PARADIGM-HF Trial Research Articles

Position paper of the Italian Society of Cardiology: The renin-angiotensin-aldosterone system (RAAS) blockade in heart failure patients - Part I: From RAAS identification to clinical trials

Renin-angiotensin-aldosterone (RAAS) system inhibition is a mainstay of the pharmacological treatment of heart failure with reduced ejection fraction and has been implemented by the introduction of angiotensin receptor-neprilysin inhibitors (ARNI), that combine RAAS inhibition with the inhibition of neprilysin, enhancing the favorable effects of natriuretic peptides. The PARADIGM-HF trial demonstrated a favorable effect of sacubitril/valsartan over enalapril in terms of mortality and heart failure hospitalization rate reduction. Then several randomized clinical trials and observational studies confirmed the favorable role of ARNI in different clinical scenarios, supporting the guideline class I recommendation for the use of sacubitril/valsartan in patients with reduced systolic function. The first part of this position paper summarizes the history of RAAS inhibition and reports the results of ARNI trials that support the recommendations of the most recent guidelines.

155 Effects on sacubitril/valsartan on natriuretic peptides in patients with a reduced ejection fraction

Abstract Aims The PARADIGM-HF trial proved the superiority of sacubitril/valsartan (Sa/Va) vs. enalapril in reducing mortality and hospitalization for heart failure (HF). Sacubitril/valsartan, new drug used in treatment of heart failure with reduced systolic function (HFrEF) has recently been shown to improve tolerance to exercise and cardiovascular performance. Methods and results We prospectively enrolled 40 outpatient patients with HFrEF with indication for therapy with sacubitril/valsartan and subjected to serial controls with blood tests, echocardiogram before and during gradual optimization of therapy, with the aim of evaluating the effects of the drug on left ventricular remodelling. We studied 40 patients treated with sacubitril/valsartan for at least 3 months. After a mean follow-up of 120 ± 40 days, 95% of patients reached the maximum dose of the drug without major side effects. The ejection fraction increased while end-diastolic and end-systolic volumes of the left ventricle decreased. We also observed a significant reduction in NT-proBNP values without significant worsening of renal function or hyperkalaemia. There NYHA functional class has improved with a positive impact on the prognosis of heart failure at 2 years (P = 0.006). Conclusions In our population, medium-term treatment with sacubitril/valsartan demonstrated a favourable effect on left ventricular remodelling and functional status, confirming the data of previous clinical trials in real life. One more follow-up long and a larger population will help confirm these to confirm these positive effects of the drug on patients with HfrEF.

Variation in early diffusion of sacubitril/valsartan and implications for understanding novel drug diffusion.

In the PARADIGM-HF trial, sacubitril/valsartan demonstrated a 20% reduction in mortality and heart failure hospitalization compared with standard angiotensin-converting enzyme inhibitor therapy. Despite this and a class I indication, drug diffusion has been much slower than anticipated. This study aims to examine the variation in early diffusion of sacubitril/valsartan and describe the factors associated with high and low rates of early use. Annual, cross-sectional analyses between January 2016 and December 2018. We created a nationally representative cohort of Medicare fee-for-service beneficiaries with heart failure with reduced ejection fraction fully enrolled in parts A, B, and D for at least 1 year between 2016 and 2018. Sacubitril/valsartan use was determined using National Drug Codes. We generated age, sex, and race-adjusted rates of sacubitril/valsartan prescribing by hospital referral region from 2016 to 2018. We also examined the factors associated with high and low rates of early use. Early use rates of sacubitril/valsartan were low: 1.9% in 2016, 3.3% in 2017, and 4.0% in 2018. Even after controlling for out-of-pocket co-payments, there was substantial geographic variation in early use, with most early use concentrated in the Northeast and South. There has been substantial variation in the early diffusion of sacubitril/valsartan. In addition to drug cost, geographic prescribing patterns appear to play a major role in early drug diffusion.

