Background and Aims Patients with established atherosclerotic cardiovascular disease (ASCVD) are at high risk of developing heart failure (HF). However, incident HF is not part of the risk assessment of current guideline-recommended models. The aim of this study was to develop and externally validate the SMART2-HF model for prediction of incident HF in patients with ASCVD.Methods SMART2-HF was developed in 7698 individuals with established ASCVD (coronary, cerebrovascular, or peripheral artery disease, or abdominal aortic aneurysm) but without prior HF from the UCC-SMART cohort. Cox proportional hazards models including sex-predictor interactions and with age as the time scale were derived to estimate the 10-year and lifetime risk of incident HF (hospitalization for HF or HF-related death), accounting for competing non-HF mortality. Predictors, limited to routinely available clinical characteristics, were aligned with the SMART2 risk model for recurrent cardiovascular (CV) risk in the same population. External validation was performed in 240 741 patients with ASCVD from six data sources: the Clinical Practice Research Datalink, the HUNT3 study, the SWEDEHEART Registry, the ASCVD-Particles cohort, the Estonian Biobank and the international REACH Registry.Results During a median follow-up of 11.2 years (interquartile range 6.1-16.4 years), 1031 incident HF events (13%) occurred in the UCC-SMART cohort. In the external validation data sources, a total of 24 885 incident HF events (10%) occurred. The pooled C-statistic was .696 (95% confidence interval .674-.717), with consistent performance in subgroups by sex and type of ASCVD. Predicted risks matched observed incidence in external validation.Conclusions The SMART2-HF model enables the prediction of incident HF in patients with ASCVD. Aligned with the guideline-recommended SMART2 model for recurrent CV risk, SMART2-HF can be used as a complementary tool in this population.

AIMS:During the past decades outcomes of first-time myocardial infarction (MI) have improved substantially. However, it is unknown if the prognosis following a recurrent MI has also improved similarly. METHODS AND RESULTS:We conducted a nationwide registry-based study including all patients with first-time recurrent MI in Denmark during 2003 to 2022. Cumulative incidences and standardized risk ratios (sRR) of mortality, hospitalisation for heart failure (HHF), and subsequent recurrent MI were reported along with stratified analyses by age, sex, and HF status at baseline. A total of 24,799 patients with recurrent MI were identified. Between 2003 and 2007 (n = 7368) and 2018-2022 (n = 4928), their median age decreased from 75 to 73 years. The prevalence of non-cardiovascular comorbidities increased. The use of lipid-lowering treatment at baseline increased (53.7% to 76.6%), as well as procedures performed in relation to recurrent MI (coronary angiogram, 41.2% to 77.4%; percutaneous coronary intervention, 26.8% to 54.0%). 5-year mortality decreased from 54.1% to 37.3% [sRR: 0.78 (0.74-0.82)], 5-year incidence of HHF decreased from 13.6% to 11.7% [sRR: 0.76 (0.68-0.84)], and 5-year incidence of subsequent recurrent MI decreased from 23.4% to 17.7% [sRR: 0.65 (0.52-0.78)]. While mortality and subsequent recurrent MI decreased consistently across subgroups, stratified analyses revealed that the 5-year incidence of HHF increased from 23.9% to 26.2% in patients with previous HF and from 14.3% to 15.9% in males aged ≥75 years. CONCLUSION:Mortality has decreased in parallel with intensified pharmacologic and invasive management of patients with recurrent MI. However, there has been little improvement in heart failure hospitalisations, underscoring that directed preventive strategies are needed to mitigate the heart failure risk in patients with recurrent MI.

