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Sacubitril/valsartan (Sac/Val) improves left ventricular ejection fraction (LVEF) in heart failure (HF) with reduced ejection fraction regardless of previous treatments. Improvements in LVEF may change eligibility for primary implantable cardioverter-defibrillator (ICD) placement. Awaiting LVEF improvement may expose patients to potential risks for arrhythmic complications.The authors sought to develop a model predicting LVEF change after Sac/Val therapy.A total of 416 persons with HF and LVEF of 35% were included in this analysis. Following initiation of Sac/Val, echocardiographic parameters were measured serially for 1 year. A machine learning algorithm was implemented to develop a risk model for predicting the persistence of LVEF of 35% after 1 year and was validated in a separate group of study participants.Baseline LVEF, left ventricular mass index, HF duration, age, N-terminal pro-B-type natriuretic peptide concentration at baseline and change by day 14, and body mass index were the most significant factors for identifying lack of LVEF improvement to ≥35% after 1 year. In the training and validation cohorts, the areas under the model curve for predicting lack of LVEF improvement were 0.92 and 0.86, respectively. Three categories of likelihood for LVEF of 35% after 1 year of Sac/Val treatment were developed based on the model predictions: 3.8%, 30.1%, and 83.7%. During follow-up, arrhythmia event rates were 0.9%, 2.9%, and 6.7% in these groups, respectively.Many persons with HF with reduced ejection fraction eligible for ICD insertion experience an increase in LVEF to ≥35% after treatment with Sac/Val. Early identification of those less likely to improve their LVEF might allow for more refined selection of primary ICD candidates. (Effects of Sacubitril/Valsartan Therapy on biomarkers, Myocardial Remodeling, and Outcomes [PROVE-HF]; NCT02887183).

Although sacubitril/valsartan (Sac/Val) is indicated for the treatment of heart failure with reduced ejection fraction (HFrEF), gaps in care continue to exist for those with newer onset HFrEF vs those with longer durations of disease.We categorized 794 persons with HFrEF (EF of ≤40%) according to a HF duration of less than 12 months, 12-24 months, 24-60 months, and more than60 months. After the initiation of Sac/Val, concentrations of N-terminal pro-B type natriuretic peptide, high sensitivity cardiac troponin T, and soluble ST2 were measured, and Kansas City Cardiomyopathy Questionnaire 23 scores were obtained serially from baseline to 12 months. The left ventricular ejection fraction was measured by echocardiography. Significant decreases in the concentrations of N-terminal pro-B type natriuretic peptide, high sensitivity cardiac troponin T, and soluble ST2 were observed regardless of HF duration (P.001). Comparable gains in Kansas City Cardiomyopathy Questionnaire 23 scores were achieved in all HF duration categories. Moreover, consistent reverse cardiac remodeling in all HF duration categories occurred, with the absolute left ventricular ejection fraction improvement by 12 months across HF duration groups of 12.2%, 6.9%, 8.5%, and 8.6% for HF duration of less than 12 months, 12-24 months, 24-60 months, and more than 60 months, respectively.The initiation of Sac/Val decreases prognostic biomarkers, improves health status, and reverses cardiac remodeling processes, regardless of HF duration.We categorized 794 persons with heart failure owing to a low ejection fraction according to disease duration into 4 groups: less than 12 months, 12-24 months, 24-60 months, and more than 60 months. After the initiation of sacubitril/valsartan (Entresto), we found that regardless of the duration of heart failure significant improvements occurred in cardiac biomarkers, patients felt better with improved health status and on testing with cardiac ultrasound examination, improvement in heart size, and function occurred. These results suggest that, regardless of heart failure duration, patients with a reduced ejection fraction would benefit from use of sacubitril/valsartan for their care.

Doses of sacubitril/valsartan (Sac/Val) achieved in clinical trials of heart failure with reduced ejection fraction (HFrEF) are often not reached in clinical practice.The purpose of this study was to investigate associations among Sac/Val doses and changes in prognostic biomarkers, health status, and cardiac remodeling among individuals with HFrEF through 12 months of treatment with Sac/Val administered per usual care.A total of 794 persons with HFrEF (ejection fraction [EF] ≤40%) were categorized according to average daily doses of Sac/Val divided into tertiles. Change from baseline to 12 months in biomarkers (N-terminal pro-B-type natriuretic peptide, high-sensitivity cardiac troponin T, soluble ST2, atrial natriuretic peptide, urinary cyclic guanosine monophosphate), Kansas City Cardiomyopathy Questionnaire-23 scores, and parameters of cardiac reverse remodeling (left ventricular EF, indexed left atrial and ventricular volumes, and E/e') were assessed.The average daily dose was 112 mg in Tertile 1 (low dose), 342 mg in Tertile 2 (moderate dose), and 379 mg in Tertile 3 (high dose). Similar changes in prognostic biomarkers were observed in all dose tertiles. Gains in Kansas City Cardiomyopathy Questionnaire-23 scores were comparable regardless of dose category. Consistent reverse cardiac remodeling in all dose categories occurred; the median absolute left ventricular EF improvement across HF dose groups was 9.3%, 8.7%, and 10.2%, for low, moderate, and high doses, respectively; similar improvements in left atrial and ventricular volumes and E/e' were also observed across dose categories.Among patients with HFrEF, similar improvement in prognostic biomarkers, health status, and cardiac remodeling were observed across various Sac/Val doses. (Effects of Sacubitril/Valsartan Therapy on Biomarkers, Myocardial Remodeling and Outcomes [PROVE-HF]; NCT02887183.

Background: NT-proBNP (N-terminal pro-B-type natriuretic peptide) is a potent predictor of death and heart failure (HF) across multiple populations. We evaluated the prognostic importance of NT-proBNP in patients with acute myocardial infarction (MI) complicated by left ventricular systolic dysfunction, pulmonary congestion, or both and ≥1 of 8 risk-augmenting factors enrolled in the PARADISE-MI trial (Prospective ARNI vs ACE Inhibitor Trial to Determine Superiority in Reducing Heart Failure Events After Myocardial Infarction). Methods: Patients were randomized to sacubitril/valsartan 200 mg or ramipril 5 mg twice daily within 0.5 to 7 days of a MI. Patients with prior HF were excluded. NT-proBNP and hs-cTnT (high-sensitivity troponin T) were collected at randomization in a prespecified substudy of 1129 patients. The primary end point of PARADISE-MI was a composite of cardiovascular death or incident HF (hospitalization or outpatient symptomatic HF), analyzed as time-to-first event; additional end points included all-cause death and the composite of fatal or nonfatal MI or stroke. Results: Median NT-proBNP was 1757 ng/L (25th–75th percentiles, 896–3462 ng/L) at randomization (4.0±1.8 days after the index MI). Patients in the highest quartile of NT-proBNP were older, more commonly women and had more hypertension, atrial fibrillation, renal dysfunction, and pulmonary congestion on presentation (all P P interaction=0.46). Conclusions: Within the first week of a high-risk MI NT-proBNP is associated with incident HF, death and atherosclerotic events. This prognostic information is independent of hs-cTnT. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02924727.

In the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS), inhibition of the IL1β inflammatory pathway by canakinumab has been shown to significantly reduce lung cancer incidence and mortality. Here we performed molecular characterization of CANTOS patients who developed lung cancer during the study, including circulating tumor DNA (ctDNA) and soluble inflammatory biomarker analysis. Catalogue of Somatic Mutations in Cancer (COSMIC) database ctDNA mutations were detected in 65% (46/71) of the CANTOS patients with lung cancer, with 51% (36/71) having detectable ctDNA at the time point closest to lung cancer diagnosis and 43% (29/67) having detectable ctDNA at trial randomization. Mutations commonly found in lung cancer were observed with no evidence of enrichment in any mutation following canakinumab treatment. Median time to lung cancer diagnosis in patients with (n = 29) versus without (n = 38) detectable COSMIC ctDNA mutations at baseline was 407 days versus 837 days (P = 0.011). For serum inflammatory biomarker analysis, circulating levels of C-reactive protein (CRP), IL6, IL18, IL1 receptor antagonist, TNFα, leptin, adiponectin, fibrinogen, and plasminogen activator inhibitor-1 were determined. Patients with the highest level of baseline CRP or IL6, both downstream of IL1β signaling, trended toward a shorter time to lung cancer diagnosis. Other inflammation markers outside of the IL1β pathway at baseline did not trend with time to lung cancer diagnosis. These results provide further evidence for the importance of IL1β-mediated protumor inflammation in lung cancer and suggest canakinumab's effect may be mediated in part by delaying disease progression of diverse molecular subtypes of lung cancer.Significance:These findings suggest that targeting the IL1β inflammatory pathway might be critical in reducing tumor-promoting inflammation and lung cancer incidence.

