PARADIGM-HF Trial Research Articles

Effects of sacubitril/valsartan on cardiac reverse remodeling and cardiac resynchronization in patients with acute myocardial infarction.

In 2014, the PARADIGM-HF trial (Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) has shown that sacubitril/valsartan can reduce the risk of hospitalization and death from cardiovascular causes more effectively than enalapril (an ACEI) in heart failure patients with reduced ejection fraction (HFrEF). Similarly, the PARADIGM-HF trial (Comparison of Sacubitril-Valsartan vs. Enalapril on Effect on NT-proBNP in Patients Stabilized from an Acute Heart Failure Episode) came to similar conclusions and extended the PARADIGM-HF trial results in 2019. Since then, numerous new studies have provided further insight in HFrEF, sacubitril/valsartan can reduce N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels, increase left ventricular ejection fraction (LVEF), reverse ventricular remodeling, and reduce other non-fatal manifestations of clinical deterioration as compared to ACEI/ARB. However, few trials have compared the effects of these drugs in patients shortly after AMI. Therefore, it is necessary to further explore the clinical efficacy and safety of sacubitril/valsartan vs. valsartan in patients with AMI. We conducted an open-label, prospective, randomized controlled trial to determine the superiority in ameliorating ventricular remodeling and preventing of heart failure in patients with AMI after percutaneous coronary intervention (PCI), 148 patients were randomly assigned (85 to sacubitril/valsartan and 63 to valsartan). LAV, LVDV, and LVSV were all decreased in the sacubitril/valsartan group when compared with before treatment, but there was no difference between the sacubitril/valsartan group and the valsartan group. In addition, compared with before treatment in the sacubitril/valsartan group, the heart global work index (GWI) and the global work efficiency (GWE) increased, while the heart global wasted work (GWW) decreased. Patients in the sacubitril/valsartan group have similar MACE and adverse side effects to those in the valsartan group. Sacubitril/valsartan has the same performance as valsartan in inhibiting ventricular remodeling and preventing heart failure after PCI in patients with AMI, and its clinical application is safe. It provides a clinical foundation for the application of sacubitril/valsartan in patients with AMI.

Neprilysin Inhibition in the Prevention of Anthracycline-Induced Cardiotoxicity.

Anthracycline-induced cardiotoxicity (AIC) poses a clinical challenge in the management of cancer patients. AIC is characterized by myocardial systolic dysfunction and remodeling, caused by cardiomyocyte DNA damage, oxidative stress, mitochondrial dysfunction, or renin-angiotensin-aldosterone system (RAAS) dysregulation. In the past decade, after positive results of a PARADIGM-HF trial, a new class of drugs, namely angiotensin receptor/neprilysin inhibitors (ARNi), was incorporated into the management of patients with heart failure with reduced ejection fraction. As demonstrated in a variety of preclinical studies of cardiovascular diseases, the cardioprotective effects of ARNi administration are associated with decreased oxidative stress levels, the inhibition of myocardial inflammatory response, protection against mitochondrial damage and endothelial dysfunction, and improvement in the RAAS imbalance. However, data on ARNi's effectiveness in the prevention of AIC remains limited. Several reports of ARNi administration in animal models of AIC have shown promising results, as ARNi prevented ventricular systolic dysfunction and electrocardiographic changes and ameliorated oxidative stress, mitochondrial dysfunction, endoplasmic reticulum stress, and the inflammatory response associated with anthracyclines. There is currently an ongoing PRADAII trial aimed to assess the efficacy of ARNi in patients receiving breast cancer treatment, which is expected to be completed by late 2025.

Effects of Sacubitril/Valsartan on Glycemic Control in Japanese Patients With Heart Failure and/or Hypertension.

Background: Post hoc analysis of the PARADIGM-HF trial showed that sacubitril/valsartan (S/V) was more effective than enalapril in lowering HbA1c in patients with heart failure and diabetes. Methods and Results: In the present study, the effect of S/V on glycemic control was retrospectively analyzed in 150 patients (median age 74 years) who were prescribed S/V for the treatment of heart failure and/or hypertension. After a median period of 13 weeks treatment, mean (±SD) HbA1c levels decreased significantly from 6.56±0.68% to 6.49±0.63%. The decrease in HbA1c was evident in patients with (n=111), but not in those without, diabetes. There were no significant changes in renal function after S/V treatment, but systolic blood pressure was significantly reduced from 141±21 to 134±19 mmHg. Ninety patients had N-terminal pro B-type natriuretic peptide (NT-proBNP) tested, and S/V significantly decreased median NT-proBNP concentrations from 1,026 to 618 pg/mL; however, there was no correlation between the degree of decrease in HbA1c and that in NT-proBNP. Multiple regression analysis revealed that being diabetic, rather than having heart failure, was a significant independent variable for a reduction in HbA1c. Conclusions: Treatment with S/V improved glycemic control in patients with heart failure and/or hypertension, especially in those with concomitant diabetes. This favorable effect on glucose metabolism may be mediated by neprilysin inhibition and is desirable in the treatment of heart failure and hypertension in diabetic patients.

