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Aims: Worsening renal function may impact long-term outcomes in heart failure (HF). However, little is known about the longitudinal trajectories in renal function in relation to HF hospitalization or how this high-risk clinical event impacts renal outcomes.Methods and Results: In PARAGON-HF, we evaluated the association between recency of prior HF hospitalization (occurring pre-randomization) and subsequent first renal composite outcome: (i) time to ≥50% decline in estimated glomerular filtration rate (eGFR); (ii) development of end-stage renal disease; or (iii) death attributable to renal causes. A total of 2306 (48.1%) patients had a history of prior HF hospitalization. Incident rates of the renal outcome were highest in those most recently hospitalized and decreased with longer time from last hospitalization. Treatment effect on the renal outcome of sacubitril/valsartan versus valsartan was similar between patients with (hazard ratio [HR] 0.43; 95% confidence interval [CI] 0.24-0.76) and without (HR 0.63; 95% CI: 0.33-1.18; pinteraction  = 0.39) a prior history of HF hospitalization and appeared consistent regardless of timing of prior hospitalization for HF (pinteraction  = 0.39). Serial eGFR measurements leading up to and after a HF hospitalization (occurring during the study period) and estimated eGFR trajectories using repeated measures regression models with restricted cubic splines were also examined. Patients experiencing a post-randomization HF hospitalization had a significant decline in eGFR prior to hospitalization while patients without HF hospitalization experienced a relatively stable eGFR trajectory (p < 0.001). A change in the rate of decline of eGFR trajectory was observed 12 months preceding a HF hospitalization, and continued in the post-discharge window to 12 months following hospitalization.Conclusions: Heart failure hospitalization denotes increased risk for kidney disease progression which continues following recovery from HF decompensation in patients with HF with preserved ejection fraction.Clinical Trial Registration: PARAGON-HF (Prospective Comparison of ARNI with ARB Global Outcomes in HF with Preserved Ejection Fraction), ClinicalTrials.gov NCT01920711. [ABSTRACT FROM AUTHOR]

Objective: To use protein biomarkers to identify people with type 2 diabetes at high risk of cardiovascular outcomes and death.Research Design and Methods: Biobanked serum from 4,957 ELIXA (Evaluation of Lixisenatide in Acute Coronary Syndrome) trial participants was analyzed. Forward-selection Cox models identified independent protein risk factors for major adverse cardiovascular events (MACE) and death that were compared with a previously validated biomarker panel.Results: NT-proBNP and osteoprotegerin predicted both outcomes. In addition, trefoil factor 3 predicted MACE, and angiopoietin-2 predicted death (C = 0.70 and 0.79, respectively, compared with 0.63 and 0.66 for clinical variables alone). These proteins had all previously been identified and validated. Notably, C statistics for just NT-proBNP plus clinical risk factors were 0.69 and 0.78 for MACE and death, respectively.Conclusions: NT-proBNP and other proteins independently predict cardiovascular outcomes in people with type 2 diabetes following acute coronary syndrome. Adding other biomarkers only marginally increased NT-proBNP's prognostic value. [ABSTRACT FROM AUTHOR]

Aims: Despite landmark heart failure (HF) with reduced ejection fraction (HFrEF) trials showing effect of mineralocorticoid receptor antagonists (MRA) on the risk of death and HF hospitalization, it has been suggested that MRAs are underutilized or frequently withdrawn. This study sought to identify temporal trends in the initiation of MRAs and the subsequent risk of withdrawal and adherence of MRAs in HF patients treated with a renin-angiotensin system inhibitor and a beta-blocker in Denmark from 2003-2017.Methods and Results: From nationwide registries, we identified patients receiving a diagnosis of HF. Use of MRA was identified by at least one prescription within 6 months after the diagnosis. The absolute risk of withdrawal with treatment was assessed with cumulative incidence, accounting for the competing risk of death. To estimate adherence, we calculated the proportion of days covered. We included 51 512 patients with incident HF. During the study period, 20 779 (40.3%) patients initiated MRA therapy. The incidence of withdrawal of MRA was 49.2% throughout the study period; 48.0% of the HF patients were adherent to the treatment. Among patients withdrawing treatment with MRA, the cumulative incidence of reinitiating was 36.6%.Conclusions: In a nationwide cohort of patients with HF, approximately half of the patients received MRA as third-line therapy within the first 6 months after diagnosis and approximately half of these withdrew MRA within 5 years. These findings warrant an increasing focus on retention to MRA treatment in a real-life setting. [ABSTRACT FROM AUTHOR]

