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Aims Sudden death is a leading cause of mortality in heart failure with reduced ejection fraction (HFrEF). In PARADIGM-HF, sacubitril/valsartan reduced the incidence of sudden death. The purpose of this post hoc study was to analyse the effect of sacubitril/valsartan, compared to enalapril, on the incidence of ventricular arrhythmias. Methods and results Adverse event reports related to ventricular arrhythmias were examined in PARADIGM-HF. The effect of randomized treatment on two arrhythmia outcomes was analysed: ventricular arrhythmias and the composite of a ventricular arrhythmia, implantable cardioverter defibrillator (ICD) shock or resuscitated cardiac arrest. The risk of death related to a ventricular arrhythmia was examined in time-updated models. The interaction between heart failure aetiology, or baseline ICD/cardiac resynchronization therapy-defibrillator (CRT-D) use, and the effect of sacubitril/valsartan was analysed. Of the 8399 participants, 333 (4.0%) reported a ventricular arrhythmia and 372 (4.4%) the composite arrhythmia outcome. Ventricular arrhythmias were associated with higher mortality. Compared with enalapril, sacubitril/valsartan reduced the risk of a ventricular arrhythmia (hazard ratio [HR] 0.76, 95% confidence interval [CI] 0.62-0.95; p = 0.015) and the composite arrhythmia outcome (HR 0.79, 95% CI 0.65-0.97; p = 0.025). The treatment effect was maintained after adjustment and accounting for the competing risk of death. Baseline ICD/CRT-D use did not modify the effect of sacubitril/valsartan, but aetiology did: HR in patients with an ischaemic aetiology 0.93 (95% CI 0.71-1.21) versus 0.53 (95% CI 0.37-0.78) in those without an ischaemic aetiology (p for interaction = 0.020). Conclusions Sacubitril/valsartan reduced the incidence of investigator-reported ventricular arrhythmias in patients with HFrEF. This effect may have been greater in patients with a non-ischaemic aetiology. [ABSTRACT FROM AUTHOR]

Aims: The 4822 patients randomized in the PARAGON‐HF trial were a subset of 5746 initially eligible patients who entered sequential run‐in periods. We identified patient factors associated with study discontinuation during the run‐in period and estimated the implications of these discontinuations for the overall study result. Methods and results: We utilized multivariable logistic regression models to identify patient factors associated with study discontinuation during the run‐in period. The efficacy of sacubitril/valsartan in a broader cohort approximating the full run‐in population was estimated by weighting randomized patients according to the inverse probability of run‐in completion. A total of 924 (16.1%) subjects failed to complete the run‐in period. In multivariable models, non‐completion was associated with region other than Central Europe, lower systolic blood pressure, lower serum sodium, lower haemoglobin, lower estimated glomerular filtration rate, higher N‐terminal pro‐B‐type natriuretic peptide, higher New York Heart Association functional class, prior heart failure (HF) hospitalization, and lack of prior use of renin–angiotensin system inhibitors or beta‐blocker. In repeat analysis of the effect of randomized treatment in PARAGON‐HF giving greater weight to participants resembling those who failed to complete the run‐in period, the incidence of HF hospitalizations and cardiovascular death was higher, and sacubitril/valsartan treatment reduced the composite of total HF hospitalizations and cardiovascular death compared with valsartan (rate ratio 0.86; 95% confidence interval 0.74–1.00). Conclusion: Patients with more advanced HF were at higher risk for non‐completion of the run‐in period in PARAGON‐HF. Re‐analysis of study outcomes accounting for the effect of run‐in non‐completion did not alter the estimated treatment effects of sacubitril/valsartan vs. valsartan. [ABSTRACT FROM AUTHOR]

Importance: Heart failure with preserved ejection fraction (HFpEF) lacks effective treatments. Based on preclinical studies, neladenoson bialanate, a first-in-class partial adenosine A1 receptor agonist, has the potential to improve several heart failure-related cardiac and noncardiac abnormalities but has not been evaluated to treat HFpEF.Objectives: To determine whether neladenoson improves exercise capacity, physical activity, cardiac biomarkers, and quality of life in patients with HFpEF and to find the optimal dose.Design, Setting, and Participants: Phase 2b randomized clinical trial conducted at 76 centers in the United States, Europe, and Japan. Patients (N = 305) with New York Heart Association class II or III HFpEF with elevated natriuretic peptide