Angiotensin Receptor Neprilysin Inhibition and Cardiovascular Outcomes Across the Kidney Function Spectrum: The PARAGON-HF Trial.

Lower estimated glomerular filtration rate (eGFR) may be one of the major reasons for hesitation or failure to initiate potentially beneficial therapies in patients with heart failure (HF). This study sought to assess if the effects of sacubitril/valsartan (vs valsartan) on cardiovascular outcomes differ according to baseline kidney function in patients with HF with preserved ejection fraction. The PARAGON-HF (Prospective Comparison of ARNI with ARB Global Outcomes in HF with Preserved Ejection Fraction) trial was global clinical trial of 4,796 patients with chronic HF and left ventricular ejection fraction (LVEF) ≥45% randomly assigned to sacubitril/valsartan or valsartan. We examined the effect of treatment on cardiovascular outcomes using Cox regression models, stratified by region, and assessed for differential treatment effects according to the baseline eGFR and ejection fraction. At randomization, mean eGFR was 67 ± 19 mL/min/1.73 m2; 1,955 (41%) participants had an eGFR <60 mL/min/1.73 m2. Compared with valsartan, sacubitril/valsartan reduced the primary cardiovascular outcome (cardiovascular death and total HF hospitalizations) to a greater extent among those with lower baseline eGFR (P interaction = 0.07 for continuous eGFR), and was most pronounced for those with eGFR ≤45 mL/min/1.73 m2 (RR: 0.69; 95% CI: 0.51-0.94). The influence of eGFR on the treatment effect for cardiovascular death was nonlinear, with the most pronounced treatment effect for those with baseline eGFR <45 mL/min/1.73 m2 (HR: 0.65; 95% CI: 0.43-0.97). In further subgroup analyses according to LVEF and eGFR, the treatment effect for the primary outcome was most pronounced among those with LVEF ≤57% and eGFR ≤45 mL/min/1.73 m2 (HR: 0.66; 95% CI: 0.45-0.97). In the PARAGON-HF trial, the benefits of sacubitril/valsartan to reduce the frequency of HF hospitalizations and cardiovascular death were most apparent in patients with lower baseline eGFR and lower ejection fraction. (Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction [PARAGON-HF]; NCT01920711).

Mc Causland FR ，Vaduganathan M ，Claggett B ，Gori M ，Jhund PS ，McGrath MM ，Neuen BL ，Packer M ，Pfeffer MA ，Rouleau JL ，Senni M ，Swedberg K ，Zannad F ，Zile M ，Lefkowitz MP ，McMurray JJV ，Solomon SD ... -  《-》

Effects of Sacubitril/Valsartan on All-Cause Hospitalizations in Heart Failure: Post Hoc Analysis of the PARADIGM-HF and PARAGON-HF Randomized Clinical Trials.

Lu H ，Claggett BL ，Packer M ，Lam CSP ，Swedberg K ，Rouleau J ，Zile MR ，Lefkowitz M ，Desai AS ，Jhund P ，McMurray JJV ，Solomon SD ，Vaduganathan M ... -  《-》

Effects of sacubitril/valsartan on renal function and outcome in patients with heart failure and reduced ejection fraction: an Italian cohort study.

Palazzuoli A ，Pirrotta F ，Cartocci A ，Delcuratolo E ，Dini FL ，Correale M ，Dattilo G ，Masarone D ，Scelsi L ，Ghio S ，Tocchetti CG ，Mercurio V ，Brunetti ND ，Nodari S ，Barillà F ，Ambrosio G ，Carluccio E ... -  《-》

Clinical Characteristics and Outcomes of Patients With Heart Failure With Preserved Ejection Fraction and With Reduced Ejection Fraction According to the Prognostic Nutritional Index: Findings From PARADIGM-HF and PARAGON-HF.

Solano S ，Yang M ，Tolomeo P ，Kondo T ，Shen L ，Jhund PS ，Anand IS ，Desai AS ，Lam CSP ，Maggioni AP ，Martinez FA ，Rouleau JL ，Vaduganathan M ，van Veldhuisen DJ ，Zannad F ，Zile MR ，Packer M ，Solomon SD ，McMurray JJV ... -  《Journal of the American Heart Association》

Race in Heart Failure: A Pooled Participant-Level Analysis of the Global PARADIGM-HF and PARAGON-HF Trials.

Mechanisms of disease pathobiology, prognosis, and potentially treatment responses might vary by race in patients with heart failure (HF). The authors aimed to examine the safety and efficacy of sacubitril/valsartan among patients with HF by self-reported race. PARADIGM-HF (Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) and PARAGON-HF (Prospective Comparison of ARNI with ARB Global Outcomes in HF With Preserved Ejection Fraction) were global, randomized clinical trials testing sacubitril/valsartan against a renin-angiotensin system inhibitor (RASi) (enalapril or valsartan, respectively) in patients with HF and left ventricular ejection fraction ≤40% (PARADIGM-HF) or left ventricular ejection fraction ≥45% (PARAGON-HF). Patients with self-reported race were categorized as White, Asian, or Black. We assessed the composite of first HF hospitalization or cardiovascular death, its components, and angioedema across races. Among 12,097 participants, 9,451 (78.1%) were White, 2,116 (17.5%) were Asian, and 530 (4.4%) were Black. Over a median follow-up of 2.5 years, Black (adjusted HR: 1.68; 95% CI: 1.42-1.98) and Asian patients (adjusted HR: 1.32; 95% CI: 1.18-1.47) experienced higher risks of the primary outcome compared with White patients. Treatment effects of sacubitril/valsartan vs RASi on the primary endpoint were consistent among White (HR: 0.84; 95% CI: 0.77-0.91), Asian (HR: 0.92; 95% CI: 0.78-1.10), and Black patients (HR: 0.79; 95% CI: 0.58-1.07; Pinteraction = 0.58). Rates of severe angioedema were higher with sacubitril/valsartan vs RASi (White: 0.2% vs 0.1%; Black: 1.5% vs 0.0%; Asian: 0.1% vs 0.1%). In a pooled experience of 2 global trials, Black and Asian patients exhibited a higher risk of cardiovascular events than White patients. The benefits of sacubitril/valsartan were consistent across races. Risks of severe angioedema were low but numerically higher with sacubitril/valsartan. (Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure [PARADIGM-HF]; NCT01035255; Prospective Comparison of ARNI with ARB Global Outcomes in HF With Preserved Ejection Fraction [PARAGON-HF]; NCT01920711).

Lu H ，Claggett BL ，Packer M ，Pabon MA ，Pfeffer MA ，Lewis EF ，Lam CSP ，Rouleau J ，Zile MR ，Lefkowitz M ，Desai AS ，Jhund PS ，McMurray JJV ，Solomon SD ，Vaduganathan M ... -  《-》