Cardiac Myosin Activation with Omecamtiv Mecarbil in Systolic Heart Failure.

BACKGROUND: The selective cardiac myosin activator omecamtiv mecarbil has been shown to improve cardiac function in patients with heart failure with a reduced ejection fraction. Its effect on cardiovascular outcomes is unknown. METHODS: We randomly assigned 8256 patients (inpatients and outpatients) with symptomatic chronic heart failure and an ejection fraction of 35% or less to receive omecamtiv mecarbil (using pharmacokinetic-guided doses of 25 mg, 37.5 mg, or 50 mg twice daily) or placebo, in addition to standard heart-failure therapy. The primary outcome was a composite of a first heart-failure event (hospitalization or urgent visit for heart failure) or death from cardiovascular causes. RESULTS: During a median of 21.8 months, a primary-outcome event occurred in 1523 of 4120 patients (37.0%) in the omecamtiv mecarbil group and in 1607 of 4112 patients (39.1%) in the placebo group (hazard ratio, 0.92; 95% confidence interval [CI], 0.86 to 0.99; P = 0.03). A total of 808 patients (19.6%) and 798 patients (19.4%), respectively, died from cardiovascular causes (hazard ratio, 1.01; 95% CI, 0.92 to 1.11). There was no significant difference between groups in the change from baseline on the Kansas City Cardiomyopathy Questionnaire total symptom score. At week 24, the change from baseline for the median N-terminal pro-B-type natriuretic peptide level was 10% lower in the omecamtiv mecarbil group than in the placebo group; the median cardiac troponin I level was 4 ng per liter higher. The frequency of cardiac ischemic and ventricular arrhythmia events was similar in the two groups. CONCLUSIONS: Among patients with heart failure and a reduced ejection, those who received omecamtiv mecarbil had a lower incidence of a composite of a heart-failure event or death from cardiovascular causes than those who received placebo. (Funded by Amgen and others; GALACTIC-HF ClinicalTrials.gov number, NCT02929329; EudraCT number, 2016-002299-28.).

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.

Associations between rheumatoid arthritis, incident heart failure, and left ventricular ejection fraction.

BACKGROUND: Rheumatoid arthritis (RA) is an independent risk factor for heart failure (HF). Yet, the association between RA and left ventricular ejection fraction (LVEF) in incident HF is not well studied, nor are outcomes of HF in RA by LVEF. METHODS: We identified incident HF patients between 2003 and 2018 through the Swedish Heart Failure Registry, enriched with data from national health registers. Using logistic regression, associations between a prior diagnosis of RA and LVEF among HF patients and vs age, sex, and geographical area matched general population controls without HF were assessed. Additionally, associations between HF with vs without a prior diagnosis of RA, by LVEF, and outcomes up to 5 years after HF diagnosis were investigated using Cox regression. LVEF was primarily dichotomized at 40% and secondarily categorized as <40%, 40% to 49%, and ≥50%. Covariates included demographics and cardiovascular comorbidities. RESULTS: Among 20,916 incident HF patients, 331 (1.6%) had RA vs 1,047/103,501 (1.0%) of HF-free controls. The odds ratio (OR) for RA was 1.4 (95% CI: 1.1-1.8) in LVEF<40% vs HF-free controls and 1.6 (95% CI: 1.3-2.0) in LVEF≥40% vs HF-free controls. Among HF patients, RA was more common in HF with LVEF ≥40% (1.9%) vs LVEF<40% (1.3%), corresponding to OR 1.4 (95% CI: 1.1-1.7). No associations between RA and cardiovascular outcomes were observed across LVEF. An association between RA and all-cause mortality was observed only for patients with LVEF<40% (hazard ratio: 1.4; 95% CI: 1.1-1.8). CONCLUSIONS: RA was independently associated with incident HF, particularly HF with LVEF≥40%. RA did not associate with cardiovascular outcomes following HF diagnosis but was associated with increased risk of all-cause mortality in HF with LVEF<40%.

Global disparities in prescription of guideline-recommended drugs for heart failure with reduced ejection fraction.

