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The characteristics, tolerability, and outcomes in patients with heart failure (HF) who are treated with sacubitril/valsartan remain unclear in Japan. We conducted a nationwide multicenter study to evaluate the features and outcomes of patients newly prescribed sacubitril/valsartan for the management of HF. We analyzed adverse events (AEs) related to sacubitril/valsartan at 3 months, which were defined as hypotension, worsening renal function, hyperkalemia, and angioedema. Additionally, the association between AEs and outcomes was examined. Among 993 patients, the mean age was 70 years and 291 (29.3 %) were female, and 22.8 % had left ventricular ejection fraction ≥50 %. Of them, 20.8 % had systolic blood pressure (sBP) <100 mmHg, and 19.5 % had estimated glomerular filtration rate (eGFR) <30 ml/min/1.73 m2 at baseline, which were the populations excluded from the eligibility in landmark trials. AEs related to sacubitril/valsartan were observed in 22.5 % of the patients at 3 months. Overall, 22.6 % of patients discontinued sacubitril/valsartan, and hypotension was the most common event leading to drug discontinuation. After adjustment, patients who had worse HF symptoms (New York Heart Association III or IV), sBP <100 mmHg, and eGFR <30 ml/min/1.73 m2 were associated with a higher risk of AEs related to sacubitril/valsartan. Additionally, patients experiencing AEs had a higher risk of cardiovascular death or HF hospitalization than those who did not. In Japan, sacubitril/valsartan was also prescribed to patients not eligible for landmark trials, and AEs were observed at a relatively high rate from soon after treatment initiation. Physicians should closely monitor patients for these events, especially in patients anticipated to have a higher risk of AEs. [Display omitted] • In Japan, sacubitril/valsartan was extensively used for HF management across LVEF subtypes. • Elderly patients and others ineligible for landmark trials were also treated with sacubitril/valsartan. • Adverse events potentially related to sacubitril/valsartan were observed in 22.5 %. • Patient who experienced adverse events had worse outcomes than those who did not. [ABSTRACT FROM AUTHOR]

Omecamtiv mecarbil improves outcomes in patients with heart failure and reduced ejection fraction (HFrEF). We examined the relationship between baseline troponin levels, change in troponin levels over time and the treatment effect of omecamtiv mecarbil in patients enrolled in the Global Approach to Lowering Adverse Cardiac Outcomes through Improving Contractility in Heart Failure (GALACTIC-HF) trial (NCT02929329). GALACTIC-HF was a double-blind, placebo-controlled trial that randomized 8256 patients with symptomatic HFrEF to omecamtiv mecarbil or placebo. High-sensitivity troponin I (cTnI) was measured serially at a core laboratory. We analyzed the relationship between both baseline cTnI and change in cTnI concentrations with clinical outcomes and the treatment effect of omecamtiv mecarbil. Higher baseline cTnI concentrations were associated with a risk of adverse outcomes (hazard ratio for the primary endpoint of time to first HF event or CV death = 1.30; 95% CI 1.28, 1.33; P < 0.001 per doubling of baseline cTnI). Although the incidence of safety outcomes was higher in patients with higher baseline cTnI, there was no difference between treatment groups. Treatment with omecamtiv mecarbil led to a modest increase in cTnI that was related to plasma concentrations of omecamtiv mecarbil, and it peaked at 6 weeks. An increase in troponin from baseline to week 6 was associated with an increased risk of the primary endpoint (P < 0.001), which was similar, regardless of treatment assignment (P value for interaction = 0.2). In a cohort of patients with HFrEF, baseline cTnI concentrations were strongly associated with adverse clinical outcomes. Although cTnI concentrations were higher in patients treated with omecamtiv mecarbil, we did not find a differential effect of omecamtiv mecarbil on either safety or efficacy based on baseline cTnI status or change in cTnI. [ABSTRACT FROM AUTHOR]