BACKGROUND AND AIMS:Guidelines recommend coronary angiography in heart donors at increased risk of coronary artery disease (age >45 years, diabetes, tobacco, or drug use), but the yield is often low. The aim of this study was to evaluate the importance of estimated donor 10-year atherosclerotic cardiovascular disease (ASCVD) risk (≤5% vs >5%) vs coronary angiogram testing for predicting short- to mid-term survival free from graft failure in adult heart transplant recipients. METHODS:Adult heart transplant recipients from the United Network for Organ Sharing database 18 October 2018, to 31 December 2023, who received hearts from donors aged >40 years, or >30 years with diabetes, hypertension, or smoking were included. The risk of a composite outcome (death or graft failure) up to 4 years post-transplant was assessed by multivariable Cox regression. RESULTS:Of 5152 recipients, 86.1% received hearts from donors with ASCVD risk ≤5%. Angiography was performed in 76.1% donors with ASCVD ≤5% and 92.9% of donors with ASCVD >5%. Using donors with ASCVD ≤5% and angiography as the reference group (n = 3378), adjusted hazard ratios for the composite outcome were .91 [95% confidence interval (CI) .74-1.11] for ASCVD ≤5% without angiography (n = 1060); 1.30 (95% CI 1.05-1.60) for ASCVD >5% with angiography (n = 663), and .88 (95% CI .36-2.13) for ASCVD >5% without angiography (n = 51). Findings were consistent when limited to donors meeting current angiography guideline criteria. CONCLUSIONS:Estimated ASCVD risk >5% independently predicts worse transplant outcomes, while routine coronary angiography in low-risk donors (ASCVD ≤5%) does not. These findings suggest that ASCVD-based risk stratification may be more useful than angiography as the initial step in donor heart selection.

BACKGROUND AND AIMS:Heart failure (HF) with preserved ejection fraction (HFpEF) constitutes a heterogeneous disease with varying prognosis. Given the rising incidence of HFpEF, accurate risk prediction for these patients is needed to identify high-risk individuals, who may benefit the most from preventive treatments. The LIFE-Preserved model was developed and validated for the prediction of individual short-term and lifetime risk for HF hospitalization or cardiovascular (CV) death in patients with HFpEF. METHODS:LIFE-Preserved was derived in 20 332 patients aged 40-90 years with a left ventricular ejection fraction ≥ 50% from the Swedish HF Registry. Cause- and sex-specific Cox models were derived to predict the risk of HF hospitalization or CV death using 14 routinely available predictors. Use of age as the timescale allowed for predictions beyond the maximum follow-up duration in the derivation data, adjusted for competing risks. External validation was performed in two trials (EMPEROR-Preserved and TOPCAT-Americas) and three registries (NHS England Secure Data Environment, Veterans Affairs, and HF-Particles). Model performance was assessed by discrimination and calibration. RESULTS:During a median follow-up of 1.8 years (interquartile range .6-4.2, maximum 19 years), 9341 first HF hospitalizations or CV deaths (46%) were observed in Swedish HF Registry. External validation included data from 28 062 patients with HFpEF [9930 (35%) first HF hospitalizations or CV deaths]. Pooled C-statistics were .714 (95% confidence interval .652-.775) in trials and .658 (95% confidence interval .599-.717 in registries, with adequate calibration in all external validation sources. Performance was similar in men and women. An interactive calculator of the LIFE-Preserved model has been made available here. CONCLUSIONS:The LIFE-Preserved model enables prediction of short-term and lifetime risk of HF hospitalization or CV death in patients with HFpEF. The model could serve as a tool to identify high-risk HFpEF patients, guiding clinical management and shared decision-making.