levels were enrolled between May 10, 2017, and December 7, 2017 (date of final follow-up: June 20, 2018).Interventions: Participants were randomized (1:2:2:2:2:3) to neladenoson (n = 27 [5 mg], n = 50 [10 mg], n = 51 [20 mg], n = 50 [30 mg], and n = 51 [40 mg]) or matching placebo (n = 76) for 20 weeks of treatment.Main Outcomes and Measures: The primary end point was change in 6-minute walk test distance from baseline to 20 weeks (minimal clinically important difference, 40 m). Key safety measures included bradyarrhythmias and adverse events. To evaluate the effects of varying doses of neladenoson, a multiple comparison procedure with 5 modeling techniques (linear, Emax, 2 variations of sigmoidal Emax, and quadratic) was used to evaluate diverse dose-response profiles.Results: Among 305 patients who were randomized (mean age, 74 years; 160 [53%] women; mean 6-minute walk test distance, 321.5 m), 261 (86%) completed the trial and were included in the primary analysis. After 20 weeks of treatment, the mean absolute changes from baseline in 6-minute walk test distance were 0.2 m (95% CI, -12.1 to 12.4 m) for the placebo group; 19.4 m (95% CI, -10.8 to 49.7 m) for the 5 mg of neladenoson group; 29.4 m (95% CI, 3.0 to 55.8 m) for 10 mg of neladenoson group; 13.8 m (95% CI, -2.3 to 29.8 m) for 20 mg of neladenoson group; 16.3 m (95% CI, -1.1 to 33.6 m) for 30 mg of neladenoson group; and 13.0 m (95% CI, -5.9 to 31.9 m) for 40 mg of neladenoson group. Because none of the neladenoson groups achieved the clinically relevant 40-m increase in 6-minute walk test distance from baseline, an optimal dose of neladenoson was not identified. There was no significant dose-response relationship for the change in 6-minute walk test distance among the 5 different dose-response models (P = .05 for Emax; P = .18 for quadratic; P = .21 for sigmoidal Emax 1; P = .39 for linear; and P = .52 for sigmoidal Emax 2). Serious adverse events were similar among the neladenoson groups (61/229 [26.6%]) and the placebo group (21/76 [27.6%]).Conclusions and Relevance: Among patients with HFpEF, there was no significant dose-response relationship detected for neladenoson with regard to the change in exercise capacity from baseline to 20 weeks. In light of these findings, novel approaches will be needed if further development of neladenoson for the treatment of patients with HFpEF is pursued.Trial Registration: ClinicalTrials.gov Identifier: NCT03098979. [ABSTRACT FROM AUTHOR]

Aims: We examined the prognostic importance of N-terminal pro B-type natriuretic peptide (NT-proBNP) and troponin T (TnT) in heart failure patients with and without diabetes.Methods and Results: We measured NT-proBNP and TnT in the biomarker substudy of the Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure trial (PARADIGM-HF). Of 1907 patients, 759 (40%) had diabetes. Median TnT in patients with diabetes was 18 (interquartile range 11-27) ng/L and 13 (9-21) ng/L in those without (P < 0.001). The TnT frequency-distribution curve was shifted to the right in patients with diabetes, compared to those without diabetes. By contrast, NT-proBNP did not differ between patients with and without diabetes. Diabetes and each biomarker were predictive of worse outcomes. Thus, patients with diabetes, an elevated TnT and a NT-proBNP level in the highest tertile (9% of all patients) had an absolute risk of cardiovascular death or heart failure hospitalization of 265 per 1000 person-years, compared to a rate of 42 per 1000 person-years in those without diabetes, a TnT < 18 ng/L and a NT-proBNP in the lowest tertile (16% of all patients). TnT remained an independent predictor of adverse outcomes in multivariable analyses including NT-proBNP.Conclusion: TnT is elevated to a greater extent in heart failure patients with diabetes compared to those without (whereas NT-proBNP is not). TnT and NT-proBNP are additive in predicting risk and when combined help identify diabetes patients at extremely high absolute risk. [ABSTRACT FROM AUTHOR]

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

