Cardiovascular and Renal Outcomes of Mineralocorticoid Receptor Antagonist Use in PARAGON-HF.

This study sought to evaluate the efficacy and safety of sacubitril/valsartan in patients with heart failure with preserved ejection fraction (HFpEF) according to background mineralocorticoid receptor antagonist (MRA) therapy. Current guidelines recommend consideration of MRAs in selected patients with HFpEF. This study assessed cardiovascular outcomes, renal outcomes, and safety of sacubitril/valsartan compared with valsartan in patients with HFpEF according to background MRA treatment. PARAGON-HF (Prospective Comparison of ARNI [angiotensin receptor-neprilysin inhibitor] with ARB [angiotensin-receptor blockers] Global Outcomes in HF with Preserved Ejection Fraction) randomized 4,796 patients with HFpEF to sacubitril/valsartan or valsartan. In a pre-specified subgroup analysis, the effect of sacubitril/valsartan versus valsartan was evaluated according to baseline MRA use on the primary study composite of total heart failure hospitalizations and cardiovascular death using semiparametric proportional rates methods, as well as the renal composite of ≥50% decrease in estimated glomerular filtration rate, development of end-stage renal disease, or death from renal causes using Cox proportional hazards regression models. Annual decline in estimated glomerular filtration rate was analyzed with repeated-measures mixed-effect models. Key safety outcomes included incidence of hypotension, hyperkalemia, and elevations in serum creatinine above predefined thresholds. Patients treated with MRAs at baseline (n = 1,239, 26%), compared with MRA nonusers (n = 3,557, 74%), were younger (72 vs. 73 years), more often male (52% vs. 47%), had lower left ventricular ejection fraction (57% vs. 58%), and a higher proportion of prior HF hospitalization (59% vs. 44%) (all p < 0.001). Efficacy of sacubitril/valsartan compared with valsartan with regard to the primary cardiovascular (for MRA users: rate ratio: 0.73; 95% confidence interval [CI]: 0.56 to 0.95; vs. for MRA nonusers: rate ratio: 0.94; 95% CI: 0.79 to 1.11; pinteraction = 0.11) and renal endpoints (for MRA users: hazard ratio: 0.31; 95% CI: 0.13 to 0.76; vs. for MRA non-users: HR: 0.59; 95% CI: 0.36 to 0.95; pinteraction = 0.21) did not significantly vary by baseline MRA use. The incidence of key safety outcomes including hypotension and severe hyperkalemia (K > 6.0 mmol/l) did not vary by baseline MRA use. However, annual decline in estimated glomerular filtration rate was less with the combination of MRA and sacubitril/valsartan (for MRA users: absolute difference favoring sacubitril/valsartan: +1.2 ml/min/1.73 m2 per year; 95% CI: 0.6 to 1.7; vs. for MRA nonusers: +0.4; 95% CI: 0.1 to 0.7; pinteraction = 0.01). Clinical efficacy of sacubitril/valsartan compared with valsartan with regard to predefined cardiorenal composite outcomes in PARAGON-HF was consistent in patients treated and not treated with MRA at baseline. Addition of sacubitril/valsartan rather than valsartan alone to MRA appears to be associated with a lesser decline in renal function and no increase in severe hyperkalemia. These data support possible added value of combination treatment with sacubitril/valsartan and MRA in patients with HFpEF. (Prospective Comparison of ARNI [angiotensin receptor -neprilysin inhibitor] with ARB [angiotensin-receptor blockers] Global Outcomes in HF with Preserved Ejection Fraction [PARAGON-HF]; NCT01920711).

Jering KS ，Zannad F ，Claggett B ，Mc Causland FR ，Ferreira JP ，Desai A ，Barkoudah E ，McMurray JJV ，Pfeffer MA ，Solomon SD ... -  《-》

Reduced Risk of Hyperkalemia During Treatment of Heart Failure With Mineralocorticoid Receptor Antagonists by Use of Sacubitril/Valsartan Compared With Enalapril: A Secondary Analysis of the PARADIGM-HF Trial.

Desai AS ，Vardeny O ，Claggett B ，McMurray JJ ，Packer M ，Swedberg K ，Rouleau JL ，Zile MR ，Lefkowitz M ，Shi V ，Solomon SD ... -  《-》

Sacubitril/valsartan in heart failure with mildly reduced or preserved ejection fraction: a pre-specified participant-level pooled analysis of PARAGLIDE-HF and PARAGON-HF.