BACKGROUND: Heart failure (HF) is a global challenge, with lower- and middle-income countries (LMICs) carrying a large share of the burden. Treatment for HF with reduced ejection fraction (HFrEF) improves survival but is often underused. Economic factors might have an important effect on the use of medicines. METHODS AND RESULTS: This analysis assessed prescription rates and doses of renin-angiotensin system (RAS) inhibitors, ß-blockers, and mineralocorticoid receptor antagonists at discharge and 6-month follow-up in 8669 patients with HFrEF (1458 from low-, 3363 from middle-, and 3848 from high-income countries) hospitalized for acute HF in 44 countries in the prospective REPORT-HF study. We investigated determinants of guideline-recommended treatments and their association with 1-year mortality, correcting for treatment indication bias.Only 37% of patients at discharge and 34% of survivors at 6 months were on all three medication classes, with lower proportions in LMICs than high-income countries (19 vs. 41% at discharge and 15 vs. 37% at 6 months). Women and patients without health insurance, or from LMICs, or without a scheduled medical follow-up within 6 months of discharge were least likely to be on guideline-recommended medical therapy at target doses, independent of confounders. Being on ≥50% of guideline-recommended doses of RAS inhibitors, and ß-blockers were independently associated with better 1-year survival, regardless of country income level. CONCLUSION: Patients with HFrEF in LMICs are less likely to receive guideline-recommended drugs at target doses. Improved access to medications and medical care could reduce international disparities in outcome.

A global perspective of racial differences and outcomes in patients presenting with acute heart failure.

Important racial differences in characteristics, treatment, and outcomes of patients with acute heart failure (AHF) have been described. The objective of this analysis of the International Registry to assess medical Practice with longitudinal observation for Treatment of Heart Failure (REPORT-HF) registry was to investigate racial differences in patients with AHF according to country income level.

Eligibility for Dapagliflozin and Empagliflozin in a Real-world Heart Failure Population.

BACKGROUND: We investigated eligibility for dapagliflozin and empagliflozin in a real-world heart failure (HF) cohort based on selection criteria of DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure), DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients with Preserved Ejection Fraction Heart Failure), and EMPEROR (Empagliflozin Outcome Trial in Patients with Chronic Heart Failure with Reduced Ejection Fraction and Empagliflozin Outcome Trial in Patients with Chronic Heart Failure with APreserved Ejection Fraction) trials. METHODS AND RESULTS: Selection criteria were applied to the Swedish HF registry outpatient population according to 3 scenarios: (i) a "trial scenario" applying all selection criteria; (ii) a "pragmatic scenario" applying the most clinically relevant criteria; and (iii) a "label scenario" following the regulatory agencies labels. Of the 49,317 patients, 55% had an ejection fraction of less than 40% and were assessed for eligibility based on DAPA-HF and EMPEROR-Reduced, 45% had ejection fraction of 40% or greater and were assessed based on EMPEROR-Preserved and DELIVER. Eligibility using trial, pragmatic, and label scenarios was 35%, 61%, and 80% for DAPA-HF; 31%, 55%, and 81% for EMPEROR-Reduced; 30%, 61%, and 74% for DELIVER; and 32%, 59%, and 75% for EMPEROR-Preserved, respectively. The main selection criteria limiting eligibility were HF duration and N-terminal pro-B type natriuretic peptide levels. Eligible patients had more severe HF, more comorbidities, higher use of HF treatments and higher mortality and morbidity.Clinical Highlights: Large clinical trials for the approval of new drugs in heart failure often apply numerous selection criteria, limiting the generalizability of trial findings to real-world populations. We assessed eligibility for dapagliflozin and empagliflozin according to trial criteria, the more practical criteria usually applied in daily practice for treatment selection, and the criteria mandated by regulatory agencies, in a real-word heart failure population. Our results from the Swedish Heart Failure Registry show that a great number of patients with heart failure might be candidates for these therapies, which have been shown to significantly decrease morbidity and mortality; therefore, their use should be implemented in clinical practice. LAY SUMMARY: When strictly applying selection criteria used in clinical trials, only one-third of a real-world heart failure population is eligible for treatment with empagliflozin and dapagliflozin. Adopting approaches that consider the most meaningful criteria, that is, those most clinically relevant or those mandated by regulatory agencies, significantly broadened eligibility. These results might contribute to future trial design taking into consideration the characteristics of real-world populations, feasibility, and potential cost benefits. CONCLUSIONS: In a real-world HF setting, eligibility for sodium glucose co-transporter-2 inhibitors was similar whether selection criteria from DAPA-HF or EMPEROR-Reduced were applied in HFrEF, or EMPEROR-Preserved or DELIVER in HFpEF. These data might help stakeholders assessing the consequences of future trial eligibility.

Cardiac resynchronization therapy with or without defibrillator in patients with heart failure.