Aims: Recurrent hospitalizations are a major part of the disease burden in heart failure (HF), but conventional analyses consider only the first event. We compared the effect of sacubitril/valsartan vs. enalapril on recurrent events, incorporating all HF hospitalizations and cardiovascular (CV) deaths in PARADIGM-HF, using a variety of statistical approaches advocated for this type of analysis.Methods and Results: In PARADIGM-HF, a total of 8399 patients were randomized and followed for a median of 27 months. We applied various recurrent event analyses, including a negative binomial model, the Wei, Lin and Weissfeld (WLW), and Lin, Wei, Ying and Yang (LWYY) methods, and a joint frailty model, all adjusted for treatment and region. Among a total of 3181 primary endpoint events (including 1251 CV deaths) during the trial, only 2031 (63.8%) were first events (836 CV deaths). Among a total of 1195 patients with at least one HF hospitalization, 410 (34%) had at least one further HF hospitalization. Sacubitril/valsartan compared with enalapril reduced the risk of recurrent HF hospitalization using the negative binomial model [rate ratio (RR) 0.77, 95% confidence interval (CI) 0.67-0.89], the WLW method [hazard ratio (HR) 0.79, 95% CI 0.71-0.89], the LWYY method (RR 0.78, 95% CI 0.68-0.90), and the joint frailty model (HR 0.75, 95% CI 0.66-0.86) (all P < 0.001). The effect of sacubitril/valsartan vs. enalapril on recurrent HF hospitalizations/CV death was similar.Conclusions: In PARADIGM-HF, approximately one third of patients with a primary endpoint (time-to-first) experienced a further event. Compared with enalapril, sacubitril/valsartan reduced both first and recurrent events. The treatment effect size was similar, regardless of the statistical approach applied. [ABSTRACT FROM AUTHOR]

Aims: Troponin levels are commonly elevated among patients hospitalized for heart failure (HF), but the prevalence and prognostic significance of early post-discharge troponin elevation are unclear. This study sought to describe the frequency and prognostic value of pre-discharge and post-discharge troponin elevation, including persistent troponin elevation from the inpatient to outpatient settings.Methods and Results: The ASTRONAUT trial (NCT00894387; http://www.clinicaltrials.gov) enrolled hospitalized HF patients with ejection fraction ≤40% and measured troponin I prior to discharge (i.e. study baseline) and at 1-month follow-up in a core laboratory (elevation defined as >0.04 ng/mL). This analysis included 1469 (91.0%) patients with pre-discharge troponin data. Overall, 41.5% and 29.9% of patients had elevated pre-discharge [median: 0.09 ng/mL; interquartile range (IQR): 0.06-0.19 ng/mL] and 1-month (median: 0.09 ng/mL; IQR: 0.06-0.15 ng/mL) troponin levels, respectively. Among patients with pre-discharge troponin elevation, 60.4% had persistent elevation at 1 month. After adjustment, pre-discharge troponin elevation was not associated with 12-month clinical outcomes. In contrast, 1-month troponin elevation was independently predictive of increased all-cause mortality [hazard ratio (HR) 1.59, 95% confidence interval (CI) 1.18-2.13] and cardiovascular mortality or HF hospitalization (HR 1.28, 95% CI 1.03-1.58) at 12 months. Associations between 1-month troponin elevation and outcomes were similar among patients with newly elevated (i.e. normal pre-discharge) and persistently elevated levels (interaction P ≥ 0.16). The prognostic value of 1-month troponin elevation for 12-month mortality was driven by a pronounced association among patients with coronary artery disease (interaction P = 0.009).Conclusions: In this hospitalized HF population, troponin I elevation was common during index hospitalization and at 1-month follow-up. Elevated troponin I level at 1 month, but not pre-discharge, was independently predictive of increased clinical events at 12 months. Early post-discharge troponin I measurement may offer a practical means of risk stratification and should be investigated as a therapeutic target. [ABSTRACT FROM AUTHOR]

Aims: Although hypokalaemia is common among patients with heart failure (HF), the prognostic significance of baseline hypokalaemia and hypokalaemia during follow-up in HF patients receiving a mineralocorticoid receptor antagonist (MRA) remains uncertain.Methods and Results: Results of the EMPHASIS-HF trial in patients (n = 2737) with HF and reduced EF with mild symptoms, randomized to eplerenone or placebo, were analysed with regard to the presence or occurrence of hypokalaemia (serum K+ <4.0 mmol/L) and the risk of cardiovascular death or hospitalization for HF (primary endpoint). Median follow-up was 21 months. Baseline hypokalaemia and hypokalaemia during follow-up were common occurrences (19.6% and 40.6%, respectively). Hypokalaemia during follow-up was associated with worse outcomes in multivariable analyses [hazard ratio (HR) 1.26, 95% confidence interval (CI) 1.05-1.52, P = 0.01] without evidence of interaction with eplerenone. In contrast, baseline hypokalaemia was associated with outcomes in the placebo group (HR 1.37, 95% CI 1.05-1.79, P = 0.02) but not in the eplerenone group (HR 0.87, 95% CI 0.62-1.23, P = 0.44; P for interaction = 0.04). Concurrently, eplerenone was found to be more protective in patients with baseline hypokalaemia vs. patients without baseline hypokalaemia compared with placebo (HR 0.44, 95% 0.30-0.64, P < 0.0001 vs. 0.69, 95% CI 0.57-0.83, P = 0.0001; P for interaction = 0.04). In patients without baseline hypokalaemia, eplerenone use decreased the rate of hypokalaemia during follow-up (HR 0.69, 95% CI 0.59-0.80, P < 0.001). A potassium level >4.0 mmol/L at 1 month after randomization mediated 26.0% (0.6-51.4%) of the eplerenone treatment effect (P = 0.04).Conclusion: In HF patients receiving optimal therapy but not treated with eplerenone, baseline hypokalaemia was associated with worse outcomes. Conversely, hypokalaemia amplified the treatment effect of eplerenone. [ABSTRACT FROM AUTHOR]