• Clinical settings influence stroke prediction scores in HFrEF with sinus rhythm. • Rivaroxaban is associated with a reduced stroke risk in HFrEF with sinus rhythm and high D-dimer. • The predictive value of stroke risk score should be evaluated further. Patients with heart failure with reduced ejection fraction (HFrEF) and sinus rhythm have a heightened risk of stroke. Whether anticoagulation benefits these patients is uncertain. In this post hoc analysis of the A Study to Assess the Effectiveness and Safety of Rivaroxaban in Reducing the Risk of Death, Myocardial Infarction, or Stroke in Participants with Heart Failure and Coronary Artery Disease Following an Episode of Decompensated Heart Failure (COMMANDER-HF) trial we evaluated how a previously validated risk model consisting of 3 variables (history of prior stroke, insulin-treated diabetes, and N-terminal pro-B-type natriuretic peptide level) would perform, compared with plasma d -dimer, for stroke prediction and estimation of the benefit of low-dose rivaroxaban. Stroke risk and treatment effect were computed across risk score and plasma d -dimer tertiles. Risk score was available in 58% of the COMMANDER-HF population (n = 2928). Over a median follow-up of 512 days (range 342–747 days), 60 patients experienced a stroke (14.6 per 1000 patient-years). The risk model did not identify patients at higher risk of stroke and showed a low overall prognostic performance (C-index = 0.53). The effect of rivaroxaban on stroke was homogeneous across risk score tertiles (P -interaction =.67). Among patients in whom the risk score was estimated, d -dimer was available in 2343 (80%). d -dimer had an acceptable discrimination performance for stroke prediction (C-index = 0.66) and higher plasma d -dimer concentrations were associated with higher rates of stroke (ie, tertile 3 vs tertile 1, hazard ratio 3.65, 95% confidence interval 1.59–8.39, P =.002). Treatment with low-dose rivaroxaban reduced the incidence of stroke in patients at highest risk by d -dimer levels (ie, >515 ng/mL, hazard ratio 0.42, 95% confidence interval 0.18–0.95, P -interaction =.074), without any safety concerns. In our analysis, plasma d -dimer concentrations performed better than a previously described 3-variable risk score for stroke prediction in patients with heart failure with reduced ejection fraction, a recent clinical worsening and sinus rhythm as enrolled in the COMMANDER-HF trial. In these patients, a raised plasma d -dimer concentration identified patients who might benefit most from rivaroxaban. [ABSTRACT FROM AUTHOR]

In the Global Approach to Lowering Adverse Cardiac Outcomes Through Improving Contractility in Heart Failure (GALACTIC-HF) trial, omecamtiv mecarbil, compared with placebo, reduced the risk of worsening heart failure (HF) events, or cardiovascular death in patients with HF and reduced ejection fraction. The primary aim of this prespecified analysis was to evaluate the safety and efficacy of omecamtiv mecarbil by randomization setting, that is, whether participants were enrolled as outpatients or inpatients. Patients were randomized either during a HF hospitalization or as an outpatient, within one year of a worsening HF event (hospitalization or emergency department visit). The primary outcome was a composite of worsening HF event (HF hospitalization or an urgent emergency department or clinic visit) or cardiovascular death. Of the 8232 patients analyzed, 2084 (25%) were hospitalized at randomization. Hospitalized patients had higher N-terminal prohormone of B-type natriuretic peptide concentrations, lower systolic blood pressure, reported more symptoms, and were less frequently treated with a renin–angiotensin system blocker or a beta-blocker than outpatients. The rate (per 100 person-years) of the primary outcome was higher in hospitalized patients (placebo group = 38.3/100 person-years) than in outpatients (23.1/100 person-years); adjusted hazard ratio 1.21 (95% confidence interval 1.12–1.31). The effect of omecamtiv mecarbil versus placebo on the primary outcome was similar in hospitalized patients (hazard ratio 0.89, 95% confidence interval 0.78–1.01) and outpatients (hazard ratio 0.94, 95% confidence interval 0.86–1.02) (interaction P =.51). Hospitalized patients with HF with reduced ejection fraction had a higher rate of the primary outcome than outpatients. Omecamtiv mecarbil decreased the risk of the primary outcome both when initiated in hospitalized patients and in outpatients. [ABSTRACT FROM AUTHOR]

• Longer duration of chronic heart failure (HF) with left ventricular ejection fraction (LVEF) ≥ 45% was associated with a higher comorbidity burden, lower baseline health status and adverse clinical outcomes in the PARAGON-HF trial. • Sacubitril/valsartan was well tolerated across the spectrum of HF duration, with consistent relative and higher absolute treatment effects in participants with the longest baseline HF durations. • Sustained focus on optimization of medical therapy at all stages of the HF disease course, in all clinical settings and across the HF spectrum, is needed to abrogate downstream disease progression. In this post hoc analysis of the PARAGON-HF (Prospective Comparison of ARNI with ARB Global Outcomes in HFpEF) trial, we evaluated clinical outcomes and responses to sacubitril/valsartan by duration of heart failure (HF) with left ventricular ejection fraction ≥ 45% at initial diagnosis. The primary outcome was a composite of total hospitalizations due to HF and cardiovascular deaths, analyzed by using a semiparametric proportional rates method, stratified by geographic region. Among 4784 (99.7%) randomized participants in the PARAGON-HF trial for whom baseline HF duration was captured, 1359 (28%) had durations of HF of < 6 months, 1295 (27%) of 6 months–2 years, and 2130 (45%) of > 2 years. Longer HF duration was associated with higher comorbidity burdens, worse health status and lower rates of prior hospitalization due to HF. Over a median follow-up of 35 months, longer HF duration was associated with a higher risk of first and recurrent primary events (per 100 patient-years): < 6 months, 12.0 (95% CI, 10.4–14.0); 6 months–2 years, 12.2 (10.6–14.2); > 2 years, 15.8 (14.2–17.5). Relative treatment effects of sacubitril/valsartan vs valsartan were consistent, irrespective of baseline HF duration on the primary endpoint (P interaction = 0.112). Clinically meaningful (≥ 5 point) improvements in Kansas City Cardiomyopathy Questionnaire-Clinical Summary Scores were also similarly observed, irrespective of HF duration; (P interaction = 0.112). Adverse events were similar between treatment arms across HF duration categories. In PARAGON-HF, longer HF duration was independently predictive of adverse HF outcomes. Treatment effects of sacubitril/valsartan were consistent, irrespective of baseline HF duration, suggesting that even ambulatory patients with longstanding HFpEF and predominantly mild symptoms stand to benefit from treatment optimization. [Display omitted] [ABSTRACT FROM AUTHOR]

