Eligibility for omecamtiv mecarbil in a real-world heart failure population: Data from the Swedish Heart Failure Registry.

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.

Sex differences in the prognostic role of achieving target doses of heart failure medications: Data from the Swedish Heart Failure Registry.

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.

Glucagon-like peptide-1 receptor agonists use and associations with outcomes in heart failure and type 2 diabetes. Data from the Swedish Heart Failure and Swedish National Diabetes Registries.

AIMS: To assess use and associations with outcomes of glucagon-like peptide-1 receptor agonists (GLP-1 RA) in a real-world population with heart failure (HF) and type 2 diabetes (T2DM). METHODS AND RESULTS: The Swedish HF Registry was linked with the National Diabetes Registry and other national registries. Independent predictors of GLP-1 RA use were assessed by multivariable logistic regressions, and associations with outcomes by Cox regressions in a 1:1 propensity score-matched cohort. Of 8188 patients enrolled in 2017-2021, 9% received a GLP-1 RA. Independent predictors of GLP-1 RA use were age<75, worse glycaemic control, impaired renal function, obesity and reduced ejection fraction (EF). GLP-1 RA use was not significantly associated with a composite of HF hospitalization (HHF) or cardiovascular (CV) death regardless of EF, but was associated with lower risk of major adverse CV events (CV death, non-fatal stroke/transient ischemic attack or myocardial infarction), CV and all-cause death. In patients with body mass index≥30 kg/m2, GLP-1 RA use was also associated with lower risk of HHF/CV death and HHF alone. CONCLUSIONS: In patients with HF and T2DM, GLP-1 RA use was independently associated with more severe T2DM, reduced EF and obesity, and was not associated with a higher risk of HHF/CV death but with longer survival and less major CV adverse events. An association with lower HHF/CV death and HHF was observed in obese patients. Our findings provide new insights into GLP-1 RA use and its safety in HF and T2DM.

Cause-specific death in heart failure across the ejection fraction spectrum: A comprehensive assessment of over 100 000 patients in the Swedish Heart Failure Registry.

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.

Does Heterogeneity Exist in Treatment Associations With Renin-Angiotensin-System Inhibitors or Beta-blockers According to Phenotype Clusters in Heart Failure with Preserved Ejection Fraction?

BACKGROUND: We explored the association between use of renin-angiotensin system inhibitors and beta-blockers, with mortality/morbidity in 5 previously identified clusters of patients with heart failure with preserved ejection fraction (HFpEF). METHODS AND RESULTS: We analyzed 20,980 patients with HFpEF from the Swedish HF registry, phenotyped into young-low comorbidity burden (12%), atrial fibrillation-hypertensive (32%), older-atrial fibrillation (24%), obese-diabetic (15%), and a cardiorenal cluster (17%). In Cox proportional hazard models with inverse probability weighting, there was no heterogeneity in the association between renin-angiotensin system inhibitor use and cluster membership for any of the outcomes: cardiovascular (CV) mortality, all-cause mortality, HF hospitalisation, CV hospitalisation, or non-CV hospitalisation. In contrast, we found a statistical interaction between beta-blocker use and cluster membership for all-cause mortality (P = .03) and non-CV hospitalisation (P = .001). In the young-low comorbidity burden and atrial fibrillation-hypertensive cluster, beta-blocker use was associated with statistically significant lower all-cause mortality and non-CV hospitalisation and in the obese-diabetic cluster beta-blocker use was only associated with a statistically significant lower non-CV hospitalisation. The interaction between beta-blocker use and cluster membership for all-cause mortality could potentially be driven by patients with improved EF. However, patient numbers were diminished when excluding those with improved EF and the direction of the associations remained similar. CONCLUSIONS: In patients with HFpEF, the association with all-cause mortality and non-CV hospitalisation was heterogeneous across clusters for beta-blockers. It remains to be elucidated how heterogeneity in HFpEF could influence personalized medicine and future clinical trial design.

Sodium-glucose cotransporter 2 inhibitors are associated with reduced risk of mortality and readmissions in heart failure.