Supplementary Data

BACKGROUND: The ratio of ucGMP (urinary cyclic guanosine monophosphate) to BNP (B-type natriuretic peptide) is thought to reflect the responsiveness of tissues to natriuretic peptides. METHODS: We examined the relationship between ucGMP/BNP ratio and clinical outcomes, the effect of sacubitril/valsartan, compared with enalapril, on the ucGMP/BNP ratio, and the efficacy of sacubitril/valsartan on clinical outcomes according to baseline ucGMP/BNP ratio in PARADIGM-HF trial (Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure). ucGMP/BNP ratio was available at baseline (N=2031), 1 month (N=1959), and 8 months after randomization (N=1746). The primary outcome was a composite of heart failure hospitalization or cardiovascular death. RESULTS: Compared with the lowest tertile of baseline ucGMP/BNP ratio, patients in the higher tertiles had a lower risk of the primary outcome (tertile 1, reference; tertile 2, hazard ratio 0.57 [95% CI, 0.45–0.71]; tertile 3, hazard ratio, 0.54 [0.43–0.67]). Compared with baseline, the ucGMP/BNP ratio at 1 month and 8 months after randomization was higher with sacubitril/valsartan than with enalapril: ratio of geometric mean ratios at 1 month, 1.38 (95% CI, 1.27–1.51) and 8 months, 1.32 (95% CI, 1.20–1.45), and this difference was consistent across tertiles of ucGMP/BNP ratio at baseline ( P interaction =0.19 and 0.91, respectively). The effect of sacubitril/valsartan, compared with enalapril, was consistent across tertiles of ucGMP/BNP ratio at baseline for all outcomes ( P interaction ≥0.31). CONCLUSIONS: In patients with heart failure and reduced ejection fraction, higher ucGMP/BNP ratio was associated with better outcomes. Sacubitril/valsartan increased the ucGMP/BNP ratio, compared with enalapril, and the effect of sacubitril/valsartan on clinical outcomes was not modified by baseline ucGMP/BNP ratio. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique Identifier: NCT01035255.

OBJECTIVES This study examined the relationship among high-sensitivity troponin-T (hs-TnT), outcomes, and treatment with sacubitril/valsartan in patients with heart failure (HF) and preserved ejection fraction (HFpEF). BACKGROUND hs-TnT is a marker of myocardial injury in HF. METHODS The PARAGON-HF trial randomized 4,796 patients with HFpEF to sacubitril/valsartan or valsartan. We compared the risk of the composite outcome of cardiovascular death (CVD) and total HF hospitalization (HHF) according to hs-TnT. We also assessed the effect of allocated treatment on hs-TnT. RESULTS hs-TnT was available in 1,141 patients (24%) at run-in (median value: 17 ng/L) and 1,260 (26%) at randomization, with 58.3% having hs-TnT >14 ng/L (upper limit of normal). During a median follow-up of 34 months, there were 393 outcome events (82 CVD, 311 HHF). Adjusting for demographics, comorbidities, left ventricular ejection fraction (LVEF), and N-terminal pro B-type natriuretic peptide (NT-proBNP), log-hs-TnT at randomization was an independent predictor of the composite outcome (HR: 1.38; 95% CI: 1.19-1.59; P < 0.001). Compared with valsartan, sacubitril/valsartan significantly reduced hs-TnT by 9% at week 16 (P < 0.001). Patients whose hs-TnT decreased from randomization to 16 weeks to at or below the median value of 17 ng/L subsequently had a lower risk of CVD/HHF compared with those with persistently elevated hs-TnT (P = 0.046). Patients with higher baseline hs-TnT (>17 ng/L) appeared to have a greater benefit from sacubitril/valsartan treatment when accounting for other potential effect modifiers (P interaction = 0.07). CONCLUSIONS Higher baseline hs-TnT was associated with increased risk of CVD/HHF, whereas hs-TnT decrease at 16 weeks led to lower subsequent risk of CVD/HHF compared with those who had persistently elevated values. Sacubitril/valsartan significantly reduced hs-TnT compared with valsartan. hs-TnT may be helpful in identifying patients with HFpEF who are more likely to benefit from sacubitril/valsartan. (J Am Coll Cardiol HF 2021;9:627-635) (c) 2021 by the American College of Cardiology Foundation.

BackgroundSystematically characterizing associations between circulating proteins and risk for subsequent clinical events may improve clinical risk prediction and shed light on unrecognized biological pathways in heart failure (HF). Large-scale assays measuring thousands of proteins now enable broad proteomic investigation in clinical trials.MethodsSerum levels of 4076 proteins were measured at baseline in the ATMOSPHERE (n=1258, 487 events over 6 years) and PARADIGM-HF (n=1257, 287 events over 4 years) trials of chronic HF with reduced ejection fraction using a modified aptamer-based proteomics assay. Proteins associated with the primary endpoint of HF hospitalization or cardiovascular death were identified in the ATMOSPHERE discovery cohort by Cox regression adjusted for age, sex, treatment arm, and anticoagulant use (false discovery rateResultsWe identified 377 serum proteins that were associated with the primary endpoint in ATMOSPHERE and replicated 167 in PARADIGM-HF. Prognostic proteins included known HF biomarkers such as Growth Differentiation Factor 15, NT-BNP, and Angiopoietin-2, and also a previously unrecognized HF biomarker: Sushi, Von Willebrand Factor Type A, EGF and Pentraxin Domain Containing 1 (SVEP1, HR 1.60 [95% CI 1.44-1.79] per standard deviation [SD], p=2×10−17). A 64-protein risk score derived in ATMOSPHERE predicted the primary endpoint in PARADIGM-HF with greater discrimination (C-statistic 0.70) than the MAGGIC clinical score (C-statistic 0.61), NT-proBNP (C-statistic 0.65), or both (C-statistic 0.66). Genetically controlled levels of BNP, WISP2, FSTL1, and CTSS were associated with the primary endpoint by Mendelian randomization.ConclusionsWe identified SVEP1, an extracellular matrix protein known to cause inflammation in vascular smooth muscle cells, as a new HF biomarker associated with risk of hospitalization or death. A 64-protein score improved risk discrimination compared with NT-proBNP and may assist in identifying high-risk patients.

This study sought to assess associations between longitudinal change in atrial natriuretic peptide (ANP) and reverse cardiac remodeling following initiation of sacubitril/valsartan in patients with heart failure with reduced ejection fraction (HFrEF).Neprilysin inhibition results in an increase of several vasoactive peptides that may mediate the beneficial effects of sacubitril/valsartan, including ANP.In a prospective study of initiation and titration of sacubitril/valsartan in patients with HFrEF, blood was collected at scheduled time points into tubes containing protease inhibitors. This pre-specified exploratory analysis included patients in whom ANP was measured at baseline and serially through 12 months of treatment.Among 144 participants (mean age: 64.5 years; left ventricular ejection fraction: 30.8%), following initiation of sacubitril/valsartan, there was an early and significant increase in ANP, with the majority of rise from 99 pg/ml at baseline to 156 pg/ml at day 14 (p 0.001). There was a further trend toward a second increase from day 30 to day 45 (p = 0.07). At maximal rise, ANP had doubled. In longitudinal analyses, early rise in ANP was followed by a subsequent increase in urinary cycle guanosine monophosphate. Larger early increase in ANP was associated with larger later improvements in left ventricular ejection fraction and left atrial volume index (p 0.001 for both).Concentrations of ANP doubled after initiation of sacubitril/valsartan in patients with HFrEF. Larger early increases in ANP were associated with a greater magnitude of subsequent reverse cardiac remodeling. (Effects of Sacubitril/Valsartan Therapy on Biomarkers, Myocardial Remodeling and Outcomes [PROVE-HF]; NCT02887183).

In the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS), inhibition of the IL1β inflammatory pathway by canakinumab has been shown to significantly reduce lung cancer incidence and mortality. Here we performed molecular characterization of CANTOS patients who developed lung cancer during the study, including circulating tumor DNA (ctDNA) and soluble inflammatory biomarker analysis. Catalogue of Somatic Mutations in Cancer (COSMIC) database ctDNA mutations were detected in 65% (46/71) of the CANTOS patients with lung cancer, with 51% (36/71) having detectable ctDNA at the time point closest to lung cancer diagnosis and 43% (29/67) having detectable ctDNA at trial randomization. Mutations commonly found in lung cancer were observed with no evidence of enrichment in any mutation following canakinumab treatment. Median time to lung cancer diagnosis in patients with (n = 29) versus without (n = 38) detectable COSMIC ctDNA mutations at baseline was 407 days versus 837 days (P = 0.011). For serum inflammatory biomarker analysis, circulating levels of C-reactive protein (CRP), IL6, IL18, IL1 receptor antagonist, TNFα, leptin, adiponectin, fibrinogen, and plasminogen activator inhibitor-1 were determined. Patients with the highest level of baseline CRP or IL6, both downstream of IL1β signaling, trended toward a shorter time to lung cancer diagnosis. Other inflammation markers outside of the IL1β pathway at baseline did not trend with time to lung cancer diagnosis. These results provide further evidence for the importance of IL1β-mediated protumor inflammation in lung cancer and suggest canakinumab's effect may be mediated in part by delaying disease progression of diverse molecular subtypes of lung cancer. Significance: These findings suggest that targeting the IL1β inflammatory pathway might be critical in reducing tumor-promoting inflammation and lung cancer incidence.