Real world clinical outcomes of angiotensin receptor-neprilysin inhibitor (ARNI) in patients with heart failure with reduced ejection fraction: A Malaysian experience

PARADIGM-HF trial showed the evidence for cardiovascular and mortality benefit of angiotensin receptor-neprilysin inhibitor (ARNI), over Angiotensin-converting enzyme inhibitors (enalapril) in patients with heart failure with reduced ejection fraction (HFrEF). However, patients from real world clinical practice may differ from those enrolled into randomized controlled trials and little is known about ARNI use & its impact in local Malaysian population.

M7. Effects of the angiotensin receptor–neprilysin inhibitor/sacubitril-valsartan administration on quality of life and outcome in heart failure with reduced ejection fraction: a meta analysis

Abstract Background and Aims Improved quality of life is a mayor treatment goal in heart failure. Based on the PARADIGM-HF trial, ARNI was found improved quality of life in heart failure with reduced ejection fraction (HFrEF). The aims of this study are to evaluate the quality of life and outcome patient HFrEF after ARNI administration. Methods and Result Published scientific articles is searched through PubMed database with inclusion criteria were Randomized Control Trial (RCT) or observational study in the last 10 years (2014 - 2021), the QoL is measured by Kansas City Cardiomyopathy Score (KCCQ). A total of 4 RCTs and 3 observational studies were selected. There was significantly increase in KCCQ Overall Summary score (MD = 2.01 [95% CI, 1.07, 2.96], p < 0.00001). There was also significantly increase in KCCQ physical limitation domain (MD = 1.21[95% CI, 0.12, 2.30], p = 0.03), QoL domain (MD = 2.66[95% CI, 0.64, 4.69], p = 0.010) and social limitation domain (MD = 1.97[95% CI, 0.98, 2.95], p < 0.0001). The relative risk in HFrEF patients for first hospital admission was 0.82 (95% CI, 0.77, 0.87, p < 0.00001) and relative risk for cardiovascular death was 0.81(95% CI, 0.76, 0.87, p < 0.00001). Hypotension was found as significant adverse event after treatment with ARNI (RR = 1.57 [95% CI, 1.41, 1.75], p < 0.00001). Conclusion ARNI was found significantly improved quality of life, reduced morbidity and mortality in patient HFrEF compared with control but might causes a serious adverse event such as hypotension. Due to limitation data of adverse event, a further investigation might be needed.

Abstract 10044: Efficacy of Sacubitril-Valsartan in Patients with Reduced Left Ventricular Ejection Fraction

Introduction: Angiotensin receptor-neprilysin inhibitor (ARNI) reduces death and heart failure (HF) hospitalization in patients with HF and reduced ejection fraction (HFrEF). In addition to the PARADIGM-HF, PARADISE-MI and LIFE trial has recently tested the safety and efficacy of ARNI in subgroups of patients with reduced left ventricular ejection fraction (LVEF) such as those patients at risk for HFrEF after myocardial infarction (without prior HF) and advanced HF patients. Methods: We performed a random-effects model meta-analysis of three randomized controlled trails investigating the effect of ARNI in patients with reduced LVEF. The main endpoints were the composite of cardiovascular death and HF hospitalization, and HF hospitalization. Results: A total of 14,395 patients were included in our analysis. The characteristics of the included studies are demonstrated on Table 1. The composite endpoint and HF hospitalization were non-significantly reduced with ARNI compared with angiotensin-converting enzyme inhibitor or angiotensin II receptor blockers (composite endpoint adjusted hazard ratio [HR] 0.9, 95% confidence intervals 0.75-1.08 and HF hospitalizations: HR 0.87, 0.72-1.04, Figure 1). The heterogeneity among trials was high (I 2 >50%). Conclusions: In line with the recently reported trials, our findings support the use of ARNI in patients with HFrEF that meet the inclusion criteria of PARADIGM-HF trial. It is important to tailor medical therapy by matching individual patient profiles to inclusion criteria of the published randomized clinical trials.

