Stable but Progressive Nature of Heart Failure: Considerations for Primary Care Physicians.
ABSTRACT: Primary care physicians play a significant role in managing heart failure (HF), with the goals of reducing mortality, avoiding hospitalization, and improving patients' quality of life. Most HF-related hospitalizations and deaths occur in patients with New York Heart Association functional class II or III, many of whom are perceived to have stable disease, which often progresses without clinical symptoms due to underlying deleterious effects of neurohormonal imbalance and endothelial dysfunction. Management includes lifestyle changes and stepped pharmacological therapy directed at the four stages of HF, with aggressive uptitration of therapies, including beta-blockers and inhibitors of the renin-angiotensin-aldosterone system. Recently, two new HF treatments have become available in clinical practice. Ivabradine was approved to reduce the risk of hospitalization for HF in patients with stable, symptomatic HF. Additionally, the angiotensin receptor-neprilysin inhibitor (ARNI), sacubitril/valsartan, was found to be significantly superior to enalapril in reducing risks of cardiovascular death and HF-related hospitalization. The respective 2016 and 2017 American College of Cardiology/American Heart Association/Heart Failure Society of America clinical practice guideline updates recommend that patients taking angiotensin-converting enzyme inhibitor/angiotensin receptor blocker therapy be switched to ARNI therapy to further reduce morbidity and mortality. For HF management to be maximally effective, physicians must be knowledgeable about the risks and benefits of treatments and stay engaged with patients to identify signs of disease progression. This article provides an overview of the progressive nature of HF in apparently stable patients and describes areas for treatment improvement that may help to optimize patient care.
Project description:The angiotensin-receptor-neprilysin inhibitor (ARNI) reduced cardiovascular deaths and heart failure hospitalization in patients with heart failure of reduced ejection fraction (HFrEF). Its role in non-HFrEF patients was not clear. This study aims to answer this question.In this retrospective study, we enrolled 928 patients diagnosed with non-HFrEF, 492 of them received angiotensin converting enzyme inhibitor (ACEI) and the rest 436 received angiotensin-receptor-neprilysin inhibitor. Outcomes were compared by Kaplan-Meier survival analysis and various clinical parameters were investigated using Cox multivariable analysis, followed by interaction analysis. Minnesota living with heart failure Questionnaire (MLHFQ) was employed as one of the criteria to assess heart failure outcome.The cardiovascular (CV) death or HF hospitalization at 24 months occurred in 49 patients in ACEI group compared with 31 in ARNI group (Hazard Ratio (HR): 1.231, 95% confidence Interval (CI): 1.080-2.460, P = .031). And ARNI showed better prognosis of HF hospitalization (HR: 1.283, 95%CI: 1.065-1.360, P = .038). Cumulative Kaplan-Meier estimates of endpoints, ARNI could reduce the incidence of CV death or HF hospitalization (P = .042) and HF hospitalization (P = .035). The stratified analysis revealed that participants with age less than 70 years old had a lower incidence of CV death or HF hospitalization (HR: 1.194, 95%CI: 1.011-1992, P = .031) after treated with ARNI. Patients received diuretics could benefit from ARNI (HR: 1.383, 95%CI: 1.082-1.471, P = .019). Similar results were also observed in patients with heart rate lower than 90 bpm (HR: 1.556, 95%CI: 1.045-2.386, P = .003) and patients with atrial fibrillation history (HR: 1.873, 95%CI: 1.420-2.809, P = .011). ARNI could improve the quality of life both from the total, emotional and physical aspects.ARNI is an efficacy treatment strategy to improve the outcome and quality of life in patients with non-HFrEF.