Catastrophic disruptions in care delivery threaten the operational efficiency and potentially the validity of clinical research efforts, in particular randomized clinical trials. Most recently, the COVID-19 pandemic affected essentially all aspects of care delivery and clinical research conduct. While consensus statements and clinical guidance documents have detailed potential mitigation measures, few real-world experiences detailing clinical trial adaptations to the COVID-19 pandemic exist, particularly among, large, global registrational cardiovascular trials. We outline the operational impact of COVID-19 and resultant mitigation measures in the Dapagliflozin Evaluation to Improve the LIVEs of Patients with Preserved Ejection Fraction Heart Failure (DELIVER) trial, one of the largest and most globally diverse experiences with COVID-19 of any cardiovascular clinical trial to date. Specifically, we address the needed coordination between academic investigators, trial leadership, clinical sites, and the supporting sponsor to ensure the safety of participants and trial staff, to maintain the fidelity of trial operations, and to prospectively adapt statistical analyses plans to evaluate the impact of COVID-19 and the pandemic at large on trial participants. These discussions included key operational issues such as ensuring delivery of study medications, adaptations to study visits, enhanced COVID-19 related endpoint adjudication, and protocol and analytical plan revisions. Our findings may have important implications for establishing consensus on prospective contingency planning in future clinical trials. Clinicaltrial.gov: NCT03619213. NCT03619213. [ABSTRACT FROM AUTHOR]

Global longitudinal strain (GLS) and global circumferential strain (GCS) have been shown to be impaired in heart failure with preserved ejection fraction. We sought to assess whether treating patients with heart failure with preserved ejection fraction with sacubitril/valsartan would significantly improve GLS and GCS compared with valsartan alone. PARAMOUNT (Prospective Comparison of ARNI With ARB on Management of Heart Failure With Preserved Ejection Fraction Trial) was a phase II, randomized, parallel-group, double-blind multicenter trial in 301 patients with New York Heart Association functional class II–III heart failure, a left ventricular ejection fraction of 45%, and an N-terminal pro-B-type natriuretic peptide of ≥400 pg/mL. Participants were randomly assigned (1:1) to sacubitril/valsartan titrated to 200 mg twice daily or valsartan titrated to 160 mg twice daily for 36 weeks. We assessed changes in the GLS and the GCS from baseline to 36 weeks, adjusting for baseline value, in patients with sufficient imaging quality for 2-dimensitonal speckle tracking analysis at both timepoints (n = 60 sacubitril/valsartan, n = 75 valsartan only). GCS was significantly improved at 36 weeks in the sacubitril/valsartan group when compared with the valsartan group (Δ4.42%, 95% confidence interval [CI] 0.67–8.17, P =.021), with no significant difference observed in GLS (Δ0.25%, 95% CI, –1.19 to 1.70, P =.73). Patients with a history of hospitalization for heart failure had a differentially greater improvement in GCS when treated with sacubitril/valsartan. In patients with heart failure with preserved ejection fraction, sacubitril/valsartan improved GCS but not GLS when compared with valsartan during a 36-week period. This trial is registered at ClinicalTrials.gov, NCT00887588. [ABSTRACT FROM AUTHOR]