AIMS: Compelling evidence from randomized trials has shown that sodium-glucose cotransporter 2 inhibitors (SGLT2is) are effective in heart failure (HF) across the spectrum of left ventricular ejection fractions. However, there are very few studies with real-world data. METHODS AND RESULTS: A retrospective cohort analysis was performed based on patient-level data from the Swedish Heart Failure Registry (SwedeHF) linked with three other national registers. Patients included had an index registration between 3 September 2013 and 31 December 2020 in SwedeHF and were on treatment with guideline-recommended therapy without or with SGLT2i 3 months before or 6 months after their index registration. Endpoints were mortality or readmissions. Association between the use of SGLT2i and endpoints was studied using adjusted Cox models. In the overall cohort, 796/22 405 patients were included with/without SGLT2i. In patients with SGLT2i, 93.5% had diabetes mellitus. In the overall cohort, SGLT2i was statistically significantly associated with all-cause mortality {hazard ratio [HR]: 0.61 [95% confidence interval (CI) 0.48-0.79], P < 0.0001}, cardiovascular mortality [HR: 0.29 (95% CI 0.17-0.50), P < 0.0001], cardiovascular mortality or HF readmission [HR: 0.89 (95% CI 0.80-1.00), P = 0.046], and all-cause readmissions [HR: 0.90 (95% CI 0.81-0.99), P = 0.038]. Similar results were obtained for the diabetes cohort. However, no association with cause-specific readmissions was observed. CONCLUSIONS: This nationwide real-world study indicates that patients with HF, in which majority coexisted with diabetes mellitus, who received SGLT2i were statistically significantly associated with lower risk for all-cause mortality, cardiovascular mortality, cardiovascular mortality or HF readmissions, and all-cause readmissions, in line with the randomized trials assessing SGLT2i.

Hypotension in heart failure is less harmful if associated with high or increasing doses of heart failure medication: Insights from the Swedish Heart Failure Registry.

AIMS: Heart failure (HF) medication may reduce blood pressure (BP). Low BP is associated with worse outcomes but how this association is modified by HF medication has not been studied. We evaluated the association between BP and outcomes according to HF medication dose in HF with reduced ejection fraction (HFrEF). METHODS AND RESULTS: We studied HFrEF patients from the Swedish HF registry (2000-2018). Associations between systolic BP (SBP) and cardiovascular death (CVD) and/or HF hospitalization (HFH) were analysed according to doses of renin-angiotensin system (RAS) inhibitors, beta-blockers and mineralocorticoid receptor antagonists (MRA). Among 42 040 patients (median age 74.0), lower baseline SBP was associated with higher risk of CVD/HFH (adjusted hazard ratio [HR] per 10 mmHg higher SBP: 0.92, 95% confidence interval [CI] 0.92-0.93), which was less high risk under optimized RAS inhibitor and beta-blocker doses (10% decrease in event rates per 10 mmHg SBP increase in untreated patients vs. 7% decrease in patients at maximum dose, both adjusted p < 0.02). Among the 13 761 patients with repeated measurements, 9.9% reported a SBP decrease >10 mmHg when HF medication doses were increased, whereas 24.6% reported a SBP decrease >10 mmHg with stable/decreasing doses. Decreasing SBP was associated with higher risk of CVD/HFH in patients with stable (HR 1.10, 95% CI 1.04-1.17) or decreasing (HR 1.29, 95% CI 1.18-1.42) HF medication dose but not in patients with an increase in doses (HR 0.94, 95% CI 0.86-1.02). CONCLUSIONS: The association of lower SBP with higher risk of CVD/HFH is attenuated in patients with optimized HF medication. These results suggest that low or declining SBP should not limit HF medication optimization.

N-terminal pro-B-type natriuretic peptide concentrations, testing and associations with worsening heart failure events.

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.

The role of multimorbidity in patients with heart failure across the left ventricular ejection fraction spectrum: Data from the Swedish Heart Failure Registry.

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.

Multimorbidity in patients with acute heart failure across world regions and country income levels (REPORT-HF): a prospective, multicentre, global cohort study.