Background Several different B-type natriuretic peptide (BNP) assays are used clinically for diagnostic and prognostic evaluation of heart failure (HF). BNP binds weakly to neprilysin and is cleaved in multiple areas adjacent to the binding sites for the antibodies used in these immunoassays. We assessed the changes in BNP following neprilysin inhibition as measured by 3 immunoassays that recognize different epitopes. Methods Among 130 participants with HF with reduced ejection fraction, blood was collected prior to treatment with sacubitril/valsartan (sac/val) and then repeatedly measured through 52 weeks of treatment. BNP concentrations were measured with 3 widely used BNP assays (Siemens, Abbott, and Quidel). Results Study participants had a mean age of 65 ± 13 years and 76% were men. The median BNP concentration at baseline was 133 ng/L by the Siemens assay, 127 ng/L by the Abbott assay, and 141 ng/L by the Quidel assay. Following initiation of sac/val, there were significantly greater declines in BNP measured by Quidel and Abbott (P = 0.009 and P < 0.001), respectively (both with N-terminal capture antibodies), compared to Siemens (with C-terminal capture antibodies). The difference from baseline was not statistically significant until after week 12 (mean –10.1% for Quidel and –14.3% for Abbott) compared to non-significant differences before 12 weeks (mean –4.5% for Quidel and –6.0% for Abbott). Conclusions Following initiation of sac/val, BNP measurements may modestly differ depending on the assay method used, particularly after a few months of treatment. Whether these differences relate to neprilysin-mediated degradation of antibody binding sites deserves further study. Study registration PROVE-HF ClinicalTrials.gov Identifier: NCT02887183.

Aims We sought to determine sex‐based differences in biomarkers, self‐reported health status, and magnitude of longitudinal changes in measures of reverse cardiac remodelling among patients with heart failure with reduced ejection fraction (HFrEF, left ventricular ejection fraction ≤40%) treated with sacubitril/valsartan (S/V). Methods and results This was a subgroup analysis of patients initiated on S/V in the Prospective Study of Biomarkers, Symptom Improvement and Ventricular Remodeling During Entresto Therapy for Heart Failure (PROVE‐HF) study. There were 226 (28.5%) women in the study. Though women had lower baseline N‐terminal pro B‐type natriuretic peptide (NT‐proBNP), they had more rapid early reduction in the biomarker after initiation of S/V. Compared to men, women had lower average baseline Kansas City Cardiomyopathy Questionnaire (KCCQ)‐23 Total Symptom score (67.6 vs. 71.9; P = 0.003) but showed greater linear improvement (7.4 vs. 5.5 points; P, A summary of differences between women and men in the PROVE‐HF study.

Objectives This study examined the effects of sacubitril/valsartan on N-terminal pro–B-type natriuretic peptide (NT-proBNP) levels and determined patient characteristics associated with favorable NT-proBNP reduction response. Background NT-proBNP levels reflect cardiac wall stress and predict event risk in patients with acute decompensated heart failure (ADHF). Methods Post-hoc analysis of the TRANSITION (Comparison of Pre- and Post-discharge Initiation of Sacubitril/Valsartan Therapy in HFrEF Patients After an Acute Decompensation Event) study, including stabilized ADHF patients with reduced ejection fraction, randomized to open-label sacubitril/valsartan initiation in-hospital (pre-discharge) versus post-discharge. NT-proBNP was measured at randomization (baseline), discharge, and 4 and 10 weeks post-randomization. A favorable NT-proBNP response was defined as reduction to ≤1,000 pg/ml or >30% from baseline. Results In patients receiving sacubitril/valsartan in-hospital, NT-proBNP was reduced by 28% at discharge, with 46% of patients obtaining favorable NT-proBNP reduction response compared with a 4% reduction and 18% favorable response rate in patients initiated post-discharge (p Conclusions In-hospital initiation of sacubitril/valsartan produced rapid reductions in NT-proBNP, statistically significant at discharge. A favorable NT-proBNP response over time was associated with a better prognosis and predicted by higher starting dose and predisposing clinical profile. (Comparison of Pre- and Post-discharge Initiation of LCZ696 Therapy in HFrEF Patients After an Acute Decompensation Event [TRANSITION]; NCT02661217)

International audience; Background: Myocardial fibrosis may contribute to the pathophysiology of heart failure with preserved ejection fraction. Given the biochemical targets of sacubitril/valsartan, this study hypothesized that circulating biomarkers reflecting the mechanisms that determine extracellular matrix homeostasis are altered by sacubitril/valsartan compared with valsartan alone.Objectives: This study investigated the effects of sacubitril/valsartan on biomarkers of extracellular matrix homeostasis and the association between biomarkers and the primary endpoint (total heart failure hospitalizations and cardiovascular death).Methods: N-terminal propeptide of collagen I and III, tissue inhibitor of matrix metalloproteinase 1, carboxyl-terminal telopeptide of collagen type I, and soluble ST2 were measured at baseline (n = 1,135) and 16 (n = 1,113) and 48 weeks (n = 1,016) after randomization. The effects of sacubitril/valsartan on these biomarkers were compared with those of valsartan alone. Baseline biomarker values and changes from baseline to 16 weeks were related to primary endpoint.Results: At baseline, all 5 biomarkers were higher than published referent control values. Sixteen weeks after randomization, sacubitril/valsartan decreased tissue inhibitor of matrix metalloproteinase 1 by 8% (95% confidence interval [CI]: 6% to 10%; p < 0.001), soluble ST2 by 4% (95% CI: 1% to 7%; p = 0.002), and N-terminal propeptide of collagen III by 3% (95% CI: 0% to 6%; p = 0.04) and increased carboxyl-terminal telopeptide of collagen type I by 4% (95% CI: 1% to 8%; p = 0.02) compared with valsartan alone, consistently in men and women and patients with left ventricular ejection fraction above or below the median of 57%. Higher levels of tissue inhibitor of matrix metalloproteinase 1 and soluble ST2 at baseline and increases in these markers at 16 weeks were associated with higher primary endpoint event rates.Conclusions: Biomarkers reflecting extracellular matrix homeostasis are elevated in heart failure with preserved ejection fraction, favorably altered by sacubitril/valsartan, and have important prognostic value. (Prospective Comparison of ARNI With ARB Global Outcomes in HF With Preserved Ejection Fraction [PARAGON-HF]; NCT01920711).

OBJECTIVES: The authors sought to evaluate the prognostic significance of baseline N-terminal pro-B-type natriuretic peptide (NT-proBNP), whether NT-proBNP modified the treatment response to sacubitril/valsartan, and the treatment effect of sacubitril/valsartan on NT-proBNP overall and in key subgroups. BACKGROUND: Sacubitril/valsartan reduces NT-proBNP in heart failure (HF) with both reduced and preserved ejection fraction (EF), but did not significantly reduce total HF hospitalizations and cardiovascular death compared with valsartan in patients with HF with preserved EF (HFpEF). METHODS: In the PARAGON-HF (Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction) trial, 4,796 patients with HFpEF and elevated NT-proBNP were randomized to sacubitril/valsartan or valsartan. NT-proBNP was measured at screening in all patients and at 5 subsequent times in >2,700 patients: before, between, and after sequential valsartan and sacubitril/valsartan run-in periods, and 16 and 48 weeks post-randomization. RESULTS: Median NT-proBNP was 911 pg/ml (interquartile range: 464 to 1,613 pg/ml) at screening. Screening NT-proBNP was strongly associated with the primary endpoint, total HF hospitalizations and cardiovascular death (rate ratio [RR]: 1.68 per log increase in NT-proBNP, 95% confidence interval [CI]: 1.53 to 1.85; p 57% (18%). Decreases in NT-proBNP predicted lower subsequent risk of the primary endpoint. CONCLUSIONS: Baseline NT-proBNP predicted HF events but did not modify the sacubitril/valsartan treatment effect in patients with HFpEF. Sacubitril/valsartan reduced NT-proBNP consistently in men and women, and in patients with lower or higher EF. (Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction [PARAGON-HF]; NCT01920711). ispartof: JACC-HEART FAILURE vol:8 issue:5 pages:372-381 ispartof: location:United States status: published

Sacubitril/valsartan (Sac/Val) improves outcomes in patients with heart failure with reduced ejection fraction (HFrEF).In this study, the authors sought to explore age differences in effects of Sac/Val on biomarkers, Kansas City Cardiomyopathy Questionnaire (KCCQ)-23 scores and cardiac remodeling.After initiation and titration of Sac/Val, concentrations of N-terminal pro-B-type natriuretic peptide (NT-proBNP), high-sensitivity troponin T (hs-cTnT), and soluble suppressor of tumorigenicity 2 (sST2) were measured and KCCQ-23 scores obtained from baseline to 12 months. Left ventricular ejection fraction (LVEF), and indexed left ventricular end-systolic (LVESVi) and indexed left ventricular end-diastolic (LVEDVi) and left atrial volume index (LAVi) volumes were measured with the use of echocardiography. Safety end points were assessed. Age-stratified analysis was performed for groups aged 65, 65-74, and ≥75 years.Among 794 participants with HFrEF (mean age 65.1 years, 28.5% women), compared with patients aged 65 years (n = 369), 65-74 years (n = 237), and those aged ≥75 years (n = 188), had similar reductions in hs-cTnT and sST2, but less NT-proBNP reduction (-45.6% vs -40.2% vs -30.5%, respectively; P = 0.02). Gains in KCCQ-23 were smaller (+11.8 vs +11.4 vs +6.0 points; P = 0.03) in patients aged ≥75 years, although similar proportions of each age group achieved ≥10-point and ≥20-point increases in KCCQ-23 by month 12. Improvements in LVEF, LVEDVi, LVESVi, and LAVi were similar among age groups. Incidence of safety end points was also similar.Sac/Val resulted in significant improvements in prognostic biomarkers and measures of cardiac remodeling and health status from baseline to month 12 across age categories. Older study participants showed somewhat blunted reduction in NT-proBNP and less improvement in KCCQ-23 overall summary scores. (Effects of Sacubitril/Valsartan Therapy on Biomarkers, Myocardial Remodeling, and Outcomes [PROVE-HF]; NCT02887183).