AIMS: Randomized data on the efficacy/safety of cardiac resynchronization therapy with vs. without defibrillator (CRT-D,-P) in heart failure with reduced ejection fraction (HFrEF) are scarce. We aimed to evaluate survival associated with use of CRT-D vs. CRT-P in a contemporary cohort with HFrEF. METHODS AND RESULTS: Patients from Swedish HF Registry treated with CRT-D/CRT-P and fulfilling criteria for primary prevention defibrillator use were included. Logistic regression was used to evaluate predictors of CRT-D non-use. All-cause mortality was compared in CRT-D vs. CRT-P by Cox regression in a 1 : 1 propensity-score-matched cohort. Of 1988 patients with CRT, 1108 (56%) had CRT-D and 880 (44%) CRT-P. Older age, higher ejection fraction (EF), female sex, and the lack of referral to HF nurse-led outpatient clinic were major determinants of CRT-D non-use. After matching, 645 CRT-D patients were compared with 645 with CRT-P. The CRT-D use was associated with lower 1- and 3-year all-cause mortality [hazard ratio (HR):0.76, 95% confidence interval (CI):0.58-0.98; HR: 0.82, 95% CI: 0.68-0.99, respectively]. Results were consistent in all pre-specified subgroups except for CRT-D use being associated with lower 3-year mortality in patients with an EF < 30% but not in those with an EF ≥ 30% (HR: 0.73, 95% CI: 0.59-0.89 and HR: 1.24, 95% CI: 0.83-1.85, respectively; P-interaction = 0.02). CONCLUSION: In a contemporary HFrEF cohort, CRT-D was associated with lower mortality compared with CRT-P. The CRT-D use was less likely in older patients, females, and in patients not referred to HF nurse-led outpatient clinic. Our findings support the use of CRT-D vs. CRT-P in HFrEF, in particular with severely reduced EF.

Association Between ß-Blockers and Outcomes in Heart Failure With Preserved Ejection Fraction: Current Insights From the SwedeHF Registry.

BACKGROUND: ß-Blockers have an uncertain effect in heart failure with a preserved ejection fraction of 50% or higher (heart failure with preserved ejection fraction [HFpEF]). METHODS AND RESULTS: We included patients with HFpEF from the Swedish Heart Failure Registry (SwedeHF) enrolled from 2011 through 2018. In a 2:1 propensity-score matched analysis (ß-blocker use vs nonuse), we assessed the primary outcome first HF hospitalization, the coprimary outcome cardiovascular (CV) death, and the secondary outcomes of all-cause hospitalization and all-cause death. We performed intention-to-treat and a per-protocol consistency analyses. There were a total of 14,434 patients (median age 79 years, IQR 71-85 years, 51% women); 80% were treated with a ß-blocker at baseline. Treated patients were younger and had higher rates of atrial fibrillation and coronary artery disease, and higher N-terminal pro-B-type natriuretic peptide levels. In the 4412:2206 patient matched cohort, at 5 years, 42% (95% CI 40%-44%) vs 44% (95% CI 41%-47%) had a HF admission and 38% (IQR 36%-40%) vs 40% (IQR 36%-42%) died from CV causes. In the intention-to-treat analysis, ß-blocker use was not associated with HF admissions (hazard ratio 0.95 [95% CI 0.87-1.05, P = .31]) or CV death (hazard ratio 0.94 [95% CI 0.85-1.03, P = .19]). In the subgroup analyses, men seemed to have a more favorable association between ß-blockers and outcomes than did women. There were no associations between ß-blocker use and secondary outcomes. CONCLUSIONS: In patients with HFpEF, ß-blocker use is common but not associated with changes in HF hospitalization or cardiovascular mortality. In the absence of a strong rational and randomized control trials the case for ß-blockers in HFpEF remains inconclusive. BULLET POINTS: ● The effect of ß-blockers with heart failure with preserved ejection fraction of 50% or greater is uncertain.● In a propensity score-matched heart failure with preserved ejection fraction analysis in the SwedeHF registry, ß-blockers were not associated with a change in risk for heart failure admissions or cardiovascular deaths. LAY SUMMARY: The optimal treatment for heart failure with a preserved pump function remains unknown. Despite the lack of scientific studies, ß-blockers are very commonly used. When matching patients with a similar risk profile in a large heart failure registry, the use of ß-blockers for the treatment of heart failure with a preserved pump function was not associated with any changes in heart failure hospital admissions or cardiovascular death.

Temporal trends in outcome and patient characteristics in dilated cardiomyopathy, data from the Swedish Heart Failure Registry 2003-2015.