BACKGROUND: Multimorbidity (two or more comorbidities) is common among patients with acute heart failure, but comprehensive global information on its prevalence and clinical consequences across different world regions and income levels is scarce. This study aimed to investigate the prevalence of multimorbidity and its effect on pharmacotherapy and prognosis in participants of the REPORT-HF study. METHODS: REPORT-HF was a prospective, multicentre, global cohort study that enrolled adults (aged ≥18 years) admitted to hospital with a primary diagnosis of acute heart failure from 358 hospitals in 44 countries on six continents. Patients who currently or recently participated in a clinical treatment trial were excluded. Follow-up data were collected at 1-year post-discharge. The primary outcome was 1-year post-discharge mortality. All patients in the REPORT-HF cohort with full data on comorbidities were eligible for the present study. We stratified patients according to the number of comorbidities, and countries by world region and country income level. We used one-way ANOVA, χ2 test, or Mann-Whitney U test for comparisons between groups, as applicable, and Cox regression to analyse the association between multimorbidity and 1-year mortality. FINDINGS: Between July 23, 2014, and March 24, 2017, 18 553 patients were included in the REPORT-HF study. Of these, 18 528 patients had full data on comorbidities, of whom 11 360 (61%) were men and 7168 (39%) were women. Prevalence rates of multimorbidity were lowest in southeast Asia (72%) and highest in North America (92%). Fewer patients from lower-middle-income countries had multimorbidity than patients from high-income countries (73% vs 85%, p<0·0001). With increasing comorbidity burden, patients received fewer guideline-directed heart failure medications, yet more drugs potentially causing or worsening heart failure. Having more comorbidities was associated with worse outcomes: 1-year mortality increased from 13% (no comorbidities) to 26% (five or more comorbidities). This finding was independent of common baseline risk factors, including age and sex. The population-attributable fraction of multimorbidity for mortality was higher in high-income countries than in upper-middle-income or lower-middle-income countries (for patients with five or more comorbidities: 61% vs 27% and 31%, respectively). INTERPRETATION: Multimorbidity is highly prevalent among patients with acute heart failure across world regions, especially in high-income countries, and is associated with higher mortality, less prescription of guideline-directed heart failure pharmacotherapy, and increased use of potentially harmful medications. FUNDING: Novartis Pharma. TRANSLATIONS: For the Arabic, French, German, Hindi, Mandarin, Russian and Spanish translations of the abstract see Supplementary Materials section.

Impact of adherence to guideline-directed therapy on risk of death in HF patients across an ejection fraction spectrum.

AIMS: How different degrees of adherence to guideline-directed medical therapy (GDMT) affect mortality risk in patients with heart failure (HF) in a real-world clinical setting is poorly understood. This study sought to investigate how different levels of adherence to GDMT were associated with the risk of all-cause mortality in patients with HF across a spectrum of left ventricular ejection fractions (LVEFs) in a real-world clinical setting. METHODS AND RESULTS: A total of 64 610 HF patients with no missing value of LVEF from the Swedish Heart Failure Registry were included in the study. Patients were divided according to different LVEFs (<30%, 30-39%, 40-49%, and≥50%) and stratified by an adherence score (good, moderate, or poor) according to the triple, double, and single one usage of GDMT: angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, beta-blockers, and mineralocorticoid receptor antagonists. The outcome is time to all-cause mortality. The mean age of the whole cohort was 73.9 ± 12.1 years, and the proportion of patients in LVEF < 30%, 30-39%, 40-49%, and≥50% groups was 27.6%, 26.9%, 22.1%, and 23.3%, respectively. Patients with LVEF < 30% had the highest mortality rate, almost 20% higher than those with LVEF ≥ 50% {hazard ratio [HR] [95% confidence interval (CI)]: 0.80 [0.71-0.90], P < 0.001}. After treatment of GDMT with good adherence, patients with LVEF < 30% had similar mortality to those with LVEF ≥ 50% [HR (95% CI): 0.97 (0.86-1.10), P = 0.664]. However, the percentage of moderate or poor GDMT was alarmingly high, with good adherence only in 20% of the patients. CONCLUSIONS: Good adherence to GDMT works best in patients with LVEF < 50%, whereas moderate adherence to GDMT varies in efficacy depending on the components of the drug combinations.

Safety of continuing mineralocorticoid receptor antagonist treatment in patients with heart failure with reduced ejection fraction and severe kidney disease: Data from Swedish Heart Failure Registry.