Aims: Compared to heart failure (HF) with reduced ejection fraction, HF with preserved ejection fraction (HFpEF), and HF with mildly reduced ejection fraction (HFmrEF) are increasing in prevalence, yet little is known about the geographic variation in patient characteristics, treatments and outcomes among these two HF phenotypes. The aim of this study was to investigate geographic differences in HFpEF and HFmrEF., Methods and Results: We conducted an individual patient analysis of five clinical trials enrolling patients with HFpEF or HFmrEF from North America (NA), Latin America (LA), Western Europe (WE), Central/Eastern Europe and Russia (CEER), and Asia-Pacific (AP). We compared regions using descriptive statistics and multivariable regression models. Among the 19 959 patients included, 4066 (23.1%) had HFmrEF and 15 353 (76.9%) HFpEF. Regardless of HF phenotype, patients from WE were oldest, and those in CEER youngest. LA had the largest portion of females and NA most black patients. Obesity and diabetes were most prevalent in NA and hypertension and coronary heart disease most common in CEER. Self-reported health status varied strikingly and was the worst in NA and best in AP. Among patients with HFmrEF, rates of the primary composite endpoint (cardiovascular death or HF hospitalization) were: NA 12.56 per 100 patient-years (/100py), AP 11.67/100py, CEER 10.12/100py, LA 8.90/100py, and WE 8.43/100py, driven by differences in the rate of HF hospitalization. The corresponding values in HFpEF were 11.47/100py, 7.80/100py, 5.47/100py, 5.92/100py, and 7.80/100py, respectively., Conclusions: There is substantial geographic variation in patient characteristics, treatment and outcomes among patients with HFpEF and HFmrEF. These findings have implications for interpretation and generalizability of trial results, design and conduct of future trials, and optimization of care for these patients., (© 2024 The Author(s). European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aim: The globalization of clinical trials has highlighted geographic differences in patient characteristics, treatments, and outcomes. We examined these differences in PARADISE-MI., Methods and Results: Overall, 23.0% were randomized in Eastern Europe/Russia, 17.5% in Western Europe, 12.2% in Southern Europe, 10.1% in Northern Europe, 12.0% in Latin America (LA), 9.3% in North America (NA), 10.0% in East/South-East Asia and 5.8% in South Asia (SA). Those from Asia, particularly SA, were different from patients enrolled in the other regions, being younger and thinner. They also differed in terms of comorbidities (high prevalence of diabetes and low prevalence of atrial fibrillation), type of myocardial infarction (more often ST-elevation myocardial infarction), and treatment (low rate of primary percutaneous coronary intervention). By contrast, patients from LA did not differ meaningfully from those randomized in Europe or NA. Use of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (34.8%) and beta-blockers (65.5%) was low in SA, whereas mineralocorticoid receptor antagonist use was lowest in NA (22%) and highest in Eastern Europe/Russia (53%). Rates of the primary composite outcome of cardiovascular death or incident heart failure varied two-fold among regions, with the lowest rate in SA (4.6/100 person-years) and the highest in LA (9.2/100 person-years). Rates of incident heart failure varied almost six-fold among regions, with the lowest rate in SA (1.0/100 person-years) and the highest in Northern Europe (5.9/100 person-years). The effect of sacubitril/valsartan was not modified by region., Conclusion: In PARADISE-MI, there were substantial regional differences in patient characteristics, treatments and outcomes. Although the generalizability of these findings to a 'real-world' unselected population may be limited, these findings underscore the importance of considering both regional and within-region differences when designing global clinical trials., (© 2023 European Society of Cardiology.)