BACKGROUND: Temporal trends in clinical composition and outcome in dilated cardiomyopathy (DCM) are largely unknown, despite considerable advances in heart failure management. We set out to study clinical characteristics and prognosis over time in DCM in Sweden during 2003-2015. METHODS: DCM patients (n = 7873) from the Swedish Heart Failure Registry were divided into three calendar periods of inclusion, 2003-2007 (Period 1, n = 2029), 2008-2011 (Period 2, n = 3363), 2012-2015 (Period 3, n = 2481). The primary outcome was the composite of all-cause death, transplantation and hospitalization during 1 year after inclusion into the registry. RESULTS: Over the three calendar periods patients were older (p = 0.022), the proportion of females increased (mean 22.5%, 26.4%, 27.6%, p = 0.0001), left ventricular ejection fraction was higher (p = 0.0014), and symptoms by New York Heart Association less severe (p < 0.0001). Device (implantable cardioverter defibrillator and/or cardiac resynchronization) therapy increased by 30% over time (mean 11.6%, 12.3%, 15.1%, p < 0.0001). The event rates for mortality, and hospitalization were consistently decreasing over calendar periods (p < 0.0001 for all), whereas transplantation rate was stable. More advanced physical symptoms correlated with an increased risk of a composite outcome over time (p = 0.0043). CONCLUSIONS: From 2003 until 2015, we observed declining mortality and hospitalizations in DCM, paralleled by a continuous change in both demographic profile and therapy in the DCM population in Sweden, towards a less affected phenotype.

Association Between Use of Primary-Prevention Implantable Cardioverter-Defibrillators and Mortality in Patients With Heart Failure: A Prospective Propensity Score-Matched Analysis From the Swedish Heart Failure Registry.

BACKGROUND: Most randomized trials on implantable cardioverter-defibrillator (ICD) use for primary prevention of sudden cardiac death in heart failure with reduced ejection fraction enrolled patients >20 years ago. We investigated the association between ICD use and all-cause mortality in a contemporary heart failure with reduced ejection fraction cohort and examined relevant subgroups. METHODS: Patients from the Swedish Heart Failure Registry fulfilling the European Society of Cardiology criteria for primary-prevention ICD were included. The association between ICD use and 1-year and 5-year all-cause and cardiovascular (CV) mortality was assessed by Cox regression models in a 1:1 propensity score-matched cohort and in prespecified subgroups. RESULTS: Of 16 702 eligible patients, only 1599 (10%) had an ICD. After matching, 1305 ICD recipients were compared with 1305 nonrecipients. ICD use was associated with a reduction in all-cause mortality risk within 1 year (hazard ratio, 0.73 [95% CI, 0.60-0.90]) and 5 years (hazard ratio, 0.88 [95% CI, 0.78-0.99]). Results were consistent in all subgroups including patients with versus without ischemic heart disease, men versus women, those aged <75 versus ≥75 years, those with earlier versus later enrollment in the Swedish heart failure registry, and patients with versus without cardiac resynchronization therapy. CONCLUSIONS: In a contemporary heart failure with reduced ejection fraction population, ICD for primary prevention was underused, although it was associated with reduced short- and long-term all-cause mortality. This association was consistent across all the investigated subgroups. These results call for better implementation of ICD therapy.

Modeling defibrillation benefit for survival among cardiac resynchronization therapy defibrillator recipients.

BACKGROUND: Patients with heart failure having a low expected probability of arrhythmic death may not benefit from implantable cardioverter defibrillators (ICDs). OBJECTIVE: The objective was to validate models to identify cardiac resynchronization therapy (CRT) candidates who may not require CRT devices with ICD functionality. METHODS: Heart failure (HF) patients with CRT-Ds and non-CRT ICDs from the National Cardiovascular Data Registry and others with no device from 3 separate registries and 3 heart failure trials were analyzed using multivariable Cox proportional hazards regression for survival with the Seattle Heart Failure Model (SHFM; estimates overall mortality) and the Seattle Proportional Risk Model (SPRM; estimates proportional risk of arrhythmic death). RESULTS: Among 60,185 patients (age 68.6 ±â€¯11.3 years, 31.9% female) meeting CRT-D criteria, 38,348 had CRT-Ds, 11,389 had non-CRT ICDs, and 10,448 had no device. CRT-D patients had a prominent adjusted survival benefit (HR 0.52, 95% CI 0.50-0.55, P < .0001 versus no device). CRT-D patients with SHFM-predicted 4-year survival ≥81% (median) and a low SPRM-predicted probability of an arrhythmic mode of death ≤42% (median) had an absolute adjusted risk reduction attributable to ICD functionality of just 0.95%/year with the majority of survival benefit (70%) attributable to CRT pacing. In contrast, CRT-D patients with SHFM-predicted survival median had substantially more ICD-attributable benefit (absolute risk reduction of 2.6%/year combined; P < .0001). CONCLUSIONS: The SPRM and SHFM identified a quarter of real-world, primary prevention CRT-D patients with minimal benefit from ICD functionality. Further studies to evaluate CRT pacemakers in these low-risk CRT candidates are indicated.