Objective: Insulin resistance (IR) may mediate heart failure (HF) development. We examined whether IR in people with newly diagnosed type 2 diabetes (T2D) increased their risk of a composite outcome of HF or death or of HF alone.Research Design and Methods: Insulin resistance (HOMA2-IR) values for UKPDS participants were derived from paired fasting plasma glucose (FPG) and insulin measures. Kaplan-Meier survival curves and multivariable survival models were used to evaluate associations between HOMA2-IR and HF/death or HF alone. We adjusted for potential confounders by including variables with univariate associations (P < 0.1) and by requiring a multivariable P < 0.05.Results: Of 5,102 UKPDS participants with newly diagnosed T2D, 4,344 had HOMA2-IR measurements. At enrollment, mean (SD) age was 52.5 (8.7) years, with HbA1c 7.2% (1.8%), and BMI 28.8 (5.5) kg/m2, and median (interquartile range) HOMA2-IR was 1.6 (1.1-2.2). HF/death occurred in 1,974 (45.4%) participants (235 first HF events, 1,739 deaths) over a median follow-up of 16.4 years. Multivariable independent associations with HF/death were older age and higher BMI, HOMA2-IR, FPG, waist-to-hip ratio, systolic blood pressure, LDL cholesterol, and heart rate as well as sex, race, smoking status, prior atrial fibrillation, and prior microalbuminuria. A doubling of HOMA2-IR was associated with a 5% greater risk of HF/death (relative risk [RR] 1.05 [95% CI 1.01-1.12], P = 0.0029) and a 14% greater risk of HF (RR 1.14, [95% CI 1.02-1.27], P = 0.017).Conclusions: Patients with newly diagnosed T2D and insulin resistance were more likely to develop HF or die than those more sensitive to insulin. [ABSTRACT FROM AUTHOR]

Aims: Patients surviving an acute myocardial infarction (AMI) are at risk of developing symptomatic heart failure (HF) or premature death. We hypothesized that sacubitril/valsartan, effective in the treatment of chronic HF, prevents development of HF and reduces cardiovascular death following high-risk AMI compared to a proven angiotensin-converting enzyme (ACE) inhibitor. This paper describes the study design and baseline characteristics of patients enrolled in the Prospective ARNI vs. ACE inhibitor trial to DetermIne Superiority in reducing heart failure Events after Myocardial Infarction (PARADISE-MI) trial.Methods and Results: PARADISE-MI, a multinational (41 countries), double-blind, active-controlled trial, randomized patients within 0.5-7 days of presentation with index AMI to sacubitril/valsartan or ramipril. Transient pulmonary congestion and/or left ventricular ejection fraction (LVEF) ≤40% and at least one additional factor augmenting risk of HF or death (age ≥70 years, estimated glomerular filtration rate <60 mL/min/1.73 m2 , diabetes, prior myocardial infarction, atrial fibrillation, LVEF <30%, Killip class ≥III, ST-elevation myocardial infarction without reperfusion) were required for inclusion. PARADISE-MI was event-driven targeting 708 primary endpoints (cardiovascular death, HF hospitalization or outpatient development of HF). Randomization of 5669 patients occurred 4.3 ± 1.8 days from presentation with index AMI. The mean age was 64 ± 12 years, 24% were women. The majority (76%) qualified with ST-segment elevation myocardial infarction; acute percutaneous coronary intervention was performed in 88% and thrombolysis in 6%. LVEF was 37 ± 9% and 58% were in Killip class ≥II.Conclusions: Baseline therapies in PARADISE-MI reflect advances in contemporary evidence-based care. With enrollment complete PARADISE-MI is poised to determine whether sacubitril/valsartan is more effective than a proven ACE inhibitor in preventing development of HF and cardiovascular death following AMI. [ABSTRACT FROM AUTHOR]