The Heart Failure Academic Research Consortium is a partnership between the Heart Failure Collaboratory (HFC) and Academic Research Consortium (ARC), comprised of leading heart failure (HF) academic research investigators, patients, United States (US) Food and Drug Administration representatives, and industry members from the US and Europe. A series of meetings were convened to establish definitions and key concepts for the evaluation of HF therapies including optimal medical and device background therapy, clinical trial design elements and statistical concepts, and study endpoints. This manuscript summarizes the expert panel discussions as consensus recommendations focused on populations and endpoint definitions; it is not exhaustive or restrictive, but designed to stimulate HF clinical trial innovation., (© Copyright 2020 European Society of Cardiology and American College of Cardiology.)

Objectives: This study assessed the efficacy and safety of dapagliflozin in patients who were or were not taking sacubitril/valsartan at baseline in the DAPA-HF (Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure) trial., Background: Both the angiotensin receptor neprilysin-inhibitor sacubitril/valsartan and the sodium glucose co-transporter 2 inhibitor dapagliflozin reduced cardiovascular death and heart failure (HF) hospitalization in patients with HF with reduced ejection fraction (HFrEF). Whether either of these classes of drugs influences the effectiveness or safety of the other remains unknown., Methods: DAPA-HF was a 4,744 patient trial that compared dapagliflozin with placebo in patients with HFrEF. Patients were analyzed according to whether they were taking sacubitril/valsartan at randomization. The efficacy of dapagliflozin on the primary composite outcome (CV death or episode of worsening heart failure), its components, and all-cause death was examined according to sacubitril/valsartan and the interaction tested. Predefined safety outcomes were examined by sacubitril/valsartan group., Results: A total of 508 patients (10.7%) enrolled in DAPA-HF were treated with sacubitril/valsartan at baseline. Patients prescribed sacubitril/valsartan were more likely to be from North America or Europe, to have lower ejection fractions and systolic and diastolic blood pressures, but were similar with respect to age, New York Heart Association functional class, history of diabetes, and use of other evidence-based HF therapies. The benefit of dapagliflozin compared with placebo was similar in patients taking sacubitril/valsartan (hazard ratio: 0.75; 95% confidence interval 0.50 to 1.13) compared with those not taking sacubitril/valsartan (hazard ratio: 0.74; 95% confidence interval 0.65 to 0.86) for the primary endpoint of cardiovascular death or worsening HF; similar findings were observed for secondary endpoints. All measures of safety, including episodes related to hypovolemia, were similar among patients randomized to dapagliflozin or placebo, whether they received background sacubitril/valsartan., Conclusions: Dapagliflozin was similarly efficacious and safe in patients who were and who were not taking sacubitril/valsartan in the DAPA-HF trial, which suggested that the use of both agents together could further lower morbidity and mortality in patients with HFrEF. (Dapagliflozin And Prevention of Adverse outcomes in Heart Failure [DAPA-HF]; NCT03036124)., (Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Reduced left ventricular ejection fraction (LVEF) after acute myocardial infarction (MI) increases risk of cardiovascular (CV) hospitalizations, but evidence regarding its association with non-CV outcome is scarce. We investigated the association between LVEF and adjudicated cause-specific hospitalizations following MI complicated with low LVEF or overt heart failure (HF)., Methods: In an individual patient data meta-analysis of 19,740 patients from 3 large randomized trials, Fine and Gray competing risk modeling was performed to study the association between LVEF and hospitalization types., Results: The most common cause of hospitalization was non-CV (n = 2,368 for HF, n = 1,554 for MI, and n = 3,703 for non-CV). All types of hospitalizations significantly increased with decreasing LVEF. The absolute risk increase associated with LVEF ≪25% (vs LVEF ≫35%) was 15.5% (95% CI 13.4-17.5) for HF, 4.7% (95% CI 3.0-6.4) for MI, and 10.4% (95% CI 8.0-12.8) for non-CV hospitalization. On a relative scale, after adjusting for confounders, each 5-point decrease in LVEF was associated with an increased risk of HF (hazard ratio [HR] 1.15, 95% CI 1.12-1.18), MI (HR 1.06, 95% CI 1.03-1.10), and non-CV hospitalization (HR 1.03, 95% CI 1.01-1.05)., Conclusions: In a high-risk population with complicated acute MI, the absolute risk increase in non-CV hospitalizations associated with LVEF ≪25% was two thirds of the absolute risk increase