Project description:AIMS:This study aimed to compare the efficacy of angiotensin receptor-neprilysin inhibitor (ARNI) therapy with angiotensin receptor blocker (ARB) therapy for cardiovascular outcomes in patients with heart failure (HF) with reduced ejection fraction. METHODS AND RESULTS:Data were obtained from the Chang Gung Research Database. The cohort entry date of the ARB group was assigned as that of the ARNI group to avoid immortal time bias. Additionally, 1:1 propensity score matching based on age, sex, and baseline left ventricular ejection fraction was conducted. The expectation-maximization imputation method with inverse probability of treatment weighting was used to compare outcomes between the two groups. The primary outcome was a composite of cardiovascular death and hospitalization for worsening HF. Patients who received ARNI therapy had a significantly lower risk of the primary composite outcome occurring than patients who received ARBs (hazard ratio, 0.74; 95% confidence interval, 0.57-0.96). The reduction of hospitalization for worsening HF contributed most to the primary outcome benefits. In addition to the primary outcome, the ARNI group had a significantly lower risk of non-fatal myocardial infarction. The improvement of ejection fraction was not significantly different between the groups. The medication doses of ARNI were lower than in clinical trials. CONCLUSIONS:In patients with HF with reduced ejection fraction, sacubitril/valsartan was superior to ARB therapy in reducing the occurrence of the primary outcome endpoint of hospitalization for worsening HF and cardiovascular death.
Project description:Importance:The addition of receptor-neprilysin inhibition to standard therapy, including a renin-angiotensin system blocker, has been demonstrated to improve outcomes in patients with heart failure with reduced ejection fraction (HFrEF) compared with standard therapy alone. The long-term absolute risk reduction from angiotensin receptor neprilysin inhibitor (ARNI) therapy, and whether it merits widespread use among diverse subpopulations, has not been well described. Objective:To calculate estimated 5-year number needed to treat (NNT) values overall and for different subpopulations for the Prospective Comparison of ARNI with Angiotensin-Converting Enzyme Inhibitor (ACEI) to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) cohort. Design, Setting, and Participants:Overall and subpopulation 5-year NNT values were estimated for different end points using data from PARADIGM-HF, a double-blind, randomized trial of sacubitril-valsartan vs enalapril. This multicenter, international study included 8399 men and women with HFrEF (ejection fraction, ?40%). The study began in December 2009 and ended in March 2014. Analyses began in March 2018. Interventions:Random assignment to sacubitril-valsartan or enalapril. Main Outcomes and Measures:Cardiovascular death or HF hospitalization, cardiovascular death, and all-cause mortality. Results:The final cohort of 8399 individuals included 1832 women (21.8%) and 5544 white individuals (66.0%), with a mean (SD) age of 63.8?(11.4) years. The 5-year estimated NNT for the primary outcome of cardiovascular death or HF hospitalization with ARNI therapy incremental to ACEI therapy in the overall cohort was 14. The 5-year estimated NNT values were calculated for different clinically relevant subpopulations and ranged from 12 to 19. The 5-year estimated NNT for all-cause mortality in the overall cohort with ARNI incremental to ACEI was 21, with values ranging from 16 to 31 among different subgroups. Compared with imputed placebo, the 5-year estimated NNT for all-cause mortality with ARNI was 11. The 5-year estimated NNT values were also calculated for other HFrEF therapies compared with controls from landmark trials for all-cause mortality and were found to be 18 for ACEI, 24 for angiotensin receptor blockers, 8 for ?-blockers, 15 for mineralocorticoid antagonists, 14 for implantable cardioverter defibrillator, and 14 for cardiac resynchronization therapy. Conclusions and Relevance:The 5-year estimated NNT with ARNI therapy incremental to ACEI therapy overall and for clinically relevant subpopulations of patients with HFrEF are comparable with those for well-established HF therapeutics. These data further support guideline recommendations for use of ARNI therapy among eligible patients with HFrEF.
Project description:The Prospective comparison of Angiotensin Receptor-neprilysin inhibitor (ARNI) with Angiotensin converting enzyme inhibitor (ACEI) to Determine Impact on Global Mortality and morbidity in Heart Failure (HF) trial (PARADIGM-HF) showed that adding a neprilysin inhibitor (sacubitril) to a renin-angiotensin system blocker (and other standard therapy) reduced morbidity and mortality in ambulatory patients with chronic HF with reduced ejection fraction (HFrEF). In PARADIGM-HF, valsartan combined with sacubitril (a so-called ARNI) was superior to the current gold standard of an ACEI, specifically enalapril, reducing the risk of the primary composite outcome of cardiovascular (CV) death or first HF hospitalization by 20% and all-cause death by 16%. Following the results of PARADIGM-HF, sacubitril/valsartan was approved by American and European regulatory authorities for the treatment of HFrEF. The burden of HF in Asia is substantial, both due to the huge population of the region and as a result of increasing CV risk factors and disease. Both the prevalence and mortality associated with HF are high in Asia. In the following review, we discuss the development of sacubitril/valsartan, the prototype ARNI, and the available evidence for its efficacy and safety in Asian patients with HFrEF.