Aims: Frailty, characterized by loss of homeostatic reserves and increased vulnerability to physiological decompensation, results from an aggregation of insults across multiple organ systems. Frailty can be quantified by counting the number of 'health deficits' across a range of domains. We assessed the frequency of, and outcomes related to, frailty in patients with heart failure and reduced ejection fraction (HFrEF).Methods and Results: Using a cumulative deficits approach, we constructed a 42-item frailty index (FI) and applied it to identify frail patients enrolled in two HFrEF trials (PARADIGM-HF and ATMOSPHERE). In keeping with previous studies, patients with FI ≤0.210 were classified as non-frail and those with higher scores were divided into two categories using score increments of 0.100. Clinical outcomes were examined, adjusting for prognostic variables. Among 13 625 participants, mean (± standard deviation) FI was 0.250 (0.10) and 8383 patients (63%) were frail (FI >0.210). The frailest patients were older and had more symptoms and signs of heart failure. Women were frailer than men. All outcomes were worse in the frailest, with high rates of all-cause death or all-cause hospitalization: 40.7 (39.1-42.4) vs. 22.1 (21.2-23.0) per 100 person-years in the non-frail; adjusted hazard ratio 1.63 (1.53-1.75) (P < 0.001). The rate of all-cause hospitalizations, taking account of recurrences, was 61.5 (59.8-63.1) vs. 31.2 (30.3-32.2) per 100 person-years (incidence rate ratio 1.76; 1.62-1.90; P < 0.001).Conclusion: Frailty is highly prevalent in HFrEF and associated with greater deterioration in quality of life and higher risk of hospitalization and death. Strategies to prevent and treat frailty are needed in HFrEF. [ABSTRACT FROM AUTHOR]

Aims: To develop a risk model for sudden cardiac death (SCD) in high-risk acute myocardial infarction (AMI) survivors.Methods and Results: Data from the Effect of Carvedilol on Outcome After Myocardial Infarction in Patients With Left Ventricular Dysfunction trial (CAPRICORN) and the Valsartan in Acute Myocardial Infarction Trial (VALIANT) were used to create a SCD risk model (with non-SCD as a competing risk) in 13 202 patients. The risk model was validated in the Eplerenone Post-AMI Heart Failure Efficacy and Survival Study (EPHESUS). The rate of SCD was 3.3 (95% confidence interval 3.0-3.5) per 100 person-years over a median follow-up of 2.0 years. Independent predictors of SCD included age > 70 years; heart rate ≥ 70 bpm; smoking; Killip class III/IV; left ventricular ejection fraction ≤30%; atrial fibrillation; history of prior myocardial infarction, heart failure or diabetes; estimated glomerular filtration rate < 60 mL/min/1.73 m2 ; and no coronary reperfusion or revascularisation therapy for index AMI. The model was well calibrated and showed good discrimination (C-statistic = 0.72), including in the early period after AMI. The observed 2-year event rates increased steeply with each quintile of risk score (1.9%, 3.6%, 6.2%, 9.0%, 13.4%, respectively).Conclusion: An easy to use SCD risk score developed from routinely collected clinical variables in patients with heart failure, left ventricular systolic dysfunction or both, early after AMI was superior to left ventricular ejection fraction. This score might be useful in identifying patients for future trials testing treatments to prevent SCD early after AMI. [ABSTRACT FROM AUTHOR]

Background: Unlike heart failure with reduced ejection fraction, there is no approved treatment for heart failure with preserved ejection fraction, the predominant phenotype in women. Therefore, there is a greater heart failure therapeutic deficit in women compared with men.Methods: In a prespecified subgroup analysis, we examined outcomes according to sex in the PARAGON-HF trial (Prospective Comparison of ARNI With ARB Global Outcomes in Heart Failure With Preserved Ejection Fraction), which compared sacubitril-valsartan and valsartan in patients with heart failure with preserved ejection fraction. The primary outcome was a composite of first and recurrent hospitalizations for heart failure and death from cardiovascular causes. We also report secondary efficacy and safety outcomes.Results: Overall, 2479 women (51.7%) and 2317 men (48.3%) were randomized. Women were older and had more obesity, less coronary disease, and lower estimated glomerular filtration rate and NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels than men. For the primary outcome, the rate ratio for sacubitril-valsartan versus valsartan was 0.73 (95% CI, 0.59-0.90) in women and 1.03 (95% CI, 0.84-1.25) in men (P interaction = 0.017). The benefit from sacubitril-valsartan was attributable to reduction in heart failure hospitalization. The improvement in New York Heart Association class and renal function with sacubitril-valsartan was similar in women and men, whereas the improvement in Kansas City Cardiomyopathy Questionnaire clinical summary score was less in women than in men. The difference in adverse events between sacubitril-valsartan and valsartan was similar in women and men.Conclusions: As compared with valsartan, sacubitril-valsartan seemed to reduce the risk of heart failure hospitalization more in women than in men. Whereas the possible sex-related modification of the effect of treatment has several potential explanations, the present study does not provide a definite mechanistic basis for this finding.Clinical Trial Registration: https://www.clinicaltrials.gov. Unique identifier: NCT01920711. [ABSTRACT FROM AUTHOR]