This study assessed changes in B-type natriuretic peptide (BNP) among patients with heart failure with reduced ejection fraction (HFrEF) treated with sacubitril/valsartan (Sac/Val) according to standard prescribing information.Through inhibition of neprilysin, Sac/Val may increase BNP concentrations.In an individual patient analysis from the EVALUATE-HF (Study of Effects of Sacubitril/Valsartan vs. Enalapril on Aortic Stiffness in Patients With Mild to Moderate HF With Reduced Ejection Fraction) (n = 221) and the PROVE-HF (Effects of Sacubitril/Valsartan Therapy on Biomarkers, Myocardial Remodeling and Outcomes) (n = 146) studies, we examined changes in BNP, N-terminal pro-BNP (NT-proBNP), and urinary cyclic guanosine monophosphate (ucGMP) from baseline to week 4 and week 12.Median (IQRs) concentration of BNP at baseline, week 4, and week 12 were 145 [IQR: 55-329], 136 [IQR: 50-338], and 135 [IQR: 51-299] ng/L, respectively. There was no significant change from baseline to week 4 (0% [-30% to +41%]; P = 0.36) or week 12 (+1% [-36% to +50%]; P = 0.97). By week 12, one-half of the study participants had a BNP decline. There was no association between Sac/Val dose and BNP changes. Change in BNP was directly associated with change in NT-proBNP (rho: = 0.81; P 0.001), which decreased by -30% (-50% to -8%) and -32% (-54% to -1%) to weeks 4 and 12 (P 0.001 for both). In contrast, change in BNP was only weakly associated with change in ucGMP (rho: = 0.19; P 0.001). Increases in ucGMP were observed regardless of whether BNP was decreased (+11% [-34% to +115%]), unchanged (+34% [-15% to +205%]), or increased (+57% [-12% to +14%]).In this pooled analysis of patients with HFrEF with standard indications for Sac/Val treatment, there was no significant overall increase in BNP concentrations, and patients demonstrated increase in ucGMP regardless of the trajectory of BNP change. (Study of Effects of Sacubitril/Valsartan vs. Enalapril on Aortic Stiffness in Patients With Mild to Moderate HF With Reduced Ejection Fraction [EVALUATE-HF]; NCT02874794) (Effects of Sacubitril/Valsartan Therapy on Biomarkers, Myocardial Remodeling and Outcomes [PROVE-HF]; NCT02887183).

Background: Sacubitril/valsartan (S/V) treatment is associated with reverse cardiac remodeling and reductions in biomarkers reflecting ventricular wall stress and myocardial injury, such as NT-proBNP (N-terminal pro-B-type natriuretic peptide), hs-cTnT (high-sensitivity cardiac troponin T), and soluble suppressor of tumorigenicity 2 (sST2). How longitudinal changes in these biomarkers analyzed collectively are associated with cardiac remodeling in patients with heart failure with reduced ejection fraction treated with S/V is uncertain. Methods: In a prospective study of S/V in patients with heart failure with reduced ejection fraction, this prespecified exploratory analysis included patients with serially collected biomarkers and echocardiographic measures of cardiac remodeling through 12 months of treatment. A multivariate latent growth curve model assessed associations between simultaneous changes in biomarkers and left ventricular ejection fraction and left atrial volume index. Results: Seven hundred fifteen out of 794 total study participants were included (mean age 65 years, 73% male). Mean baseline left ventricular ejection fraction and left atrial volume index were 29% and 40 mL/m 2 , respectively. Adjusted geometric mean baseline concentrations for biomarkers included NT-proBNP of 649 pg/mL, hs-cTnT of 15.9 ng/L, and sST2 of 24.7 ng/mL. Following initiation of S/V, circulating concentrations of NT-proBNP, hs-cTnT, and sST2 significantly decreased within 30 days and remained significantly different than baseline at all subsequent timepoints. From baseline to month 12, decreases in adjusted biomarker concentrations averaged −27.9% (95% CI, −35.1% to −20.7%; P P P Conclusions: Following initiation of S/V, NT-proBNP, hs-cTnT, and sST2 concentrations decreased significantly. Longitudinal changes in NT-proBNP and hs-cTnT together associated with left atrial and left ventricular reverse remodeling. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02887183.

Aims Circulating high-sensitivity cardiac troponin (hsTn) and soluble ST2 (sST2) reflect myocardial stress in patients with heart failure (HF). Production of cyclic guanosine 3′5′ monophosphate (cGMP) in response to activation of natriuretic peptide receptors reduces cardiac afterload and preload. We assessed the effects of sacubitril/valsartan on these biomarkers in patients with reduced ejection fraction and acute decompensated HF (ADHF). Methods and results PIONEER-HF was a randomized, double-blind trial of sacubitril/valsartan vs. enalapril in hospitalized patients with ADHF following haemodynamic stabilization. We measured circulating hsTnT, sST2, and urinary cGMP at baseline, 1, 2 (sST2, cGMP), 4, and 8 weeks (n = 694 with all baseline biomarkers). Ratios of geometric means (timepoint/baseline) were determined and compared as a ratio for sacubitril/valsartan vs. enalapril. Compared with enalapril, sacubitril/valsartan led to a significantly greater decline in hsTnT and sST2. This effect emerged as early as 1 week for sST2 and was significant for both at 4 weeks with a 16% greater reduction in hsTnT (P Conclusion Biomarkers of myocardial stress are elevated in patients with ADHF and associated with outcome. Compared with enalapril, sacubitril/valsartan reduces myocardial injury and haemodynamic stress as reflected by biomarkers, with an onset that is apparent within 1–4 weeks. Clinical trials registration NCT 02554890 clinical.trials.gov

This study examined the relationship among high-sensitivity troponin-T (hs-TnT), outcomes, and treatment with sacubitril/valsartan in patients with heart failure (HF) and preserved ejection fraction (HFpEF).hs-TnT is a marker of myocardial injury in HF.The PARAGON-HF trial randomized 4,796 patients with HFpEF to sacubitril/valsartan or valsartan. We compared the risk of the composite outcome of cardiovascular death (CVD) and total HF hospitalization (HHF) according to hs-TnT. We also assessed the effect of allocated treatment on hs-TnT.hs-TnT was available in 1,141 patients (24%) at run-in (median value: 17 ng/L) and 1,260 (26%) at randomization, with 58.3% having hs-TnT14 ng/L (upper limit of normal). During a median follow-up of 34 months, there were 393 outcome events (82 CVD, 311 HHF). Adjusting for demographics, comorbidities, left ventricular ejection fraction (LVEF), and N-terminal pro B-type natriuretic peptide (NT-proBNP), log-hs-TnT at randomization was an independent predictor of the composite outcome (HR: 1.38; 95% CI: 1.19-1.59; P 0.001). Compared with valsartan, sacubitril/valsartan significantly reduced hs-TnT by 9% at week 16 (P 0.001). Patients whose hs-TnT decreased from randomization to 16 weeks to at or below the median value of 17 ng/L subsequently had a lower risk of CVD/HHF compared with those with persistently elevated hs-TnT (P = 0.046). Patients with higher baseline hs-TnT (17 ng/L) appeared to have a greater benefit from sacubitril/valsartan treatment when accounting for other potential effect modifiers (P interaction = 0.07).Higher baseline hs-TnT was associated with increased risk of CVD/HHF, whereas hs-TnT decrease at 16 weeks led to lower subsequent risk of CVD/HHF compared with those who had persistently elevated values. Sacubitril/valsartan significantly reduced hs-TnT compared with valsartan. hs-TnT may be helpful in identifying patients with HFpEF who are more likely to benefit from sacubitril/valsartan.