Background: Atrial fibrillation (AF) and heart failure (HF) often coexist. We investigated the prognostic impact of biomarkers on the development of HF and death in patients with AF and different left ventricular systolic function considering the influence of competing events.Methods: The study included 11,818 patients with AF from the ARISTOTLE trial who at entry had information on history of HF, an estimate of left ventricular function and plasma samples for determination of biomarkers representing cardiorenal dysfunction (NT-proBNP, troponin T, cystatin C) and inflammation (GDF-15, IL-6, CRP). Patients were categorized into: (I) HF with reduced ejection fraction (HFrEF, n = 2,048), (II) HF with preserved ejection fraction (HFpEF, n = 2,520), and (III) No HF (n = 7,250). Biomarker associations with HF hospitalization and death were analyzed using a multi-state model accounting also for repeated events.Results: Baseline levels of NT-proBNP, troponin T, cystatin C, GDF-15, IL-6, and CRP were highest in HFrEF and lowest in No HF. During median 1.9 years follow-up, 546 patients were hospitalized at least once for HF and 819 died. Higher levels of all investigated biomarkers were associated with both outcomes (all P< .0001), with highest event rates in HFrEF and lowest in No HF. The associations remained after adjustments and were more pronounced for first than for recurrent events.Conclusions: In anticoagulated patients with AF, biomarkers indicating cardiorenal dysfunction and inflammation improve the identification of patients at risk of developing HF or worsening of already existing HF. These biomarkers might be useful for targeting novel HF therapies in patients with AF. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The accepted understanding of the patient journey in heart failure (HF) is one of recurrent episodes of deterioration which accelerate in frequency as the patient approaches death. However, this may not be true when different modes of death are considered separately. We explored patterns of HF hospitalizations (HFH) in patients who died from either sudden death or death due to progressively worsening heart failure ("pump failure") in a contemporary cohort of patients with HFrEF. We examined timing of HF hospitalizations in the PARADIGM-HF and ATMOSPHERE trials. Inclusion and exclusion for these trials were similar; NYHA class II-IV, LVEF≤35% (PARADIGM-HF LVEF≤40% reduced to ≤35% by amendment) and elevated natriuretic peptide levels. In PARADIGM-HF, patients were randomized to sacubitril-valsartan or enalapril, in ATMOSPHERE treatments were enalapril, aliskiren or both. The number of hospitalizations per patient was calculated and cross tabulated with cause of CV death. Rates of total HFH were calculated according to different causes of CV death. HFH were visualized using recurrent event plots. Of the 15415 patients enrolled, 2518 had at least 1 hospitalization after randomization and between them these 2518 participants accrued a total of 4318 admissions. There were 2872 CV deaths which accounted for 83% of all deaths. Of the 2872 CV deaths 1332 (46%) occurred suddenly and 735 (26%) were due to worsening heart failure. Of patients experiencing sudden death, only 205 (15%) had a preceding hospitalization compared with 569 (77%) patients dying from pump failure. Rates of HFH per 100 patient years were 17 [95% CI 15-19] in patients with sudden death, 93 [95% CI 88-98]) in the pump failure death group and 7 [95% CI 6-7] in patients without CV death. Recurrent event plots show a greater density of HFH in patients with pump failure deaths as compared with other CV deaths. This analysis shows that the accepted patient trajectory in HFrEF is true for individuals who die from progressive worsening of heart failure but not for sudden death where only a minority of patients experience preceding HFH. [ABSTRACT FROM AUTHOR]

FREEDOM, a cardiovascular outcome trial with a GLP-1 receptor agonist, testing a continuous subcutaneous infusion of exenatide (ITCA 650), recently reported its findings. We meta-analysed its results with eight prior GLP-1 receptor agonists trials. GLP-1 receptor agonists reduced MACE by 13% (HR 0.87 [95% CI 0.81–0.94]; p = 0.00065) and all-cause mortality by 11% (HR 0.89 [0.83–0.95]; p = 0.00084). However, FREEDOM results appear dissimilar to prior GLP-1 receptor agonist trials. FREEDOM results should not influence current considerations about the benefits or harms of approved formulations of GLP-1 receptor agonists. There is also an ongoing debate about the safety of ITCA 650. • The FREEDOM Cardiovascular Outcomes trial results were recently published. • Its results appear different to other GLP-1 receptor agonist outcome trials in a trial meta-analysis. • This and other concerns mean FREEDOM should not influence current perceptions about the benefits of GLP-1 receptor agonists. [ABSTRACT FROM AUTHOR]

Kidney dysfunction often leads to reluctance to start or continue life-saving heart failure (HF) therapy. This study sought to examine the efficacy and safety of mineralocorticoid receptor antagonists (MRAs) in patients with HF with reduced ejection fraction experiencing significant kidney dysfunction. We pooled individual patient data from the RALES (Randomized Aldactone Evaluation Study) and EMPHASIS-HF (Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure) trials. The association between MRA treatment and outcomes was assessed according to whether the estimated glomerular filtration rate (eGFR) declined to <30 mL/min/1.73 m2 or not. The primary outcome was cardiovascular death or HF hospitalization. Among 4,355 patients included, 295 (6.8%) experienced a deterioration of eGFR after randomization to <30 mL/min/1.73 m2. These patients had more impaired baseline cardiac and kidney function (eGFR 47.3 ± 13.4 mL/min/1.73 m2 vs 70.5 ± 21.8 mL/min/1.73 m2) and had a higher risk of the primary outcome than patients without eGFR deterioration (HR: 2.49; 95% CI: 2.01-3.08; P < 0.001). However, the risk reduction in the primary outcome with MRA therapy was similar in those who experienced a decrease in eGFR to <30 mL/min/1.73 m2 (HR: 0.65; 95% CI: 0.43-0.99) compared with those who did not (HR: 0.63; 95% CI: 0.56-0.71) (P interaction = 0.87). In patients with a decrease in eGFR to <30 mL/min/1.73 m2, 21 fewer individuals (per 100 person-years) experienced the primary outcome with MRA treatment, vs placebo, compared with an excess of 3 more patients with severe hyperkalemia (>6.0 mmol/L). Because patients experiencing a decrease in eGFR to <30 mL/min/1.73 m2 are at very high risk, the absolute risk reduction with an MRA in these patients is large and this decline in eGFR should not automatically lead to treatment discontinuation. [Display omitted] [ABSTRACT FROM AUTHOR]