in HF hospitalizations and twice the absolute risk increase in MI hospitalizations. LVEF was an independent predictor of all types of hospitalization and appears as an integrative marker of sicker patient status., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Aims: Nearly 60% of the world's population lives in Asia but little is known about the characteristics and outcomes of Asian patients with heart failure with reduced ejection fraction (HFrEF) compared to other areas of the world., Methods and Results: We pooled two, large, global trials, with similar design, in 13 174 patients with HFrEF (patient distribution: China 833, India 1390, Japan 209, Korea 223, Philippines 223, Taiwan 199 and Thailand 95, Western Europe 3521, Eastern Europe 4758, North America 613, and Latin America 1110). Asian patients were younger (55.0-63.9 years) than in Western Europe (67.9 years) and North America (66.6 years). Diuretics and devices were used less, and digoxin used more, in Asia. Mineralocorticoid receptor antagonist use was higher in China (66.3%), the Philippines (64.1%) and Latin America (62.8%) compared to Europe and North America (range 32.8% to 49.6%). The rate of cardiovascular death/heart failure hospitalization was higher in Asia (e.g. Taiwan 17.2, China 14.9 per 100 patient-years) than in Western Europe (10.4) and North America (12.8). However, the adjusted risk of cardiovascular death was higher in many Asian countries than in Western Europe (except Japan) and the risk of heart failure hospitalization was lower in India and in the Philippines than in Western Europe, but significantly higher in China, Japan, and Taiwan., Conclusion: Patient characteristics and outcomes vary between Asia and other regions and between Asian countries. These variations may reflect several factors, including geography, climate and environment, diet and lifestyle, health care systems, genetics and socioeconomic influences., (© 2018 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Importance: Patients with cardiac amyloidosis demonstrate reduced myocardial strain with associated sparing of the cardiac apex. In the APOLLO randomized clinical trial, patisiran, an RNA interference therapeutic that inhibits transthyretin synthesis, improved left ventricular (LV) global longitudinal strain (LV GLS) compared with placebo in patients with hereditary transthyretin-mediated (hATTR) amyloidosis with polyneuropathy and evidence of cardiac involvement., Objective: To evaluate the treatment association of patisiran with regional LV myocardial strain in cardiac manifestation in hATTR amyloidosis., Design, Setting, and Participants: This exploratory analysis of APOLLO, a randomized, double-blind, placebo-controlled, phase 3, multicenter international clinical trial that was conducted from December 2013 to January 2016, included patients with hATTR amyloidosis with polyneuropathy who were randomized 2:1 to receive patisiran or placebo. The prespecified cardiac subpopulation (126 of 225 [56%]) comprised patients with a baseline LV wall thickness of 13 mm or more and no history of hypertension or aortic valve disease. This post hoc data analysis was performed between September 2018 and January 2019., Intervention: Placebo or patisiran, 0.3 mg/kg, via intravenous infusion once every 3 weeks for 18 months., Main Outcomes and Measures: The association of patisiran with LV regional longitudinal strain at 18 months., Results: Of the 126 patients included in the prespecified cardiac subpopulation, 36 patients (28.6%) received placebo (median [interquartile range] age, 62 [57-72] years) and 90 patients (71.4%) received patisiran (median [interquartile range] age, 60 [54-66] years); 98 (77.8%) were men, 28 (22.2%) were from North America, and 43 (34.1%) were from Western Europe. At baseline, LV GLS was impaired and regional longitudinal strains were lowest in the basal segments with apical sparing. There were no differences in regional longitudinal strains between the treatment groups at baseline. Patisiran improved the absolute GLS (least-squares mean [SE] difference, 1.4% [0.6%]; 95% CI, 0.3%-2.5%; P = .02) compared with placebo at 18 months, with the greatest differential increase observed in the basal region (overall least-squares mean [SE] difference, 2.1% [0.8%]; 95% CI, 0.6%-3.6%; P = .006) and no significant differences in the mid and apical regions among groups., Conclusions and Relevance: Patisiran prevented the deterioration of LV GLS over 18 months, driven primarily by attenuating disease progression in the basal region, suggesting that basal longitudinal strain may be a more sensitive marker of treatment associations with the cardiac manifestation in hATTR amyloidosis and that basal region may be influenced by disease-modifying therapies more than other ventricular regions., Trial Registration: ClinicalTrials.gov identifier: NCT01960348.