Background and Objectives:The prognostic significance of ischemic evaluation in patients with new-onset heart failure is not well understood and may differ according to age and sex. In a real-world cohort, we analyzed the long-term mortality risk after undergoing an ischemic evaluation. Methods:All new-diagnosed heart failure patients 2008-2018 without prior ischemic evaluation, known coronary artery disease, or acute myocardial infarction were identified from the Danish National patient registry. The association of an ischemic evaluation within 90 days of heart failure diagnosis with long-term mortality was analyzed by inverse probability weighted Cox regression models. Results:A total of 61,475 patients were included (mean age 73.3±13.9 years, 46% women), of which 12,503 (20%) underwent an ischemic evaluation. During a mean follow-up of 4.6 years, 37% of patients died, corresponding to a mortality rate of 8.0 (7.9-8.1) per 100 person-years. The multivariable-adjusted hazard ratio of death was 0.92 (95% confidence interval, 0.90-0.95) for patients who underwent ischemic evaluation, compared with patients who did not. An ischemic evaluation was associated with a lower hazard ratio in males than females: 0.87 (0.84-0.90) vs. 0.98 (0.94-1.02), and in middle-aged vs. older or younger individuals: 0.91 (0.75-1.12) in patients ≤50 years, 0.82 (0.72-0.93) in 51-60 years, 0.83 (0.79-0.87) in 61-75 years, 0.93 (0.88-0.97) in >75-85 years, and 1.02 (0.97-1.07) in >85 years, respectively. Conclusions:Obtaining an ischemic evaluation was associated with marginal to no improvement in long-term mortality for many new-diagnosed heart failure patients, including the very elderly.

Transthoracic echocardiography derived left ventricular ejection fraction (LVEF) is a cornerstone in heart failure risk prevention. However, the lower limits of normal LVEF remains imprecisely defined. We aimed to define normal LVEF ranges by sex, age group, and self-reported race/ethnicity using data from population-based echocardiographic studies. We systematically searched MEDLINE for studies published between January 1, 2000, and January 3, 2025, that reported the mean and standard deviation of LVEF measured by 2D or 3D echocardiography in healthy, community-based adult populations. In 10 studies (n = 10,427; female sex, 48

BACKGROUND:Albuminuria is strongly associated with cardiorenal morbidity and mortality. However, real-world prevalence and the associated risks remain unclear. OBJECTIVES:This study aims to investigate the prevalence of patients with type 2 diabetes (T2D) with and without albuminuria and the subsequent risk of cardiorenal outcomes, and the eligibility for treatment with cardiovascular and renoprotective drugs. METHODS:Using the Danish nationwide registers, we identified patients ≥18 years with T2D at index January 1, 2015, with a urinary albumin-to-creatinine ratio (UACR) and a creatinine level measured within 365 days prior. Patients were grouped by albuminuria (UACR ≥30 mg/g) and normoalbuminuria (UACR <30 mg/g). The primary endpoint was a composite of heart failure, myocardial infarction, stroke, or all-cause death, and the secondary endpoint was a composite of end-stage renal disease or a sustained decrease in the estimated glomerular filtration rate ≥50%. Absolute 4-year risks were calculated using the Kaplan-Meier and Aalen-Johansen estimators. RESULTS:We included 74,014 patients, of whom 29,581 (40%) had albuminuria. Patients with albuminuria had a longer duration of diabetes (8.2 vs 6.9 years), lower estimated glomerular filtration rate (76 vs 83) and males were over-represented (62.6% vs 50.5%). The absolute 4-year risk of the primary outcome was 28.6% (95% CI: 28.1%-29.1%) vs 18.7% (95% CI: 18.4%-19.1%) for albuminuria vs normoalbuminuria, and for the secondary outcome, it was 8.7% (95% CI: 8.4%-9.0%) vs 2.9% (95% CI: 2.8%-3.1%), respectively. CONCLUSIONS:The prevalence of patients with T2D and albuminuria was 40% and may benefit from cardiovascular and renoprotective drugs, whereas 60% with normoalbuminuria still have a high residual risk of cardiovascular disease, warranting increased focus.