The Kidney Disease Improving Global Outcomes (KDIGO) classification integrates both estimated glomerular filtration rate and urine-albumin-creatinine ratio to stratify risk more comprehensively in patients with chronic kidney disease. There are limited data assessing whether this classification system is associated with prognosis and treatment response in heart failure populations. The aim of this study was to evaluate the relative treatment effects of sacubitril/valsartan across the KDIGO risk categories in patients with HFrEF. PARADIGM-HF (Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) was a global randomized controlled trial evaluating sacubitril/valsartan vs enalapril in patients with heart failure with reduced ejection fraction (HFrEF). Patients were classified according to low, moderate, and high/very high KDIGO risk. Treatment responses were assessed according to baseline KDIGO risk. The primary outcome was a composite of cardiovascular (CV) death or heart failure hospitalization. A renal composite outcome was defined as sustained decline in estimated glomerular filtration rate by ≥40% or end-stage kidney disease. Among 1,910 (23% of total) participants with available data, 42%, 32%, and 26% were classified as low, moderate, and high/very high KDIGO risk, respectively. Patients in the highest KDIGO risk categories experienced the highest rates of the primary composite outcome (7.6 per 100 person-years [95% CI: 6.5-9.0 per 100 person-years], 9.4 per 100 person-years [95% CI: 7.9-11.2 per 100 person-years], and 14.9 per 100 person-years [95% CI: 12.7-17.6 per 100 person-years]; P < 0.001). Sacubitril/valsartan had a similar safety profile and demonstrated consistent effects on the risk of both the primary outcome (P Interaction = 0.31) and the renal composite outcome (P Interaction = 0.50) across the spectrum of KDIGO risk. One in 4 patients with HFrEF were classified as at least high KDIGO kidney risk; these individuals faced concordantly the highest risks of CV events. Sacubitril/valsartan exhibited consistent CV and kidney protective benefits as well as safety across the spectrum of baseline kidney risk. These data further support initiation of sacubitril/valsartan in HFrEF across a broad range of kidney risk. (This Study Will Evaluate the Efficacy and Safety of LCZ696 Compared to Enalapril on Morbidity and Mortality of Patients With Chronic Heart Failure [PARADIGM-HF]; NCT01035255) [Display omitted] [ABSTRACT FROM AUTHOR]

Conventional time-to-first-event analyses cannot incorporate recurrent hospitalizations and patient well-being in a single outcome. To overcome this limitation, we tested an integrated measure that includes days lost from death and hospitalization, and additional days of full health lost through diminished well-being. The effect of dapagliflozin on this integrated measure was assessed in the DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) trial, which examined the efficacy of dapagliflozin, compared with placebo, in patients with NYHA functional class II to IV heart failure and a left ventricular ejection fraction ≤40%. Over 360 days, patients in the dapagliflozin group (n = 2,127) lost 10.6 ± 1.0 (2.9%) of potential follow-up days through cardiovascular death and heart failure hospitalization, compared with 14.4 ± 1.0 days (4.0%) in the placebo group (n = 2,108), and this component of all measures of days lost accounted for the greatest between-treatment difference (−3.8 days [95% CI: −6.6 to −1.0 days]). Patients receiving dapagliflozin also had fewer days lost to death and hospitalization from all causes vs placebo (15.5 ± 1.1 days [4.3%] vs 20.3 ± 1.1 days [5.6%]). When additional days of full health lost (ie, adjusted for Kansas City Cardiomyopathy Questionnaire–overall summary score) were added, total days lost were 110.6 ± 1.6 days (30.7%) with dapagliflozin vs 116.9 ± 1.6 days (32.5%) with placebo. The difference in all measures between the 2 groups increased over time (ie, days lost by death and hospitalization −0.9 days [−0.7%] at 120 days, −2.3 days [−1.0%] at 240 days, and −4.8 days [−1.3%] at 360 days). Dapagliflozin reduced the total days of potential full health lost due to death, hospitalizations, and impaired well-being, and this benefit increased over time during the first year. (Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure; NCT03036124) [Display omitted] [ABSTRACT FROM AUTHOR]

