Jonathan W Cunningham1, Muthiah Vaduganathan2, Brian L Claggett3, Michael R Zile4, Inder S Anand5, Milton Packer6, Faiez Zannad7, Carolyn S P Lam8, Stefan Janssens9, Pardeep S Jhund10, Lars Kober11, Jean Rouleau12, Sanjiv J Shah13, Vijay K Chopra14, Victor C Shi15, Martin P Lefkowitz15, Margaret F Prescott15, Marc A Pfeffer3, John J V McMurray10, Scott D Solomon16. 1. Brigham and Women's Hospital, Division of Cardiovascular, Boston, Massachusetts. Electronic address: https://twitter.com/JonWCunningham. 2. Brigham and Women's Hospital, Division of Cardiovascular, Boston, Massachusetts. Electronic address: https://twitter.com/mvaduganathan. 3. Brigham and Women's Hospital, Division of Cardiovascular, Boston, Massachusetts. 4. RHJ Department of Veterans Affairs Medical Center and Medical University of South Carolina, Charleston, South Carolina. 5. VA Medical Center and University of Minnesota, Minneapolis, Minnesota. 6. Baylor University Medical Center, Dallas, Texas. 7. Centre d'Investigations Cliniques-Plurithématique 1433, and INSERM U1116, CHRU, F-CRIN INI-CRCT (Cardiovascular and Renal Clinical Trialists), Nancy, France. 8. National Heart Centre Singapore and Duke-National University of Singapore, Singapore; Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands; The George Institute for Global Health, Australia. 9. Department of Cardiology, University Hospitals, Leuven, Belgium. 10. BHF Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom. 11. Rigshospitalet Copenhagen University Hospital, Copenhagen, Denmark. 12. Montreal Heart Institute and Université de Montréal, Montreal, Canada. 13. Northwestern University Feinberg School of Medicine, Chicago, Illinois. 14. Heart Failure Unit, Medanta Medicity, Gurugram, Haryana, India. 15. Novartis, East Hanover, New Jersey. 16. Brigham and Women's Hospital, Division of Cardiovascular, Boston, Massachusetts. Electronic address: ssolomon@rics.bwh.harvard.edu.
Abstract
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 >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 < 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 <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 <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 < 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 >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).
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 >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 < 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 <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 <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 < 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 >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).
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