Aims The effects of serelaxin, a recombinant form of human relaxin-2 peptide, on vascular function in the coronary microvascular and systemic macrovascular circulation remain largely unknown. This mechanistic, clinical study assessed the effects of serelaxin on myocardial perfusion, aortic stiffness, and safety in patients with stable coronary artery disease (CAD). Methods and results In this multicentre, double-blind, parallel-group, placebo-controlled study, 58 patients were randomized 1:1 to 48 h intravenous infusion of serelaxin (30 µg/kg/day) or matching placebo. The primary endpoints were change from baseline to 47 h post-initiation of the infusion in global myocardial perfusion reserve (MPR) assessed using adenosine stress perfusion cardiac magnetic resonance imaging, and applanation tonometry-derived augmentation index (AIx). Secondary endpoints were: change from baseline in AIx and pulse wave velocity, assessed at 47 h, Day 30, and Day 180; aortic distensibility at 47 h; pharmacokinetics and safety. Exploratory endpoints were the effect on cardiorenal biomarkers [N-terminal pro-brain natriuretic peptide (NT-proBNP), high-sensitivity troponin T (hsTnT), endothelin-1, and cystatin C]. Of 58 patients, 51 were included in the primary analysis (serelaxin, n = 25; placebo, n = 26). After 2 and 6 h of serelaxin infusion, mean placebo-corrected blood pressure reductions of −9.6 mmHg (P = 0.01) and −13.5 mmHg (P = 0.0003) for systolic blood pressure and −5.2 mmHg (P = 0.02) and −8.4 mmHg (P = 0.001) for diastolic blood pressure occurred. There were no between-group differences from baseline to 47 h in global MPR (−0.24 vs. −0.13, P = 0.44) or AIx (3.49% vs. 0.04%, P = 0.21) with serelaxin compared with placebo. Endothelin-1 and cystatin C levels decreased from baseline in the serelaxin group, and there were no clinically relevant changes observed with serelaxin for NT-proBNP or hsTnT. Similar numbers of serious adverse events were observed in both groups (serelaxin, n = 5; placebo, n = 7) to 180-day follow-up. Conclusion In patients with stable CAD, 48 h intravenous serelaxin reduced blood pressure but did not alter myocardial perfusion.

Supplemental Digital Content is available in the text., Background: Among patients with heart failure and reduced ejection fraction (left ventricular (LV) ejection fraction ≤40%), sacubitril/valsartan (S/V) treatment is associated with improved health status and reverse cardiac remodeling. Data regarding racial and ethnic differences in response to S/V are lacking. Methods: This was an analysis from the PROVE-HF study (Prospective Study of Biomarkers, Symptom Improvement and Ventricular Remodeling During Entresto Therapy for Heart Failure). Longitudinal changes in NT-proBNP (N-terminal pro-B-type natriuretic peptide), cardiac reverse remodeling, and health status scores were compared between groups using multivariate latent growth curve modeling. Results: Among the 782 patients included in this study, 22.7% were non-Hispanic Black (from here referred to as Black), 14.9% were Hispanic, and 62.4% were non-Hispanic White (from here referred to as White). At baseline, compared with White patients, Black and Hispanic patients had lower NT-proBNP (g=0.34) and differences between groups in baseline values for LV end-diastolic volume index and LV end-systolic volume index were negligible (g

Objective This study sought to determine whether patients with heart failure and reduced ejection fraction (HFrEF) with type 2 diabetes mellitus (T2DM) have similar reverse cardiac remodeling with sacubitril/valsartan as patients without T2DM. Background Sacubitril/valsartan promotes reverse cardiac remodeling and improves outcomes in patients with HFrEF. Patients with HFrEF with T2DM have worse prognosis than those without T2DM. Methods In this post hoc analysis of PROVE-HF (Prospective Study of Biomarkers, Symptom Improvement, and Ventricular Remodeling During Sacubitril/Valsartan Therapy for Heart Failure), we examined changes in N-terminal pro–b-type natriuretic peptide (NT-proBNP), measures of cardiac remodeling, and Kansas City Cardiomyopathy Questionnaire Overall Summary (KCCQ-OS) scores from baseline to 12 months following initiation of sacubitril/valsartan between patients with HFrEF with and without T2DM. Using latent growth curve modeling, we evaluated the longitudinal association between changes in NT-proBNP, left ventricular ejection fraction, and KCCQ-OS. Results Among 794 patients enrolled, 361 (45.5%) had T2DM. NT-proBNP concentrations were modestly higher at baseline among patients with T2DM but were reduced after initiation of sacubitril/valsartan. Cross-sectional improvement was observed in left ventricular ejection fraction (T2DM: 28.3% at baseline and 37% at 12 months vs. non-T2DM: 28.1% at baseline and 38.3% at 12 months) and KCCQ-OS (T2DM: 71 at baseline and 83 at 12 months vs. non-T2DM: 76 at baseline and 88 at 12 months). Similar changes were also observed for other echocardiographic measures. In longitudinal analyses, the average NT-proBNP change was similar in patients with T2DM (–5.6% vs. –7.1% per 90-day interval; p = 0.64), whereas improvements in KCCQ-OS scores were slightly smaller (2.1 vs. 3.46 per 90-day interval; p = 0.07). Conclusions Sacubitril/valsartan favorably affects natriuretic peptide levels, reverse cardiac remodeling, and health status in patients with HFrEF with and without T2DM. (Effects of Sacubitril/Valsartan Therapy on Biomarkers, Myocardial Remodeling and Outcomes [PROVE-HF]; NCT02887183 )

Background Treatment of heart failure with reduced ejection fraction (EF) may improve patient-reported health outcomes. Objectives The purpose of this study was to determine timing and magnitude of change in Kansas City Cardiomyopathy Questionnaire (KCCQ)-23 scores following initiation of sacubitril/valsartan and interaction with change in amino-terminal pro–B-type natriuretic peptide (NT-proBNP) concentrations. Methods From a single-arm, open-label study of patients initiated on sacubitril/valsartan, KCCQ-23 scores and NT-proBNP were obtained at baseline and follow-up through 12 months. Cross-sectional and longitudinal analyses evaluated magnitude and rate of change in KCCQ-23 scores and associations with NT-proBNP. Patient-level data from the randomized EVALUATE-HF study were used as historic controls. Results The analysis cohort (n = 678, age 64.7 years, 71.5% men, EF 28.9%) had a baseline KCCQ-23 overall score (OS) of 65.6. Following sacubitril/valsartan initiation, the majority (n = 412; 60.8%) of participants experienced a rise in KCCQ-23 OS ≥10 points; 26.0% increased by ≥20 points. Comparable improvement in KCCQ-23 scores was seen in various subgroups. Change in KCCQ-23 OS was inversely associated with change in circulating NT-proBNP concentrations. Among a control group of patients in EVALUATE-HF, linear rate of change in KCCQ-12 OS/14-day interval in the enalapril arm was 0.37 points (p = 0.06), whereas in the sacubitril/valsartan arm, scores increased at a rate of 1.19 points (p Conclusions Treatment of heart failure with reduced EF with sacubitril/valsartan is associated with rapid and significant improvement in KCCQ-23 scores which was significantly related to change in NT-proBNP. (Effects of Sacubitril/Valsartan Therapy on Biomarkers, Myocardial Remodeling and Outcomes [PROVE-HF]; NCT02887183 )

We assessed the relative contributions of N-terminal pro-B-type natriuretic peptide (NTBNP) and high sensitivity cardiac troponin (hsTnT) to the prediction of death and cardiovascular (CV) events in 5597 (with complete data) of 8561 patients with type 2 diabetes (T2DM) and CV disease (CVD) and/or chronic kidney disease (CKD) enrolled in the Aliskiren Trial in Type 2 Diabetes Using Cardiorenal Endpoints (ALTITUDE). We analysed Harrell’s C-statistics (Cs) to estimate Cox model performance to predict death (n= 473) and a CV composite outcome (CVCO: CV death, resuscitated cardiac arrest, nonfatal myocardial infarction, stroke or heart failure hospitalization, n= 1129) after a median follow-up of 2.6 years, using a base model (BM) of 19 clinical baseline variables. The Cs for predicting death in the BM (0.724) was augmented by adding hsTnT (0.744, p= 0.002) which was further improved by NTBNP (0.779, p Disclosure M.V.B. Malachias: Speaker’s Bureau; Self; Biolab Sanus Farmaceutica, Libbs Farmaceutica. P. Jhund: Advisory Panel; Self; Cytokinetics Inc. Research Support; Self; Boehringer Ingelheim International GmbH. Speaker’s Bureau; Self; Novartis AG. Other Relationship; Self; AstraZeneca. B. Claggett: None. M.O. Wijkman: None. R. Bentley-Lewis: Consultant; Self; Novo Nordisk Inc. Research Support; Self; Janssen Pharmaceuticals, Inc. P.C. Brunel: Consultant; Self; Novartis AG. N. Chaturvedi: Consultant; Self; AstraZeneca. A.S. Desai: Consultant; Self; Abbott, Alnylam Pharmaceuticals, AstraZeneca, Biofourmis, Boehringer Ingelheim Pharmaceuticals, Inc., Boston Scientific, DalCor Pharmaceuticals, Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Regeneron Pharmaceuticals, Relypsa, Inc. Research Support; Self; Alnylam Pharmaceuticals, AstraZeneca, Novartis Pharmaceuticals Corporation. S.M. Haffner: None. H.D. Parving: None. M.F. Prescott: Employee; Self; Novartis Pharmaceuticals Corporation. S. Solomon: Consultant; Self; AstraZeneca, Theracos, Inc. Research Support; Self; AstraZeneca, Theracos, Inc. D. de Zeeuw: Advisory Panel; Self; AbbVie Inc., Bayer AG, Boehringer Ingelheim International GmbH, Fresenius Medical Care, Janssen Pharmaceuticals, Inc., Mitsubishi Tanabe Pharma Corporation. J.J. McMurray: Other Relationship; Self; AbbVie Inc., Alnylam Pharmaceuticals, Amgen, AstraZeneca, Bayer Healthcare Pharmaceuticals Inc., Bristol-Myers Squibb, Cardurion, GlaxoSmithKline plc., Novartis Pharmaceuticals Corporation, Theracos, Inc. M.A. Pfeffer: Consultant; Self; AstraZeneca, CinCor, Correvio, Corvidia, DalCor Pharmaceuticals, GlaxoSmithKline plc., Innovative Science, Jazz Pharmaceuticals, MyoKardia, Inc., Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., PharmaScience, Sanofi US, Servier, Takeda Development Center Americas, Inc. Research Support; Self; Novartis Pharmaceuticals Corporation. Funding Novartis Pharmaceuticals (NCT00549757)