Higher blood pressure in elderly hypertensive females, with increased arterial stiffness and blood pressure in females with the Fibrillin-1 2/3 genotype.

BACKGROUND: Elderly patients have a relatively high cardiovascular risk due to increased arterial stiffness, elevated blood pressure and decreased amounts of elastin in the arteries. The composition of the media layer in the arterial wall, comprising elastin, collagen, smooth muscle cells, proteoglycans, fibronectin and fibrillin-1, influences its mechanical properties. Mutations in the fibrillin-1 gene leads to increased aortic stiffness, elevated pulse pressure and aortic root dilatation. This study investigates whether there is a sex difference among hypertensive elderly patients regarding blood pressure, arterial stiffness and fibrillin-1 genotypes. METHODS: A total of 315 hypertensive subjects (systolic blood pressure > 140 mmHg) were included in this study (155 men and 160 women aged 71-88 years). Aortic pulse wave velocity and augmentation index were determined using SphygmoCor, and brachial blood pressure was measured using an oscillometric technique. Fibrillin-1 was genotyped by polymerase chain reaction and with a capillary electrophoresis system. RESULTS: Females showed a significantly higher peripheral mean arterial pressure (females; 107.20 mmHg, males 101.6 mmHg, p = 0.008), central mean arterial pressure (females; 107.2 mmHg, males 101.6 mmHg p = 0.008), central systolic blood pressure (females; 148.1 mmHg, males 139.2 mmHg, p <  0.001) and central pulse pressure (females; 68.9 mmHg, males 61.6 mmHg, p = 0.035) than males. Females with the Fibrillin-1 2/3 genotype showed a significantly higher augmentation index (FBN1 2/3; 39.9%, FBN1 2/2 35.0%, FBN1 2/4 35.8, p = 0.029) and systolic blood pressure (FBN1 2/3; 174.6 mmHg, FBN1 2/2168.9 mmHg, FBN1 2/4169.9 mmHg, p = 0.025) than females with the 2/2 and 2/4 genotypes. CONCLUSION: The findings of this study may indicate that hypertensive elderly females, especially elderly females with Fibrillin-1 2/3, have increased systolic blood pressure and arterial stiffness.

Limited value of NT-proBNP as a prognostic marker of all-cause mortality in patients with heart failure with preserved and mid-range ejection fraction in primary care: A report from the swedish heart failure register.

Aim: The prognostic value of natriuretic peptides in the management of heart failure (HF) patients with ejection fraction (EF) <40% is well established, but is less known for those with EF ≥40% managed in primary care (PC). Therefore, the aim of this study is to describe the prognostic significance of plasma NT-proBNP in such patients managed in PC.Subjects: We included 924 HF patients (48% women) with EF ≥40% and NT-proBNP registered in the Swedish Heart Failure Registry. Follow-up was 1100 ± 687 days.Results: One-, three- and five-year mortality rates were 8.1%, 23.9% and 44.7% in patients with EF 40-50% (HFmrEF) and 7.3%, 23.6% and 37.2% in patients with EF ≥50% (HFpEF) (p = 0.26). Patients with the highest mean values of NT-proBNP had the highest all-cause mortality but wide standard deviations (SDs). In univariate regression analysis, there was an association only between NT-proBNP quartiles and all-cause mortality. In HFmrEF patients, hazard ratio (HR) was 1.96 (95% CI 1.60-2.39) p < 0.0001) and in HFpEF patients, HR was 1.72 (95% CI 1.49-1.98) p < 0.0001). In a multivariate Cox proportional hazard regression analysis, adjusted for age, NYHA class, atrial fibrillation and GFR class, this association remained regarding NT-proBNP quartiles [HR 1.83 (95% CI 1.38-2.44), p < 0.0001] and [HR 1.48 (95% CI 1.16-1.90), p = 0.0001], HFmrEF and HFpEF, respectively.Conclusion: NT-proBNP has a prognostic value in patients with HF and EF ≥40% managed in PC. However, its clinical utility is limited due to high SDs and the fact that it is not independent in this population which is characterized by high age and much comorbidity.Key pointsIt is uncertain whether NT-proBNP predicts risk in heart failure with preserved ejection fraction (EF > 40%, HFpEF) managed in primary care.We show that high NT-proBNP predicts increased all-cause mortality in HFpEF-patients managed in primary care.The clinical use is however limited due to large standard deviations, many co-morbidities and high age.Many of these co-morbidities contribute to all-cause mortality and management of these patients should also focus on these co-morbidities.