Abstract 12332: Comparative Cost-Effectiveness of Sacubitril-Valsartan, Dapagliflozin, and Empagliflozin in Heart Failure With Reduced Ejection Fraction

Introduction: The 2022 American College of Cardiology/American Heart Association (ACC/AHA) guidelines established angiotensin receptor-neprilysin inhibitors and sodium-glucose cotransporter-2 inhibitors as Class I therapies in heart failure with reduced ejection fraction (HFrEF). Previous analyses have demonstrated the cost-effectiveness of these drugs, but use of different methodologies limit comparison. The objective of this study was to use a singular model to compare the cost-effectiveness of these agents in HFrEF. Methods: A 2-state Markov model was developed to compare the incremental cost-effectiveness ratios of sacubitril-valsartan, dapagliflozin, and empagliflozin. The enalapril arm of the PARADIGM-HF trial served as the control. Data from the PARADIGM-HF, DAPA-HF, and EMPEROR-Reduced trials were used to simulate treatment with sacubitril-valsartan, dapagliflozin, and empagliflozin, respectively. The model used a lifetime time horizon from a United States healthcare perspective. All costs and quality-adjusted life years were discounted 3% annually. The primary outcome was the incremental cost-effectiveness ratio of each treatment compared to control. Results: The incremental cost-effectiveness ratios of sacubitril-valsartan, dapagliflozin, empagliflozin, were $74,111, $72,048, and $118,253, respectively. Figure 1 shows the incremental cost-effectiveness ratios and incremental quality-adjusted life years in the present analysis compared to previously published analyses. Conclusions: In a singular model of patients with HFrEF, sacubitril-valsartan, dapagliflozin, and empagliflozin all met the threshold for intermediate value ($50,000-$150,000 per quality-adjusted life year gained) set by the ACC/AHA.

Evaluating the evidence for sacubitril/valsartan across the continuum of heart failure.

Since initial publication of the PARADIGM-HF trial in 2014, sacubitril/valsartan has been investigated in various settings to establish optimal use, further expanding its indications in patients with heart failure (HF). Although numerous studies have been published, until recently these have primarily involved post hoc analyses from the PARADIGM-HF study itself with a consistent focus on use of sacubitril/valsartan in patients with HF with reduced ejection fraction (HFrEF). This has led to a gap in the literature regarding utility of sacubitril/valsartan in other HF subpopulations. The aim of this review is to provide a summary of recent clinical trials further expanding use and guideline recommendations for sacubitril/valsartan. The findings of 15 studies, including clinical trials and post hoc analyses, are summarized and describe the use of sacubitril/valsartan in additional HF subpopulations, such as HFrEF following hospitalization for acute decompensated HF and advanced HF, HF with preserved ejection fraction (HFpEF), and HF postmyocardial infarction. In addition, three studies investigating timing of initiation, dose titration regimens, and cost-effectiveness are examined. Select ongoing trials are also reviewed to demonstrate the continued commitment to further advance care of patients with HF. This comprehensive review serves as a resource for health care providers who pursue optimal utilization of sacubitril/valsartan in their respective clinical practices.

Aptamer proteomics for biomarker discovery in heart failure with reduced ejection fraction

Abstract Background Though current heart failure (HF) biomarkers are highly prognostic, systematically characterizing associations between circulating proteins and risk of subsequent events may improve clinical risk prediction and illuminate new biological pathways. Large-scale assays measuring thousands of proteins now enable unbiased proteomic investigation in clinical trials. Purpose To identify and replicate serum proteins associated with HF events in patients with chronic HF with reduced ejection fraction (HFrEF), and to develop and validate a proteomic risk score. Methods Serum levels of 4076 proteins were measured at baseline in the ATMOSPHERE (n=1261, 487 events over 6 years) and PARADIGM-HF (n=1257, 287 events over 4 years) trials of chronic HFrEF using a modified aptamer-based proteomics assay. Proteins associated with the primary endpoint, HF hospitalization or cardiovascular death, were identified in the ATMOSPHERE discovery cohort (false discovery rate<0.05) by Cox regression adjusted for age, sex, treatment arm, and anticoagulant use, and replicated in PARADIGM-HF (Bonferroni-corrected p<0.05). A proteomic risk score was derived in ATMOSPHERE using Cox LASSO penalized regression and evaluated in PARADIGM-HF compared to the MAGGIC clinical risk score and N-terminal pro-B-type natriuretic peptide (NT-proBNP). For proteins associated with the primary endpoint, pathway analysis was conducted using Ingenuity Pathway analysis and an exploratory two-sample Mendelian randomization was performed using genetic and outcome data from both trials and protein quantitative trait loci from deCODE to infer which identified proteins contribute to HF prognosis. Results We identified 377 serum proteins associated with the primary endpoint in ATMOSPHERE and replicated 167 in PARADIGM-HF. Prognostic proteins included known HF biomarkers Growth Differentiation Factor 15, NT-proBNP, 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=2x10–17) (Table 1). Proteins related to hepatic fibrosis, granulocyte adhesion, and inhibition of matrix metalloproteinases were over-represented. A 64-protein risk score derived in ATMOSPHERE predicted clinical events 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) (Figure 1). Genetically predicted levels of NT-proBNP, WISP2, FSTL1, and CTSS were associated with the primary endpoint by Mendelian randomization. Conclusions We identify SVEP1, an extracellular matrix protein known to cause inflammation in vascular smooth muscle cells, as a previously unrecognized HF biomarker. A 64-protein score improved risk discrimination compared with NT-proBNP and may assist in identifying high-risk patients for clinical trials or disease management programs. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): The ATMOSPHERE and PARADIGM-HF trials were sponsored by Novartis

A comprehensive study of the incremental prognostic value of novel biomarkers in PARADIGM-HF (Bio-PREDICT-HF)

