Early B-Type Natriuretic Peptide Change in HFrEF Patients Treated With Sacubitril/Valsartan: A Pooled Analysis of EVALUATE-HF and PROVE-HF.

This study assessed changes in B-type natriuretic peptide (BNP) among patients with heart failure with reduced ejection fraction (HFrEF) treated with sacubitril/valsartan (Sac/Val) according to standard prescribing information. Through inhibition of neprilysin, Sac/Val may increase BNP concentrations. In an individual patient analysis from the EVALUATE-HF (Study of Effects of Sacubitril/Valsartan vs. Enalapril on Aortic Stiffness in Patients With Mild to Moderate HF With Reduced Ejection Fraction) (n = 221) and the PROVE-HF (Effects of Sacubitril/Valsartan Therapy on Biomarkers, Myocardial Remodeling and Outcomes) (n = 146) studies, we examined changes in BNP, N-terminal pro-BNP (NT-proBNP), and urinary cyclic guanosine monophosphate (ucGMP) from baseline to week 4 and week 12. Median (IQRs) concentration of BNP at baseline, week 4, and week 12 were 145 [IQR: 55-329], 136 [IQR: 50-338], and 135 [IQR: 51-299] ng/L, respectively. There was no significant change from baseline to week 4 (0% [-30% to +41%]; P = 0.36) or week 12 (+1% [-36% to +50%]; P = 0.97). By week 12, one-half of the study participants had a BNP decline. There was no association between Sac/Val dose and BNP changes. Change in BNP was directly associated with change in NT-proBNP (rho: = 0.81; P < 0.001), which decreased by -30% (-50% to -8%) and -32% (-54% to -1%) to weeks 4 and 12 (P < 0.001 for both). In contrast, change in BNP was only weakly associated with change in ucGMP (rho: = 0.19; P < 0.001). Increases in ucGMP were observed regardless of whether BNP was decreased (+11% [-34% to +115%]), unchanged (+34% [-15% to +205%]), or increased (+57% [-12% to +14%]). In this pooled analysis of patients with HFrEF with standard indications for Sac/Val treatment, there was no significant overall increase in BNP concentrations, and patients demonstrated increase in ucGMP regardless of the trajectory of BNP change. (Study of Effects of Sacubitril/Valsartan vs. Enalapril on Aortic Stiffness in Patients With Mild to Moderate HF With Reduced Ejection Fraction [EVALUATE-HF]; NCT02874794) (Effects of Sacubitril/Valsartan Therapy on Biomarkers, Myocardial Remodeling and Outcomes [PROVE-HF]; NCT02887183).

Myhre PL ，Prescott MF ，Murphy SP ，Fang JC ，Mitchell GF ，Ward JH ，Claggett B ，Desai AS ，Solomon SD ，Januzzi JL ... -  《-》

Sacubitril/Valsartan in Pediatric Heart Failure (PANORAMA-HF): A Randomized, Multicenter, Double-Blind Trial.

Shaddy R ，Burch M ，Kantor PF ，Solar-Yohay S ，Garito T ，Zhang S ，Kocun M ，Mao C ，Cilliers A ，Wang X ，Canter C ，Rossano J ，Wallis G ，Menteer J ，Daou L ，Kusa J ，Tokel K ，Dilber D ，Xu Z ，Xiao T ，Halnon N ，Daly KP ，Bock MJ ，Zuckerman W ，Singh TP ，Chakrabarti M ，Levitas A ，Senni M ，Grutter G ，Kim GB ，Song J ，Lee HD ，Chen CK ，Sanchez-de-Toledo J ，Law Y ，Wanitkun S ，Cui Y ，Anjos R ，Mese T ，Bonnet D ... -  《-》

Association of Sacubitril/Valsartan vs Valsartan With Blood Pressure Changes and Symptomatic Hypotension: the PARAGLIDE-HF Trial.

In PARAGLIDE-HF, in patients with ejection fraction (EF) > 40%, stabilized after worsening heart failure (WHF), sacubitril/valsartan led to greater reduction in plasma NT-proBNP levels and was associated with clinical benefit compared to valsartan alone, despite more symptomatic hypotension (SH). Concern about SH may be limiting the use of sacubitril/valsartan in appropriate patients. We characterized patients by the occurrence of SH (investigator-reported) after randomization to either sacubitril/valsartan or valsartan. A key trial inclusion criterion was systolic blood pressure (SBP) ≥ 100 mmHg for the preceding 6 hours and no SH. We also compared outcomes based on baseline SBP stratified by the median blood pressure. The primary endpoint was time-averaged proportional change in NT-proBNP levels from baseline through weeks 4 and 8. A secondary hierarchical outcome (win ratio) consisted of: (1) cardiovascular death; (2) hospitalizations due to HF; (3) urgent HF visits; and (4) change in NT-proBNP levels. Among 466 randomized patients, 92 (19.7%) experienced SH (sacubitril/valsartan, n = 56 [24.0%]; valsartan, n = 36 [15.5%]; P = 0.020). The median time to the first SH event was similar between treatment arms (18 days vs 15 days, respectively; P = 0.42) as was the proportion of first SH events classified as serious by investigators. Patients who experienced SH with sacubitril/valsartan were more likely to be white (OR 1.87 [95% CI: 0.31, 11.15]), to have a lower baseline SBP (per 10 mmHg increase, OR 0.68 [95% CI: 0.55, 0.85]), or to have a left ventricular ejection fraction (LVEF) of > 60% (OR 2.21 [95% CI: 1.05, 4.65]). Time-averaged change in NT-proBNP levels did not differ between patients with baseline SBP ≥ 128 mmHg vs SBP < 128 mmHg (interaction, P = 0.43). The composite hierarchical outcome for sacubitril/valsartan in patients with baseline SBP ≥ 128 mmHg had a win ratio of 1.34 ([95% CI: 0.91, 1.99]; P = 0.096) vs SBP < 128 mmHg with a win ratio of 1.09 ([95%CI: 0.73, 1.66]; P = 0 .62; interaction P value = 0.42). Among patients with LVEF > 40% stabilized after WHF, incident SH was more common with sacubitril/valsartan compared with valsartan. SH was associated with lower baseline SBP, being white, and having higher LVEF. Treatment benefits with sacubitril/valsartan may be more pronounced in patients with higher baseline SBP and lower LVEF (≤ 60%). (Funded by Novartis Pharmaceutical Corporation; ClinicalTrials.gov number, NCT03988634.).

Fudim M ，Cyr DD ，Ward JH ，Hernandez AF ，Lepage S ，Morrow DA ，Sharma K ，Claggett BL ，Starling RC ，Velazquez EJ ，Williamson KM ，Desai AS ，Zieroth S ，Solomon SD ，Braunwald E ，Mentz RJ ，PARAGLIDE-HF investigators ... -  《-》

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 ... -  《-》