Abstract 12257: The Utility of PREDICT-HF Score in High-Risk Asian Heart Failure Patients Receiving Sacubitril/Valsartan Treatment

Introduction: Although the efficacy and safety of sacubitril/valsartan (Sac/val) for treating patients with heart failure and reduced ejection fraction (HFrEF) have been shown in global clinical trials, long-term tolerability and effectiveness data from Asian patients are limited. Hypothesis: The aim of this study was to investigate the effectiveness and tolerability of Sac/val in clinical practice and the utility of PREDICT-HF score for outcome prediction in Asian heart failure patients with difference risk profiles. Methods: The TAROT-HF study was a multicenter, single-arm, observational study. Totally 1,187 outpatients with HFrEF treated with Sac/val were enrolled and categorized by: (1) high-risk group with one or more of the following three risk factors: old age (≥80 years), low baseline systolic blood pressure (<100mmHg), and renal impairment (eGFR <30ml/min/1.73 m2), and (2) standard-risk group, those who did not have any risk factors. Clinical outcomes were assessed using the PREDICT-HF risk model. Results: A total of 305 (25.7%) patients matched the criteria for the high-risk group. The event rates of cardiovascular death or first unplanned heart failure hospitalization (HFH) among the overall population, high-risk, and standard-risk groups were 13.7, 24.9, and 10.8 events per 100 patient-years, respectively. The C statistics for the PREDICT-HF model in the overall cohort and high-risk group for cardiovascular death or first unplanned HFH at 2 years were 0.73 (95% CI 0.70-0.76) and 0.71 (95% CI 0.65-0.76), respectively. Conclusions: Real-world outcomes of the TAROT-HF study showed good tolerability of Sac/val. Although the current study enrolled high-risk patients not included in the PARADIGM-HF trial, the PREDICT-HF model performed well in real-world Asian HFrEF patients. Three easily detected clinical profiles of age, renal function, and systolic BP could help to identify patients at risk before initiating Sac/val therapy.

Abstract 11131: Discharge on Sacubitril/Valsartan vs. ACEi/ARB in Older Patients with HFrEF: A Decision Analysis Approach

Introduction: Based on the results of PARADIGM-HF and PIONEER-HF, angiotensin-receptor neprilysin inhibitors (ARNI) offer improved survival and lower readmission rates for HFrEF compared to angiotensin converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB). However, there is concern that increased hypotension and higher drug costs may limit the effectiveness of ARNIs in clinical practice, especially among older adults with Part D prescription coverage. The aim of this study is to use decision analytic modeling to estimate the association between discharge on ARNI vs. ACEi/ARB and patient outcomes, and then determine if it varies by age. Methods: We then used a 2-state absorbing Markov chain model with a 1-month cycle length to simulate 5-year survival for patients discharged on ARNI or ACEi/ARB, accounting for the risks of death and readmission, estimated from trials, as well as the risk of in-hospital mortality, drug switching, and discontinuation, estimated from Medicare claims data. In the model, the weighted averages for mortality and readmission reduction were estimated published risk reductions from the PIONEER-HF trials (first two months) and PARADIGM-HF (subsequent 8 months) trials. Results: Across all age groups, patients discharged on ARNI had higher 5-year survival compared to patients discharged on ACEi/ARB ( Table 1 ). Moreover, the absolute and relative benefit of ARNI over ACEi/ARB, even after accounting for drug discontinuation and switching, was similar across age groups. The number needed to treat (NNT) with ARNI rather than ACEi/ARB to prevent 1 death over 5 years ranged from 56-63. Conclusions: There is a small, but clinically significant, survival benefit to discharge on ARNI vs. ACEi/ARB across all age groups, even after accounting for drug switching and discontinuation. Additional work is needed to determine if there is additional heterogeneity of treatment effect in subgroups of high-risk, older adults.

Heart Failure Population with Therapeutic Response to Sacubitril/Valsartan, Spironolactone and Candesartan: FDA Perspective.

