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Aims Methods Conclusion Benefits of mineralocorticoid receptor antagonists (MRAs) in heart failure with preserved and mildly reduced ejection fraction (HFpEF/HFmrEF) have not been established. Conventional randomized controlled trials are complex and expensive. The Spironolactone Initiation Registry Randomized Interventional Trial in Heart Failure with Preserved Ejection Fraction (SPIRRIT‐HFpEF) is a unique pragmatic registry‐based randomized controlled trial.SPIRRIT‐HFpEF is a multicentre, prospective, randomized, open‐label, blinded endpoint trial conducted on platforms in the Swedish Heart Failure Registry (SwedeHF) and the United States (US) Trial Innovation Network. Patients with HFpEF/HFmrEF are randomized 1:1 to spironolactone (or eplerenone) in addition to usual care, versus usual care alone. The primary outcome is total number of cardiovascular deaths and hospitalizations for heart failure. Outcomes are collected from Swedish administrative complete coverage registries and a US call centre and subsequently adjudicated. Simple eligibility criteria were based on data available in SwedeHF: heart failure as outpatient or at discharge from hospital, left ventricular ejection fraction ≥40%, N‐terminal pro‐B‐type natriuretic peptide >300 ng/L (in sinus rhythm) or >750 ng/L (in atrial fibrillation), with pre‐specified adjustment for elevated body mass index, and chronic loop diuretic use. Power and sample size assessments were based on an event‐driven design allowing enrolment over approximately 6 years, and application of hazard ratios from the TOPCAT trial, Americas subset. The final sample size is expected to be approximately 2400 patients.SPIRRIT‐HFpEF will be informative on the effectiveness of generic MRAs in HFpEF and HFmrEF, and on the feasibility of conducting pragmatic and registry‐based trials in heart failure and other chronic conditions. [ABSTRACT FROM AUTHOR]

Aims Methods and results Conclusion We analysed baseline characteristics and guideline‐directed medical therapy (GDMT) use and decisions in the European Society of Cardiology (ESC) Heart Failure (HF) III Registry.Between 1 November 2018 and 31 December 2020, 10 162 patients with acute HF (AHF, 39%, age 70 [62–79], 36% women) or outpatient visit for HF (61%, age 66 [58–75], 33% women), with HF with reduced (HFrEF, 57%), mildly reduced (HFmrEF, 17%) or preserved (HFpEF, 26%) ejection fraction were enrolled from 220 centres in 41 European or ESC‐affiliated countries. With AHF, 97% were hospitalized, 2.2% received intravenous treatment in the emergency department, and 0.9% received intravenous treatment in an outpatient clinic. AHF was seen by most by a general cardiologist (51%) and outpatient HF most by a HF specialist (48%). A majority had been hospitalized for HF before, but 26% of AHF and 6.1% of outpatient HF had de novo HF. Baseline use, initiation and discontinuation of GDMT varied according to AHF versus outpatient HF, de novo versus pre‐existing HF, and by ejection fraction. After the AHF event or outpatient HF visit, use of any renin–angiotensin system inhibitor, angiotensin receptor–neprilysin inhibitor, beta‐blocker, mineralocorticoid receptor antagonist and loop diuretics was 89%, 29%, 92%, 78%, and 85% in HFrEF; 89%, 9.7%, 90%, 64%, and 81% in HFmrEF; and 77%, 3.1%, 80%, 48%, and 80% in HFpEF.Use and initiation of GDMT was high in cardiology centres in Europe, compared to previous reports from cohorts and registries including more primary care and general medicine and regions more local or outside of Europe and ESC‐affiliated countries. [ABSTRACT FROM AUTHOR]