Aims: Growth differentiation factor-15 (GDF-15) is associated with adverse prognosis in cardiovascular (CV) and non-CV diseases. We evaluated the association of GDF-15 with CV and non-CV outcomes in the PARADIGM-HF trial.Methods and Results: In 1935 patients with heart failure and reduced ejection fraction (HFrEF) in PARADIGM-HF, median GDF-15 values were elevated and similar in sacubitril/valsartan and enalapril patients (1626 ng/L and 1690 ng/L, respectively). Diabetes, age, creatinine, high-sensitive troponin T, N-terminal pro-B-type natriuretic peptide, and New York Heart Association class III/IV were most strongly associated with elevated GDF-15 values (all P < 0.001) (adjusted R2 = 0.3857). Baseline GDF-15 and changes in GDF-15 at both 1 month and 8 months (log-transformed) were associated with subsequent mortality and CV events. Each 20% increment in baseline GDF-15 value was associated with a higher risk of mortality [adjusted hazard ratio (HR) 1.13, 95% confidence interval (CI) 1.08-1.18, P < 0.001], the combined endpoint of CV death or hospitalization for heart failure (adjusted HR 1.09, 95% CI 1.05-1.14, P < 0.001) and heart failure death (adjusted HR 1.16, 95% CI 1.05-1.28, P < 0.001). Changes in GDF-15 were not influenced by assigned therapy (all P-values ≥ 0.1).Conclusion: In patients with ambulatory HFrEF, GDF-15 is not modified by sacubitril/valsartan and is strongly associated with mortality and CV outcomes, suggesting that GDF-15 is a marker of poor outcomes in these patients.Clinical Trial Registration: ClinicalTrials.gov Identifier NCT01035255. [ABSTRACT FROM AUTHOR]

Aims: Inhibition of neprilysin, an enzyme degrading natriuretic and other vasoactive peptides, is beneficial in heart failure with reduced ejection fraction (HFrEF), as shown in PARADIGM-HF which compared the angiotensin receptor-neprilysin inhibitor (ARNI) sacubitril/valsartan with enalapril. As neprilysin is also one of many enzymes clearing amyloid-β peptides from the brain, there is a theoretical concern about the long-term effects of sacubitril/valsartan on cognition. Therefore, we have examined dementia-related adverse effects (AEs) in PARADIGM-HF and placed these findings in the context of other recently conducted HFrEF trials.Methods and Results: In PARADIGM-HF, patients with symptomatic HFrEF were randomized to sacubitril/valsartan 97/103 mg b.i.d. or enalapril 10 mg b.i.d. in a 1:1 ratio. We systematically searched AE reports, coded using the Medical Dictionary for Regulatory Activities (MedDRA), using Standardized MedDRA Queries (SMQs) with 'broad' and 'narrow' preferred terms related to dementia. In PARADIGM-HF, 8399 patients aged 18-96 years were randomized and followed for a median of 2.25 years (up to 4.3 years). The narrow SMQ search identified 27 dementia-related AEs: 15 (0.36%) on enalapril and 12 (0.29%) on sacubitril/valsartan [hazard ratio (HR) 0.73, 95% confidence interval (CI) 0.33-1.59]. The broad search identified 97 (2.30%) and 104 (2.48%) AEs (HR 1.01, 95% CI 0.75-1.37), respectively. The rates of dementia-related AEs in both treatment groups in PARADIGM-HF were similar to those in three other recent trials in HFrEF.Conclusion: We found no evidence that sacubitril/valsartan, compared with enalapril, increased dementia-related AEs, although longer follow-up may be necessary to detect such a signal and more sensitive tools are needed to detect lesser degrees of cognitive impairment. Further studies to address this question are warranted. [ABSTRACT FROM AUTHOR]

