Cost-effectiveness analysis of sacubitril/valsartan vs enalapril in patients with heart failure and reduced ejection fraction

Importance  The angiotensin receptor neprilysin inhibitor sacubitril/valsartan was associated with a reduction in cardiovascular mortality, all-cause mortality, and hospitalizations compared with enalapril. Sacubitril/valsartan has been approved for use in heart failure (HF) with reduced ejection fraction in the United States and cost has been suggested as 1 factor that will influence the use of this agent. Objective  To estimate the cost-effectiveness of sacubitril/valsartan vs enalapril in the United States. Design, Setting, and Participants  Data from US adults (mean [SD] age, 63.8 [11.5] years) with HF with reduced ejection fraction and characteristics similar to those in the PARADIGM-HF trial were used as inputs for a 2-state Markov model simulated HF. Risks of all-cause mortality and hospitalization from HF or other reasons were estimated with a 30-year time horizon. Quality of life was based on trial EQ-5D scores. Hospital costs combined Medicare and private insurance reimbursement rates; medication costs included the wholesale acquisition cost for sacubitril/valsartan and enalapril. A discount rate of 3% was used. Sensitivity analyses were performed on key inputs including: hospital costs, mortality benefit, hazard ratio for hospitalization reduction, drug costs, and quality-of-life estimates. Main Outcomes and Measures  Hospitalizations, quality-adjusted life-years (QALYs), costs, and incremental costs per QALY gained. Results  The 2-state Markov model of US adult patients (mean age, 63.8 years) calculated that there would be 220 fewer hospital admissions per 1000 patients with HF treated with sacubitril/valsartan vs enalapril over 30 years. The incremental costs and QALYs gained with sacubitril/valsartan treatment were estimated at $35 512 and 0.78, respectively, compared with enalapril, equating to an incremental cost-effectiveness ratio (ICER) of$45 017 per QALY for the base-case. Sensitivity analyses demonstrated ICERs ranging from $35 357 to$75 301 per QALY. Conclusions and Relevance  For eligible patients with HF with reduced ejection fraction, the Markov model calculated that sacubitril/valsartan would increase life expectancy at an ICER consistent with other high-value accepted cardiovascular interventions. Sensitivity analyses demonstrated sacubitril/valsartan would remain cost-effective vs enalapril

Aeroservoelastic Wind-Tunnel Test of the SUGAR Truss Braced Wing Wind-Tunnel Model

The Subsonic Ultra Green Aircraft Research (SUGAR) Truss-Braced Wing (TBW) aeroservoelastic (ASE) wind-tunnel test was conducted in the NASA Langley Transonic Dynamics Tunnel (TDT) and was completed in April, 2014. The primary goals of the test were to identify the open-loop flutter boundary and then demonstrate flutter suppression. A secondary goal was to demonstrate gust load alleviation (GLA). Open-loop flutter and limit cycle oscillation onset boundaries were identified for a range of Mach numbers and various angles of attack. Two sets of control laws were designed for the model and both sets of control laws were successful in suppressing flutter. Control laws optimized for GLA were not designed; however, the flutter suppression control laws were assessed using the TDT Airstream Oscillation System. This paper describes the experimental apparatus, procedures, and results of the TBW wind-tunnel test. Acquired system ID data used to generate ASE models is also discussed.2 study

Widening racial differences in risks for coronary heart disease

The incidence of coronary heart disease (CHD) has been declining in the United States, but these improvements appear to be lagging in blacks compared to whites. To understand racebased patterns in contributions to risk over time, we investigated temporal trends in the prevalence of major risk factors and their attributable hazards for CHD in a large sample of black and white adults living in 4 different communities and followed over the last two decades

Racial disparities in risks of stroke

To the Editor: The incidence of stroke in the United States has been decreasing as efforts have been made to control vascular risk factors. However, the extent to which modifications in changes in the risk of stroke have occurred in blacks as compared with whites has not been widely studied