Hypotension is a potential adverse effect of sacubitril/valsartan, but there are limited data regarding the predictors and implications of treatment-related hypotension in heart failure (HF) with mildly reduced and preserved ejection fraction. We investigated predictors of treatment-associated hypotension, clinical outcomes after hypotension, and the relationship between left ventricular ejection fraction (LVEF) and incidence of hypotension in the PARAGON-HF (Prospective Comparison of ARNI with ARB Global Outcomes in HF with Preserved Ejection Fraction) trial. PARAGON-HF randomized patients with chronic HF (≥45%) to sacubitril/valsartan or valsartan. Following randomization, hypotension was defined as investigator-reported hypotension with a systolic blood pressure <100 mm Hg. Predictors of hypotension were assessed using multivariable Cox models. Associations between hypotension and clinical outcomes were evaluated in time-updated Cox models. The relationship among treatment, LVEF, and incident rates of hypotension and clinical outcomes was estimated using Poisson regression models. Of 4,796 patients in PARAGON-HF, 637 (13%) experienced hypotension, more frequently in the sacubitril/valsartan arm (P < 0.001). Following documented hypotension, patients had higher risk of cardiovascular death and total HF hospitalizations (adjusted RR: 1.63; 95% CI: 1.27-2.09; P < 0.001) and all-cause death (adjusted HR: 1.62; 95% CI: 1.28-2.05; P < 0.001). LVEF modified the association between sacubitril/valsartan and risk of hypotension (P interaction = 0.019) such that patients with LVEF ≥60% experienced substantially higher treatment-related risks of hypotension. In PARAGON-HF, a higher LVEF was associated with an increased risk of hypotension in patients treated with sacubitril/valsartan compared with valsartan. Because these subjects are also less likely to derive clinical benefit from sacubitril/valsartan, our data reinforce that the benefit/risk ratio favors the use of sacubitril/valsartan in patients with LVEF below normal, but not at higher LVEF. (Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction [PARAGON-HF]; NCT01920711) [Display omitted] [ABSTRACT FROM AUTHOR]

Patients who sustain an acute myocardial infarction (AMI), including ST-segment elevation myocardial infarction (STEMI) and non–ST-segment elevation myocardial infarction (NSTEMI), remain at high risk for heart failure (HF), coronary events, and death. Angiotensin-converting enzyme inhibitors have been shown to significantly decrease the risk for cardiovascular events in both STEMI and NSTEMI patients. The objectives were to determine whether angiotensin-receptor blockade and neprilysin inhibition with sacubitril/valsartan, compared with ramipril, has impact on reducing cardiovascular events according to the type of AMI. The PARADISE-MI (Prospective ARNI versus ACE inhibitor trial to DetermIne Superiority in reducing heart failure Events after Myocardial Infarction) trial enrolled patients with AMI complicated by left ventricular dysfunction and/or pulmonary congestion and at least 1 risk-enhancing factor. Patients were randomized to either sacubitril/valsartan or ramipril. The primary endpoint was death from cardiovascular causes or incident HF. In this prespecified analysis, we stratified patients according to AMI type. Of 5,661 enrolled patients, 4,291 (75.8%) had STEMI. These patients were younger and had fewer comorbidities and cardiovascular risk factors than NSTEMI patients. After adjustment for potential confounders, the risk for the primary outcome was marginally higher in NSTEMI vs STEMI patients (adjusted HR: 1.19; 95% CI: 1.00-1.41), with borderline statistical significance (P = 0.05). The primary composite outcome occurred at similar rates in patients randomized to sacubitril/valsartan vs ramipril in STEMI (10% vs 12%; HR: 0.87; 95% CI: 0.73-1.04; P = 0.13) and NSTEMI patients (17% vs 17%; HR: 0.97; 95% CI: 0.75-1.25; P = 0.80; P interaction = 0.53). Compared with ramipril, sacubitril/valsartan did not significantly decrease the risk for cardiovascular death and HF in patients with AMI complicated by left ventricular dysfunction, irrespective of the type of AMI. (Prospective ARNI vs ACE Inhibitor Trial to Determine Superiority in Reducing Heart Failure Events After MI; NCT02924727) [Display omitted] [ABSTRACT FROM AUTHOR]

Sodium-glucose cotransporter-2 (SGLT2) inhibitors are guideline recommended in the management of heart failure (HF). Although these therapies can be initiated even in patients with comorbid chronic kidney disease, some patients may face deterioration of kidney function over time. In this study, the authors sought to examine the safety and efficacy of continuing SGLT2 inhibitors in HF when the estimated glomerular filtration rate (eGFR) falls below thresholds for initiation. Associations between a deterioration of eGFR to <25 mL/min/1.73 m2, efficacy, and safety outcomes and treatment with dapagliflozin were evaluated in time-updated Cox proportional hazard models in a participant-level pooled analysis of 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) and DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure) trials. Among 11,007 patients, 347 (3.2%) experienced a deterioration of eGFR to <25 mL/min/1.73 m2 at least once in follow-up. These patients had a higher risk of the primary composite outcome (HR: 1.87; 95% CI: 1.48-2.35; P < 0.001). The risk of the primary outcome was lower with dapagliflozin compared with placebo among patients who did (HR: 0.53; 95% CI: 0.33-0.83) as well as did not (HR: 0.78; 95% CI: 0.72-0.86) experience deterioration of eGFR to <25 mL/min/1.73 m2 (P interaction = 0.17). The risk of safety outcomes, including drug discontinuation, was higher among patients with deterioration of eGFR to <25 mL/min/1.73 m2; however, rates remained similar between treatment groups including among those who remained on study drug. Patients with deterioration of eGFR to <25 mL/min/1.73 m2 had elevated risks of cardiovascular outcomes yet appeared to benefit from continuation of dapagliflozin with no excess in safety outcomes between treatment groups. The benefit-to-risk ratio may favor continuation of dapagliflozin treatment in patients with HF experiencing deterioration of kidney function. Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure [DAPA-HF]; NCT03036124 ; and Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure [DELIVER]; NCT03619213) [Display omitted] [ABSTRACT FROM AUTHOR]