Aims: In this analysis, we utilized data from PARADIGM-HF to test the hypothesis that participants who exhibited any dose reduction during the trial would have similar benefits from lower doses of sacubitril/valsartan relative to lower doses of enalapril.Methods and Results: In a post-hoc analysis from PARADIGM-HF, we characterized patients by whether they received the maximal dose (200 mg sacubitril/valsartan or 10 mg enalapril twice daily) throughout the trial or had any dose reduction to lower doses (100/50/0 mg sacubitril/valsartan or 5/2.5/0 mg enalapril twice daily). The treatment effect for the primary outcome was estimated, stratified by dose level using time-updated Cox regression models. In the two treatment arms, participants with a dose reduction (43% of those randomized to enalapril and 42% of those randomized to sacubitril/valsartan) had similar baseline characteristics and similar baseline predictors of the need for dose reduction. In a time-updated analysis, any dose reduction was associated with a higher subsequent risk of the primary event [hazard ratio (HR) 2.5, 95% confidence interval (CI) 2.2-2.7]. However, the treatment benefit of sacubitril/valsartan over enalapril following a dose reduction was similar (HR 0.80, 95% CI 0.70-0.93, P < 0.001) to that observed in patients who had not experienced any dose reduction (HR 0.79, 95% CI 0.71-0.88, P < 0.001).Conclusions: In PARADIGM-HF, study medication dose reduction identified patients at higher risk of a major cardiovascular event. The magnitude of benefit for patients on lower doses of sacubitril/valsartan relative to those on lower doses of enalapril was similar to that of patients who remained on target doses of both drugs. [ABSTRACT FROM AUTHOR]

Aims: To assess the tolerability of initiating/uptitrating sacubitril/valsartan (LCZ696) from 50 to 200 mg twice daily (target dose) over 3 and 6 weeks in heart failure (HF) patients (ejection fraction ≤35%).Methods and Results: A 5-day open-label run-in (sacubitril/valsartan 50 mg twice daily) preceded an 11-week, double-blind, randomization period [100 mg twice daily for 2 weeks followed by 200 mg twice daily ('condensed' regimen) vs. 50 mg twice daily for 2 weeks, 100 mg twice daily for 3 weeks, followed by 200 mg twice daily ('conservative' regimen)]. Patients were stratified by pre-study dose of angiotensin-converting enzyme inhibitor/angiotensin-receptor blocker (ACEI/ARB; low-dose stratum included ACEI/ARB-naïve patients). Of 540 patients entering run-in, 498 (92%) were randomized and 429 (86.1% of randomized) completed the study. Pre-defined tolerability criteria were hypotension, renal dysfunction and hyperkalaemia; and adjudicated angioedema, which occurred in ('condensed' vs. 'conservative') 9.7% vs. 8.4% (P = 0.570), 7.3% vs. 7.6% (P = 0.990), 7.7% vs. 4.4% (P = 0.114), and 0.0% vs. 0.8% of patients, respectively. Corresponding proportions for pre-defined systolic blood pressure <95 mmHg, serum potassium >5.5 mmol/L, and serum creatinine >3.0 mg/dL were 8.9% vs. 5.2% (P = 0.102), 7.3% vs. 4.0% (P = 0.097), and 0.4% vs. 0%, respectively. In total, 378 (76%) patients achieved and maintained sacubitril/valsartan 200 mg twice daily without dose interruption/down-titration over 12 weeks (77.8% vs. 84.3% for 'condensed' vs. 'conservative'; P = 0.078). Rates by ACEI/ARB pre-study dose stratification were 82.6% vs. 83.8% (P = 0.783) for high-dose/'condensed' vs. high-dose/'conservative' and 84.9% vs. 73.6% (P = 0.030) for low-dose/'conservative' vs. low-dose/'condensed'.Conclusions: Initiation/uptitration of sacubitril/valsartan from 50 to 200 mg twice daily over 3 or 6 weeks had a tolerability profile in line with other HF treatments. More gradual initiation/uptitration maximized attainment of target dose in the low-dose ACEI/ARB group. [ABSTRACT FROM AUTHOR]