Background: Canagliflozin is a sodium glucose cotransporter 2 inhibitor that reduces the risk of cardiovascular events. We report the effects on heart failure (HF) and cardiovascular death overall, in those with and without a baseline history of HF, and in other participant subgroups., Methods: The CANVAS Program (Canagliflozin Cardiovascular Assessment Study) enrolled 10 142 participants with type 2 diabetes mellitus and high cardiovascular risk. Participants were randomly assigned to canagliflozin or placebo and followed for a mean of 188 weeks. The primary end point for these analyses was adjudicated cardiovascular death or hospitalized HF., Results: Participants with a history of HF at baseline (14.4%) were more frequently women, white, and hypertensive and had a history of prior cardiovascular disease (all P<0.001). Greater proportions of these patients were using therapies such as blockers of the renin angiotensin aldosterone system, diuretics, and β-blockers at baseline (all P<0.001). Overall, cardiovascular death or hospitalized HF was reduced in those treated with canagliflozin compared with placebo (16.3 versus 20.8 per 1000 patient-years; hazard ratio [HR], 0.78; 95% confidence interval [CI], 0.67-0.91), as was fatal or hospitalized HF (HR, 0.70; 95% CI, 0.55-0.89) and hospitalized HF alone (HR, 0.67; 95% CI, 0.52-0.87). The benefit on cardiovascular death or hospitalized HF may be greater in patients with a prior history of HF (HR, 0.61; 95% CI, 0.46-0.80) compared with those without HF at baseline (HR, 0.87; 95% CI, 0.72-1.06; P interaction =0.021). The effects of canagliflozin compared with placebo on other cardiovascular outcomes and key safety outcomes were similar in participants with and without HF at baseline (all interaction P values >0.130), except for a possibly reduced absolute rate of events attributable to osmotic diuresis among those with a prior history of HF ( P=0.03)., Conclusions: In patients with type 2 diabetes mellitus and an elevated risk of cardiovascular disease, canagliflozin reduced the risk of cardiovascular death or hospitalized HF across a broad range of different patient subgroups. Benefits may be greater in those with a history of HF at baseline., Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifiers: NCT01032629 and NCT01989754.

Unlabelled: Early intervention with cardiac resynchronization therapy with defibrillator (CRT-D) in mild heart failure (HF) patients with a left bundle branch block (LBBB) ECG pattern was associated with a significant reduction in mortality in the long-term MADIT-CRT trial. Whether patients in MADIT-CRT enrolled from centers in the USA and in Europe have different long-term clinical response to CRT-D remains unknown. We compared the baseline clinical characteristics and clinical and echocardiographic long-term clinical response to CRT-D between MADIT-CRT patients with LBBB who were enrolled in USA (n = 871) and European centers (n = 392). Although European patients had more advanced heart disease than US patients, CRT-D was associated with similar 60 % (p < 0.001) reductions in the risk of HF in US and European patients when compared to ICD-only therapy after adjustment for relevant baseline clinical covariates. US patients had significant long-term mortality reduction (38 %, p = 0.02) while among European patients the survival benefit associated with CRT-D was not statistically significant (HR 0.73, p = 0.18); subgroup analyses revealed a significantly greater CRT-D benefit among women who were enrolled in the USA, whereas no significant gender difference in the clinical benefit of CRT-D was observed in the European cohort. Reverse remodeling at 1 year was associated with significantly better clinical outcomes in both groups. Despite differences in baseline disease severity, European and US patients with LBBB experienced a similar clinical and echocardiographic response to cardiac resynchronization therapy during long-term follow-up., Clinical Trial Registration: http://clinicaltrials.gov/ct2/show/NCT00180271 .