Sacubitril/valsartan was approved by the Food and Drug Administration in 2015 to reduce the risk of cardiovascular death and hospitalization for heart failure (HHF) in patients with chronic heart failure with reduced ejection fraction defined as left ventricular ejection fraction (LVEF) ≤ 40%. This approval was based on PARADIGM-HF trial. Subsequently, PARAGON-HF was conducted to support a claim for sacubitril/valsartan in patients with heart failure with preserved ejection fraction (HFpEF), defined as LVEF ≥ 45%. PARAGON-HF failed to meet the pre-defined threshold for statistical significance for the primary composite endpoint.However, analysis of the primary endpoint by LVEF as a continuous variable demonstrated that sacubitril/valsartan was efficacious in patients with mildly abnormal LVEF similar to patients with LVEF ≤ 40% evaluated in PARADIGM-HF. This led to a broader indication for sacubitril/valsartan-"to reduce the risk of cardiovascular death and hospitalization for heart failure in adult patients with chronic heart failure. Benefits are most clearly evident in patients with left ventricular ejection fraction (LVEF) below normal. LVEF is a variable measure, so use clinical judgment in deciding whom to treat." This article describes the rationale for a revised indication for sacubitril/valsartan, emphasizes the need to go beyond a dichotomous classification of HF based on a traditional LVEF cut-off and clarifies that the product label for sacubitril/valsartan does not refer to HFpEF.

Cost-Effectiveness Analysis of Sacubitril/Valsartan Compared to Enalapril for Heart Failure Patients in Indonesia.

ObjectiveSacubitril/valsartan is a relatively new medication that is more effective than the usual enalapril for heart failure patients with reduced ejection fraction. Therefore, this study aims to determine the cost-effectiveness of sacubitril/valsartan compared to enalapril in Indonesia’s healthcare system.MethodsIn this study, a Markov decision-analytic model was developed to estimate the total cost, health outcomes, and cost-effectiveness of sacubitril/valsartan compared to enalapril from Indonesia’s healthcare perspective. The input parameters for the cost-effectiveness were predominantly from the PARADIGM-HF trial. Subsequently, the country-specific data were synthesized for medication and hospitalization costs, cardiovascular and non-cardiovascular death, as well as re-hospitalization rate. The incremental cost-effectiveness ratio (ICER) per quality-adjusted life years (QALYs) gained was estimated to determine the cost-effectiveness. Deterministic and probabilistic sensitivity analyses were conducted to assess the impact of parameter uncertainty.Results and DiscussionIn the base case, sacubitril/valsartan was more costly and effective than enalapril with a total cost of IDR 91,783,325,865 (USD 6,487,522) vs IDR 68,101,971,241 (USD 4,813,653) and a total QALYs of 19,680 vs 18,795, resulting in an ICER of IDR 26,742,098 (USD 1890). Based on the willingness to pay threshold GDP per capita in Indonesia, it can be considered cost-effective. The most influential drivers of cost-effectiveness in deterministic sensitivity analysis were risk of mortality outside hospitalization, hospital admission rate, and cost of sacubitril/valsartan. The vast majority of simulation results from probabilistic analysis suggested that sacubitril/valsartan was likely resulted in higher cost and improved QALYs compared with enalapril, indicating the robustness of the model.ConclusionBased on the current price in Indonesia, sacubitril/valsartan can be considered a cost-effective option, although this depends heavily on the willingness to pay threshold. Further studies that incorporate real-world evidence with sacubitril/valsartan are needed to inform the decision-making process.

Efficiency Comparison of Analysis Methods for Recurrent Event and Time-to-First Event Endpoints in the Presence of Terminal Events—Application to Clinical Trials in Chronic Heart Failure