Background: Both BNP (B-type natriuretic peptide) and NT-proBNP (N-terminal pro B-type natriuretic peptide) are widely used to aid diagnosis, assess the effect of therapy, and predict outcomes in heart failure and reduced ejection fraction. However, little is known about how these 2 peptides compare in heart failure and reduced ejection fraction, especially with contemporary assays. Both peptides were measured at screening in the PARADIGM-HF trial (Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure). Methods: Eligibility criteria in PARADIGM-HF included New York Heart Association functional class II to IV, left ventricular ejection fraction ≤40%, and elevated natriuretic peptides: BNP ≥150 pg/mL or NT-proBNP ≥600 pg/mL (for patients with HF hospitalization within 12 months, BNP ≥100 pg/mL or NT-proBNP ≥400 pg/mL). BNP and NT-proBNP were measured simultaneously at screening and only patients who fulfilled entry criteria for both natriuretic peptides were included in the present analysis. The BNP/NT-proBNP criteria were not different for patients in atrial fibrillation. Estimated glomerular filtration rate 2 was a key exclusion criterion. Results: The median baseline concentration of NT-proBNP was 2067 (Q1, Q3: 1217–4003) and BNP 318 (Q1, Q3: 207–559), and the ratio, calculated from the raw data, was ≈6.25:1. This ratio varied considerably according to rhythm (atrial fibrillation 8.03:1; no atrial fibrillation 5.75:1) and with age, renal function, and body mass index but not with left ventricular ejection fraction. Each peptide was similarly predictive of death (all-cause, cardiovascular, sudden and pump failure) and heart failure hospitalization, for example, cardiovascular death: BNP hazard ratio, 1.41 (95% CI, 1.33–1.49) per 1 SD increase, P P Conclusions: The ratio of NT-proBNP to BNP in heart failure and reduced ejection fraction appears to be greater than generally appreciated, differs between patients with and without atrial fibrillation, and increases substantially with increasing age and decreasing renal function. These findings are important for comparison of natriuretic peptide concentrations in heart failure and reduced ejection fraction.

Aims: Elevated serum uric acid concentration (SUA) has been associated with an increased risk of cardiovascular disease, but this may be due to unmeasured confounders. We examined the association between SUA and outcomes as well as the effect of sacubitril/valsartan on SUA in patients with heart failure with reduced ejection fraction (HFrEF) in PARADIGM-HF. Methods and results: The association between SUA and the primary composite outcome of cardiovascular death or heart failure (HF) hospitalization, its components, and all-cause mortality was examined using Cox regression analyses among 8213 patients using quintiles (Q1–Q5) of SUA adjusted for baseline prognostic variables including estimated glomerular filtration rate (eGFR), diuretic dose, and log N-terminal pro-brain natriuretic peptide. Change in SUA from baseline over 12 months was also evaluated in each treatment group. Patients in Q5 (SUA ≥8.6 mg/dL) compared with Q1 (

Sacubitril/valsartan (LCZ696) is indicated for the treatment of patients with heart failure and reduced ejection fraction (HFrEF). Since patients with HFrEF may receive sacubitril/valsartan and sildenafil, both increasing cyclic guanosine monophosphate, the present study evaluated the pharmacokinetic and pharmacodynamic drug interaction potential between sacubitril/valsartan and sildenafil. In this open‐label, three‐period, single sequence study, patients with mild‐to‐moderate hypertension (153.8 ± 8.2 mmHg mean systolic blood pressure (SBP)) received a single dose of sildenafil 50 mg, sacubitril/valsartan 400 mg once daily for 5 days, and sacubitril/valsartan and sildenafil coadministration. When coadministered with sildenafil, the AUC and Cmax of valsartan decreased by 29% and 39%, respectively. Coadministration of sacubitril/valsartan and sildenafil resulted in a greater decrease in BP (–5/–4/–4 mmHg mean ambulatory SBP/DBP/MAP (mean arterial pressure)) than with sacubitril/valsartan alone. Both treatments were generally safe and well tolerated in this study; however, the additional BP reduction suggests that sildenafil should be administered cautiously in patients receiving sacubitril/valsartan. Unique identifier: NCT01601470.

Aims We evaluated the added prognostic value of a multi-time point-based multimarker panel of biomarkers in patients with acute heart failure (AHF). Methods and results Seven circulating biomarkers [NT-proBNP, high sensitivity cardiac troponin T (hs-cTnT), soluble ST2 (sST2), growth differentiation factor 15 (GDF-15), cystatin-C, galectin-3, and high sensitivity C-reactive protein (hs-CRP)] were measured at baseline and on days 2, 5, 14, and 60 in 1161 patients enrolled in the RELAX-AHF trial. Patients with BNP ≥350 ng/L or NT-proBNP ≥1400 ng/L, mild to moderate renal impairment, and systolic blood pressure >125 mmHg were included in the trial. Time-dependent Cox regression analysis was utilized to evaluate the incremental value of serial measurement of biomarkers. Added value of individual biomarkers and their combination, on top of a pre-specified baseline model, was quantified with the gain in the C-index. Serial biomarker evaluation showed incremental predictive value over baseline measurements alone for the prediction of 180-day cardiovascular mortality except for galectin-3. While a repeat measurement as early as day 2 was adequate for NT-proBNP and cystatin-C in terms of maximizing discriminatory accuracy, further measurements on days 14 and 60 provided added value for hs-cTnT, GDF-15, sST2, and hs-CRP. Individual biomarker additions on top of the baseline model showed additional prognostic value. The greatest prognostic gain was, however, attained with the combination of NT-proBNP, hs-cTnT, GDF-15, and sST2, which yielded 0.08 unit absolute increment in the C-index to 0.87 (95% confidence interval 0.83–0.91]. Conclusion In patients with AHF and mild to moderate renal impairment, a multimarker approach based on a panel of serially evaluated biomarkers provides the greatest prognostic improvement unmatched by a single time point-based single marker strategy.

Background NT-proBNP has diagnostic and prognostic value in patients with heart failure (HF). Compared with enalapril, sacubitril/valsartan (S/V) significantly reduced NT-proBNP within 1 week (wk) of administration and reduced HF re-hospitalisation in patients with acute decompensated HF (ADHF) in PIONEER-HF. Identification of predictors of NT-proBNP reduction with S/V could aid prognostication following hospitalisation. Methods TRANSITION (NCT02661217) is an open label study in stabilised ADHF patients with HFrEF that compared S/V initiation pre- versus post-discharge (within 2 wk of discharge). Baseline NT-proBNP was measured at randomisation in both S/V groups (n=950). Clinical predictors of favourable response of NT-proBNP to S/V therapy (defined as reduction to 30% reduction vs. baseline) were studied at discharge, 4 wk and 10 wk post-randomisation. Results Median NT-proBNP at randomisation was similar in patients with S/V started pre- and post-discharge (1919 vs 1659 pg/ml). In patients receiving S/V in-hospital, NT-proBNP was reduced by 28% at discharge, compared to a 3% reduction in patients receiving optimised standard of care (between group p Conclusion In-hospital initiation of sacubitril/valsartan shortly after stabilisation was associated with a prompt improvement of NT-proBNP already at discharge, whereas higher baseline levels of NT-proBNP, higher starting dose, absence of AFib and MI history, de novo HF and ACEI/ARB naïve status were associated with favourable NT-proBNP response in the vulnerable phase after discharge. Acknowledgement/Funding The TRANSITION study was funded by Novartis

IMPORTANCE: In patients with heart failure and reduced ejection fraction (HFrEF), treatment with sacubitril-valsartan reduces N-terminal pro–b-type natriuretic peptide (NT-proBNP) concentrations. The effect of sacubitril-valsartan on cardiac remodeling is uncertain. OBJECTIVE: To determine whether NT-proBNP changes in patients with HFrEF treated with sacubitril-valsartan correlate with changes in measures of cardiac volume and function. DESIGN, SETTING, AND PARTICIPANTS: Prospective, 12-month, single-group, open-label study of patients with HFrEF enrolled in 78 outpatient sites in the United States. Sacubitril-valsartan was initiated and the dose adjusted. Enrollment commenced on October 25, 2016, and follow-up was completed on October 22, 2018. EXPOSURES: NT-proBNP concentrations among patients treated with sacubitril-valsartan. MAIN OUTCOMES AND MEASURES: The primary outcome was the correlation between changes in log(2)–NT-proBNP concentrations and left ventricular (LV) EF, LV end-diastolic volume index (LVEDVI), LV end-systolic volume index (LVESVI), left atrial volume index (LAVI), and ratio of early transmitral Doppler velocity/early diastolic annular velocity (E/e′) at 12 months. RESULTS: Among 794 patients (mean age, 65.1 years; 226 women [28.5%]; mean LVEF = 28.2%), 654 (82.4%) completed the study. The median NT-proBNP concentration at baseline was 816 pg/mL (interquartile range [IQR], 332-1822) and 455 pg/mL (IQR, 153-1090) at 12 months (difference, P