Abstract Background Although multiple novel biomarkers have individually been shown to predict outcomes in patients with HFrEF, the value of these over and above conventional clinical and laboratory variables, plus natriuretic peptides, is uncertain. Purpose To test the incremental predictive value of 11 novel biomarkers added to a recent prognostic model 1 (PREDICT-HF) derived in PARADIGM-HF and validated in ATMOSPHERE and the Swedish heart failure registry. The PREDICT-HF model includes clinical variables, standard laboratory variables, and BNP or NT-proBNP. Methods 1559 participants enrolled in PARADIGM-HF had all 11 biomarkers of interest measured. These reflected different pathophysiological pathways: (i) myocyte injury (high sensitivity cardiac troponin T), (ii) cardiac remodelling and inflammation (growth stimulation expressed gene 2, growth differentiation factor-15 and galectin-3), (iii) extracellular matrix remodelling (matrix metalloproteinase-2, matrix metalloproteinase-9, tissue inhibitor of metalloproteinase-1), (iv) neurohormonal pathways (aldosterone) and (v) renal dysfunction and injury (cystatin C, kidney injury molecule-1 and urinary albumin to creatinine ratio). The incremental prognostic value of these biomarkers was evaluated using Harrell's C statistic. Results The mean age of participants studied was 67.3 (SD 9.9) years, 1254 (80%) were men and 1103 (71%) were in NYHA class II. During a median follow-up of 31 months, 197 patients died and 300 experienced the primary composite outcome (cardiovascular death or heart failure hospitalization). When each candidate biomarker (log unit) was added individually to the PREDICT-HF base model, GDF-15, ST2, TIMP1, cystatin C, hsTnT and UACR were independent predictors of all-cause mortality (Table 1). GDF-15, TIMP1, hs-TnT and cystatin C consistently increased the risk of both all-cause mortality and the primary outcome. Individuals who had all 4 biomarkers elevated (compared to none elevated) had the highest risk: HR for all-cause mortality 3.65 (2.01–6.64), p<0.0001. Adding these 4 biomarkers to the baseline PREDICT HF model improved the C statistic for all-cause mortality from 0.726 to 0.745. Conclusion Several novel biomarkers provide meaningful additional prognostic information in patients with HFrEF. A multimarker approach incorporating biomarkers reflecting different pathophysiological pathways added most information. This approach may be useful in refining risk and targeting treatment. Funding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): The PARADIGM-HF trial was funded by Novartis.J.J.V.M is supported by a British Heart Foundation Centre of Excellence Grant

Heart failure with improved ejection fraction (HFimpEF) in patients treated with sacubitril/valsartan (SV)

Abstract Introduction Several studies demonstrated that patients with improvement of left ventricular ejection fraction (LVEF) and symptoms had good prognosis in heart failure with reduced ejection fraction (HFrEF). Based on these results, new classification of HF according to LVEF was currently proposed. Sacubitril/valsartan (SV) is recommended as one of the first-line therapy of HFrEF patients. SV reduced hospitalization for HF and cardiovascular mortality compared to enalapril in PARADIGM-HF trial. However, it is unclear that patients with improvement of LVEF also have better prognosis compared to patients without LVEF improvement among patients treated with SV. Purpose We aimed to evaluate the clinical characteristics and outcomes of heart failure with improved ejection fraction (HFimpEF) in heart failure with reduced ejection fraction (HFrEF) patients treated with SV. Methods We analyzed 230 patients with HFrEF taking SV in a multicenter retrospective cohort (RECORD-SV registry) from 2017 to 2019. Enrolled 230 patients were performed baseline and 1-year follow-up echocardiography. Based on 2 echocardiographic results, we defined “HFimpEF” as HF with a baseline LVEF ≤40%, ≥10% increase from baseline LVEF and a follow-up measurement of LVEF >40%. Others were defined as “Persistent HFrEF”. We analyzed and compared clinical characteristics and outcomes between two groups. Primary endpoint was a composite outcome of all-cause death and hospitalization for HF (HHF). Results From 230 patients, 65 patients with HFimpEF and 165 patients with Persistent HFrEF were analyzed. The median follow-up duration was 557 days (interquartile range 364 to 727 days). Patients with HFimpEF had a higher prevalence of female gender (50.8% vs. 30.3%) and de novo HF (44.6% vs. 21.2%). There were no significant differences for age, etiology (ischemic vs. non-ischemic), diabetes, atrial fibrillation, hypertension, and HF medications including SV dose between two groups. Patients with HFimpEF showed lower rate of all-cause death or HHF as a primary endpoint compared to patients with persistent HFrEF (6.2% vs. 22.4%; IPTW adjusted HR 0.24; 95% CI 0.13–0.46; p<0.001) (Table 1). It was also shown that HFimpEF patients had a reduced risk of primary endpoint in the Kaplan-Meier curves compared with persistent HFrEF (Log-rank p=0.045) (Figure 1). We demonstrated that Non-prior MI (adjusted OR 7.29; 95% CI 1.50–35.36; p=0.014) and de novo HF (adjusted OR 4.33; 95% CI 1.70–11.04; p=0.002) were independent prognostic factors of HFimpEF in HFrEF patients treated with SV. Conclusions HFimpEF patients had better clinical outcomes compared to those with persistent HFrEF in HFrEF patients treated with SV. Non-prior MI and de novo HF were independent predictors of HFimpEF in patients treated with SV. Funding Acknowledgement Type of funding sources: None.