Association between renin-angiotensin system inhibitor use and mortality/morbidity in elderly patients with heart failure with reduced ejection fraction: a prospective propensity score-matched cohort study.

Aims: In heart failure with reduced ejection fraction (HFrEF), renin-angiotensin system inhibitors (RASi) improve morbidity and mortality. However, patients aged >80 years constituted a small minority in trials. We assessed the association between RASi use and mortality/morbidity in HFrEF patients aged >80 years. Methods and results: We included patients with ejection fraction <40% and age >80 years from the Swedish Heart Failure Registry. Propensity scores for RASi use were calculated from 37 variables. Cox regression models for RASi vs. non-RASi with all-cause mortality and all-cause mortality/heart failure (HF) hospitalization as outcomes were fitted in a 1:1 propensity-score-matched cohort. To assess consistency, the same analyses were performed in a 'positive control' cohort aged ≤80 years. Of 6710 patients [median age (interquartile range) 85 (82-87) years; 38% women], 5384 (80%) received RASi. Propensity-score matching yielded 2416 patients, [age 86 (83-91) years]. RASi use was associated with hazard ratio (HR) (95% confidence interval) 0.78 (0.72-0.86) for all-cause mortality and 0.86 (0.79-0.94) for all-cause mortality/HF hospitalization. In positive control patients aged ≤80 years (17 842 patients in the overall cohort, 2126 after matching), HR for all-cause mortality was 0.81 (0.71-0.91), whereas it was 0.85 (0.76-0.94) for all-cause mortality/HF hospitalization. Conclusion: In HFrEF patients with age >80 years, RASi were relatively underused compared with in younger patients, despite similar association with reduced morbidity and mortality and no apparent association with risk of syncope-related hospitalization. These results may be interpreted as hypothesis generating for randomized clinical trials on RASi in this elderly HFrEF subpopulation.

Comorbidity health pathways in heart failure patients: A sequences-of-regressions analysis using cross-sectional data from 10,575 patients in the Swedish Heart Failure Registry.

BACKGROUND: Optimally treated heart failure (HF) patients often have persisting symptoms and poor health-related quality of life. Comorbidities are common, but little is known about their impact on these factors, and guideline-driven HF care remains focused on cardiovascular status. The following hypotheses were tested: (i) comorbidities are associated with more severe symptoms and functional limitations and subsequently worse patient-rated health in HF, and (ii) these patterns of association differ among selected comorbidities. METHODS AND FINDINGS: The Swedish Heart Failure Registry (SHFR) is a national population-based register of HF patients admitted to >85% of hospitals in Sweden or attending outpatient clinics. This study included 10,575 HF patients with patient-rated health recorded during first registration in the SHFR (1 February 2008 to 1 November 2013). An a priori health model and sequences-of-regressions analysis were used to test associations among comorbidities and patient-reported symptoms, functional limitations, and patient-rated health. Patient-rated health measures included the EuroQol-5 dimension (EQ-5D) questionnaire and the EuroQol visual analogue scale (EQ-VAS). EQ-VAS score ranges from 0 (worst health) to 100 (best health). Patient-rated health declined progressively from patients with no comorbidities (mean EQ-VAS score, 66) to patients with cardiovascular comorbidities (mean EQ-VAS score, 62) to patients with non-cardiovascular comorbidities (mean EQ-VAS score, 59). The relationships among cardiovascular comorbidities and patient-rated health were explained by their associations with anxiety or depression (atrial fibrillation, odds ratio [OR] 1.16, 95% CI 1.06 to 1.27; ischemic heart disease [IHD], OR 1.20, 95% CI 1.09 to 1.32) and with pain (IHD, OR 1.25, 95% CI 1.14 to 1.38). Associations of non-cardiovascular comorbidities with patient-rated health were explained by their associations with shortness of breath (diabetes, OR 1.17, 95% CI 1.03 to 1.32; chronic kidney disease [CKD, OR 1.23, 95% CI 1.10 to 1.38; chronic obstructive pulmonary disease [COPD], OR 95% CI 1.84, 1.62 to 2.10) and with fatigue (diabetes, OR 1.27, 95% CI 1.13 to 1.42; CKD, OR 1.24, 95% CI 1.12 to 1.38; COPD, OR 1.69, 95% CI 1.50 to 1.91). There were direct associations between all symptoms and patient-rated health, and indirect associations via functional limitations. Anxiety or depression had the strongest association with functional limitations (OR 10.03, 95% CI 5.16 to 19.50) and patient-rated health (mean difference in EQ-VAS score, -18.68, 95% CI -23.22 to -14.14). HF optimizing therapies did not influence these associations. Key limitations of the study include the cross-sectional design and unclear generalisability to other populations. Further prospective HF studies are required to test the consistency of the relationships and their implications for health. CONCLUSIONS: Identification of distinct comorbidity health pathways in HF could provide the evidence for individualised person-centred care that targets specific comorbidities and associated symptoms.