Project description:Sacubitril/valsartan significantly reduced heart failure hospitalization and mortality in PARADIGM-HF (Prospective Comparison of Angiotensin Receptor-Neprilysin Inhibitor With an Angiotensin-Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure). However, real-world data from its use are lacking.We retrospectively assessed all baseline and follow-up data of consecutive heart failure patients with reduced ejection fraction receiving therapy with sacubitril/valsartan for Class I recommendation between December 2016 and July 2017. Baseline characteristics and dose titration of sacubitril/valsartan were compared between patients in clinical practice and in PARADIGM-HF. A total of 120 patients (81% male) were switched from angiotensin-converting enzyme inhibitor or angiotensin receptor blocker to sacubitril/valsartan. A total of 20.1% of patients received dose uptitration. Patients were treated with an equipotential dose of renin-angiotensin system blockers before and after uptitration of sacubitril/valsartan (57 ± 29% vs. 53 ± 29% of target dose indicated by European Society of Cardiology guidelines; P = 0.286). However, they received a lower dose of sacubitril/valsartan in comparison with those in the PARADIGM-HF (219 ± 12 vs. 375 ± 75 mg; P < 0.001). In comparison with the patients receiving sacubitril/valsartan in PARADIGM-HF, patients in clinical practice were older and had a higher serum creatinine, higher New York Heart Association functional classification, and lower left ventricular ejection fraction (all P-value <0.05). Even in comparison with patients who experienced dropout during the run-in phase of PARADIGM-HF, real-world patients exhibited baseline characteristics indicative of more disease severity. Patients were at high absolute baseline risk for adverse outcome as illustrated by the EMPHASIS-HF (Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure) risk score of 6 (inter-quartile range 3), in comparison with 5 (inter-quartile range 4) in PARADIGM-HF. After initiation of sacubitril/valsartan, New York Heart Association class significantly improved (P < 0.001), but systolic blood pressure dropped more than was reported in PARADIGM-HF (7.1 ± 8.0 vs. 3.2 ± 0.4 mmHg; P < 0.001).Patients in clinical practice exhibit baseline characteristics associated with more severe disease, which might lead to prescription of lower doses. Nevertheless, patients in clinical practice are at high risk of adverse outcome as illustrated by the EMPHASIS-HF risk score, underscoring the large potential for sacubitril/valsartan therapy to reduce the risk of heart failure hospitalization and all-cause mortality.
Project description:BACKGROUND:Guidelines recommend that patients with heart failure with reduced ejection fraction (HFrEF) have medical therapy titrated to target doses derived from clinical trials, as tolerated. The degree to which titration occurs in contemporary U.S. practice is unknown. OBJECTIVES:This study sought to characterize longitudinal titration of HFrEF medical therapy in clinical practice and to identify associated factors and reasons for medication changes. METHODS:Among 2,588 U.S. outpatients with chronic HFrEF in the CHAMP-HF (Change the Management of Patients with Heart Failure) registry with complete medication data and no contraindications to medical therapy, use and dose of angiotensin-converting enzyme inhibitor (ACEI)/angiotensin II receptor blocker (ARB), angiotensin receptor-neprilysin inhibitor (ARNI), beta-blocker, and mineralocorticoid receptor antagonist (MRA) were examined at baseline and at 12-month follow-up. RESULTS:At baseline, 658 (25%), 525 (20%), 287 (11%), and 45 (2%) patients were receiving target doses of MRA, beta-blocker, ACEI/ARB, and ARNI therapy, respectively. At 12 months, proportions of patients with medication initiation or dose increase were 6% for MRA, 10% for beta-blocker, 7% for ACEI/ARB, and 10% for ARNI; corresponding proportions with discontinuation or dose decrease were 4%, 7%, 11%, and 3%, respectively. Over 12 months, <1% of patients were simultaneously treated with target doses of ACEI/ARB/ARNI, beta-blocker, and MRA. In multivariate analysis, across the classes of medications, multiple patient characteristics were associated with a higher likelihood of initiation or dose increase (e.g., previous HF hospitalization, higher blood pressure, lower ejection fraction) and discontinuation or dose decrease (e.g., previous HF hospitalization, impaired quality of life, more severe functional class). Medical reasons were the most common reasons for discontinuations and dose decreases of each therapy, but the relative contributions from patient preference, health team, and systems-based reasons varied by medication. CONCLUSIONS:In this contemporary U.S. registry, most eligible HFrEF patients did not receive target doses of medical therapy at any point during follow-up, and few patients had doses increased over time. Although most patients had no alterations in medical therapy, multiple clinical factors were independently associated with medication changes. Further quality improvement efforts are urgently needed to improve guideline-directed medication titration for HFrEF.