AIMS: Mineralocorticoid receptor antagonists (MRAs) improve outcomes in heart failure with reduced ejection fraction (HFrEF) but remain underused and are often discontinued especially in patients with chronic kidney disease (CKD) due to concerns on renal safety. Therefore, in a real-world HFrEF population we investigated the safety of MRA use, in terms of risk of renal events, any mortality and any hospitalization, across the estimated glomerular filtration rate (eGFR) spectrum including severe CKD. METHODS AND RESULTS: We analysed patients with HFrEF (ejection fraction <40%), not on dialysis, from the Swedish Heart Failure Registry. We performed multivariable logistic regression models to investigate patient characteristics independently associated with MRA use, and univariable and multivariable Cox regression models to assess the associations between MRA use and outcomes. Of 33 942 patients, 17 489 (51%) received MRA, 32%, 45%, 54%, 54% with eGFR <30, 30-44, 45-59 or ≥60 ml/min/1.73 m2 , respectively. An eGFR ≥60 ml/min/1.73 m2 and patient characteristics linked with more severe HF were independently associated with more likely MRA use. In multivariable analyses, MRA use was consistently not associated with a higher risk of renal events (i.e. composite of dialysis/renal death/hospitalization for renal failure or hyperkalaemia) (hazard ratio [HR] 1.04, 95% confidence interval [CI] 0.98-1.10), all-cause death (HR 1.02, 95% CI 0.97-1.08) as well as of all-cause hospitalization (HR 0.99, 95% CI 0.95-1.02) across the eGFR spectrum including also severe CKD. CONCLUSIONS: The use of MRAs in patients with HFrEF decreased with worse renal function; however their safety profile was demonstrated to be consistent across the entire eGFR spectrum.

Changing health related quality of life and outcomes in heart failure by age, sex and subtype.

Background: There are calls to integrate serial recordings of health related quality of life (HRQoL) into routine care, clinical trials and prognosis. Little is known about the relationship between change in HRQoL and outcomes in heart failure (HF) patients by age, sex and HF subtype. Method: From the Swedish Heart Failure Registry (SwedeHF; 2008-2019), patients were categorised by reduced (<40%, HFrEF), mildly-reduced (40-49%, HFmrEF) and preserved (≥50%, HFpEF) ejection fraction. HRQoL was measured using Euro-QoL-5D visual analogue scale (EQ5D-vas), collected at baseline and 1-year. Baseline EQ5D-vas scores were categorised by: "best" (76-100), "good" (51-75), "bad" (26-50), and "worst" (0-25). Change in EQ5D-vas was categorised as 'no significant change' (<5 points increase/decrease); some worsening (5-9 points decrease); considerable worsening (≥10 points decrease); some improvement (5-9 points increase); considerable improvement (≥10 points increase). Associations with admission and death were estimated and interactions with patient sub-groups tested. Findings: Among 23,553 patients (median age 74 [66-81] years, 8000 [34%] female), baseline EQ5D-vas was worse in older patients, women, and those with HFpEF compared to their respective counterparts. Compared to patients with the "best" EQ5D-vas, the adjusted associations for admission for those with "good", "bad" and "worst" EQ5D-vas were, respectively: HR 1.09 (1.04, 1.14), 1.27 (1.21, 1.33) and 1.39 (1.28, 1.51). Compared to no significant change in EQ5D-vas, the adjusted estimates for admission following some improvement, considerable improvement, some worsening and considerable worsening were, respectively: HR 0.91 (0.82, 1.01), 0.75 (0.70, 0.81), 1.04 (0.92, 1.16) and 1.25 (1.16, 1.35). Results were similar amongst groups and for HF admission and death. Interpretation: Change in HRQoL was an independent indicator of risk of admission and death in people with all HF subtypes, irrespective of age and sex. Funding: NIHR.

Global Variations According to Sex in Patients Hospitalized for Heart Failure in the REPORT-HF Registry.