BACKGROUND:Heart failure with reduced ejection fraction (HFrEF) and metabolic dysfunction-associated steatotic liver disease (MASLD) are both associated with liver fibrosis. HFrEF patients may develop liver fibrosis due to hepatic congestion, MASLD, or a combination of both. The Fibrosis-4 (FIB-4) score calculated using age, aspartate aminotransferase, alanine aminotransferase, and platelet count, serves as a screening tool for advanced liver fibrosis. This study examines the association between the FIB-4 score and all-cause mortality, cardiovascular mortality, and major adverse liver outcomes (MALO) in patients with HFrEF. METHOD AND RESULTS:This study included 4523 HFrEF patients from the Danish Heart Failure Registry. Based on FIB-4 score, 25.5 % were low-risk, 45.7 % were indeterminate-risk, and 28.8 % were high-risk for advanced liver fibrosis. After five years, the cumulative incidence of all-cause mortality was 43 % for the high-risk group, 36 % for the indeterminate-risk group, and 23 % for the low-risk group. The indeterminate-risk and high-risk group had an increased hazard ratio (HR) for all-cause mortality (HR 1.33, 95 % confidence interval [CI] 1.16-1.52; HR 1.51, 95 % CI 1.31-1.74) compared to the low-risk group. Similarly, HRs were elevated for cardiovascular mortality (HR 1.61, 95 % CI 1.27-2.05; HR 2.14, 95 % CI 1.67-2.74) and MALO (HR 1.77, 95 % CI 1.01-3.31; HR 2.54, 95 % CI 1.43-4.52). CONCLUSION:A high FIB-4 score in patients with HFrEF is associated with increased mortality and MALO.

Heart failure (HF) is a major contributor to global morbidity and mortality. While distinct clinical subtypes, defined by etiology and left ventricular ejection fraction, are well recognized, their genetic determinants remain inadequately understood. In this study, we report a genome-wide association study of HF and its subtypes in a sample of 1.9 million individuals. A total of 153,174 individuals had HF, of whom 44,012 had a nonischemic etiology (ni-HF). A subset of patients with ni-HF were stratified based on left ventricular systolic function, where data were available, identifying 5,406 individuals with reduced ejection fraction and 3,841 with preserved ejection fraction. We identify 66 genetic loci associated with HF and its subtypes, 37 of which have not previously been reported. Using functionally informed gene prioritization methods, we predict effector genes for each identified locus, and map these to etiologic disease clusters through phenome-wide association analysis, network analysis and colocalization. Through heritability enrichment analysis, we highlight the role of extracardiac tissues in disease etiology. We then examine the differential associations of upstream risk factors with HF subtypes using Mendelian randomization. These findings extend our understanding of the mechanisms underlying HF etiology and may inform future approaches to prevention and treatment.

BACKGROUND:It is uncertain whether recent advances in heart failure (HF) management have translated into improved survival among the very elderly. OBJECTIVES:The objective of the study was to examine 20-year trends in 2-year mortality among Danish octogenarians with new-onset HF and identify-associated factors. METHODS:This nationwide cohort study included all Danish patients aged ≥80 years diagnosed with incident HF from 2002 to 2021. Two-year mortality rates were assessed overall and across subgroups defined by age (≥85 years), sex, frailty, and comorbidities. Use of evidence-based HF therapies-angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, angiotensin receptor-neprilysin inhibitors, β-blockers, and mineralocorticoid receptor antagonists-was evaluated over time. RESULTS:Among 46,943 octogenarians with incident HF, the crude 2-year mortality risk declined by 8% from 2002 to 2006 to 2017 to 2021. Adjusted analysis showed a 28% reduction in the hazard of mortality in the later period compared to the earlier period. Diagnoses increasingly occurred in outpatient settings, and patients had more recorded comorbidities over time. Mortality improvements were observed across all subgroups, although with variable magnitude. Use of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers/angiotensin receptor-neprilysin inhibitors, and β-blockers increased, whereas mineralocorticoid receptor antagonists use slightly declined (2002-2006: 31.6%; 95% CI: 30.7%-32.5%; 2017-2021: 27.4%; 95% CI: 26.6%-28.3%). CONCLUSIONS:Over the past 2 decades, 2-year mortality rates in octogenarians with HF have improved despite an increase in comorbidities recorded at the time of diagnosis.