Project description:OBJECTIVES:This study sought to describe the short-term health status benefits of angiotensin-neprilysin inhibitor (ARNI) therapy in patients with heart failure and reduced ejection fraction (HFrEF). BACKGROUND:Although therapy with sacubitril/valsartan, a neprilysin inhibitor, improved patients' health status (compared with enalapril) at 8 months in the PARADIGM-HF (Prospective Comparison of ARNI with ACE inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure) study, the early impact of ARNI on patients' symptoms, functions, and quality of life is unknown. METHODS:Health status was assessed by using the 12-item Kansas City Cardiomyopathy Questionnaire (KCCQ) in 3,918 outpatients with HFrEF and left ventricular ejection fraction ?40% across 140 U.S. centers in the CHAMP-HF (Change the Management of Patients with Heart Failure) registry. ARNI therapy was initiated in 508 patients who were matched 1:2 to 1,016 patients who were not initiated on ARNI (no-ARNI), using a nonparsimonious time-dependent propensity score (6 sociodemographic factors, 23 clinical characteristics), prior KCCQ overall summary (KCCQ-OS) score, and angiotensin-converting enzyme inhibitor/angiotensin receptor blocker status. RESULTS:Multivariate linear regression demonstrated a greater mean improvement in KCCQ-OS in patients initiated on ARNI therapy (5.3 ± 19 vs. 2.5 ± 17.4, respectively; p < 0.001) over a median (interquartile range [IQR]) of 57 (32 to 104) days. The proportions of ARNI versus no-ARNI groups with ?10-point (large) and ?20-point (very large) improvements in KCCQ-OS were 32.7% versus 26.9%, respectively, and 20.5% versus 12.1%, respectively, consistent with numbers needed to treat of 18 and 12, respectively. CONCLUSIONS:In routine clinical care, ARNI therapy was associated with early improvements in health status, with 20% experiencing a very large health status benefit compared with 12% who were not started on ARNI therapy. These findings support the use of ARNI to improve patients' symptoms, functions, and quality of life.
Project description:Background The angiotensin-receptor neprilysin inhibitor (ARNI) sacubitril/valsartan was shown to be superior to the angiotensin-converting enzyme inhibitor enalapril in terms of reducing cardiovascular mortality in the PARADIGM-HF (Prospective Comparison of ARNI with angiotensin-converting enzyme inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure) study. However, the impact of ARNI on cardiac reverse remodeling (CRR) has not been established. Methods and Results We conducted a meta-analysis to compare the effects of ARNI versus angiotensin-converting enzyme inhibitors or angiotensin receptor blockers on CRR indices. We searched databases for studies published between 2010 and 2019 that reported CRR indices following ARNI administration. Effect size was expressed as mean difference (MD) with 95% CIs. Twenty studies enrolling 10 175 patients were included. ARNI improved functional capacity in patients with heart failure (HF) and a reduced ejection fraction (EF), including increasing New York Heart Association functional class (MD -0.79, 95% CI -0.86, -0.71) and 6-minute walking distance (MD 27.62 m, 95% CI 15.76, 39.48). ARNI outperformed angiotensin-converting enzyme inhibitors/angiotensin receptor blockers in terms of CRR indices, with striking changes in left ventricular EF, diameter, and volume. However, there were no significant improvements in indices except left ventricular mass index (MD -3.25 g/m2, 95% CI -3.78, -2.72) and left atrial volume (MD -7.20 mL, 95% CI -14.11, -0.29) in HF patients with preserved EF treated with ARNI. Improvements in CRR indices were observed at 3 months and became more significant with longer follow-up to 12 months. The regression equation for the relationship between left ventricular EF and end-diastolic dimension was y=0.041+0.071x+0.045x2+0.006x3. Conclusions ARNI distinctly improved left ventricular size and hypertrophy compared with angiotensin-converting enzyme inhibitors/angiotensin receptor blockers in HF with reduced EF patients, even after short-term follow-up. Patients appeared to benefit more in terms of CRR treated with ARNI as early as possible and for at least 3 months. Further large sample trials are required to determine the effects of ARNI on CRR in HF with preserved EF patients.