BACKGROUND: Previous reports suggest that risk factors, management, and outcomes of acute heart failure (AHF) may differ by sex, but they rarely extended analysis to low- and middle-income countries. OBJECTIVES: In this study, the authors sought to analyze sex differences in treatment and outcomes in patients hospitalized for AHF in 44 countries. METHODS: The authors investigated differences between men and women in treatment and outcomes in 18,553 patients hospitalized for AHF in 44 countries in the REPORT-HF (Registry to Assess Medical Practice With Longitudinal Observation for the Treatment of Heart Failure) registry stratified by country income level, income disparity, and world region. The primary outcome was 1-year all-cause mortality. RESULTS: Women (n = 7,181) were older than men (n = 11,372), were more likely to have heart failure with preserved left ventricular ejection fraction, had more comorbid conditions except for coronary artery disease, and had more severe signs and symptoms at admission. Coronary angiography, cardiac stress tests, and coronary revascularization were less frequently performed in women than in men. Women with AHF and reduced left ventricular ejection fraction were less likely to receive an implanted device, regardless of region or country income level. Women were more likely to receive treatments that could worsen HF than men (18% vs 13%; P < 0.0001). In countries with low-income disparity, women had better 1-year survival than men. This advantage was lost in countries with greater income disparity (Pinteraction < 0.001). CONCLUSIONS: Women were less likely to have diagnostic testing or receive guideline-directed care than men. A survival advantage for women was observed only in countries with low income disparity, suggesting that equity of HF care between sexes remains an unmet goal worldwide.

Hospitalization for acute heart failure during non-working hours impacts on long-term mortality: the REPORT-HF registry.

AIMS: Hospital admission during nighttime and off hours may affect the outcome of patients with various cardiovascular conditions due to suboptimal resources and personnel availability, but data for acute heart failure remain controversial. Therefore, we studied outcomes of acute heart failure patients according to their time of admission from the global International Registry to assess medical practice with lOngitudinal obseRvation for Treatment of Heart Failure. METHODS AND RESULTS: Overall, 18 553 acute heart failure patients were divided according to time of admission into 'morning' (7:00-14:59), 'evening' (15:00-22:59), and 'night' (23:00-06:59) shift groups. Patients were also dichotomized to admission during 'working hours' (9:00-16:59 during standard working days) and 'non-working hours' (any other time). Clinical characteristics, treatments, and outcomes were compared across groups. The hospital length of stay was longer for morning (odds ratio: 1.08; 95% confidence interval: 1.06-1.10, P < 0.001) and evening shift (odds ratio: 1.10; 95% confidence interval: 1.07-1.12, P < 0.001) as compared with night shift. The length of stay was also longer for working vs. non-working hours (odds ratio: 1.03; 95% confidence interval: 1.02-1.05, P < 0.001). There were no significant differences in in-hospital mortality among the groups. Admission during working hours, compared with non-working hours, was associated with significantly lower mortality at 1 year (hazard ratio: 0.88; 95% confidence interval: 0.80-0.96, P = 0.003). CONCLUSIONS: Acute heart failure patients admitted during the night shift and non-working hours had shorter length of stay but similar in-hospital mortality. However, patients admitted during non-working hours were at a higher risk for 1 year mortality. These findings may have implications for the health policies and heart failure trials.

Real-world use of sodium-glucose cotransporter 2 inhibitors in patients with heart failure and reduced ejection fraction: Data from the Swedish Heart Failure Registry.