Sodium-glucose cotransporter-2 (SGLT2) inhibitors and GLP-1 receptor agonists (GLP-1 RAs) reduce adverse cardiovascular outcomes in type 2 diabetes (T2D). However, the efficacy of combination therapy is unclear. The aim of this study was to evaluate the effects of GLP-1 RAs on cardiovascular outcomes in patients with T2D treated with or without SGLT2 inhibitors. Post hoc analysis of Harmony Outcomes (Albiglutide and Cardiovascular Outcomes in Patients With Type 2 Diabetes and Cardiovascular Disease) evaluating the effect of albiglutide in T2D with cardiovascular disease by background SGLT2 inhibitor use. Additionally, a trial-level meta-analysis of Harmony Outcomes and AMPLITUDE-O (Effect of Efpeglenatide on Cardiovascular Outcomes), which evaluated T2D with cardiovascular or renal disease, was performed, combining the treatment effect estimates according to SGLT2 inhibitor use. Of the 9,462 participants in Harmony Outcomes, 575 (6.1%) were treated with SGLT2 inhibitors at baseline. The effect of albiglutide on reducing the composite of cardiovascular death, myocardial infarction, or stroke (major adverse cardiovascular events) was consistent with or without SGLT2 inhibitors (P interaction = 0.70). The effect of albiglutide on secondary outcomes and adverse events was not modified by SGLT2 inhibitors. A meta-analysis of Harmony Outcomes and AMPLITUDE-O included 13,538 patients, of whom 1,193 (8.8%) used SGLT2 inhibitors. Compared to placebo, GLP1-RAs reduced major adverse cardiovascular events without effect modification by SGLT2 inhibitor use (HR: 0.77; 95% CI: 0.68-0.87 without SGLT2 inhibitors; and HR: 0.78; 95% CI: 0.49-1.24 with SGLT2 inhibitors) (P for interaction = 0.95) and reduced heart failure hospitalization (HR: 0.72; 95% CI: 0.55-0.92 vs HR: 0.34; 95% CI: 0.12-0.96) (P for interaction = 0.18). In patients with T2D and cardiovascular disease, GLP-1 RAs reduced cardiovascular events independently of SGLT2 inhibitor use. These findings suggest that the combination of GLP-1 RAs with SGLT2 inhibitors may further reduce cardiovascular risk. Clinical trials with combination therapy are needed. [Display omitted] [ABSTRACT FROM AUTHOR]

Limited data exist to characterize novel measures of right ventricular (RV) function and the coupling to pulmonary circulation in patients with heart failure and preserved left ventricular ejection fraction (HFpEF). This study sought to assess the clinical implications of RV function, the association with N-terminal pro–B-type natriuretic peptide, and the risk for adverse events among patients with HFpEF. This study analyzed measures of RV function by assessing absolute RV free wall longitudinal strain (RVFWLS) and its ratio to estimated pulmonary artery systolic pressure (PASP) (RVFWLS/PASP ratio) in 528 patients (mean age 74 ± 8 years, 56% female) with adequate echocardiographic images quality enrolled in the PARAGON-HF trial. Associations with baseline N-terminal pro–B-type natriuretic peptide and with total HF hospitalizations and cardiovascular death were assessed, after accounting for confounders. Overall, 311 patients (58%) had evidence of RV dysfunction, defined as absolute RVFWLS <20%, and among the 388 patients (73%) with normal tricuspid annular planar systolic excursion and RV fractional area change, more than one-half showed impaired RV function. Lower values of RVFWLS and RVFWLS/PASP ratios were significantly associated with higher circulating N-terminal pro–B-type natriuretic peptide. With a median follow-up of 2.8 years, there were 277 total HF hospitalizations and cardiovascular deaths. Both absolute RVFWLS (HR: 1.39; 95% CI: 1.05-1.83; P = 0.018) and RVFWLS/PASP ratio (HR: 1.43; 95% CI: 1.13-1.80; P = 0.002) were significantly associated with the composite outcome. Treatment effect of sacubitril/valsartan was not modified by measures of RV function. Worsening RV function and its ratio to pulmonary pressure is common and significantly associated with an increased risk of HF hospitalizations and cardiovascular death in patients with HFpEF. (Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction [PARAGON-HF]; NCT01920711) [Display omitted] [ABSTRACT FROM AUTHOR]