Project description:Although the focus of therapeutic intervention has been on neurohormonal pathways thought to be harmful in heart failure (HF), such as the renin-angiotensin-aldosterone system (RAAS), potentially beneficial counter-regulatory systems are also active in HF. These promote vasodilatation and natriuresis, inhibit abnormal growth, suppress the RAAS and sympathetic nervous system, and augment parasympathetic activity. The best understood of these mediators are the natriuretic peptides which are metabolized by the enzyme neprilysin. LCZ696 belongs to a new class of drugs, the angiotensin receptor neprilysin inhibitors (ARNIs), which both block the RAAS and augment natriuretic peptides.Patients with chronic HF, NYHA class II-IV symptoms, an elevated plasma BNP or NT-proBNP level, and an LVEF of ?40% were enrolled in the Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortailty and morbidity in Heart Failure trial (PARADIGM-HF). Patients entered a single-blind enalapril run-in period (titrated to 10 mg b.i.d.), followed by an LCZ696 run-in period (100 mg titrated to 200 mg b.i.d.). A total of 8436 patients tolerating both periods were randomized 1:1 to either enalapril 10 mg b.i.d. or LCZ696 200 mg b.i.d. The primary outcome is the composite of cardiovascular death or HF hospitalization, although the trial is powered to detect a 15% relative risk reduction in cardiovascular death.PARADIGM-HF will determine the place of the ARNI LCZ696 as an alternative to enalapril in patients with systolic HF. PARADIGM-HF may change our approach to neurohormonal modulation in HF.NCT01035255.
Project description:AIMS:Although the effect of the angiotensin receptor blocker neprilysin inhibitor (ARNI) sacubitril/valsartan on heart failure (HF) hospitalizations and cardiovascular death has been evaluated, its effects on functional capacity in patients with HF and ejection fraction (EF) >40% has yet to be determined. In addition, no prior studies have compared sacubitril/valsartan with angiotensin-converting enzyme inhibitor therapy. We sought to compare the effect of ARNI to background-medication-based individualized comparators (BMICs) on N-terminal pro-B-type natriuretic peptide (NT-proBNP), functional capacity [6 min walk distance (6MWD)], symptoms, and quality of life [Kansas City Cardiomyopathy Questionnaire (KCCQ)] in patients with HF and EF >40% in a randomized clinical trial. METHODS:PARALLAX is a prospective, randomized, controlled, double-blind multicentre clinical trial in patients with chronic symptomatic HF with EF >40%, New York Heart Association (NYHA) class II-IV symptoms, elevated natriuretic peptides, and evidence of structural heart disease. Eligible patients are randomized to sacubitril/valsartan vs. BMIC for cardiovascular and related co-morbidities. BMIC includes (i) enalapril, (ii) valsartan, and (iii) placebo depending on the type of medical therapy prior to enrolment. The primary endpoints are the change in plasma NT-proBNP concentration from baseline to 12 weeks and the change from baseline in 6MWD distance at 24 weeks. The secondary endpoints assess quality of life and symptom burden. CONCLUSIONS:PARALLAX will determine if sacubitril/valsartan compared with standard medical therapy for co-morbidities improves NT-proBNP levels, exercise capacity, quality of life, and symptom burden in HF patients with EF >40%.