AIMS: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) reduce mortality/morbidity in heart failure (HF). We explored the implementation of SGLT2i over time, and patient characteristics associated with their use, in a large, nationwide population with HF with reduced ejection fraction (HFrEF). METHODS AND RESULTS: Patients with HFrEF (ejection fraction <40%), no type 1 diabetes, estimated glomerular filtration rate (eGFR) <20 ml/min/1.73 m2 and/or on dialysis, registered in the Swedish HF Registry between 1 November 2020 and 5 August 2022 were included. Independent predictors of use were investigated by multivariable logistic regressions. Of 8192 patients, 37% received SGLT2i. Use increased overall from 20.5% to 59.0% over time, from 46.2% and 12.5% to 69.8% and 55.4% in patients with and without type 2 diabetes, from 14.7% and 22.3% to 58.0% and 59.8% in eGFR <60 versus ≥60 ml/min/1.73 m2 , from 21.0% and 18.9% to 61.6% and 52.0% in males versus females, from 24.2% and 18.0% to 60.8% and 57.7% in patients with versus without recent HF hospitalization, from 26.1% and 19.8% to 54.7% and 59.6% in inpatients versus outpatients, and from 20.2% and 21.2% to 59.2% and 58.7% in those with HF duration <6 versus ≥6 months, respectively. Important characteristics associated with SGLT2i use were male sex, recent HF hospitalization, specialized HF follow-up, lower ejection fraction, type 2 diabetes, higher education level, use of other HF/cardiovascular interventions. Older age, higher blood pressure, atrial fibrillation and anaemia were associated with less use. Discontinuation rate at 6 and 12 months was 13.1% and 20.0%, respectively. CONCLUSIONS: Use of SGLT2i increased three-fold over 2 years. Although this indicates a more rapid translation of trial results and guidelines into clinical practice compared to previous HF drugs, further efforts are advocated to complete the implementation process while avoiding inequities across different patient subgroups and discontinuations.

Association between a hospitalization for heart failure and the initiation/discontinuation of guideline-recommended treatments: An analysis from the Swedish Heart Failure Registry.

AIMS: To investigate whether a heart failure (HF) hospitalization is associated with initiation/discontinuation of guideline-directed medical HF therapy (GDMT) and consequent outcomes. METHODS AND RESULTS: Among patients in the Swedish HF registry with an ejection fraction <50% enrolled in 2009-2018, initiation/discontinuation of GDMT was investigated by assessing dispensations of GDMT in those with versus without a HF hospitalization. Of 14 737 patients, 6893 (47%) were enrolled when hospitalized for HF. Initiation of GDMT was more likely than discontinuation following a HF hospitalization compared to a control group of patients without a HF hospitalization (odds ratio range 2.1-4.0 vs. 1.4-1.6 for the individual medications), although the proportion of patients not on GDMT was still high (8.1-44.0%). Key patient characteristics triggering less use of GDMT (i.e. less initiation or more discontinuation) were older age and worse renal function. Following a HF hospitalization, initiation of renin-angiotensin system inhibitors/angiotensin receptor-neprilysin inhibitors or beta-blockers was associated with lower and their discontinuation with higher mortality risk, but no association with mortality was observed for initiation/discontinuation of mineralocorticoid receptor antagonists. CONCLUSIONS: Following a HF hospitalization, initiation of GDMT was more likely than discontinuation, although still limited. Perceived or actual low tolerance were barriers to GDMT implementation. Early re-/initiation of GDMT was associated with better survival. Our findings represent a call for further implementing the current guideline recommendation for an early re-/initiation of GDMT following a HF hospitalization.

Eligibility for vericiguat in a real-world heart failure population according to trial, guideline and label criteria: Data from the Swedish Heart Failure Registry.

AIM: We investigated the eligibility for vericiguat in a real-world heart failure (HF) population based on trial, guideline and label criteria. METHODS AND RESULTS: From the Swedish HF registry, 23 573 patients with HF with reduced ejection fraction (HFrEF) enrolled between 2000 and 2018, with a HF duration ≥6 months, were considered. Eligibility for vericiguat was calculated based on criteria from (i) the Vericiguat Global Study in Subjects with Heart Failure and Reduced Ejection Fraction (VICTORIA) trial; (ii) European and American guidelines on HF; (iii) product labelling according to the Food and Drug Administration and European Medicines Agency. Estimated eligibility for vericiguat in the trial, guidelines, and label scenarios was 21.4%, 47.4%, and 47.4%, respectively. Prior HF hospitalization within 6 months was the criterion limiting eligibility the most in all scenarios (met by 49.1% of the population). In the trial scenario, other criteria meaningfully limiting eligibility were elevated N-terminal pro-B-type natriuretic peptide levels and nitrate use. In all scenarios, eligibility was higher among patients hospitalized for HF at baseline (44.3% vs. 21.4% [trial scenario] and 97.3% vs. 47.4% [guideline/label scenarios] for hospitalized vs. non-hospitalized patients). Overall, eligible patients were older, had more severe HF, more comorbidities, and consequently higher cardiovascular mortality and HF hospitalization rates compared with ineligible patients across all scenarios. CONCLUSION: In a large and contemporary real-world HFrEF cohort, we estimated that 21.4% of patients would be eligible for vericiguat according to the VICTORIA trial selection criteria, 47.4% based on guidelines and labelling. Eligibility for vericiguat translated into the selection of a population at high risk of morbidity/mortality.