Aims Children of patients with early-onset myocardial infarction (MI) are at increased risk, but the importance of concordant vs. discordant parent-offspring risk factor profiles on MI risk is largely unknown. We quantified the long-term absolute risk of MI according to shared risk factors in adulthood.Methods and results We sampled data on familial predisposed offspring and their parents from the Framingham Heart Study. Early MI was defined as a history of parental MI onset before age 55 in men or 65 in women. Individuals were matched 3:1 with non-predisposed offspring. Cardiovascular risk factors included obesity, smoking, hypertension, high cholesterol, and diabetes. We estimated the absolute 20-year incidence of MI using the Aalen-Johansen estimator. At age 40, the 20-year risk of MI varied by cholesterol level [high cholesterol 25.7% (95% confidence interval 11.2-40.2%) vs. non-high cholesterol 3.4% (0.5-6.4)] among predisposed individuals, and this difference was greater than in controls [high cholesterol 9.3% (1.5-17.0) vs. non-high cholesterol 2.5% (1.1-3.8)]. Similar results were observed for prevalent hypertension [26.7% (10.8-42.5) vs. 4.0% (0.9-7.1) in predisposed vs. 10.8% (3.2-18.3) and 2.1% (0.8-3.4) in controls]. Among offspring without risk factors, parental risk factors carried a residual impact on 20-year MI risk in offspring [0% (0-11.6) for 0-1 parental risk factors vs. 3.3% (0-9.8) for >= 2 parent risk factors at age 40, vs. 2.9% (0-8.4) and 8.5% (0-19.8) at age 50 years].Conclusion Children of patients with early-onset MI have low absolute risks of MI in the absence of midlife cardiovascular risk factors, especially if the parent also had a low risk factor burden prior to MI. Children of patients with early-onset myocardial infarction (MI) are at a higher risk of disease themselves. Cardiovascular risk factor control is important to lower the risk of disease, but little is known about how the offspring's risk differs based on risk factor controls. Using multi-generational data from the Framingham Heart Study, we observed that adult children of people with early-onset MI have low absolute 20-year risk of developing an MI if they do not have any cardiovascular risk factors, especially if the parent also had low risk factor burden prior to MI, suggesting that close surveillance for risk factor development in offspring is warranted. In offspring of parents with early-onset MI who did not have any risk factors, the number of risk factors in the parent seemed to slightly impact the risk of MI. Improved clarity of the interplay between risk factors in parents and offspring can help medical doctors provide accurate guidance in terms of preventing the development of MI. Our findings suggest that in the absence of risk factors, assessment of the parents' risk factors burden may be helpful for further risk stratification. Graphical Abstract

Background Heart failure (HF) and frailty often coexist. However, it is unknown how the interplay between HF and frailty at HF onset impacts prognosis of frail patients with HF and how this has evolved over time.Methods and Results We identified 131 235 patients with new-onset HF (median age 74 years, 39.7% women) from Danish nationwide registers in 1999 to 2017. Stratification according to the Hospital Frailty Risk Score resulted in (1) 102 635 (78%) nonfrail, (2) 26 054 (20%) moderately frail, and (3) 2609 (2%) severely frail patients. The proportion of moderately frail patients increased from 13.2% to 24.9%. Five-year absolute risks of all-cause mortality, HF hospitalization, and non-HF hospitalization were calculated using the Kaplan-Meier and Aalen-Johansen estimators. From 1999 to 2002 to 2003 to 2017, all-cause mortality risk (95% CI) declined from 56.4% (55.8%-57.0%) to 33.3% (32.6%-34.1%), 79.8% (78.5%-81.0%) to 58.6% (57.2%-60.1%), and 90.8% (85.6%-96.0%) to 79.8% (76.4%-83.2%) in nonfrail, moderately frail, and severely frail patients, respectively. HF hospitalization risk remained almost constant over the study period. Non-HF hospitalization risk declined from 74.0% (73.5%-74.5%) to 65.8% (65.0%-66.5%) in nonfrail patients and remained stable overall in moderately frail and severely frail patients over the study period.Conclusions We observed an increase in frail patients. Mortality decreased for all frailty groups but remained high for severely frail patients. These findings indicate the need for further evidence on the optimization of care for frail patients with HF, and future research should address the development of comprehensive management strategies, integrating frailty assessment into standard clinical care and focused care for older patients with HF.