Aims: Several mechanisms have been identified in the aetiopathogenesis of heart failure with preserved ejection fraction (HFpEF). Among these, coronary microvascular dysfunction (CMD) may play a key pathophysiological role. We performed a systematic review and meta‐analysis to investigate the prevalence, echocardiographic correlates, and prognostic implications of CMD in patients with HFpEF. Methods and results: A systematic search for articles up to 1 May 2023 was performed. The primary aim was to assess the prevalence of CMD. Secondary aims were to compare key echocardiographic parameters (E/e′ ratio, left atrial volume index [LAVi], and left ventricular mass index [LVMi]), clinical outcomes [death and hospitalization for heart failure (HF)], and prevalence of atrial fibrillation (AF) between patients with and without CMD. Meta‐regressions according to baseline patient characteristics and study features were performed to explore potential heterogeneity sources. We identified 14 observational studies, enrolling 1138 patients with HFpEF. The overall prevalence of CMD was 58%. Compared with patients without CMD, patients with HFpEF and CMD had larger LAVi [mean difference (MD) 3.85 confidence interval (CI) 1.19–6.5, P < 0.01)], higher E/e′ ratio (MD 2.76 CI 1.54–3.97; P < 0.01), higher prevalence of AF (odds ratio 1.61 CI 1.04–2.48, P = 0.03) and higher risk of death or hospitalization for HF [hazard ratio 3.19, CI 1.04–9.57, P = 0.04]. Conclusions: CMD is present in little more than half of the patients with HFpEF and is associated with echocardiographic evidence of more severe diastolic dysfunction and a higher prevalence of AF, doubling the risk of death or HF hospitalization. [ABSTRACT FROM AUTHOR]

Aims: Many patients with heart failure (HF) have chronic kidney disease (CKD) and may not tolerate mineralocorticoid receptor antagonists. We investigated the efficacy and safety of the novel mineralocorticoid receptor modulator balcinrenone in combination with dapagliflozin in a phase 2b study. Methods and results: From January 2021 to October 2023, we randomized 133 adults with symptomatic HF, ejection fraction <60%, estimated glomerular filtration rate (eGFR) ≥30 to ≤60 ml/min/1.73 m2 and urinary albumin‐to‐creatinine ratio (UACR) ≥30 to <3000 mg/g, to receive balcinrenone 15, 50 or 150 mg/day plus dapagliflozin 10 mg/day, or dapagliflozin 10 mg/day plus placebo, for 12 weeks. Enrolment was stopped early because of slow recruitment. Relative reductions in UACR from baseline to week 12 (primary endpoint) were not significantly different between the balcinrenone plus dapagliflozin groups versus dapagliflozin plus placebo. There was no clear balcinrenone dose–response relationship. There were possible dose‐dependent increases in serum potassium levels, reduced eGFR in the highest dose group, and non‐significant trends towards reduced N‐terminal pro‐B‐type natriuretic peptide levels. Hyperkalaemia adverse events led to discontinuation in two participants receiving balcinrenone plus dapagliflozin and none in those receiving dapagliflozin plus placebo. Conclusion: While the smaller than planned sample size limits interpretation, we did not see significant reduction in UACR in patients treated with balcinrenone plus dapagliflozin compared with dapagliflozin plus placebo. [ABSTRACT FROM AUTHOR]

Guideline‐directed medical therapy (GDMT) in patients with heart failure and reduced ejection fraction (HFrEF) reduces morbidity and mortality, but its implementation is often poor in daily clinical practice. Barriers to implementation include clinical and organizational factors that might contribute to clinical inertia, i.e. avoidance/delay of recommended treatment initiation/optimization. The spectrum of strategies that might be applied to foster GDMT implementation is wide, and involves the organizational set‐up of heart failure care pathways, tailored drug initiation/optimization strategies increasing the chance of successful implementation, digital tools/telehealth interventions, educational activities and strategies targeting patient/physician awareness, and use of quality registries. This scientific statement by the Heart Failure Association of the ESC provides an overview of the current state of GDMT implementation in HFrEF, clinical and organizational barriers to implementation, and aims at suggesting a comprehensive framework on how to overcome clinical inertia and ultimately improve implementation of GDMT in HFrEF based on up‐to‐date evidence. [ABSTRACT FROM AUTHOR]