Alkaline phosphatase and bilirubin combined are a powerful predictor of outcome in patients with heart failure and reduced ejection fraction: an analysis of the ATMOSPHERE and PARADIGM-HF trials

Abstract Introduction Bilirubin is a recognized predictor of adverse outcomes in patients with heart failure and reduced ejection fraction (HFrEF), possibly because it is a marker of congestion. Alkaline phosphatase (ALP) is an enzyme produced in many tissues including the biliary ducts and elevated levels are also associated with congestion. Purpose To examine the prognostic value of ALP alone and in combination with bilirubin in patients with HFrEF. Methods The study population was ambulatory patients with HFrEF enrolled in 2 recent clinical trials with similar inclusion and exclusion criteria: ATMOSPHERE (derivation cohort) and PARADIGM-HF (validation). Cut points to define elevated bilirubin and alkaline phosphatase were >17mg/dL and >120 U/L respectively. The composite of cardiovascular death or HF hospitalization, its components, and all-cause death related to elevation of one, other or both of bilirubin and ALP was examined using Cox regression. Univariable and multivariable models with adjustment for other recognized prognostic variables including NT-proBNP were analyzed. Results Of 7016 patients with HFrEF enrolled in ATMOSPHERE, 6870 had a measurement of both bilirubin and ALP at baseline: mean age 63 years, 22% women, mean LVEF 28% and proportion NYHA class III/IV 37%. Bilirubin and ALP were both normal in 4810 (70.0%) patients, bilirubin was elevated in 1393 (20.3%), ALP was elevated in 360 (5.2%) and both were elevated in 307 (4.5%) patients. Patients with elevation of both ALP and bilirubin were older, had lower systolic blood pressure, higher heart rate, higher NT-pro BNP, more clinical features of congestion, more atrial fibrillation and a greater proportion were treated with diuretics and digoxin. The primary endpoint rates (per 100 person-years) were 10.4 (95% CI 9.9–11.0) when both markers were normal, 15.1 (13.9–16.4) when bilirubin was elevated, 12.4 (10.4–14.9) when alkaline phosphatase was elevated, and 25.6 (22.0–29.9) when both markers were elevated (Figure 1). The adjusted hazard ratios (95% CI) were (both biomarkers normal = reference): elevated bilirubin 1.19 (1.07–1.31), P=0.001; elevated ALP 1.03 (0.84–1.26), P=0.81; both elevated 1.45 (1.21–1.73), P<0.001. Elevation of both bilirubin and ALP was a significant independent predictor of the components of the primary outcome and all-cause death, the corresponding hazard ratios for all cause death were 1.12 (0.99–1.25), p=0.06; 1.19 (0.96–1.47), p=0.12; and 1.51 (1.25–1.82), p<0.001. These findings were validated in PARADIGM-HF (Table 1). Conclusions Elevation of ALP in combination with elevated bilirubin identifies a small group of patients at very high risk of adverse outcomes. This may reflect more significant congestion. ALP and bilirubin, inexpensive and routinely measured biochemical tests, are useful prognostic markers in patients with HFrEF. Funding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship.

Prognostic implications of NYHA class and NT-proBNP levels in mild heart failure: a PARADIGM-HF analysis

Abstract Background Treatment recommendations for heart failure (HF) with reduced ejection fraction are primarily centered on New York Heart Association (NYHA) classification, such that apparently asymptomatic patients might not be eligible for disease-modifying therapies. NYHA classification, however, may be particularly limited to discriminate mild forms of HF. Purpose The present study aimed to determine the relationship between NYHA classification and an objective measure of HF severity (N-terminal pro–B-type natriuretic peptide [NT pro-BNP]), and their association with long-term prognosis in the PARADIGM-HF trial. Methods We compared PARADIGM-HF patients classified as NYHA class I, II, and III at randomization (NYHA class IV patients or with unavailable NYHA class were excluded [n=73]). We present kernel density estimation (KDE) plots–a non-parametric way to describe the underlying distribution of a variable–to compare NT-proBNP levels across NYHA classes. Logistic regression and the area under the receiver operating characteristic curve (AUC) were used to assess the ability to predict a patient's NYHA class using NT-proBNP levels. Time-to-event data were calculated with Kaplan–Meier estimates and NYHA class were further stratified by median baseline NT-proBNP (< or ≥1600 pg/ml). The primary outcome was cardiovascular death or first HF hospitalization. Results 8326 patients were included in this analysis (median age, 64 years; women, 22%; and median left ventricular ejection fraction, 30%). Of 389 patients classified as NYHA class I at randomization, 228 (59%) changed functional class during the first year after randomization. For log-transformed NT-proBNP, KDE overlapped substantially across NYHA classes (Figure 1A). NT-proBNP levels were a poor predictor of NYHA classification: for NYHA class I vs. II, AUC (95% confidence interval [CI]) was 0.51 (0.48–0.54); for NHYA I vs. III, 0.57 (0.54–0.60); and for NYHA II vs. III, 0.56 (0.54–0.57). NYHA class III patients displayed a distinctively higher rate of cardiovascular deaths or first HF hospitalizations (Figure 1B). NYHA class I and II patients revealed lower event rates that were not significantly different (NYHA II vs. I, HR 1.24 [0.97–1.58]). Stratification by NT-proBNP levels identified subgroups with distinctive risk, such that NYHA I patients with high NT-proBNP levels (n=175) had a higher event rate than patients with low NT-proBNP with any NYHA class (Figure 1C). Conclusion NYHA class I and II patients overlapped substantially in objective HF measures and long-term prognosis. NYHA classification remains a powerful predictor of cardiovascular events but might be limited to differentiate mild forms of HF, as apparently asymptomatic patients based on physician-defined functional class might become symptomatic within a year and conceal subjects at substantial risk for adverse outcomes. Funding Acknowledgement Type of funding sources: None.