In clinical trials investigating treatments for chronic heart failure (CHF), a standard primary endpoint is the time to the first composite of hospitalization for heart failure or cardiovascular death (CVD). Since many patients experience several hospitalizations, there is interest in including recurrent hospitalizations into the primary endpoint to better capture disease burden. Several analysis methods have been proposed for recurrent event endpoints, mostly for the situation without a terminal event such as CVD. Only some methods explicitly account for terminal events, for example, the joint frailty model. We compare the power and Type I error rate of recurrent event methods with those of time-to-first event methods in the presence of terminal events. A special focus is the situation where treatment affects the risk of CVD. Our investigations are based on a simulation study, for which the scenarios are motivated by CHF trials, and based on bootstraping data from the Val-HeFT and PARADIGM-HF trials. We find that recurrent event methods can in many situations increase power considerably. But this is not always the case, for example, when there is high probability of treatment discontinuation after the first hospitalization. Also, for both recurrent and time-to-first event methods, the Type I error rate can be inflated in case of a detrimental treatment effect on CVD. Based on the simulation results we give recommendations on the choice of endpoint and analysis method for CHF trials.

A comparison of semiparametric approaches to evaluate composite endpoints in heart failure trials

In heart failure (HF) trials efficacy is usually assessed by a composite endpoint including cardiovascular death (CVD) and heart failure hospitalizations (HFHs), which has traditionally been evaluated with a time-to-first-event analysis based on a Cox model. As a considerable fraction of events is ignored that way, methods for recurrent events were suggested, among others the semiparametric proportional rates models by Lin, Wei, Yang, and Ying (LWYY model) and Mao and Lin (Mao-Lin model). In our work we apply least false parameter theory to explain the behavior of the composite treatment effect estimates resulting from the Cox model, the LWYY model, and the Mao-Lin model in clinically relevant scenarios parameterized through joint frailty models. These account for both different treatment effects on the two outcomes (CVD, HFHs) and the positive correlation between their risk rates. For the important setting of beneficial outcome-specific treatment effects we show that the correlation results in composite treatment effect estimates, which are decreasing with trial duration. The estimate from the Cox model is affected more by the attenuation than the estimates from the recurrent event models, which both demonstrate very similar behavior. Since the Mao-Lin model turns out to be less sensitive to harmful effects on mortality, we conclude that, among the three investigated approaches, the LWYY model is the most appropriate one for the composite endpoint in HF trials. Our investigations are motivated and compared with empirical results from the PARADIGM-HF trial (ClinicalTrials.gov identifier: NCT01035255), a large multicenter trial including 8399 chronic HF patients.

Clinical Experience of Use of Sacubitril/Valsartan in a Patient with Dilated Cardiomyopathy, Chronic Heart Failure with Reduced Ejection Fraction and Ventricular Arrhythmias

Chronic heart failure is the final stage of the cardiovascular continuum, which is an important cause of disability and reduced life expectancy in developed countries. Optimal medical therapy recommended for patients with symptomatic HF and reduced left ventricular ejection fraction includes angiotensin-converting enzyme inhibitors (or angiotensin II receptor antagonists), beta-blockers and mineralocorticoid receptor antagonists. However, the use of optimal medical therapy does not always lead to the elimination of symptoms, improvement of the quality of life and functional capabilities of patients.
 Sakubitril/valsartan is a novel combination drug that includes the angiotensin II receptor blocker valsartan and the neprilisin inhibitor sacubitril. In a large PARADIGM-HF clinical trial it demonstrated a 20% reduction in cardiovascular mortality and hospitalization due to decompensation of heart failure compared with standard therapy with enalapril. We report a case of successful use of sacubitril/valsartan in a 61-year-old patient with dilated cardiomyopathy, chronic heart failure with reduced ejection fraction and ventricular arrhythmias. After 6 months of therapy, the patient achieved marked positive dynamics of the clinical status, laboratory and instrumental parameters in absence of any adverse reactions and complications.

Renal protection in chronic heart failure: focus on sacubitril/valsartan.