Associations With and Prognostic and Discriminatory Role of N-Terminal Pro-B-Type Natriuretic Peptide in Heart Failure With Preserved Versus Mid-range Versus Reduced Ejection Fraction.

BACKGROUND: The aim of this study was to characterize N-terminal pro-B-type natriuretic peptide (NT-proBNP) in terms of determinants of levels and of its prognostic and discriminatory role in heart failure with mid-range (HFmrEF) versus preserved (HFpEF) and reduced (HFrEF) ejection fraction. METHODS AND RESULTS: In 9847 outpatients with HFpEF (n = 1811; 18%), HFmrEF (n = 2122; 22%) and HFrEF (n = 5914; 60%) enrolled in the Swedish Heart Failure Registry, median NT-proBNP levels were 1428, 1540, and 2288 pg/mL, respectively. Many determinants of NT-proBNP differed by ejection fraction, with atrial fibrillation (AF) more important in HFmrEF and HFpEF, diabetes and hypertension in HFmrEF, and age and body mass index in HFrEF and HFmrEF, whereas renal function, New York Heart Association functional class, heart rate, and anemia were similar. Hazard ratios for death and death/HF hospitalization for NT-proBNP above the median ranged from 1.48 to 2.00 and were greatest for HFmrEF and HFpEF. Areas under the receiver operating characteristic curve for death and death/HF hospitalization were greater in HFmrEF than in HFpEF and HFrEF and were reduced by AF in HFpEF and HFmrEF but not in HFrEF. CONCLUSIONS: In HFpEF and especially HFmrEF, NT-proBNP was more prognostic and discriminatory, but also more affected by confounders such as AF. These data support the use of NT-proBNP for eligibility, enrichment, and surrogate end points in HFpEF and HFmrEF trials, and suggest that cutoff levels for eligibility should be carefully tailored to comorbidity.

Can BNP-guided therapy improve health-related quality of life, and do responders to BNP-guided heart failure treatment have improved health-related quality of life? Results from the UPSTEP study.

BACKGROUND: To investigate whether B-type natriuretic peptide (NP)-guided treatment of heart failure (HF) patients improved their health related quality of life (Hr-QoL) compared to routine HF treatment, and whether changes in Hr-QoL differed depending on whether the patient was a responder to NP-guided therapy or not. METHODS: A secondary analysis of the UPSTEP-study, a Scandinavian multicentre study using a prospective, randomized, open, blinded evaluation design on patients with HF with New York Heart Association (NYHA) class II-IV. NP-guiding was aimed to reduce BNP <150 ng/L if < 75 years or BNP < 300 ng/L if > 75 years. A responder was defined as a patient with a BNP < 300 ng/L and/or a decrease in BNP of at least 40% in week 16 compared to study start. Short form-36 (SF-36) was used to measure Hr-QoL. At the study start, 258 patients presented evaluable SF-36 questionnaires, 131 in the BNP group and 127 in the control group. At the study end 100 patients in the NP-guided group and 98 in the control group, presenting data from both the study start and the study end. RESULTS: There were no significant differences in Hr-QoL between NP-guided HF treatment and control group; however significant improvements could be seen in four of the eight domains in the NP-guided group, whereas in the control group improvements could be seen in six of the domains. Among the responders improvements could be noted in four domains whereas in the non-responders improvements could be seen in only one domain evaluating within group changes. CONCLUSIONS: Improved Hr-QoL could be demonstrated in several of the domains in both the NP-guided and the control group. In the responder group within group analyses showed more increased Hr-QoL compared to the non-responder group. However, all groups demonstrated increase in Hr-QoL.

Association between renin-angiotensin system antagonist use and mortality in heart failure with severe renal insufficiency: a prospective propensity score-matched cohort study.