Stroke in patients with heart failure and reduced ejection fraction without atrial fibrillation: external validation of a risk model

Abstract Background Heart failure (HF) ranks only second to atrial fibrillation (AF) as a cause of cardio-embolic stroke. Although anticoagulation reduces this risk in HF patients not in AF, the risk/benefit profile in relatively unselected populations is not favourable. Identification of patients at high risk of stroke may allow targeted and safer use of prophylactic anticoagulant therapy. Previously, we proposed a simple risk model for stroke in patients with HF and reduced ejection fraction (HFrEF). However, this model was derived from the two older trials (published in 2007/2008) and was not externally validated. Purpose We aimed to evaluate the current incidence of stroke in patients with HFrEF not in AF receiving modern pharmacological therapy and to validate our stroke prediction model. Methods We examined patient-level data from the PARADIGM-HF, ATMOSPHERE, and DAPA-HF trials. The risk score was calculated following: 7.39×(insulin-treated diabetes) + 6.53×(previous stroke) + 2.80×[ln(NT-proBNP (pg/ml)) × 0.1182]). According to the tertile of risk score, we divided the patients into three groups. Patients with AF were defined as those with either AF on an ECG or a history of AF. Results Of the total of 20,159 patients (who experienced 590 strokes) enrolled in the three trials, 12,751 patients did not have AF at baseline. Of those, 1,143 patients (9%) had insulin-treated diabetes, 873 patients (6.8%) had a history of the previous stroke, and the median value of NT-proBNP was 1,243 pg/ml. During a median follow-up of 2.0 years, 346 (2.7%) experienced a stroke (11.7 per 1000 patient-years). Figure 1 shows cumulative incidence function plots for stroke according to the tertile of risk score in 12,331 patients whose risk score can be calculated. The number of strokes in tertile 1, 2 and 3 were 80, 102 and 149, respectively. The 3-year cumulative incidence function rates of stroke were 2.0 (95% CI: 1.5–2.5) % in tertile 1, 2.6 (95% CI: 2.1–3.2) % in tertile 2, and 4.3 (95% CI: 3.6–5.2) % in tertile 3, respectively. In patients with tertile 3, the stroke rate was 18.1 per 1000 patient-years (compared to 20.1 per 1000 patient-years in patients with AF not receiving anticoagulation). In the Cox model, risk for stroke increased according to the elevation in the risk score (tertile 2: HR 1.47 (95% CI 1.09–1.97), tertile 3: HR 2.53 (95% CI 1.92–3.33), with tertile 1 as reference). Figure 2 shows calibration plots by comparing observed and predicted probabilities of stroke at 1 to 3 years. Discrimination evaluated using the overall c-index 0.84 (95% CI: 0.75–0.91) was good. Conclusions These findings validate a previously described predictive model and confirm that it is possible to identify a subset of HFrEF patients without AF who have a risk of stroke that approximates to that in patients with AF. In these patients, the risk/benefit balance might justify the use of prophylactic anticoagulation, but this hypothesis needs to be tested prospectively. Funding Acknowledgement Type of funding sources: Foundation.

Maximum dose sacubitril/valsartan in heart failure with reduced ejection fraction: does atrial fibrillation compromise the benefits?

Abstract Background In the PARADIGM-HF trial, sacubitril/valsartan (SV) was shown to be superior to enalapril in reducing hospitalizations for worsening heart failure (HF), cardiovascular mortality, and all-cause mortality in patients with heart failure with reduced ejection fraction (HFrEF). The 2021 ESC Guidelines recommends SV as a replacement for angiotensin-converting-enzyme inhibitors to reduce the risk of HF hospitalization and death. There is little information regarding the effects of SV according to atrial fibrillation (AF) status. Purpose The aim of this study was to compare the effects of maximum dose SV regarding symptomatic improvement, change in natriuretic peptides levels (NP) and left ventricular ejection fraction (LVEF) in patients with HFrEF with and without AF. Methods Retrospective analysis of 137 patients with HFrEF on maximum dose SV (97/103mg twice daily). Patients were divided into two groups according to AF status. Age, gender, relevant comorbidities, usual medication, baseline symptomatic status, NP levels and LVEF were assessed using the Mann-Whitney U or χ2 test (according to variable type) to ensure comparability between groups. Variation in NYHA class, NP levels and LVEF between baseline and 6-month follow-up was evaluated and compared between groups. Results Comparison between groups is presented in Table 1. In our studied population, ischemic aetiology was more common in the sinus rhythm group (49.5% vs 30.4%; p 0.034). There were no significant differences between groups regarding age, gender, hypertension, diabetes, and beta-blocker and mineralocorticoid receptor antagonist usage. At baseline, the AF group had higher NT-proBNP levels [median 1421 mg/dL (IQR 743–3087) vs 467 mg/dL (IQR 140–797); p<0.001]. There were no significant differences regarding baseline NYHA class or LVEF. After 6 months of follow-up, reductions in NYHA class [−1 (IQR −2, −1) for AF; −1 (IQR −1, 0) for SR; p=0.437] and NT-proBNP levels [−358 mg/dL (IQR −2275, −47) for AF; −162 mg/dL (IQR −364, 27) for SR; p=0.156], as well as LVEF improvement [11% (IQR 3–15) for AF; 12% (IQR 7–21) for SR; p=0.201], displayed no statistically significant differences between the two groups. Conclusions Our study shows that the beneficial effects of SV on symptomatic status, NP levels and LVEF were not compromised by the presence of AF at baseline. Funding Acknowledgement Type of funding sources: None.