Declining Lung Function and Cardiovascular Risk: The ARIC Study

Background: Pulmonary dysfunction predicts incident cardiovascular disease (CVD). Objectives: The purpose of this study was to evaluate whether longitudinal decline in lung function is associated with incident heart failure (HF), coronary heart disease (CHD), and stroke. Methods: Among 10,351 participants in the ARIC (Atherosclerosis Risk In Communities) study free of CVD, rapid lung function decline was defined as the greatest quartile (n = 2,585) of decline in either forced expiratory volume in 1 s (FEV1) (>1.9% decline/year) or forced vital capacity (FVC) (>2.1% decline/year) over 2.9 ± 0.2 years. The relationship between rapid decline in FEV1 or FVC and subsequent incident HF, CHD, stroke, or a composite of these was assessed using multivariable Cox regression adjusting for the baseline spirometry value, demographics, height, body mass index, heart rate, diabetes, hypertension, low-density lipoprotein, use of lipid-lowering medication, N-terminal fragment of prohormone for B-type natriuretic peptide, and smoking. Results: The mean age was 54 ± 6 years, 56% were women, and 81% were white. At 17 ± 6 years of follow-up, HF occurred in 14%, CHD 11%, stroke 6%, and the composite in 24%. Rapid decline in FEV1 and in FVC were both associated with a heightened risk of incident HF (hazard ratio [HR]: 1.17; 95% confidence interval [CI]: 1.04 to 1.33; p = 0.010; and HR: 1.27; 95% CI: 1.12 to 1.44; p < 0.001; respectively), with rapid decline in FEV1 most prognostic in the first year of follow-up (HR: 4.22; 95% CI: 1.34 to 13.26; p = 0.01). Rapid decline in FEV1 was also associated with incident stroke (HR: 1.25; 95% CI: 1.04 to 1.50; p = 0.015). Conclusions: A rapid decline in lung function, assessed by serial spirometry, is associated with a higher incidence of subsequent CVD, particularly incident HF

B-Type Natriuretic Peptide and Cardiac Troponin I Are Associated With Adverse Outcomes in Stable Kidney Transplant Recipients

Approximately 200,000 kidney transplant recipients are living in the US; they are at increased risk for cardiovascular and other adverse outcomes. Biomarkers predicting these outcomes are needed. Using specimens collected during the FAVORIT (Folic Acid for Vascular Outcome Reduction In Transplantation) trial, we determined whether plasma levels of B-type natriuretic peptide (BNP) and cardiac troponin I are associated with adverse outcomes in stable kidney transplant recipients

Estimating lifetime benefits of comprehensive disease-modifying pharmacological therapies in patients with heart failure with reduced ejection fraction: a comparative analysis of three randomised controlled trials

