood pressure, peak VO2, presence of intraventricular conduction defects, and serum sodium. Subjects were divided into high-, medium-, and low-risk strata for HFSS and VO2 based on previous cutpoints. Survival curves were derived using Kaplan-Meier analysis and compared by log-rank analysis. Follow-up averaged 929 days. For women, 1-year event-free survival in the low- (>14), medium- (10.1 to 14), and high-risk (<10 ml/kg/min) VO2 strata was 93%, 84%, and 80%, respectively. For the HFSS, 1-year event-free survival in the low- (>or=8.10), medium- (7.20 to 8.09), and high-risk (

Women who experience heart failure (HF) exhibit distinct differences from men. Because women are a minority in major HF trials and because diagnostic criteria have been variable in epidemiologic surveys, many questions remain unanswered. This article describes differences in sex hormone effects and responses to injury, pressure overload, and aging, which may account for differences observed in epidemiology, risk factors and causes, mechanisms for disease development, response to treatment, and outcomes. Hypertension,diastolic dysfunction, diabetes, obesity, and inactivity are more important factors in women, whereas ischemic heart disease and systolic dysfunction are more important factors in men. Women appear to benefit less from established treatments but have better survival. Future studies directed exclusively at women may be warranted to confirm or establish benefits of existing and future treatments.