Aims: We assessed eligibility for omecamtiv mecarbil (OM) in a real-world cohort with heart failure with reduced ejection fraction (HFrEF) according to the selection criteria of the GALACTIC-HF trial (trial scenario) and selected trial´s criteria more likely to impact real-world use (pragmatic scenario). Methods and results: We included 31,015 patients with HFrEF lasting ≥3 months and registered in the Swedish HF registry between 2000–2021. Trial eligibility was calculated by applying all the GALACTIC-HF selection criteria. The pragmatic scenario considered only the New York Heart Association class, history of worsening HF, N-terminal pro-B-type natriuretic peptides (NT-proBNP), blood pressure and renal failure criteria defined as in the trial. Eligibility for OM in chronic HFrEF was 21% and 36% in the trial and pragmatic scenarios, respectively. Eligibility was higher in those with EF<30% (trial: 27%, pragmatic: 44%), in-patients (trial:30%, pragmatic:57%), severe HF (trial: 35%, pragmatic: 60%), NYHA class III-IV (trial: 26%, pragmatic: 45%), and NT-proBNP≥5,000pg/mL (trial: 30%, pragmatic: 51%). The criteria that most limited eligibility were history of a recent worsening HF event (60% eligible in chronic HFrEF), elevated NT-proBNP (82% eligible), and deviating blood pressure (82% eligible). Overall, eligible patients were characterized by more severe HF and higher CV event-rates in both scenarios, and higher comorbidity burden in the pragmatic scenario. Conclusion: Approximately 21% of real-world chronic HFrEF patients would be eligible for OM according to the GALACTIC-HF selection criteria, and 36% according to the criteria more likely to affect OM use in clinical practice. Criteria in both scenarios identified a patient-group with severe HF and high CV event-rates. [ABSTRACT FROM AUTHOR]

Aims: Guidelines recommend target doses (TD) of heart failure (HF) with reduced ejection fraction (HFrEF) medications regardless of sex. Differences in pharmacokinetics and pharmacodynamics may explain heterogeneity in treatment response, adverse reactions, and tolerability issues across sexes. The aim of this study was to explore sex‐based differences in the association between TD achievement and mortality/morbidity in HFrEF. Methods and results: Patients with HFrEF and HF duration ≥6 months registered in the Swedish HF Registry between May 2000 and December 2020 (follow‐up until December 2021) were analysed. Treatments of interest were renin–angiotensin system inhibitors (RASI) or angiotensin receptor–neprilysin inhibitors (ARNI), and beta‐blockers. Multivariable Cox regression models were performed to explore the risk of cardiovascular mortality or hospitalization for HF across dose categories in females versus males. A total of 17 912 patients were analysed (median age 77.0 years, interquartile range [IQR] 70.0–83.0), 29% were female. Over a median follow‐up of 1.33 years (IQR 0.29–3.22), for RASI/ARNI there was no significant difference in outcome for females achieving 50–99% versus 100% of TD (hazard ratio 0.92, 95% confidence interval 0.83–1.03), whereas males showed a gradual lowering in risk together with the achievement of higher % of TD (p‐interaction = 0.030). For beta‐blockers the achievement of TD was associated with the lowest risk of outcome regardless of sex. Conclusions: Our findings suggest that females and males might differently benefit from the same dose of RASI/ARNI, and do represent a general call for randomized controlled trials to consider sex‐specific up‐titration schemes when testing HFrEF treatments in need of up‐titration. [ABSTRACT FROM AUTHOR]

Aim: To assess cause‐specific death in patients with heart failure with preserved, mildly reduced, and reduced ejection fraction (HFpEF, HFmrEF, and HFrEF). Methods and results: Data were analysed from the Swedish Heart Failure Registry (SwedeHF) and the National Patient Register of patients enrolled in SwedeHF 2000–2021. Cox proportional hazards regression models were performed and adjusted for age, sex and time period. Among 100 584 patients (23% HFpEF, 23% HFmrEF, 53% HFrEF), median age (interquartile range) was 75 (66–82) and 36% were female. Of those who died within 5 years, most deaths were ascribed to cardiovascular (CV) causes across all ejection fraction (EF) categories. Within 5 years, HFpEF had higher adjusted risk of non‐CV death (hazard ratio [HR] 1.33, 95% confidence interval [CI] 1.28–1.38, p < 0.001) and lower adjusted risk of CV death (HR 0.85, 95% CI 0.82–0.88, p < 0.001) compared to HFrEF. Ischaemic heart disease (IHD) and cancer were the most common causes of CV and non‐CV death regardless of EF category. The incidence rate of CV death due to IHD was highest in HFrEF while incidence rates of CV death due to pulmonary vascular disease, stroke, valvular heart disease and atrial fibrillation increased with increasing EF. The incidence rates of non‐CV deaths due to cancer, respiratory disease, and infections increased with increasing EF. Conclusion: Cardiovascular death was more common than non‐CV death across all EF categories although the risk of non‐CV death within 5 years was higher with increasing EF. IHD and cancer were the most common causes of CV and non‐CV deaths, respectively, regardless of EF category. [ABSTRACT FROM AUTHOR]