Background: Three drug classes (mineralocorticoid receptor antagonists [MRAs], angiotensin receptor–neprilysin inhibitors [ARNIs], and sodium/glucose cotransporter 2 [SGLT2] inhibitors) reduce mortality in patients with heart failure with reduced ejection fraction (HFrEF) beyond conventional therapy consisting of angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) and β blockers. Each class was previously studied with different background therapies and the expected treatment benefits with their combined use are not known. Here, we used data from three previously reported randomised controlled trials to estimate lifetime gains in event-free survival and overall survival with comprehensive therapy versus conventional therapy in patients with chronic HFrEF. Methods: In this cross-trial analysis, we estimated treatment effects of comprehensive disease-modifying pharmacological therapy (ARNI, β blocker, MRA, and SGLT2 inhibitor) versus conventional therapy (ACE inhibitor or ARB and β blocker) in patients with chronic HFrEF by making indirect comparisons of three pivotal trials, EMPHASIS-HF (n=2737), PARADIGM-HF (n=8399), and DAPA-HF (n=4744). Our primary endpoint was a composite of cardiovascular death or first hospital admission for heart failure; we also assessed these endpoints individually and assessed all-cause mortality. Assuming these relative treatment effects are consistent over time, we then projected incremental long-term gains in event-free survival and overall survival with comprehensive disease-modifying therapy in the control group of the EMPHASIS-HF trial (ACE inhibitor or ARB and β blocker). Findings: The hazard ratio (HR) for the imputed aggregate treatment effects of comprehensive disease-modifying therapy versus conventional therapy on the primary endpoint of cardiovascular death or hospital admission for heart failure was 0·38 (95% CI 0·30–0·47). HRs were also favourable for cardiovascular death alone (HR 0·50 [95% CI 0·37–0·67]), hospital admission for heart failure alone (0·32 [0·24–0·43]), and all-cause mortality (0·53 [0·40–0·70]). Treatment with comprehensive disease-modifying pharmacological therapy was estimated to afford 2·7 additional years (for an 80-year-old) to 8·3 additional years (for a 55-year-old) free from cardiovascular death or first hospital admission for heart failure and 1·4 additional years (for an 80-year-old) to 6·3 additional years (for a 55-year-old) of survival compared with conventional therapy. Interpretation: Among patients with HFrEF, the anticipated aggregate treatment effects of early comprehensive disease-modifying pharmacological therapy are substantial and support the combination use of an ARNI, β blocker, MRA, and SGLT2 inhibitor as a new therapeutic standard

Cardio-Renal-Metabolic Overlap, Outcomes, and Dapagliflozin in Heart Failure With Mildly Reduced or Preserved Ejection Fraction

Background: Cardio-renal-metabolic (CRM) conditions are individually common among patients with heart failure (HF), but the prevalence and influence of overlapping CRM conditions in this population have not been well-studied. Objectives: This study aims to evaluate the impact of overlapping CRM conditions on clinical outcomes and treatment effects of dapagliflozin in HF. Methods: In this post hoc analysis of DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure), we evaluated the prevalence of comorbid CRM conditions (atherosclerotic cardiovascular disease, chronic kidney disease, and type 2 diabetes), their impact on the primary outcome (cardiovascular death or worsening HF), and treatment effects of dapagliflozin by CRM status. Results: Among 6,263 participants, 1,952 (31%), 2,245 (36%), and 1,236 (20%) had 1, 2, and 3 additional CRM conditions, respectively. HF alone was uncommon (13%). Greater CRM multimorbidity was associated with older age, higher body mass index, longer-duration HF, worse health status, and lower left ventricular ejection fraction. Risk of the primary outcome increased with higher CRM overlap, with 3 CRM conditions independently associated with highest risk of primary events (adjusted HR: 2.16 [95% CI: 1.72-2.72]; P &lt; 0.001) compared with HF alone. Relative benefits of dapagliflozin on the primary outcome were consistent irrespective of the type of CRM overlap (Pinteraction = 0.773) and by the number of CRM conditions (Pinteraction = 0.734), with greatest absolute benefits among those with highest CRM multimorbidity. Estimated 2-year numbers needed to treat with dapagliflozin to prevent 1 primary event were approximately 52, 39, 33, and 24 for participants with 0, 1, 2, and 3 additional CRM conditions at baseline, respectively. Adverse events between treatment arms were similar across the CRM spectrum. Conclusions: CRM multimorbidity was common and associated with adverse outcomes among patients with HF and left ventricular ejection fraction &gt;40% in DELIVER. Dapagliflozin was safe and effective across the CRM spectrum, with greater absolute benefits among those with highest CRM overlap (Dapagliflozin Evaluation to Improve the LIVEs of Patients With Preserved Ejection Fraction Heart Failure [DELIVER]; NCT03619213).</p

Relationship Between Alcohol Consumption and Cardiac Structure and Function in the Elderly: The Atherosclerosis Risk in Communities Study

