Insights into implementation of sacubitril/valsartan into clinical practice.

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.

Martens P ，Beliën H ，Dupont M ，Mullens W ... -  《ESC Heart Failure》

Comparative Effectiveness of Sacubitril-Valsartan Versus ACE/ARB Therapy in Heart Failure With Reduced Ejection Fraction.

This paper aims to compare the effectiveness of sacubitril-valsartan and angiotensin-converting enzyme inhibitor (ACE)/angiotensin receptor blocker (ARB) in systolic heart failure (HF). Sacubitril-valsartan reduced risks of death and hospitalization for HF versus enalapril in ambulatory patients with HF and reduced ejection fraction in the PARADIGM-HF (Prospective Comparison of Angiotensin II Receptor Blocker Neprilysin Inhibitor with Angiotensin Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in HF) trial. However, the comparative effectiveness of sacubitril-valsartan and ACE/ARB in patients treated in routine clinical practice is unclear. We identified patients with systolic HF in a U.S. administrative claims database treated with sacubitril-valsartan or ACE/ARB from July 1, 2015, to February 2, 2018. One-to-one propensity score matching was used to balance patients on 29 clinical variables. Cox models were used to compare outcomes between treatment groups. A total of 7,893 matched pairs were included; mean (SD) follow-up was 6.3 (5.4) months. Sacubitril-valsartan was associated with lower risks of all-cause mortality or all-cause hospitalization (hazard ratio [HR]: 0.86, 95% confidence interval (CI): 0.81 to 0.91; p < 0.001), all-cause mortality (HR: 0.80, 95% CI: 0.66 to 0.97; p = 0.027), and all-cause hospitalization (HR: 0.86, 95% CI: 0.80 to 0.91; p < 0.001), but not HF hospitalization (HR: 1.07, 95% CI: 0.96 to 1.19; p = 0.26). A lower risk of the primary outcome with sacubitril-valsartan was observed in white patients (HR: 0.83, 95% CI: 0.76 to 0.90) but not black patients (21% of population, HR: 1.00, 95% CI: 0.88 to 1.15; interaction p = 0.032). No statistically significant differences in treatment response by sex or age were observed. Sacubitril-valsartan was associated with lower risks of death and hospitalization compared with ACE/ARB in a heterogeneous cohort of patients with systolic HF. However, our finding that outcomes with sacubitril-valsartan and ACE/ARBs were similar in black patients warrants further evaluation.

Tan NY ，Sangaralingham LR ，Sangaralingham SJ ，Yao X ，Shah ND ，Dunlay SM ... -  《-》

Systolic blood pressure, cardiovascular outcomes and efficacy and safety of sacubitril/valsartan (LCZ696) in patients with chronic heart failure and reduced ejection fraction: results from PARADIGM-HF.

Compared to heart failure patients with higher systolic blood pressure (SBP), those with lower SBP have a worse prognosis. To make matters worse, the latter patients often do not receive treatment with life-saving therapies that might lower blood pressure further. We examined the association between SBP and outcomes in the Prospective Comparison of angiotensin receptor-neprilysin inhibitor (ARNI) with an angiotensin-converting enzyme (ACE) inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure trial (PARADIGM-HF), as well as the effect of sacubitril/valsartan, compared with enalapril, according to baseline SBP. We analysed the effect of treatment on SBP and on the primary composite outcome (cardiovascular death or heart failure hospitalization), its components and all-cause death. We examined baseline SBP as a categorical (<110, 110 to < 120, 120 to < 130, 130 to < 140 and ≥140 mmHg) and continuous variable, as well as average in-trial SBP and time-updated SBP. All-cause and cardiovascular mortality rates were highest in patients with the lowest SBP whereas there was a U-shaped relationship between SBP and the rate of heart failure hospitalization. The benefit of sacubitril/valsartan over enalapril was consistent across all baseline SBP categories for all outcomes. For example, the sacubitril/valsartan versus enalapril hazard ratio for the primary endpoint was 0.88 (95%CI 0.74-1.06) in patients with a baseline SBP <110 mmHg and 0.81 (0.65-1.02) for those with a SBP ≥140 mmHg (P for interaction = 0.55). Symptomatic hypotension, study drug dose-reduction and discontinuation were more frequent in patients with a lower SBP. In PARADIGM-HF, patients with lower SBP at randomization, notably after tolerating full doses of both study drugs during a run-in period, were at higher risk but generally tolerated sacubitril/valsartan and had the same relative benefit over enalapril as patients with higher baseline SBP.

Böhm M ，Young R ，Jhund PS ，Solomon SD ，Gong J ，Lefkowitz MP ，Rizkala AR ，Rouleau JL ，Shi VC ，Swedberg K ，Zile MR ，Packer M ，McMurray JJV ... -  《-》

Influence of Ejection Fraction on Outcomes and Efficacy of Sacubitril/Valsartan (LCZ696) in Heart Failure with Reduced Ejection Fraction: The Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure (

The angiotensin receptor neprilysin inhibitor sacubitril/valsartan (LCZ696) reduced cardiovascular morbidity and mortality compared with enalapril in patients with heart failure (HF) and reduced ejection fraction (EF) in the Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial. We evaluated the influence of EF on clinical outcomes and on the effectiveness of sacubitril/valsartan compared with enalapril. Eight thousand three hundred ninety-nine patients with New York Heart Association class II to IV HF with reduced EF [left ventricular EF (LVEF) ≤40%] were randomized to sacubitril/valsartan 97/103 mg twice daily versus enalapril 10 mg twice daily and followed for a median of 27 months. The primary study end point was cardiovascular death or HF hospitalization. LVEF was assessed at the sites and recorded on case report forms. We related LVEF to study outcomes and assessed the effectiveness of sacubitril/valsartan across the LVEF spectrum. The mean LVEF in PARADIGM-HF, reported by sites, was 29.5 (interquartile range, 25-34). The risk of all outcomes increased with decreasing LVEF. Each 5-point reduction in LVEF was associated with a 9% increased risk of cardiovascular death or HF hospitalization (hazard ratio, 1.09; 95% confidence interval, 1.05-1.13; P<0.001), a 9% increased risk for CV death (hazard ratio, 1.09; 95% confidence interval, 1.04-1.14), a 9% increased risk in HF hospitalization (hazard ratio, 1.09; 95% confidence interval, 1.04-1.14) and a 7% increased risk in all-cause mortality (hazard ratio, 1.07; 95% confidence interval, 1.03-1.12) in adjusted analyses. Sacubitril/valsartan was effective across the LVEF spectrum, with no evidence of heterogeneity, when modeled either in tertiles (P interaction=0.87) or continuously (P interaction=0.95). In patients with HF and reduced EF enrolled in PARADIGM-HF, LVEF was a significant and independent predictor of all outcomes. Sacubitril/valsartan was effective at reducing cardiovascular death and HF hospitalization throughout the LVEF spectrum. URL: http://www.clinicaltrials.gov. Unique identifier: NCT01035255.

Solomon SD ，Claggett B ，Desai AS ，Packer M ，Zile M ，Swedberg K ，Rouleau JL ，Shi VC ，Starling RC ，Kozan Ö ，Dukat A ，Lefkowitz MP ，McMurray JJ ... -  《-》

Impact of sacubitril/valsartan on heart failure admissions: insights from real-world patient prescriptions.

Martens P ，Lambeets S ，Lau CW ，Dupont M ，Mullens W ... -  《-》