Background:\ud Myocardial fibrosis is an important pathophysiological mechanism underlying the development of heart failure (HF). Given the biochemical targets of sacubitril/valsartan, we hypothesized that circulating biomarkers reflecting the mechanisms that determine extracellular matrix (ECM) homeostasis, including collagen synthesis, processing, and degradation, are altered by sacubitril/valsartan in comparison to enalapril.\ud \ud Objectives:\ud The purpose of this study was to examine the effects of sacubitril/valsartan on biomarkers of ECM homeostasis and the association between the rate of primary composite outcome (cardiovascular death or HF hospitalization) and these biomarkers.\ud \ud Methods:\ud Biomarkers at baseline (n = 2,067) and both baseline and 8 months after randomization (n = 1,776) included aldosterone, soluble ST2 (sST2), tissue inhibitor of matrix metalloproteinase (TIMP)-1, matrix metalloproteinase (MMP)-2, MMP-9, Galectin-3 (Gal-3), N-terminal propeptide of collagen I (PINP), and N-terminal propeptide of collagen III (PIIINP). The effects of sacubitril/valsartan on biomarkers were compared with enalapril. Baseline biomarker values and changes from baseline to 8 months were related to primary outcome.\ud \ud Results:\ud At baseline, the profibrotic biomarkers aldosterone, sST2, TIMP-1, Gal-3, PINP, and PIIINP were higher, and biomarkers associated with collagen degradation, MMP-2 and -9, were lower than published referent control values. Eight months after randomization, aldosterone, sST2, TIMP-1, MMP-9, PINP, and PIIINP had decreased more in the sacubitril/valsartan than enalapril group. At baseline, higher values of sST-2, TIMP-1, and PIIINP were associated with higher primary outcome rates. Changes from baseline to 8 months in sST-2 and TIMP-1 were associated with change in outcomes.\ud \ud Conclusions:\ud Biomarkers associated with profibrotic signaling are altered in HF with reduced ejection fraction, sacubitril/valsartan significantly decreased many of these biomarkers, and these biomarkers have important prognostic value. These findings suggest that sacubitril/valsartan may reduce profibrotic signaling, which may contribute to the improved outcomes. (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)

Background: Sacubitril/valsartan (S/V) treatment is associated with reverse cardiac remodeling and reductions in biomarkers reflecting ventricular wall stress and myocardial injury, such as NT-proB...

Objectives The aim of this study was to determine if a baseline high-sensitivity troponin T (hsTnT) value ≤99th percentile upper reference limit (0.014 μg/l [“low hsTnT”]) identifies patients at low risk for adverse outcomes. Background Approximately 85% of patients who present to emergency departments with acute heart failure are admitted. Identification of patients at low risk might decrease unnecessary admissions. Methods A post-hoc analysis was conducted from the RELAX-AHF (Serelaxin, Recombinant Human Relaxin-2, for Treatment of Acute Heart Failure) trial, which randomized patients within 16 h of presentation who had systolic blood pressure >125 mm Hg, mild to moderate renal impairment, and N-terminal pro–brain natriuretic peptide ≥1,600 ng/l to serelaxin versus placebo. Linear regression models for continuous endpoints and Cox models for time-to-event endpoints were used. Results Of the 1,076 patients with available baseline hsTnT values, 107 (9.9%) had low hsTnT. No cardiovascular (CV) deaths through day 180 were observed in the low-hsTnT group compared with 79 CV deaths (7.3%) in patients with higher hsTnT. By univariate analyses, low hsTnT was associated with lower risk for all 5 primary outcomes: 1) days alive and out of the hospital by day 60; 2) CV death or rehospitalization for heart failure or renal failure by day 60; 3) length of stay; 4) worsening heart failure through day 5; and 5) CV death through day 180. After multivariate adjustment, only 180-day CV mortality remained significant (hazard ratio: 0.0; 95% confidence interval: 0.0 to 0.736; p = 0.0234; C-index = 0.838 [95% confidence interval: 0.798 to 0.878]). Conclusions No CV deaths through day 180 were observed in patients with hsTnT levels ≤0.014 μg/l despite high N-terminal pro–brain natriuretic peptide levels. Low baseline hsTnT may identify patients with acute heart failure at very low risk for CV mortality.

SummaryAims Concomitant renin–angiotensin–aldosterone system blockade and natriuretic peptide system enhancement may provide unique therapeutic benefits to patients with heart failure and reduced ejection fraction (HFrEF). This study assessed the pharmacodynamics and pharmacokinetics of LCZ696 in patients with HFrEF. Methods This was an open-label, noncontrolled single-sequence study. After a 24-h run-in period, patients (n = 30) with HFrEF (EF ≤ 40%; NYHA class II–IV) received LCZ696 100 mg twice daily (bid) for 7 days and 200 mg bid for 14 days, along with standard treatment for heart failure (HF) (except angiotensin-converting enzyme inhibitors [ACEIs] or angiotensin receptor blockers [ARBs]). Results On Day 21, significant increases were observed in the plasma biomarkers indicative of neprilysin and RAAS inhibition (ratio-to-baseline: cyclic guanosine monophosphate [cGMP], 1.38; renin concentration and activity, 3.50 and 2.27, respectively; all, P

Background: Increased activity of IGFBP7 (insulin-like growth factor–binding protein-7) is associated with cellular senescence, tissue aging, and obesity. IGFBP7 may be related to heart failure with preserved ejection fraction, a disease of elderly obese people. Methods and Results: In a subset of patients with heart failure with preserved ejection fraction (N=228) randomized to receive sacubitril/valsartan versus valsartan, IGFBP7 concentrations were measured at baseline, 12 weeks, and 36 weeks. Patient characteristics and echocardiographic measures including left atrial (LA) size and volume, ratio of early mitral inflow velocity/annular diastolic velocity, and ratio of early diastole/peak late diastolic velocity were assessed as a function of IGFBP7 concentration. Effect of sacubitril/valsartan on IGFBP7 concentrations was analyzed. With increasing baseline IGFBP7 quartiles, LA size and LA volume index (LAVi) were higher (both P P =0.03) and early diastole/peak late diastolic velocity ratio ( P =0.04) was also seen. IGFBP7 concentrations were higher in those with LAVi ≥34 mL/m 2 compared with lower LAVi at all time points (all P P Conclusions: Among patients with heart failure with preserved ejection fraction, concentrations of the cellular senescence biomarker IGFBP7 were associated with abnormalities in diastolic filling and LA dilation. Treatment with sacubitril/valsartan resulted in lower IGFBP7 concentrations compared with valsartan. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT00887588.

Objectives:\ud The purpose of this study was to evaluate the renal effects of sacubitril/valsartan in patients with heart failure and reduced ejection fraction.\ud \ud Background:\ud Renal function is frequently impaired in patients with heart failure with reduced ejection fraction and may deteriorate further after blockade of the renin–angiotensin system.\ud \ud Methods:\ud In the PARADIGM-HF (Prospective Comparison of ARNI with ACE inhibition to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial, 8,399 patients with heart failure with reduced ejection fraction were randomized to treatment with sacubitril/valsartan or enalapril. The estimated glomerular filtration rate (eGFR) was available for all patients, and the urinary albumin/creatinine ratio (UACR) was available in 1872 patients, at screening, randomization, and at fixed time intervals during follow-up. We evaluated the effect of study treatment on change in eGFR and UACR, and on renal and cardiovascular outcomes, according to eGFR and UACR.\ud \ud Results:\ud At screening, the eGFR was 70 ± 20 ml/min/1.73 m2 and 2,745 patients (33%) had chronic kidney disease; the median UACR was 1.0 mg/mmol (interquartile range: 0.4 to 3.2 mg/mmol) and 24% had an increased UACR. The decrease in eGFR during follow-up was less with sacubitril/valsartan compared with enalapril (−1.61 ml/min/1.73 m2/year; [95% confidence interval: −1.77 to −1.44 ml/min/1.73 m2/year] vs. −2.04 ml/min/1.73 m2/year [95% CI: −2.21 to −1.88 ml/min/1.73 m2/year ]; p < 0.001) despite a greater increase in UACR with sacubitril/valsartan than with enalapril (1.20 mg/mmol [95% CI: 1.04 to 1.36 mg/mmol] vs. 0.90 mg/mmol [95% CI: 0.77 to 1.03 mg/mmol]; p < 0.001). The effect of sacubitril/valsartan on cardiovascular death or heart failure hospitalization was not modified by eGFR, UACR (p interaction = 0.70 and 0.34, respectively), or by change in UACR (p interaction = 0.38).\ud \ud Conclusions:\ud Compared with enalapril, sacubitril/valsartan led to a slower rate of decrease in the eGFR and improved cardiovascular outcomes, even in patients with chronic kidney disease, despite causing a modest increase in UACR.