The PARAGLIDE-HF trial demonstrated reductions in natriuretic peptides with sacubitril/valsartan compared with valsartan in patients with heart failure (HF) with mildly reduced or preserved ejection fraction who had a recent worsening HF event, but was not adequately powered to examine clinical outcomes. PARAGON-HF included a subset of PARAGLIDE-HF-like patients who were recently hospitalized for HF. Participant-level data from PARAGLIDE-HF and PARAGON-HF were pooled to better estimate the efficacy and safety of sacubitril/valsartan in reducing cardiovascular and renal events in HF with mildly reduced or preserved ejection fraction. Both PARAGLIDE-HF and PARAGON-HF were multicentre, double-blind, randomized, active-controlled trials of sacubitril/valsartan vs. valsartan in patients with HF with mildly reduced or preserved left ventricular ejection fraction (LVEF >40% in PARAGLIDE-HF and ≥45% in PARAGON-HF). In the pre-specified primary analysis, we pooled participants in PARAGLIDE-HF (all of whom were enrolled during or within 30 days of a worsening HF event) with a 'PARAGLIDE-like' subset of PARAGON-HF (those hospitalized for HF within 30 days). We also pooled the entire PARAGLIDE-HF and PARAGON-HF populations for a broader context. The primary endpoint for this analysis was the composite of total worsening HF events (including first and recurrent HF hospitalizations and urgent visits) and cardiovascular death. The secondary endpoint was the pre-specified renal composite endpoint for both studies (≥50% decline in estimated glomerular filtration rate from baseline, end-stage renal disease, or renal death). Compared with valsartan, sacubitril/valsartan significantly reduced total worsening HF events and cardiovascular death in both the primary pooled analysis of participants with recent worsening HF [n = 1088; rate ratio (RR) 0.78; 95% confidence interval (CI) 0.61-0.99; P = 0.042] and in the pooled analysis of all participants (n = 5262; RR 0.86; 95% CI: 0.75-0.98; P = 0.027). In the pooled analysis of all participants, first nominal statistical significance was reached by Day 9 after randomization, and treatment benefits were larger in those with LVEF ≤60% (RR 0.78; 95% CI 0.66-0.91) compared with those with LVEF >60% (RR 1.09; 95% CI 0.86-1.40; Pinteraction = 0.021). Sacubitril/valsartan was also associated with lower rates of the renal composite endpoint in the primary pooled analysis [hazard ratio (HR) 0.67; 95% CI 0.43-1.05; P = 0.080] and the pooled analysis of all participants (HR 0.60; 95% CI 0.44-0.83; P = 0.002). In pooled analyses of PARAGLIDE-HF and PARAGON-HF, sacubitril/valsartan reduced cardiovascular and renal events among patients with HF with mildly reduced or preserved ejection fraction. These data provide support for use of sacubitril/valsartan in patients with HF with mildly reduced or preserved ejection fraction, particularly among those with an LVEF below normal, regardless of care setting.

Vaduganathan M ，Mentz RJ ，Claggett BL ，Miao ZM ，Kulac IJ ，Ward JH ，Hernandez AF ，Morrow DA ，Starling RC ，Velazquez EJ ，Williamson KM ，Desai AS ，Zieroth S ，Lefkowitz M ，McMurray JJV ，Braunwald E ，Solomon SD ... -  《-》

Angiotensin Receptor Neprilysin Inhibition in Heart Failure With Preserved Ejection Fraction: Rationale and Design of the PARAGON-HF Trial.