Aims: The use of an erythropoesis-stimulating agent, darbepoetin alfa (DA), to treat anaemia in patients with diabetes mellitus and chronic kidney disease was associated with a heightened risk of stroke and neutral efficacy in the Trial to Reduce Cardiovascular Events with Aranesp Therapy (TREAT), despite epidemiological data suggesting the contrary. However, this association has not been evaluated in another randomized, placebo-controlled trial.Methods and Results: Reduction of Events by Darbepoetin Alfa in Heart Failure (RED-HF) was a randomized placebo-controlled trial of DA in 2278 patients with systolic heart failure and anaemia, enrolled from 2006 to 2012 and followed for a median of 28 months. Within RED-HF, 816 patients had diabetes mellitus and chronic kidney disease [estimated glomerular filtration rate (eGFR) 20-60 mL/min/1.73 m(2) ] and met inclusion criteria for TREAT. TREAT-like RED-HF patient data were analysed alone and combined at the patient level with the 4038 TREAT patients. In RED-HF, the annualized event rate of stroke was 2.3 in patients on DA and 1.1 in patients randomized to placebo (P = 0.051). Analysis of the combined group (n = 4854) confirmed a nearly two-fold increase in stroke risk [hazard ratio (HR) 1.94, 95% confidence interval (CI) 1.43-2.63] and an overall neutral effect on mortality (HR 1.00, 95% CI 0.89-1.12) of raising haemoglobin with DA.Conclusion: The placebo-controlled cohort of heart failure patients with anaemia, diabetes mellitus, and chronic kidney disease from RED-HF provides confirmation of the increased stroke risk associated with DA use identified in TREAT. [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]

Background: Circulating high-sensitivity cardiac troponin T (hsTnT) predominantly reflects myocardial injury, and higher levels are associated with a higher risk of worsening heart failure and death in patients with heart failure with reduced ejection fraction. Less is known about the prognostic significance of changes in hsTnT over time, the effects of dapagliflozin on clinical outcomes in relation to baseline hsTnT levels, and the effect of dapagliflozin on hsTnT levels.Methods: DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) was a randomized, double-blind, placebo-controlled trial of dapagliflozin (10 mg daily) in patients with New York Heart Association class II to IV symptoms and left ventricular ejection fraction ≤40% (median follow-up, 18.2 months). hsTnT (Roche Diagnostics) was measured at baseline in 3112 patients and at 1 year in 2506 patients. The primary end point was adjudicated worsening heart failure or cardiovascular death. Clinical end points were analyzed according to baseline hsTnT and change in hsTnT from baseline to 1 year. Comparative treatment effects on clinical end points with dapagliflozin versus placebo were assessed by baseline hsTnT. The effect of dapagliflozin on hsTnT was explored.Results: Median baseline hsTnT concentration was 20.0 (25th-75th percentile, 13.7-30.2) ng/L. Over 1 year, 67.9% of patients had a ≥10% relative increase or decrease in hsTnT concentrations, and 43.5% had a ≥20% relative change. A stepwise gradient of higher risk for the primary end point was observed across increasing quartiles of baseline hsTnT concentration (adjusted hazard ratio Q4 versus Q1, 3.44 [95% CI, 2.46-4.82]). Relative and absolute increases in hsTnT over 1 year were associated with higher subsequent risk of the primary end point. The relative reduction in the primary end point with dapagliflozin was consistent across quartiles of baseline hsTnT (P-interaction=0.55), but patients in the top quartile tended to have the greatest absolute risk reduction (absolute risk difference, 7.5% [95% CI, 1.0%-14.0%]). Dapagliflozin tended to attenuate the increase in hsTnT over time compared with placebo (relative least squares mean reduction, -3% [-6% to 0%]; P=0.076).Conclusions: Higher baseline hsTnT and greater increase in hsTnT over 1 year are associated with worse clinical outcomes. Dapagliflozin consistently reduced the risk of the primary end point, irrespective of baseline hsTnT levels. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03036124. [ABSTRACT FROM AUTHOR]