Objectives: This study sought to determine the characteristics and outcomes of young adults with heart failure (HF)., Background: Few studies have focused on young and very young adults with HF., Methods: Patients were categorized into 5 age groups: 20 to 39, 40 to 49, 50 to 59, 60 to 69, and ≥70 years., Results: The youngest patients with HF were more likely to be obese (youngest vs. oldest: body mass index ≥35 kg/m(2): 23% vs. 6%), of black ethnicity (18% vs. 2%), and have idiopathic-dilated cardiomyopathy (62% vs. 9%) (all p < 0.0001). They were less likely to adhere to medication (nonadherence in youngest vs. oldest: 24% vs. 7%, p = 0.001), salt intake, and other dietary measures (21% vs. 9%, p = 0.002). The youngest patients were less likely to have clinical and radiological signs of HF during hospitalization. Quality of life was worse, but all-cause mortality was lowest in the youngest age group (3-year mortality rates across the respective age categories: 12%, 13%, 13%, 19%, and 31%, respectively). Compared with the referent age group of 60 to 69 years, both all-cause and cardiovascular mortality were lower in the youngest group even after multivariable adjustment (hazard ratio: 0.60, 95% confidence interval: 0.36 to 1.00; p = 0.049, and hazard ratio: 0.71, 95% confidence interval: 0.42 to 1.18, p = 0.186, respectively). Three-year HF hospitalization rates were 24%, 15%, 15%, 22%, and 28% in ages 20 to 39, 40 to 49, 50 to 59, 60 to 69, and ≥70 years, respectively (p < 0.0001)., Conclusions: Beyond divergent etiology and comorbidities, younger patients exhibited striking differences in presentation and outcomes compared with older counterparts. Clinical and radiological signs of HF were less common, yet quality of life was more significantly impaired. Fatal and nonfatal outcomes were discordant, with better survival despite higher hospitalization rates., (Copyright © 2013 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: There are limited data on the prognostic implications of brain natriuretic peptide (BNP) assessment in patients with mildly symptomatic heart failure (HF) who receive cardiac resynchronization therapy with a defibrillator (CRT-D)., Methods and Results: The effect of elevated baseline and 1-year BNP levels (dichotomized at the upper tertile BNP of 120 pg/mL) on the risk of HF or death was assessed among the cohort of 1197 patients with baseline BNP data enrolled in MADIT (Multicenter Automated Defibrillator Implantation Trial)-CRT. Elevated baseline BNP was associated with a significant 68% (P=0.007) and 58% (P=0.02) increase in the risk of HF or death among MADIT-CRT patients allocated to CRT-D and implantable cardioverter defibrillator-only therapy, respectively. At 1 year of follow-up, patients allocated to CRT-D displayed significantly greater reductions in BNP (26% reduction) levels compared with implantable cardioverter defibrillator-only patients (8% increase; P=0.005). Patients with CRT-D in whom 1-year BNP levels were reduced or remained low experienced a significantly lower risk of subsequent HF or death as compared with patients in whom 1-year BNP levels were high. Similarly, the echocardiographic response to CRT-D was highest among those who maintained low BNP levels or in whom BNP level at 1-year was reduced., Conclusions: Our findings suggest that assessment of baseline and follow-up BNP provides important prognostic implications in patients with mildly symptomatic HF who receive CRT.

Background: Despite benefits of cardiac resynchronization therapy (CRT) in patients with severe but less symptomatic heart failure, approximately 30% of patients do not fully respond to treatment. We hypothesized that a combined assessment of left ventricular (LV) dyssynchrony and contractile function by strain-based imaging would identify patients who would most benefit from CRT., Methods and Results: We studied 1077 patients with New York Heart Association class I/II, LV ejection fraction ≤30% and QRS width ≥130 ms enrolled in the Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy trial with sufficient echocardiographic image quality for cardiac deformation analysis (implantable cardioverter-defibrillator [ICD], n=416; CRT, n=661). Patients were assigned to CRT plus an ICD or to ICD alone in 3:2 random assignment. We assessed the degree to which baseline echocardiographic assessments of dyssynchrony, measured as the standard deviation of time-to-peak transverse strain over 12 segments, contractile function, measured as global longitudinal strain, or both predicted the effect of treatment on the primary outcome of death or heart failure. With 213 primary events occurring over a mean of 2.4 years, the benefit of CRT plus an ICD relative to ICD alone was greatest in patients with mild to moderate dyssynchrony (time-to-peak transverse strain standard deviation, 142 to 230 ms) and greater baseline contractile function (global longitudinal strain ≤-8.7%). Overall, those patients with mild to moderate dyssynchrony and those with best contractile function at baseline demonstrated the greatest benefit from CRT (adjusted hazards ratio, 0.20; 95% confidence interval, 0.09 to 0.44). Dyssynchrony and global longitudinal strain predicted response to CRT independent of each other, QRS width, LV ejection fraction, and presence versus absence of left bundle-branch block, although the observed benefit remained greatest in patients with left bundle-branch block., Conclusions: Both mechanical dyssynchrony and contractile function are important independent correlates of benefit from CRT., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00180271.