Chronic kidney disease (CKD) is highly prevalent in patients with chronic heart failure (CHF) and increases the risk of overall and cardiovascular (CV) mortality. Despite evidence supporting the effectiveness of angiotensin-converting enzyme inhibitors (ACE-Is), angiotensin receptor blockers, and mineralocorticoid receptor antagonists in decreasing mortality in patients with CHF, CKD hampers the optimization of standard pharmacologic therapy for heart failure. Therefore, other treatment options are needed to optimize treatment outcomes in CHF patients with CKD. The first-in-class angiotensin receptor-neprilysin inhibitor, sacubitril/valsartan, has a complementary activity that counteracts the potential unwanted long-term effects of over-activation of the renin–angiotensin–aldosterone system. Sacubitril/valsartan reduced the risk of CV mortality compared to standard therapy with an ACE-I in patients with heart failure with reduced ejection fraction (HFrEF) in the PARADIGM-HF trial and has been shown to be safe and effective in a broad range of HFrEF patients. However, data on the efficacy and tolerability of sacubitril/valsartan in patients with more advanced CKD are limited. This review discusses the evidence for the role of sacubitril/valsartan in providing additional renal benefit in patients with HFrEF. Data from clinical trials and real-world experience in patients with HFrEF and advanced CKD support the benefits of dual angiotensin/neprilysin inhibition across the breadth of kidney disease stages, including patients with significant renal impairment that was not reported in the pivotal PARADIGM-HF trial, and suggests a central role for the cardiac benefits of sacubitril/valsartan in nephroprotection.

Incidence and Outcomes of Pneumonia in Patients With Heart Failure

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

Should SGLT2i be used prior to transcatheter edge-to-edge repair for secondary mitral regurgitation?

Should SGLT2i be used prior to transcatheter edge-to-edge repair for secondary mitral regurgitation?

Sacubitril/valsartan: from the PARADIGM-HF trial results to heart failure patients in internal medicine. A narrative review

Data regarding the treatment of heart failure (HF) patients derived from randomized, controlled clinical trials, which, with rare exceptions, appear to be distant from the real world of internal medicine. Many trials have been conducted in cardiology departments: however, the characteristics of patients admitted to cardiology wards are largely different from those of patients hospitalized in internal medicine wards. Recently, the PARADIGM-HF study established the efficacy of sacubitril-valsartan – the first drug of the angiotensin II receptor neprilysin inhibitor (ARNI) class - versus enalapril in increasing survival and reducing hospitalizations in a selected population of HF patients with reduced ventricular function. Although practical guidance on the use of ARNI has been published, it is not specific to HF patients admitted to internal medicine wards. In this review, we examine all available data in order to understand if the characteristics of HF patients followed in internal medicine departments hinder or contraindicate the use of sacubitril-valsartan and what indications appear more appropriate in this setting.

Dynamic changes in cardiovascular and systemic parameters prior to sudden cardiac death in heart failure with reduced ejection fraction: a PARADIGM-HF analysis.

Prognostic models of sudden cardiac death (SCD) typically incorporate data at only a single time-point. We investigated independent predictors of SCD addressing the impact of integrating time-varying covariates to improve prediction assessment. We studied 8399 patients enrolled in the PARADIGM-HF trial and identified independent predictors of SCD (n=561, 36% of total deaths) using time-updated multivariable-adjusted Cox models, classification and regression tree (CART), and logistic regression analysis. Compared with patients who were alive or died from non-sudden cardiovascular deaths, patients who suffered a SCD displayed a distinct temporal profile of New York Heart Association (NYHA) class, heart rate and levels of three biomarkers (albumin, uric acid and total bilirubin), with significant differences observed more than 1year prior to the event (Pinteraction < 0.001). In multivariable models adjusted for baseline covariates, seven time-updated variables independently contributed to SCD risk (incremental likelihood chi-square=46.2). CART analysis identified that baseline variables (implantable cardioverter-defibrillator use and N-terminal prohormone of B-type natriuretic peptide levels) and time-updated covariates (NYHA class, total bilirubin, and total cholesterol) improved risk stratification. CART-defined subgroup of highest risk had nearly an eightfold increment in SCD hazard (hazard ratio 7.7, 95% confidence interval 3.6-16.5; P < 0.001). Finally, changes over time in heart rate, NYHA class, blood urea nitrogen and albumin levels were associated with differential risk of sudden vs. non-sudden cardiovascular deaths (P < 0.05). Beyond single time-point assessments, distinct changes in multiple cardiac-specific and systemic variables improved SCD risk prediction and were helpful in differentiating mode of death in chronic heart failure.