Background: The incidence of pneumonia and subsequent outcomes has not been compared in patients with heart failure and reduced ejection fraction (HFrEF) and preserved ejection fraction (HFpEF).Objectives: This study aimed to examine the rate and impact of pneumonia in the PARADIGM-HF (Prospective Comparison of Angiotensin Receptor-Neprilysin Inhibitor With Angiotensin Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure) and PARAGON-HF (Prospective Comparison of ARNI with ARB Global Outcomes in Heart Failure with Preserved Ejection Fraction) trials.Methods: The authors analyzed the incidence of investigator-reported pneumonia and the rates of HF hospitalization, cardiovascular death, and all-cause death before and after the occurrence of pneumonia, and estimated risk after the first occurrence of pneumonia in unadjusted and adjusted analyses (the latter including N-terminal pro-B-type natriuretic peptide).Results: In PARADIGM-HF, 528 patients (6.3%) developed pneumonia after randomization, giving an incidence rate of 29 (95% CI: 27 to 32) per 1,000 patient-years. In PARAGON-HF, 510 patients (10.6%) developed pneumonia, giving an incidence rate of 39 (95% CI: 36 to 42) per 1,000 patient-years. The subsequent risk of all trial outcomes was elevated after the occurrence of pneumonia. In PARADIGM-HF, the adjusted hazard ratio (HR) for the risk of death from any cause was 4.34 (95% CI: 3.73 to 5.05). The corresponding adjusted HR in PARAGON-HF was 3.76 (95% CI: 3.09 to 4.58).Conclusions: The incidence of pneumonia was high in patients with HF, especially HFpEF, at around 3 times the expected rate. A first episode of pneumonia was associated with 4-fold higher mortality. (Prospective Comparison of Angiotensin Receptor-Neprilysin Inhibitor With Angiotensin-Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure [PARADIGM-HF], NCT01035255; Prospective Comparison of ARNI [Angiotensin Receptor-Neprilysin Inhibitor] With ARB [Angiotensin Receptor Blocker] Global Outcomes in Heart Failure With Preserved Ejection Fraction [PARAGON-HF], NCT01920711). [ABSTRACT FROM AUTHOR]

Background: Guidelines recommend targeting systolic blood pressure (SBP) <130 mm Hg in heart failure with preserved ejection fraction (HFpEF) with limited data.Objectives: This study sought to determine the optimal achieved SBP and whether the treatment effects of sacubitril/valsartan on outcomes are related to BP lowering, particularly among women who derive greater benefit from sacubitril/valsartan.Methods: Using 4,795 trial participants, this study related baseline and time-updated mean achieved SBP quartiles (<120, 120 to 129, 130 to 139, ≥140 mm Hg) to the primary outcome (cardiovascular death and total heart failure hospitalization), its components, myocardial infarction or stroke, and a renal composite outcome. At the 16-week visit, the study assessed the relationship between SBP change and Kansas City Cardiomyopathy Questionnaire overall summary score (KCCQ-OSS) and N-terminal pro-B-type natriuretic peptide (NT-proBNP). The study analyzed whether the BP-lowering effects of sacubitril/valsartan accounted for its treatment effects.Results: Average age was 73 ± 8 years, and 52% of participants were women. After multivariable adjustment, baseline and mean achieved SBP of 120 to 129 mm Hg demonstrated the lowest risk for all outcomes. Sacubitril/valsartan reduced SBP by 5.2 mm Hg (95% confidence interval: 4.4 to 6.0) compared with valsartan at 4 weeks, which was not modified by baseline SBP. However, sacubitril/valsartan reduced SBP more in women (6.3 mm Hg) than men (4.0 mm Hg) (interaction p = 0.005). Change in SBP was directly associated with change in NT-proBNP (p < 0.001) but not KCCQ-OSS (p = 0.40). The association between sacubitril/valsartan and the primary outcome was not modified by baseline SBP (interaction p = 0.50) and was similar when adjusting for time-updated SBP, regardless of sex.Conclusions: Baseline and mean achieved SBP of 120 to 129 mm Hg identified the lowest risk patients with HFpEF. Baseline SBP did not modify the treatment effect of sacubitril/valsartan, and the BP-lowering effects of sacubitril/valsartan did not account for its effects on outcomes, regardless of sex. (Prospective Comparison of ARNI With ARB Global Outcomes in HF With Preserved Ejection Fraction [PARAGON-HF]; NCT01920711). [ABSTRACT FROM AUTHOR]