Effects of angiotensin receptor-neprilysin inhibitors (ARNIs) on the glucose and fat metabolism biomarkers leptin and fructosamin

Abstract Background Heart Failure with reduced ejection fraction (HFrEF) has a life time risk about 20% among adults aged 40 years or older and a 5-year mortality rate about 60% [1,2]. However novel therapies have shown to improve this outcome. One novel agent are angiotensin receptor-neprilysin inhibitors (ARNIs) that increase the BNP levels via inhibiting neprilsyin [3]. This has beneficial effects on heart failure by reducing preload, inflammation and fibrosis. Neprilysin also interacts with leptin and is known to correlate with the incidence and progression of heart failure if chronically elevated [4]. Furthermore beneficial affects of ARNI therapy on glucose metabolism were reported in a post-hoc analysis of the PARADIGM-HF trial [5]. In this study we aim to investigate the effect of ARNI therapy on the fat metabolism markers leptin and on the glucose metabolism marker fructosamin. Methods In total, we included 74 patients with HFrEF with ischemic (N=37) and non-ischemic (n=37) origin in the present study. The mean NYHA class was II–III, the mean BMI 28 (SD 6.3). Patients had well established heart failure therapy before starting ARNI therapy with sacubitril/valsartan. 88% of patients were on ACE-inhibitors, 86% on beta blockers and 68% on mineralocorticoid receptor antagonists. Serum samples were obtained and analyzed for leptin, fructosamin and pBNP before and 3–6 month after ARNI therapy. The clinical parameters LVEF and NYHA class were assessed before and 3–6 month after ARNI therapy. Results Baseline leptin level was 15.0 (SD 17.2), baseline fructosamin level was 370.1 (SD 167.7) and baseline pBNP level was 1494.9 (SD 1281.4). Under therapy a significant improvement of ejection fraction from 29,8% to 37,5% (7,7 SD 8,5 P≤0.001), an improvement of NYHA stadium from 2.46 (SD 0.62) to 1.96 (SD 0.63, p=0.005) and a significant decrease of pBNP (562.1 SD 1256.4, p=0.018) was found. Along with that, a significant increase in leptin levels (3.6 SD 8.85, p=0.012) and a significant increase in fructosamine levels (93.5 SD 160.6, p=0.013) was shown. Conclusion Under therapy with ARNI we showed a sufficient therapy response with improvement of ejection fraction and decrease of pBNP in line with literature. Surprisingly metabolism biomarkers did significantly worsen under the first three to six month after new ARNI therapy. To distinguish between a side effect of ARNI therapy or consequence of heart failure itself further investigations are needed. Funding Acknowledgement Type of funding sources: None.

EFFECTIVENESS, SAFETY, AND TOLERABILITY OF SACUBITRIL/VALSARTAN OVER 3 YEARS OF FOLLOW-UP IN CANADIAN PRACTICE: INSIGHTS FROM THE PARTHENON REGISTRY

The PARADIGM-HF trial demonstrated the superiority of sacubitril/valsartan over enalapril in reducing the risk of CV death or HF hospitalization in patients with HFrEF. The generalisability of these data as well as safety and medication persistence to unselected, real world patients remained to be evaluated. The PARTHENON (PAtient RegisTry assessing effectiveness and safety of HEart failure treatment with LCZ696 acrOss CaNada) registry study was conducted to evaluate the effects of sacubitril/valsartan use in Canadian patients with HFrEF.

Predicting stroke in heart failure and reduced ejection fraction without atrial fibrillation.

Patients with heart failure with reduced ejection fraction (HFrEF) are at significant risk of stroke. Anticoagulation reduces this risk in patients with and without atrial fibrillation (AF), but the risk-to-benefit balance in the latter group, overall, is not favourable. Identification of patients with HFrEF, without AF, at the highest risk of stroke may allow targeted and safer use of prophylactic anticoagulant therapy. In a pooled patient-level cohort of the PARADIGM-HF, ATMOSPHERE, and DAPA-HF trials, a previously derived simple risk model for stroke, consisting of three variables (history of prior stroke, insulin-treated diabetes, and plasma N-terminal pro-B-type natriuretic peptide level), was validated. Of the 20 159 patients included, 12 751 patients did not have AF at baseline. Among patients without AF, 346 (2.7%) experienced a stroke over a median follow up of 2.0 years (rate 11.7 per 1000 patient-years). The risk for stroke increased with increasing risk score: fourth quintile hazard ratio (HR) 2.35 [95% confidence interval (CI) 1.60-3.45]; fifth quintile HR 3.73 (95% CI 2.58-5.38), with the first quintile as reference. For patients in the top quintile, the rate of stroke was 21.2 per 1000 patient-years, similar to participants with AF not receiving anticoagulation (20.1 per 1000 patient-years). Model discrimination was good with a C-index of 0.84 (0.75-0.91). It is possible to identify a subset of HFrEF patients without AF with a stroke-risk equivalent to that of patients with AF who are not anticoagulated. In these patients, the risk-to-benefit balance might justify the use of prophylactic anticoagulation, but this hypothesis needs to be tested prospectively.