BACKGROUND:Sodium-glucose cotransporter-2 inhibitors (SGLT2i) increase haemoglobin and haematocrit levels, potentially causing secondary erythrocytosis-defined as a haemoglobin level above 16.5 g/dL in men and 16.0 g/dL in women-which is associated with an elevated thromboembolic risk. This study investigated the incidence of erythrocytosis and its association with thromboembolic events in patients with heart failure with reduced ejection fraction (HFrEF) treated with SGLT2i. METHODS:In this nationwide cohort study, we included 3138 patients with new-onset HFrEF who initiated SGLT2i treatment after diagnosis, and 3138 propensity score-matched untreated controls. Haemoglobin was measured at baseline and six-month follow-up. Erythrocytosis incidence at follow-up was assessed using Poisson regression. Cox models were used to evaluate the association between erythrocytosis and one-year risk of fatal and non-fatal thromboembolic events (myocardial infarction, stroke, pulmonary embolism, or deep venous thrombosis), stratified by SGLT2i treatment. RESULTS:Erythrocytosis developed in 207 patients (3.3%). Incidence was higher among SGLT2i-treated patients (109.5 vs. 26.8 per 1000 person-years), with an adjusted incidence rate ratio of 4.10 (95% CI 2.95-5.83). No significant association was observed between erythrocytosis and one-year thromboembolic risk in the total population (HR: 0.85 95% CI 0.44-1.65), even when stratified by SGLT2i-treated (HR: 0.81 95% CI 0.38-1.74) and untreated patients (HR: 0.75, 95% CI 0.19-3.05) (interaction P = 0.77). CONCLUSION:Although erythrocytosis incidence was higher in SGLT2i-treated HFrEF patients, it was not associated with an increased one-year thromboembolic risk.

BACKGROUND:Despite advances in heart failure care reducing mortality in clinical trials, it remains unclear whether real-life cohorts have had similar improvements in life expectancy across the age spectrum. We aimed to investigate how mortality trends changed in patients with heart failure over the past 25 years, stratified by age groups. METHODS:Using Danish nationwide registries, we identified patients with new-onset heart failure aged 18-95 years. The 5-year all-cause mortality risk and the absolute risk difference of mortality between patients with heart failure and age-matched and sex-matched heart failure-free controls were assessed using Kaplan-Meier estimates and multivariable Cox regression models. Mortality trends were analysed across five calendar periods (1996-2000, 2001-05, 2006-10, 2011-15, and 2016-20) and three age groups (<65 years, 65-79 years, and ≥80 years). FINDINGS:194 997 patients with heart failure were included. Mortality significantly decreased from 1996-2000 (66% [95% CI 65·5-66·4]) to 2016-20 (43% [42·1-43·4]), with similar results shown in all age groups (<65 years: 35% [33·9-36·1] to 15% [14·6-16·3]; 65-79 years: 64% [63·1-64·5] to 39% [37·6-39·6]; and ≥80 years: 84% [83·1-84·3] to 73% [71·7-73·9]). Adjusted mortality rates supported these associations. The absolute risk difference declined notably in younger age groups (<65 years: 29·9% [28·8-31·0] to 12·7% [12·0-13·4] and 65-79 years: 41·1% [40·3-41·9] to 25·1% [24·4-25·8]), remaining relatively stable in those aged 80 years or older (30·6% [29·9-31·3] to 28% [27·2-28·8]). INTERPRETATION:Over 25 years, there has been a consistent decrease in mortality among patients with heart failure across age groups, albeit less prominently in patients aged 80 years or older. Further insight is needed to identify effective strategies for improving disease burden in older patients with heart failure. FUNDING:None. TRANSLATION:For the Danish translation of the abstract see Supplementary Materials section.