Background: Soluble ST2 (sST2) is associated with cardiac remodeling and fibrosis. In chronic heart failure, the predictive value of sST2 has not been evaluated in a model that includes both NT-proBNP (N-terminal pro-B-type natriuretic peptide) and hs-TnT (high-sensitivity cardiac troponin T), in a trial in which treatment had a major impact. Therefore, the effects of treatment on sST2 levels in PARADIGM-HF trial (Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure), the relationships between sST2 and outcomes, and the prognostic utility of various sST2 partition values were examined. Methods and Results: Baseline (n=2002), 1-month (n=1936), and 8-month postrandomization (n=1758) sST2 levels were compared between treatment groups (sacubitril/valsartan versus enalapril). Relationships between baseline sST2 and (1) heart failure hospitalization, (2) cardiovascular death, and (3) combined heart failure hospitalization and cardiovascular death were assessed using restricted cubic spline models. Adjusted Cox proportional hazards models were used to examine the impact of sST2 change from baseline to 1 month on the hazard of experiencing each outcome. Sacubitril/valsartan led to more reductions and fewer increases in sST2 levels versus enalapril. After adjusting for other predictors, including NT-proBNP and hs-TnT, baseline sST2 remained an independent predictor of outcomes. Associations between baseline sST2 and outcomes were linear. sST2 increases at 1 month were associated with worse subsequent outcomes and decreased with better outcomes ( P =0.001, 0.012, and 0.009 for the 3 outcomes, respectively). Conclusions: Sacubitril/valsartan resulted in greater reductions and less increases in sST2 levels than enalapril. No specific threshold was associated with risk, as linear relationships between baseline sST2 and outcomes were observed. Changes in sST2 from baseline to 1 month were independently associated with the risk of outcomes. Clinical Trial Registration : URL: https://www.clinicaltrials.gov . Unique identifier: NCT01035255.

AimsTroponin elevation is common in acute heart failure (AHF) and may be useful for prognostication; however, available data are mixed and many previous studies used older, less sensitive assays. We examined the association between serial measurements of high-sensitivity cardiac troponin T (hs-cTnT) and outcomes in RELAX-AHF. Methods and resultsHs-cTnT was measured at baseline and days 2, 5, and 14. We assessed the relationship between baseline, peak and peak change hs-cTnT with dyspnoea relief by visual analogue scale, cardiovascular death, or HF/renal hospitalization to 60days and cardiovascular mortality to 180days. Models were adjusted for clinical variables and treatment assignment. Whether baseline troponin status affected the treatment effect of serelaxin was assessed using interactions terms. In 1074 patients, the median baseline troponin was 0.033 mu g/L, and 90% of patients were above the 99th upper reference limit (URL). Patients with hs-cTnT >median were more likely to be men with ischaemic heart disease, worse renal function, and higher N-terminal pro-brain natriuretic peptide. Higher baseline or peak hs-cTnT and greater peak change were associated with worse outcomes independent of adjustment for covariates, but relationships were generally strongest for 180-day cardiovascular mortality (hazard ratio per doubling of baseline hs-cTnT=1.36, 95% confidence interval 1.15-1.60). Troponin was most strongly associated with death from heart failure or from other cardiovascular causes. The treatment effect of serelaxin did not differ by baseline troponin levels. ConclusionHs-cTnT was elevated above the 99% URL in the majority of AHF patients. Baseline, peak, and peak change hs-cTnT were associated with worse outcomes, with the strongest relationship with 180-day cardiovascular mortality.

Background Growth differentiation factor 15 (GDF-15) was found to be upregulated in patients with chronic heart failure (HF) and associated with disease severity, however, data on patients with acute heart failure (AHF) is lacking. Methods and results Levels of GDF-15 were measured at pre-specified time-points (baseline and at days 2, 5, 14, and 60) in patients enrolled in the placebo-controlled RELAXin in Acute Heart Failure (RELAX-AHF) study, which examined the effect of serelaxin in 1161 patients with AHF, systolic blood pressure >125 mmHg, and mild to moderate renal impairment. Neither baseline nor changes in GDF-15 were associated with the degree of dyspnoea or dyspnoea relief. After adjustment for baseline characteristics, baseline GDF-15 was not associated with the composite endpoint of heart failure or renal failure (HF/RF) readmission at 60 days/cardiovascular (CV) death or CV death at 180 days. In contrast, larger increases in GDF-15 levels at days 2 and 14 were associated with a greater risk of 60-day HF/RF rehospitalizations/CV death and CV death at 180 days. Serelaxin treatment was associated with significantly larger decreases of GDF-15 at days 2 and 5 than placebo. Conclusions In AHF patients enrolled in the RELAX-AHF study, increases in GDF-15 levels, but not baseline measurements, were associated with a greater likelihood of adverse outcomes. Serelaxin administration was associated with greater decreases in GDF-15 compared with placebo.

Aims The purpose of this study was to determine the prognostic significance and associated clinical profile of early post-discharge N-terminal pro-B-type natriuretic peptide (NT-proBNP) trajectory among patients hospitalized for worsening chronic heart failure (HHF). Methods and results This post-hoc analysis of the Aliskiren Trial in Acute Heart Failure Outcomes (ASTRONAUT) included 1351 HHF patients with ejection fraction (EF) ≤40%, elevated B-type natriuretic peptide ≥400 pg/mL or NT-proBNP ≥1600 pg/mL at admission, and available NT-proBNP measurements (from a central core laboratory) at baseline (median 5 days after admission) and 1-month follow-up. The co-primary endpoints were all-cause mortality and cardiovascular mortality or HHF within 12 months. Median follow-up was 11.3 months. Patients with decreasing post-discharge NT-proBNP trajectory tended to be younger and have non-ischaemic HF aetiology. The presence of baseline atrial fibrillation was associated with high NT-proBNP at 1 month (i.e. above the median), regardless of the baseline value. After adjustment for patient characteristics and 1-month NT-proBNP level, every twofold increase in continuous NT-proBNP change from baseline to 1 month was predictive of increased cardiovascular mortality or HHF (hazard ratio 1.14; 95% confidence interval 1.02–1.26), but not all-cause mortality (hazard ratio 0.95; 95% confidence interval 0.81–1.11). Conclusion In this cohort of HHF patients with reduced EF, early post-discharge NT-proBNP trajectory was associated with a distinct clinical profile and carried independent prognostic value after adjustment for patient characteristics and absolute NT-proBNP level. Future prospective study of serial NT-proBNP measurement during the hospital and early post-discharge periods is warranted to validate these findings and evaluate post-discharge NT-proBNP trajectory as a therapeutic target.

Circulating levels of natriuretic peptides (NP) are inversely related to body mass index (BMI), and obese patients with heart failure (HF) have lower brain natriuretic peptide (BNP) and N-terminal pro-brain natriuretic peptide (NT-proBNP) concentrations than nonobese patients.1,2 These observations have raised concerns about the prognostic value of NP in patients with HF with an elevated BMI. Prior observational studies suggested that NP may retain their capacity to predict mortality across all BMI categories in HF with individuals with reduced ejection fraction.3,4 Nevertheless, these studies included a relatively small number of events and did not evaluate additional cardiovascular end points. Because it remains uncertain whether BMI may influence the prognostic utility of NP in patients with HF, we examined the influence of BMI on the predictive value of NT-proBNP and BNP in patients with reduced ejection fraction from the PARADIGM-HF trial (Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure; URL: http://www.clinicaltrials.gov. Unique identifier: NCT01035255). The design and primary results of the PARADIGM-HF trial have been previously described.5 The patients randomized in the trial (n=8399) were required to have a plasma BNP ≥150 pg/mL or an NT-proBNP ≥600 pg/mL or, if they were hospitalized for HF within the previous …

Background Sacubitril/valsartan is an angiotensin receptor–neprilysin inhibitor indicated for the treatment of patients with chronic heart failure (HF) with reduced ejection fraction; however, its mechanism of benefit remains unclear. Biomarkers that are linked to ventricular remodeling, myocardial injury, and fibrosis may provide mechanistic insight and important clinical guidance regarding sacubitril/valsartan use. Methods This 52-week, multicenter, open-label, single-arm study is designed to (1) correlate biomarker changes with cardiac remodeling parameters, cardiovascular outcomes, and patient-reported outcome data and (2) determine short- and long-term changes in concentrations of biomarkers related to potential mechanisms of action and effects of sacubitril/valsartan therapy. Approximately 830 patients with HF with reduced ejection fraction will be initiated and titrated on sacubitril/valsartan according to United States prescribing information. Primary efficacy end points include the changes in N-terminal pro–B-type natriuretic peptide concentrations and cardiac remodeling from baseline to 1 year. Secondary end points include changes in concentrations of N-terminal pro–B-type natriuretic peptide and remodeling to 6 months, and changes in patient-reported outcomes using the Kansas City Cardiomyopathy Questionnaire-23 from baseline to 1 year. In addition, several other relevant biomarkers will be measured. Biomarker changes relative to the number of cardiovascular events in 12 months will also be assessed as exploratory end points. Conclusions Results from the Prospective Study of Biomarkers, Symptom Improvement, and Ventricular Remodeling During Sacubitril/Valsartan Therapy for Heart Failure (PROVE-HF) will help establish a mechanistic understanding of angiotensin receptor–neprilysin inhibitor therapeutic benefits and provide clinicians with clarity on how to interpret information on biomarkers during treatment (PROVE-HF ClinicalTrials.gov identifier: NCT02887183 ).