Effects of sacubitril/valsartan on glycemia in patients with diabetes and heart failure: the PARAGON-HF and PARADIGM-HF trials

BackgroundCompared with enalapril, sacubitril/valsartan lowered HbA1c and reduced new insulin therapy in patients with heart failure with reduced ejection fraction (HFrEF) and diabetes in the PARADIGM-HF trial. We sought to assess the glycemic effects of sacubitril/valsartan in heart failure with preserved ejection fraction (HFpEF) and diabetes, and across the spectrum of left ventricular ejection fraction (LVEF) in heart failure and diabetes.MethodsWe compared the effect of sacubitril/valsartan, relative to valsartan, on HbA1c, new insulin therapy and hypoglycemia in the randomized controlled trial PARAGON-HF, and performed pooled analyses of PARAGON-HF and PARADIGM-HF.ResultsAmong 2395 patients with HFpEF and diabetes in PARAGON-HF, sacubitril/valsartan compared with valsartan reduced HbA1c (baseline-adjusted between-group difference in HbA1c change at 48 weeks: − 0.24%, 95% CI − 0.33 to − 0.16%, P < 0.001). Numerically, new insulin treatment was initiated less often in the sacubitril/valsartan group than in the valsartan group, but the difference was not statistically significant (12.8% vs. 16.1%; HR: 0.80, 95% CI 0.62–1.02, P = 0.07). Hypoglycemia adverse event reports were low, but more frequent in those receiving sacubitril/valsartan than in the valsartan group (4.2% vs. 2.6%; HR: 1.64, 95% CI 1.05–2.56, P = 0.030). In a pooled analysis of PARAGON-HF and PARADIGM-HF, the effect of sacubitril/valsartan on change in HbA1c was not significantly modified by LVEF (Pinteraction = 0.56). Across the spectrum of LVEF, sacubitril/valsartan reduced new insulin therapy (HR: 0.75, 95% CI 0.63–0.89, P = 0.001), compared with enalapril or valsartan.ConclusionsSacubitril/valsartan reduced HbA1c and new insulin therapy in patients with heart failure and diabetes across the spectrum of LVEF but may be associated with a slightly higher risk for hypoglycemia.Trial registration ClinicalTrials.gov NCT01920711

Comparison of major adverse cardiovascular events between sacubitril-valsartan versus ACEI/ARB therapy in patients with heart failure with reduced ejection fraction

Abstract Funding Acknowledgements Type of funding sources: None. Background Sacubitril-valsartan (S-V) reduced risks of Major Adverse Cardiovascular Events (MACE) for heart failure (HF) versus enalapril in ambulatory patients with HF and reduced ejection fraction (HFrEF) in the PARADIGM-HF trial. However, the comparative MACE of S-V and Angiotensin Converting Enzyme Inhibitors (ACEI)/angiotensin receptor blocker (ARB) in patients treated in routine clinical practice is unclear. Purpose This study aims to compare the MACE of S-V and ACEI/ARB in HFrEF patients. Methods Retrospective study of patients with HFrEF observed in a HF clinic between Jan 2018 and Dec 2018, with a follow up at Sept 2021. We defined MACE as composite of death from cardiovascular (CV) causes or hospitalization for HF. One-to-one propensity score matching was used to balance patients on 20 clinical variables. Cox models were used to compare outcomes between treatment groups. Results A total of 130 HFrEF patients were included, 45 (34,6%) and 85 (65,4%) adults filling a prescription for S-V or ACEI/ARB, respectively. Before matching, patients taking S-V had a mean age of 61,3±10,8 and were more often men (38; 84%). In the group of patients treated with ACEI/ARB, the mean age was 60,7±11,6 and 69 (81%) were male. The most frequent aetiologies for HF were ischemic cardiomyopathy (22; (48,9%) in S-V group and 37 (43,5%) in ACEI/ARB group) and dilated cardiomyopathy (21; (46,7%) in S-V group and (45; 52,9%) in ACEI/ARB group). The final propensity-matched cohort included 34 pairs taking S-V or ACE/ARB. The median follow-up time was 42 (IQR: 34-61) months. MACE occurred in 11 (32,4%) patients treated with S-V and in 10 (29,4%) patients taking ACEI/ARBs. During follow-up, 7 (20,6%) patients treated with S-V died, compared with 8 (23,5%) treated with ACEI/ARB. The proportion of CV mortality was 4 (11,8%) for S-V patients and 3 (9%) for ACEI/ARB patients. HF hospitalization occurred in 9 (26,5%) patients taking S-V vs 10 (29%) patients taking ACEI/ARBs, of which 6 (17,6%) and 4 (12%), respectively, were rehospitalised for HF. The same number of patients in both groups (8; 23,5%) required inotropic support. The median time to the first hospitalization was 17 months (IQR: 7 -35) in the S-V group and 6 months (IQR: 2 -14) in the ACEI/ARB group. There were no statistically significant differences between S-V vs ACEI/ARB in respect to MACE (p=0,499), all-cause mortality (p=0,919), CV mortality (p=0,594) and HF hospitalization (p=0,207) during follow-up. There was a statistically significant difference between the two groups in respect to the median time to first hospitalization (p=0,032). Conclusion In our cohort of patients with HFrEF, sacubitril-valsartan was not associated with lower risks of death and hospitalization compared with ACEI/ARB. Nonetheless, patients treated with sacubitril-valsartan had a median time to first hospitalization higher than the group of patients treated with ACEI/ARB.