AbstractAimsChronic kidney disease (CKD) is a well‐established risk factor for heart failure (HF); however, patients with an estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2 have been systematically excluded from clinical trials. This study investigated the incidence of HF and kidney outcomes in HF patients with and without advanced CKD, that is, eGFR < 30.MethodsFrom nationwide registries, HF patients were identified from 2014 to 2018 and categorized into three groups according to baseline eGFR (eGFR ≥ 60, 60 > eGFR ≥ 30 and eGFR < 30). The incidence of primary outcomes (all‐cause mortality, HF hospitalization, end‐stage kidney disease and sustained 50% eGFR decline) was estimated using cumulative incidence functions.ResultsOf the 21 959 HF patients included, the median age was 73.9 years, and 30% of patients had an eGFR between 30 and 60 and 7% had an eGFR < 30. The 4 year incidence of all‐cause mortality was highest for patients with eGFR < 30 (28.3% for patients with eGFR ≥ 60, 51.6% for patients with 60 > eGFR ≥ 30 and 72.2% for patients with eGFR < 30). The 4 year incidence of HF hospitalization was comparable between the groups (25.8%, 29.8% and 26.1% for patients with eGFR ≥ 60, 60 > eGFR ≥ 30 and eGFR < 30, respectively). For patients with eGFR < 30, kidney outcomes were four times more often the first event than patients with eGFR > 30 (4 year incidence of kidney outcome as the first event was 5.0% for eGFR ≥ 60, 4.8% for 60 > eGFR ≥ 30 and 20.1% for eGFR < 30).ConclusionsPatients with advanced CKD had a higher incidence of mortality and poorer kidney outcomes than those without advanced CKD, but a similar incidence of HF hospitalizations.

AimsAlthough recent randomized clinical trials have demonstrated the advantages of heart failure (HF) therapy in both frail and not frail patients, there is insufficient information on the use of HF therapy based on frailty status in a real-world setting. The aim was to examine how frailty status in HF patients associates with use of HF therapy and with clinical outcomes.Methods and resultsPatients with new-onset HF between 2014 and 2021 were identified using the nationwide Danish registers. Patients across the entire range of ejection fraction were included. The associations between frailty status (using the Hospital Frailty Risk Score) and use of HF therapy and clinical outcomes (all-cause mortality, HF hospitalization, and non-HF hospitalization) were evaluated using multivariable-adjusted Cox models adjusting for age, sex, diagnostic setting, calendar year, comorbidities, pharmacotherapy, and socioeconomic status. Of 35 999 participants (mean age 69.1 years), 68% were not frail, 26% were moderately frail, and 6% were severely frail. The use of HF therapy was significantly lower in frailer patients. The hazard ratio (HR) for angiotensin-converting enzyme inhibitor/angiotensin receptor blocker initiation was 0.74 (95% confidence interval 0.70-0.77) and 0.48 (0.43-0.53) for moderate frailty and severe frailty, respectively. For beta-blockers, the corresponding HRs were 0.74 (0.71-0.78) and 0.51 (0.46-0.56), respectively, and for mineralocorticoid receptor antagonists, 0.83 (0.80-0.87) and 0.58 (0.53-0.64), respectively. The prevalence of death and non-HF hospitalization increased with frailty status. The HR for death was 1.55 (1.47-1.63) and 2.32 (2.16-2.49) for moderate and severe frailty, respectively, and the HR for non-HF hospitalization was 1.37 (1.32-1.41) and 1.82 (1.72-1.92), respectively. The association between frailty status and HF hospitalization was not significant (HR 1.08 [1.02-1.14] and 1.08 [0.97-1.20], respectively).ConclusionIn real-world HF patients, frailty was associated with lower HF therapy use and with a higher incidence of clinical outcomes including mortality and non-HF hospitalization.