Aims: In patients with heart failure (HF), we aimed to assess (i) the time trends in N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP) testing; (ii) patient characteristics associated with NT‐proBNP testing; (iii) distribution of NT‐proBNP levels, focusing on the subgroups with (WHFE) vs. without (NWHFE) a worsening HF event, defined as an HF hospitalization; and (iv) changes of NT‐proBNP levels over time. Methods and results: NT‐proBNP testing and levels were investigated in HF patients enrolled in the Swedish Heart Failure Registry (SwedeHF) linked with the Stockholm CREAtinine Measurements project from January 2011 to December 2018. Index date was the first registration in SwedeHF. Patterns of change in NT‐proBNP levels before (in the previous 6 ± 3 months) and after (in the following 6 ± 3 months) the index date were categorized as follows: (i) <3000 ng/L at both measurements = stable low; (ii) <3000 ng/L at the first measurement and ≥3000 ng/L at the second measurement = increased; (iii) ≥3000 ng/L at the first measurement and <3000 ng/L at the second measurement = decreased; and (iv) ≥3000 ng/L at both measurements = stable high. Univariable and multivariable logistic regression models, expressed as odds ratios (ORs) and 95% confidence intervals (95% CIs), were performed to assess the associations between (i) clinical characteristics and NT‐proBNP testing and (ii) changes in NT‐proBNP from 6 months prior to the index date and the index date and a WHFE. Consistency analyses were performed in HF with reduced ejection fraction (HFrEF) alone. A total of 4424 HF patients were included (median age 74 years, women 34%, HFrEF 53%), 33% with a WHFE. NT‐proBNP testing increased over time, up to 55% in 2018, and was almost two‐fold as frequent, and time to testing was less than half, in patients with WHFE vs. NWHFE. Independent predictors of testing were WHFE, higher heart rate, diuretic use, and preserved ejection fraction. Median NT‐proBNP was 3070 ng/L (Q1–Q3: 1220–7395), approximately three‐fold higher in WHFE vs. NWHFE. Compared with stable low NT‐proBNP levels, increased (OR 4.27, 95% CI 2.47–7.37) and stable high levels (OR 2.48, 95% CI 1.58–3.88) were independently associated with a higher risk of WHFE. Results were consistent in the HFrEF population. Conclusions: NT‐proBNP testing increased over time but still was only performed in half of the patients. Testing was associated with a WHFE, with features of more severe HF and for differential diagnosis purposes. Increased and stable high levels were associated with a WHFE. Overall, our data highlight the potential benefits of carrying further implementation of NT‐proBNP testing in clinical practice. [ABSTRACT FROM AUTHOR]

Aims: The aim of this analysis was to provide data on the overall comorbidity burden, both cardiovascular (CV) and non‐CV, in a large real‐world heart failure (HF) population across the ejection fraction (EF). Methods and results: Patients with HF from the Swedish HF Registry between 2000 and 2021 were included. Of 91 463 patients (median age 76 years [interquartile range 67–82]), 98% had at least one among the 17 explored comorbidities (94% at least one CV and 85% at least one non‐CV comorbidity). All comorbidities, except for coronary artery disease (CAD), were more frequent in HF with preserved EF (HFpEF). Patients with multiple comorbidities were older, more likely female, inpatients, with HFpEF, worse New York Heart Association class and higher N‐terminal pro‐B‐type natriuretic peptide levels. In a multivariable Cox model, 12 comorbidities were independently associated with a higher risk of death from any cause. The highest risk was associated with dementia (hazard ratio [HR] 1.55, 95% confidence interval [CI] 1.45–1.65), chronic kidney disease (HR 1.37, 95% CI 1.34–1.41), chronic obstructive pulmonary disease (HR 1.32, 95% CI 1.28–1.35). Obesity was associated with a lower risk of all‐cause death (HR 0.81, 95% CI 0.79–0.84). CAD and valvular heart disease were associated with a higher risk of all‐cause and CV mortality, but not non‐CV mortality, whereas cancer and musculo‐skeletal disease increased the risk of non‐CV mortality. A significant interaction with EF was observed for several comorbidities. Occurrence of CV and non‐CV outcomes was related to the number of CV and non‐CV comorbidities, respectively. Conclusion: The burden of both CV and non‐CV comorbidities was high in HF regardless of EF, but overall higher in HFpEF. Multimorbidity was associated with a high risk of death with a different burden on CV or non‐CV outcomes. [ABSTRACT FROM AUTHOR]