BACKGROUND: Excessive alcohol consumption is associated with cardiomyopathy, but the influence of moderate alcohol use on cardiac structure and function is largely unknown. METHODS AND RESULTS: We studied 4466 participants from visit 5 of the Atherosclerosis Risk in Communities (ARIC) study (76±5 years and 60% women) who underwent transthoracic echocardiography, excluding former drinkers and those with significant valvular disease. Participants were classified into 4 categories based on self-reported alcohol intake: nondrinkers, drinkers of ≤7, ≥7 to 14, and ≥14 drinks per week. We related alcohol intake to measures of cardiac structure and function, stratified by sex, and fully adjusted for covariates. In both genders, increasing alcohol intake was associated with larger left ventricular diastolic and systolic diameters and larger left atrial diameter (P<0.05). In men, increasing alcohol intake was associated with greater left ventricular mass (8.2±3.8 g per consumption category; P=0.029) and higher E/E' ratio (0.82±0.33 per consumption category; P=0.014). In women, increasing alcohol intake was associated with lower left ventricular ejection fraction (-1.9±0.6% per consumption category; P=0.002) and a tendency for worse left ventricular global longitudinal strain (0.45±0.25% per consumption category; P=0.07). CONCLUSIONS: In an elderly community-based population, increasing alcohol intake is associated with subtle alterations in cardiac structure and function, with women appearing more susceptible than men to the cardiotoxic effects of alcohol

Effects of sacubitril/valsartan on N-terminal pro-B-type natriuretic peptide in heart failure with preserved ejection fraction

Objectives: The authors sought to evaluate the prognostic significance of baseline N-terminal pro–B-type natriuretic peptide (NT-proBNP), whether NT-proBNP modified the treatment response to sacubitril/valsartan, and the treatment effect of sacubitril/valsartan on NT-proBNP overall and in key subgroups. Background: Sacubitril/valsartan reduces NT-proBNP in heart failure (HF) with both reduced and preserved ejection fraction (EF), but did not significantly reduce total HF hospitalizations and cardiovascular death compared with valsartan in patients with HF with preserved EF (HFpEF). Methods: In the PARAGON-HF (Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction) trial, 4,796 patients with HFpEF and elevated NT-proBNP were randomized to sacubitril/valsartan or valsartan. NT-proBNP was measured at screening in all patients and at 5 subsequent times in &gt;2,700 patients: before, between, and after sequential valsartan and sacubitril/valsartan run-in periods, and 16 and 48 weeks post-randomization. Results: Median NT-proBNP was 911 pg/ml (interquartile range: 464 to 1,613 pg/ml) at screening. Screening NT-proBNP was strongly associated with the primary endpoint, total HF hospitalizations and cardiovascular death (rate ratio [RR]: 1.68 per log increase in NT-proBNP, 95% confidence interval [CI]: 1.53 to 1.85; p &lt; 0.001). This relationship was stronger in patients with atrial fibrillation (adjusted RR: 2.33 [95% CI: 1.89 to 2.87] vs. 1.58 [95% CI: 1.42 to 1.75] in patients without atrial fibrillation; p interaction &lt;0.001) and weaker in obese patients (adjusted RR: 1.50 [95% CI: 1.31 to 1.71] vs. 1.92 [95% CI: 1.70 to 2.17] in nonobese patients; p interaction &lt;0.001). Screening NT-proBNP did not modify the treatment effect of sacubitril/valsartan compared with valsartan (p interaction = 0.96). Sacubitril/valsartan reduced NT-proBNP by 19% (95% CI: 14% to 23%; p &lt; 0.001) compared with valsartan 16 weeks post-randomization, with similar reductions in men (20%) and women (18%), and in patients with left ventricular EF ≤57% (20%) and &gt;57% (18%). Decreases in NT-proBNP predicted lower subsequent risk of the primary endpoint. Conclusions: Baseline NT-proBNP predicted HF events but did not modify the sacubitril/valsartan treatment effect in patients with HFpEF. Sacubitril/valsartan reduced NT-proBNP consistently in men and women, and in patients with lower or higher EF. (Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction [PARAGON-HF]; NCT01920711