The PARAGON-HF (Prospective Comparison of ARNI with ARB Global Outcomes in HF With Preserved Ejection Fraction) trial is designed to determine the efficacy and safety of the angiotensin receptor neprilysin inhibitor sacubitril/valsartan compared with valsartan in patients with chronic heart failure and preserved ejection fraction (HFpEF). HFpEF is highly prevalent, associated with substantial morbidity and mortality, and in need of effective therapies that improve outcomes. The angiotensin receptor neprilysin inhibitor (ARNI) sacubitril/valsartan, which has been shown to benefit patients with heart failure (HF) and reduced ejection fraction, demonstrated favorable physiologic effects in a phase II HFpEF trial. The PARAGON-HF trial is a randomized, double-blind, parallel group, active-controlled, event-driven trial comparing the long-term efficacy and safety of valsartan and sacubitril/valsartan in patients with chronic HFpEF (left ventricular ejection fraction ≥45%), New York Heart Association functional class II to IV symptoms, elevated natriuretic peptides, and evidence of structural heart disease. Before randomization, all patients entered sequential single-blind run-in periods to ensure tolerability of both drugs at half the target doses (i.e., valsartan titrated to 80 mg bid followed by sacubitril/valsartan 49/51 mg [100 mg] bid). The primary outcome is the composite of cardiovascular death and total (first and recurrent) HF hospitalizations. PARAGON-HF will determine whether sacubitril/valsartan is superior to angiotensin receptor blockade alone in patients with chronic symptomatic HFpEF. (Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction [PARAGON-HF]; NCT01920711).

Solomon SD ，Rizkala AR ，Gong J ，Wang W ，Anand IS ，Ge J ，Lam CSP ，Maggioni AP ，Martinez F ，Packer M ，Pfeffer MA ，Pieske B ，Redfield MM ，Rouleau JL ，Van Veldhuisen DJ ，Zannad F ，Zile MR ，Desai AS ，Shi VC ，Lefkowitz MP ，McMurray JJV ... -  《-》

Prior Heart Failure Hospitalization, Clinical Outcomes, and Response to Sacubitril/Valsartan Compared With Valsartan in HFpEF.

The period shortly after hospitalization for heart failure (HF) represents a high-risk window for recurrent clinical events, including rehospitalization or death. This study sought to determine whether the efficacy and safety of sacubitril/valsartan varies in relation to the proximity to hospitalization for HF among patients with HF with preserved ejection fraction (HFpEF). In this post hoc analysis of PARAGON-HF (Prospective Comparison of ARNI [Angiotensin Receptor-Neprilysin Inhibitor] with ARB [Angiotensin Receptor Blocker] Global Outcomes in HFpEF), we assessed the risk of clinical events and response to sacubitril/valsartan in relation to time from last HF hospitalization among patients with HFpEF (≥45%). The primary outcome was composite total HF hospitalizations and cardiovascular death, analyzed by using a semiparametric proportional rates method, stratified by geographic region. Of 4,796 validly randomized patients in PARAGON-HF, 622 (13%) were screened during hospitalization or within 30 days of prior hospitalization, 555 (12%) within 31 to 90 days, 435 (9%) within 91 to 180 days, and 694 (14%) after 180 days; 2,490 (52%) were never previously hospitalized. Over a median follow-up of 35 months, risk of total HF hospitalizations and cardiovascular death was inversely and nonlinearly associated with timing from prior HF hospitalization (p < 0.001). There was a gradient in relative risk reduction in primary events with sacubitril/valsartan from patients hospitalized within 30 days (rate ratio: 0.73; 95% confidence interval: 0.53 to 0.99) to patients never hospitalized (rate ratio: 1.00; 95% confidence interval: 0.80 to 1.24; trend in relative risk reduction: pinteraction = 0.15). With valsartan alone, the rate of total primary events was 26.7 (≤30 days), 24.2 (31 to 90 days), 20.7 (91 to 180 days), 15.7 (>180 days), and 7.9 (not previously hospitalized) per 100 patient-years. Compared with valsartan, absolute risk reductions with sacubitril/valsartan were more prominent in patients enrolled early after hospitalization: 6.4% (≤30 days), 4.6% (31 to 90 days), and 3.4% (91 to 180 days), whereas no risk reduction was observed in patients screened >180 days or who were never hospitalized (trend in absolute risk reduction: pinteraction = 0.050). Recent hospitalization for HFpEF identifies patients at high risk for near-term clinical progression. In the PARAGON-HF trial, the relative and absolute benefits of sacubitril/valsartan compared with valsartan in HFpEF appear to be amplified when initiated in the high-risk window after hospitalization and warrant prospective validation. (PARAGON-HF; NCT01920711).

Vaduganathan M ，Claggett BL ，Desai AS ，Anker SD ，Perrone SV ，Janssens S ，Milicic D ，Arango JL ，Packer M ，Shi VC ，Lefkowitz MP ，McMurray JJV ，Solomon SD ... -  《-》