Some patients with heart failure may experience transient changes in kidney function upon transition to sacubitril/valsartan. Whether such changes portend adverse outcomes or influence long-term treatment benefits with sacubitril/valsartan continuation is unknown. This investigation aimed to evaluate the association between the occurrence of moderate estimated glomerular filtration rate (eGFR) decline (>15%) after initial exposure to sacubitril/valsartan and subsequent cardiovascular outcomes and its treatment benefits in PARADIGM-HF and PARAGON-HF. In sequential run-in phases, patients were titrated to enalapril 10 mg twice daily and then sacubitril/valsartan 97 mg/103 mg twice daily (in PARADIGM-HF) or valsartan 80 mg twice daily and then sacubitril/valsartan 49 mg/51 mg twice daily (in PARAGON-HF). Among randomized participants, 11% in PARADIGM-HF and 10% in PARAGON-HF experienced eGFR decline (>15%) during sacubitril/valsartan run-in. eGFR partially recovered (from nadir to postrandomization week 16) regardless of sacubitril/valsartan continuation or switch to renin-angiotensin system inhibitor (RASi) postrandomization. Initial eGFR decline was not consistently associated with clinical outcomes in either trial. Treatment benefits of sacubitril/valsartan vs RASi on primary outcomes were similar irrespective of run-in eGFR decline in PARADIGM-HF (eGFR decline, HR: 0.69; 95% CI: 0.53-0.90; and no eGFR decline, HR: 0.80; 95% CI: 0.73-0.88; P interaction = 0.32) and PARAGON-HF (eGFR decline, rate ratio [RR]: 0.84; 95% CI: 0.52-1.36 and no eGFR decline, RR: 0.87; 95% CI: 0.75-1.02, P interaction = 0.92). The treatment effect of sacubitril/valsartan remained consistent across a range of eGFR declines. Moderate eGFR decline when transitioning from RASi to sacubitril/valsartan is not consistently associated with adverse outcomes, and its long-term benefits are retained in heart failure across a broad range of eGFR declines. Early eGFR changes should not deter continuation of sacubitril/valsartan or stall uptitration. (Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction [PARAGON-HF]; NCT01920711 ; Prospective Comparison of Angiotensin Receptor-Neprilysin Inhibitors with Angiotensin-Converting Enzyme Inhibitors to Determine Impact on Global Mortality and Morbidity in Heart Failure [PARADIGM-HF]; NCT01035255) [Display omitted] [ABSTRACT FROM AUTHOR]

Background: Recent guidelines support consideration of sodium-glucose cotransporter-2 inhibitors in the long-term management of heart failure (HF) with mildly reduced or preserved ejection fraction. Patients and clinicians may be interested in the expected lifetime benefits of sodium-glucose cotransporter-2 inhibitors in this population.Objectives: This study aimed to estimate event-free survival gains from long-term use of dapagliflozin in patients with HF with mildly reduced or preserved ejection fraction overall and in clinically relevant subgroups.Methods: In this prespecified analysis of DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure), we applied validated nonparametric age-based methods to extrapolate potential gains in survival free from the primary endpoint (cardiovascular death or worsening HF event) from long-term use of dapagliflozin. Eligible participants had symptomatic HF, left ventricular ejection fraction >40%, elevated natriuretic peptide levels, and structural heart disease. For every year between the ages of 55 and 85 years, we estimated event-free survival using age at randomization rather than time from randomization as the time horizon. Residual lifespan free from a primary endpoint was estimated based on area under the survival curve in each arm.Results: Among 6,263 participants, mean survival free from the primary endpoint for a 65-year-old participant was 12.1 years (95% CI: 11.0-13.2 years) with dapagliflozin and 9.7 years (95% CI: 8.8-10.7 years) with placebo, representing a 2.3-year (95% CI: 0.9-3.8 years) event-free survival gain (P = 0.002). Treatment gains in survival free from the primary endpoint ranged from 2.0 years (95% CI: -0.6 to 4.6 years) in a 55-year-old to 1.2 years (95% CI: -0.1 to 2.4 years) in a 75-year-old patient. Mean event-free survival was greater with dapagliflozin than with placebo across all 14 subgroups.Conclusions: Treatment with dapagliflozin is projected to extend event-free survival by up to 2.0 to 2.5 years among middle-aged and older individuals with HF with mildly reduced or preserved ejection fraction. (DELIVER [Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure]; NCT03619213). [ABSTRACT FROM AUTHOR]

With the current landscape of approved therapies for heart failure (HF), there is a need to determine the role of a standard background therapy against which novel therapies are studied. The Heart Failure Collaboratory convened a multistakeholder group of clinical investigators, clinicians, patients, government representatives including U.S. Food and Drug Administration and National Institutes of Health participants, payers, and industry in March 2021 to discuss whether standardization of background drug therapy is necessary in clinical trials in patients with HF. The current paper summarizes the discussion and provides potential conceptual approaches, with a focus on therapies indicated for HF with reduced ejection fraction. [ABSTRACT FROM AUTHOR]