Abstract 264: Tachyarrhythmias Associated With Sacubitril-valsartan - A Pharmacovigilance Analysis:

Background: Sacubitril-valsartan is a combination of a neprilysin inhibitor and an angiotensin II receptor blocker respectively. Sacubitril-valsartan has become a standard of care in the treatment of patients with Congestive Heart Failure (CHF) with reduced EF. During its clinical trials and upon review of U.S. Food and Drug Administration (FDA) approval, sacubitril-valsartan exhibited a side effect profile including hyperkalemia, hypotension, renal dysfunction, and angioedema. Recently, sacubitril-valsartan was also approved for the treatment of CHF patients with preserved EF. Objective: In view of new indications and increased usage, it is important to establish the updated safety profile of sacubitril-valsartan in the general population since the PARADIGM-HF trial. Methods: We explored reported Adverse Events (AEs) of sacubitril-valsartan using the FDA Adverse Event Reporting System. A total of 57,958 AEs were reported until August 2021. Total of 16,658 (28.7%) AEs were reported by HCPs, which were further analyzed. AEs were analyzed in men (56.7%) vs women (25.3%), and also in 3 age groups of 18-64, 65-85, &gt;85. Results: Out of 16,658 AEs, the most frequently reported AE was hypotension (17.2%). Other commonly reported AEs were renal dysfunction (14.3%), allergic reactions including angioedema (10.8%), GI distress (8.8%), tachyarrhythmias (5.8%), hyperkalemia (4.5%), and cough (3.0%). Out of 16,658 AEs, 11,631 (69%) were deemed serious and 4,422 (26.5%) resulted in hospitalization. Deaths were attributed to 3,909 serious AEs (23.5%). In the age group of 18-64, events of atrial fibrillation were less among women compared to men (1% vs 3%), while total events of ventricular tachycardia were noted more among men compared to women (2% vs 0.5%). Conclusion: Most of the reported AEs were consistent with the observed AEs from PARADIGM-HF except for tachyarrhythmia. There are few reports documenting arrhythmias followed by the use of sacubitril-valsartan, however, the clear mechanism is unknown. Despite the wide use of sacubitril-valsartan, there is currently limited data on the safety profile. In future with the increasing use, further randomized controlled trials (RCTs) are needed to better understand the safety profile of the medication.

Conventional medical therapy in heart failure patients eligible for the PARADIGM-HF, DAPA-HF, and SHIFT trials

BackgroundRecent trials on novel heart failure (HF) treatments (angiotensin receptor-neprilysin inhibitor, sodium-glucose cotransporter 2 inhibitor, and ivabradine) emphasize the use of conventional medical therapy (angiotensin-converting enzyme inhibitors, beta-blockers [BB], and mineral corticosteroid receptor antagonists). We aimed to evaluate the prescription rate of conventional medical therapy and its association with long-term outcomes in patients eligible for recent trials. MethodsWe examined 1295 consecutive patients with HF with reduced ejection fraction (HFrEF) from a multicenter registry (WET-HF registry). We assessed conventional medical therapy implementation among patients meeting the PARADIGM-HF/DAPA-HF and SHIFT enrollment criteria. We also examined the association between conventional medical therapy use and long-term outcomes within each enrollment criterion. ResultsOverall, 62.2% and 35.3% of HFrEF patients met the enrollment criteria of the PARADIGM-HF/DAPA-HF and SHIFT trials. Only 33.9% and 31.9% received full conventional medical therapy within each patient subset. Notably, 84.2% of patients who met the SHIFT enrollment criteria were on BB, and only 23.0% and 4.4% were on ≥50% or the full recommended dose, respectively. Implementation of full conventional medical therapy use was associated with lower 2-year mortality and HF readmission rates in the PARADIGM-HF/ DAPA-HF eligible group (HR 0.68, 95% CI 0.50–0.92). The use of BB at ≥50% of the recommended dose was associated with lower 2-year mortality and HF readmission rates in the SHIFT-eligible group (HR 0.50, 95% CI 0.30–0.84). ConclusionsConventional medical therapy was underutilized among patients eligible for novel trials within a Japanese HF registry. Further efforts to optimize conventional medical therapy are needed.

Patterns Of Recurrent Heart Failure Hospitalizations In Relation To Cardiovascular Death In Heart Failure With Reduced Ejection Fraction

<h3>Introduction</h3> The accepted understanding of the patient journey in heart failure (HF) is one of recurrent episodes of deterioration which accelerate in frequency as the patient approaches death. However, this may not be true when different modes of death are considered separately. We explored patterns of HF hospitalizations (HFH) in patients who died from either sudden death or death due to progressively worsening heart failure ("pump failure") in a contemporary cohort of patients with HFrEF. <h3>Methods</h3> We examined timing of HF hospitalizations in the PARADIGM-HF and ATMOSPHERE trials. Inclusion and exclusion for these trials were similar; NYHA class II-IV, LVEF≤35% (PARADIGM-HF LVEF≤40% reduced to ≤35% by amendment) and elevated natriuretic peptide levels. In PARADIGM-HF, patients were randomized to sacubitril-valsartan or enalapril, in ATMOSPHERE treatments were enalapril, aliskiren or both. The number of hospitalizations per patient was calculated and cross tabulated with cause of CV death. Rates of total HFH were calculated according to different causes of CV death. HFH were visualized using recurrent event plots. <h3>Results</h3> Of the 15415 patients enrolled, 2518 had at least 1 hospitalization after randomization and between them these 2518 participants accrued a total of 4318 admissions. There were 2872 CV deaths which accounted for 83% of all deaths. Of the 2872 CV deaths 1332 (46%) occurred suddenly and 735 (26%) were due to worsening heart failure. Of patients experiencing sudden death, only 205 (15%) had a preceding hospitalization compared with 569 (77%) patients dying from pump failure. Rates of HFH per 100 patient years were 17 [95% CI 15-19] in patients with sudden death, 93 [95% CI 88-98]) in the pump failure death group and 7 [95% CI 6-7] in patients without CV death. Recurrent event plots show a greater density of HFH in patients with pump failure deaths as compared with other CV deaths. <h3>Conclusions</h3> This analysis shows that the accepted patient trajectory in HFrEF is true for individuals who die from progressive worsening of heart failure but not for sudden death where only a minority of patients experience preceding HFH.