Identifying distinct clinical clusters in heart failure with mildly reduced ejection fraction.

INTRODUCTION: Heart failure (HF) is a heterogeneous syndrome, and the specific sub-category HF with mildly reduced ejection fraction (EF) range (HFmrEF; 41-49% EF) is only recently recognised as a distinct entity. Cluster analysis can characterise heterogeneous patient populations and could serve as a stratification tool in clinical trials and for prognostication. The aim of this study was to identify clusters in HFmrEF and compare cluster prognosis. METHODS AND RESULTS: Latent class analysis to cluster HFmrEF patients based on their characteristics was performed in the Swedish HF registry (n = 7316). Identified clusters were validated in a Dutch cross-sectional HF registry-based dataset CHECK-HF (n = 1536). In Sweden, mortality and hospitalisation across the clusters were compared using a Cox proportional hazard model, with a Fine-Gray sub-distribution for competing risks and adjustment for age and sex. Six clusters were discovered with the following prevalence and hazard ratio with 95% confidence intervals (HR [95%CI]) vs. cluster 1: 1) low-comorbidity (17%, reference), 2) ischaemic-male (13%, HR 0.9 [95% CI 0.7-1.1]), 3) atrial fibrillation (20%, HR 1.5 [95% CI 1.2-1.9]), 4) device/wide QRS (9%, HR 2.7 [95% CI 2.2-3.4]), 5) metabolic (19%, HR 3.1 [95% CI 2.5-3.7]) and 6) cardio-renal phenotype (22%, HR 2.8 [95% CI 2.2-3.6]). The cluster model was robust between both datasets. CONCLUSION: We found robust clusters with potential clinical meaning and differences in mortality and hospitalisation. Our clustering model could be valuable as a clinical differentiation support and prognostic tool in clinical trial design.

Heart failure pharmacological treatments and outcomes in heart failure with mildly reduced ejection fraction.

BACKGROUND: Guideline recommendations for the treatment of heart failure with mildly reduced ejection fraction (HFmrEF) derive from small subgroups in post-hoc analyses of randomized trials. OBJECTIVES: We investigated predictors of renin-angiotensin system inhibitors/angiotensin receptor neprilysin inhibitors (RASI/ARNI) and beta-blockers use, and the associations between these medications and mortality/morbidity in a large real-world cohort with HFmrEF. METHODS AND RESULTS: Patients with HFmrEF (EF 40-49%) from the Swedish HF Registry were included. The associations between medications and cardiovascular (CV) mortality/HF hospitalization (HFH), and all-cause mortality were assessed through Cox regressions in a 1:1 propensity score-matched cohort. A positive control analysis was performed in patients with EF < 40%, while a negative control outcome analysis had cancer-related hospitalization as endpoint. Of 12 421 patients with HFmrEF, 84% received RASI/ARNI and 88% beta-blockers. Shared-independent predictors of RASI/ARNI and beta-blockers use were younger age, being an outpatient, follow-up in specialty care, and hypertension. In the matched cohorts, use of both RASI/ARNI and beta-blocker use was separately associated with lower risk of CV mortality/HFH [hazard ratio (HR) = 0.90, 95% confidence interval (CI): 0.83-0.98 and HR = 0.82, 95% CI: 0.74-0.90, respectively] and of all-cause mortality (HR = 0.75, 95% CI: 0.69-0.81 and HR = 0.79, 95% CI: 0.72-0.87, respectively). Results were consistent at the positive control analysis, and there were no associations between treatment use and the negative control outcome. CONCLUSIONS: RASI/ARNI and beta-blockers were extensively used in this large real-world cohort with HFmrEF. Their use was safe since associated with lower mortality and morbidity. Our findings confirm the real-world evidence from previous post-hoc analyses of trials, and represent a further call for implementing guideline recommendations.