Background: The period shortly after hospitalization for heart failure (HF) represents a high-risk window for recurrent clinical events, including rehospitalization or death.Objectives: This study sought to determine whether the efficacy and safety of sacubitril/valsartan varies in relation to the proximity to hospitalization for HF among patients with HF with preserved ejection fraction (HFpEF).Methods: In this post hoc analysis of PARAGON-HF (Prospective Comparison of ARNI [Angiotensin Receptor-Neprilysin Inhibitor] with ARB [Angiotensin Receptor Blocker] Global Outcomes in HFpEF), we assessed the risk of clinical events and response to sacubitril/valsartan in relation to time from last HF hospitalization among patients with HFpEF (≥45%). The primary outcome was composite total HF hospitalizations and cardiovascular death, analyzed by using a semiparametric proportional rates method, stratified by geographic region.Results: Of 4,796 validly randomized patients in PARAGON-HF, 622 (13%) were screened during hospitalization or within 30 days of prior hospitalization, 555 (12%) within 31 to 90 days, 435 (9%) within 91 to 180 days, and 694 (14%) after 180 days; 2,490 (52%) were never previously hospitalized. Over a median follow-up of 35 months, risk of total HF hospitalizations and cardiovascular death was inversely and nonlinearly associated with timing from prior HF hospitalization (p < 0.001). There was a gradient in relative risk reduction in primary events with sacubitril/valsartan from patients hospitalized within 30 days (rate ratio: 0.73; 95% confidence interval: 0.53 to 0.99) to patients never hospitalized (rate ratio: 1.00; 95% confidence interval: 0.80 to 1.24; trend in relative risk reduction: pinteraction = 0.15). With valsartan alone, the rate of total primary events was 26.7 (≤30 days), 24.2 (31 to 90 days), 20.7 (91 to 180 days), 15.7 (>180 days), and 7.9 (not previously hospitalized) per 100 patient-years. Compared with valsartan, absolute risk reductions with sacubitril/valsartan were more prominent in patients enrolled early after hospitalization: 6.4% (≤30 days), 4.6% (31 to 90 days), and 3.4% (91 to 180 days), whereas no risk reduction was observed in patients screened >180 days or who were never hospitalized (trend in absolute risk reduction: pinteraction = 0.050).Conclusions: Recent hospitalization for HFpEF identifies patients at high risk for near-term clinical progression. In the PARAGON-HF trial, the relative and absolute benefits of sacubitril/valsartan compared with valsartan in HFpEF appear to be amplified when initiated in the high-risk window after hospitalization and warrant prospective validation. (PARAGON-HF; NCT01920711). [ABSTRACT FROM AUTHOR]

Background: The DAPA-HF trial (Dapagliflozin and Prevention of Adverse-Outcomes in Heart Failure) showed that dapagliflozin added to other guideline-recommended therapies reduced the risk of mortality and heart failure hospitalization and improved symptoms in patients with heart failure and reduced ejection fraction. We examined the effects of dapagliflozin according to age, given potential concerns about the efficacy and safety of therapies in the elderly.Methods: Patients in New York Heart Association functional class II or greater with a left ventricular ejection fraction ≤40% and a modest elevation of NT-proBNP (N-terminal pro-B-type natriuretic peptide) were eligible. Key exclusion criteria included systolic blood pressure <95 mm Hg and estimated glomerular filtration rate <30 mL·min-1·1.73 m-2. The primary outcome was the composite of an episode of worsening heart failure (heart failure hospitalization or urgent heart failure visit) or cardiovascular death, whichever occurred first.Results: A total of 4744 patients 22 to 94 years of age (mean age, 66.3 [SD 10.9] years) were randomized: 636 patients (13.4%) were <55 years of age, 1242 (26.2%) were 55 to 64 years of age, 1717 (36.2%) were 65 to 74 years of age, and 1149 (24.2%) were ≥75 years of age. The rate of the primary outcome (per 100 person-years, placebo arm) in each age group was 13.6 (95% CI, 10.4-17.9), 15.7 (95% CI, 13.2-18.7), 15.1 (95% CI, 13.1-17.5), and 18.0 (95% CI, 15.2-21.4) with corresponding dapagliflozin/placebo hazard ratios of 0.87 (95% CI, 0.60-1.28), 0.71 (95% CI, 0.55-0.93), 0.76 (95% CI, 0.61-0.95), and 0.68 (95% CI, 0.53-0.88; P for interaction=0.76). Consistent benefits were observed for the components of the primary outcome, all-cause mortality, and symptoms. Although adverse events and study drug discontinuation increased with age, neither was significantly more common with dapagliflozin in any age group.Conclusions: Dapagliflozin reduced the risk of death and worsening heart failure and improved symptoms across the broad spectrum of age studied in DAPA-HF. There was no significant imbalance in tolerability or safety events between dapagliflozin and placebo, even in elderly individuals.Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT03036124. [ABSTRACT FROM AUTHOR]