AIMS: In heart failure (HF) with reduced ejection fraction (EF), renin-angiotensin receptor (RAS) antagonists reduce mortality. However, severe renal insufficiency was an exclusion criterion in trials. We tested the hypothesis that RAS antagonists are associated with reduced mortality also in HF with severe renal insufficiency. METHODS AND RESULTS: We studied patients with EF ≤39% registered in the prospective Swedish Heart Failure Registry. In patients with creatinine >221 µmol/L or creatinine clearance <30 mL/min, propensity scores for RAS-antagonist use were derived from 36 variables. The association between RAS antagonist use and all-cause mortality was assessed with Cox regression in a cohort matched 1:1 based on age and propensity score. To assess consistency, we performed the same analysis as a 'positive control' in patients without severe renal insufficiency. Between 2000 and 2013, there were 24 283 patients of which 2410 [age, mean (SD), 82 (9), 45% women] had creatinine >221 µmol/L or creatinine clearance <30 mL/min and were treated (n = 1602) or not treated (n = 808) with RAS antagonists. In the matched cohort of 602 vs. 602 patients [age 83 (8), 42% women], RAS antagonist use was associated with 55% [95% confidence interval (CI) 51-59] vs. 45% (41-49) 1-year survival, P < 0.001, with a hazard ratio (HR) for mortality of 0.76 (95% CI 0.67-0.86, P < 0.001). In positive control patients without severe renal insufficiency [n = 21 873; age 71 (12), 27% women], the matched HR was 0.79 (95% CI 0.72-0.86, P < 0.001). CONCLUSION: In HF with severe renal insufficiency, the use of RAS antagonists was associated with lower all-cause mortality. Prospective randomized trials are needed before these findings can be applied to clinical practice.

Determinants of Utility Based on the EuroQol Five-Dimensional Questionnaire in Patients with Chronic Heart Failure and Their Change Over Time: Results from the Swedish Heart Failure Registry.

BACKGROUND: There is limited information on drivers of utilities in patients with chronic heart failure (CHF). OBJECTIVES: To analyze determinants of utility in CHF and drivers of change over 1 year in a large sample from clinical practice. METHODS: We included 5334 patients from the Swedish Heart Failure Registry with EuroQol five-dimensional questionnaire information available following inpatient or outpatient care during 2008 to 2010; 3495 had 1-year follow-up data. Utilities based on Swedish and UK value sets were derived. We applied ordinary least squares (OLS) and two-part models for utility at inclusion and OLS regression for change over 1 year, all with robust standard errors. We assessed the predictive accuracy of both models using cross-validation. RESULTS: Patients' mean age was 73 years, 65% were men, 19% had a left ventricular ejection fraction of 50% or more, 23% had 40% to 49%, 27% had 30% to 39%, and 31% had less than 30%. For both models and value sets, utility at inclusion was affected by sex, age, New York Heart Association class, ejection fraction, hemoglobin, blood pressure, lung disease, diabetes, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, nitrates, antiplatelets, and diuretics. The OLS model performed slightly better than did the two-part model on a population level and for capturing utility ranges. Change in utility over 1 year was influenced by age, sex, and (measured at inclusion) disease duration, New York Heart Association class, blood pressure, ischemic heart disease, lung disease, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, and antiplatelets. CONCLUSIONS: Utilities in CHF and their change over time are influenced by diverse demographic and clinical factors. Our findings can be used to target clinical interventions and for economic evaluations of new therapies.

Gender, underutilization of cardiac resynchronization therapy, and prognostic impact of QRS prolongation and left bundle branch block in heart failure.

AIMS: It has been suggested that cardiac resynchronization therapy (CRT) is less utilized, dyssynchrony occurs at narrower QRS, and CRT is more beneficial in women compared with men. We tested the hypotheses that (i) CRT is more underutilized and (ii) QRS prolongation and left bundle branch block (LBBB) are more harmful in women. METHODS AND RESULTS: We studied 14 713 patients (28% women) with left ventricular ejection fraction (LVEF) <40% in the Swedish Heart Failure Registry. In women vs. men, CRT was present in 4 vs. 7% (P < 0.001) and was absent but with indication in 30 vs. 31% (P = 0.826). Next, among 13 782 patients (28% women) without CRT, 9% of women and 17% of men had non-specific intraventricular conduction delay (IVCD) and 27% of women and 24% of men had LBBB. One-year survival with narrow QRS was 85% in women and 88% in men, with IVCD 74 and 78%, and with LBBB 84 and 82%, respectively. Compared with narrow QRS, IVCD had a multivariable hazard ratio of 1.24 (95% CI 1.05-1.46, P = 0.011) in women and 1.30 (95% CI 1.19-1.42, P < 0.001) in men, and LBBB 1.03 (95% CI 0.91-1.16, P = 0.651) in women and 1.16 (95% CI 1.07-1.26, P < 0.001) in men, P for interaction between gender and QRS morphology, 0.241. CONCLUSIONS: While the proportion with CRT was lower in women, CRT was equally underutilized in both genders. QRS prolongation with or without LBBB was not more harmful in women than in men. Efforts to improve CRT implementation should be directed equally towards women and men.