Updates in pharmacotherapy of heart failure with reduced ejection fraction.

Heart failure is a common entity encountered in healthcare with a vast socioeconomic impact. Recent advances in pharmacotherapy have led to the development of novel therapies with mortality benefits, improvement in heart failure symptoms and hospitalizations. This article is intended to explore those newer pharmacotherapies and summarize the evidence behind guideline directed medical therapy (GDMT) for heart failure with reduced ejection fraction (HFrEF). It has been several years since any significant advances in pharmacotherapy of heart failure have resulted in survival benefit. Angiotensin-neprilysin inhibitors through the PARADIGM-HF and PIONEER-HF trials have shown mortality benefits and a reduction in heart failure hospitalizations and are considered landmark trials in heart failure. Vericiguat is an oral guanylate cyclase stimulator that through the recent VICTORIA trial showed a 10% relative difference in death from cardiovascular cause or hospitalization for heart failure. The sodium-glucose transport protein 2 (SGLT2) inhibitors are another class of medications that have shown promise in the treatment of patients with HFrEF and diabetes mellitus. The CANVAS and EMPA-REG OUTCOME trials showed the potential benefit of SGLT2 inhibitors on cardiovascular mortality, DECLARE-TIMI 58 trial showed that treatment with dapagliflozin reduced the risk of cardiovascular death or hospitalization for heart failure to a greater extent in patients with reduced ejection fraction (EF). Although novel pharmacotherapy is the current focus of intense research, there have been numerous studies on potential benefit of iron supplementation in ferropenic patients with heart failure. Another rapidly expanding area of research in the realm of heart failure is precision medicine and its impact on the development, progression, and treatment of heart failure. The field of heart failure is dynamic and with the influx of data from recent and ongoing trials, newer therapies with morbidity and mortality benefits in HFrEF are now available, nonetheless, much work is still needed.

Narrative review in the current role of angiotensin receptor-neprilysin inhibitors.

Heart failure (HF) accounts for a tremendous burden on health care systems and the society. Since the landmark PARADIGM-HF trial, sacubitril/valsartan, the first in the class of angiotensin receptor neprilysin inhibitor (ARNI) showed superiority to enalapril in patients with HF with reduced ejection fraction (HFrEF). We performed a narrative literature review, hand-searched the reference lists of included articles and relevant reviews. Inhibition of neprilysin increases bradykinin, natriuretic peptides and adrenomedullin levels counteract the neurohormal activation that leads to sodium retention, vasoconstriction, and cardiac remodeling. In PARADIGM-HF the primary outcome of CV death or HF hospitalization was reduced 20% in the ARNI group (HR 0.80, P<0.001) similar to mortality due to cardiovascular cause (HR 0.80, P<0.001) in patients with HFrEF, rendering a number needed to treat of 21 patients. This effect was consistent across subgroups. The safety of starting ARNI inpatient once the acute decompensation of HF is stabilized was demonstrated in PIONEER-HF trial. With willingness-to-pay thresholds commonly acceptable in the United States, sacubitril/valsartan is likely to be cost effective, which might not be in other health systems. Although its safety has been reassured in some clinical trials, common side effects are hypotension, worsening kidney function, hyperkalemia and angioedema. In HFpEF (PARAGON-HF), sacubitril/valsartan showed decrease in the level of the cardiac biomarkers, with improve functional NYHA and decrease in hospitalizations, predominately in women and patients with borderline ejection fraction. Some ongoing studies aim to demonstrate the effects of ARNI in acute coronary syndrome, stable ischemic heart disease, advanced HF, mitral regurgitation, aortic impedance and pulmonary hypertension. In conclusion, sacubitril/valsartan has proven to be an effective addition to the HFrEF arsenal, with safety comparable to current standard of care. In HFpEF, it improves quality of life, particularly in women and in patients with borderline ejection fraction, with no effect on mortality.