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)
| Original language | English (US) |
|---|---|
| Pages (from-to) | 372-381 |
| Number of pages | 10 |
| Journal | JACC: Heart Failure |
| Volume | 8 |
| Issue number | 5 |
| DOIs | |
| State | Published - May 2020 |
Keywords
- clinical outcomes
- heart failure with preserved ejection fraction
- natriuretic peptides
ASJC Scopus subject areas
- Cardiology and Cardiovascular Medicine
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Effects of Sacubitril/Valsartan on N-Terminal Pro-B-Type Natriuretic Peptide in Heart Failure With Preserved Ejection Fraction. / Cunningham, Jonathan W.; Vaduganathan, Muthiah; Claggett, Brian L.; Zile, Michael R.; Anand, Inder S.; Packer, Milton; Zannad, Faiez; Lam, Carolyn S.P.; Janssens, Stefan; Jhund, Pardeep S.; Kober, Lars; Rouleau, Jean; Shah, Sanjiv J.; Chopra, Vijay K.; Shi, Victor C.; Lefkowitz, Martin P.; Prescott, Margaret F.; Pfeffer, Marc A.; McMurray, John J.V.; Solomon, Scott D.
In: JACC: Heart Failure, Vol. 8, No. 5, 05.2020, p. 372-381.Research output: Contribution to journal › Article › peer-review
TY - JOUR
T1 - Effects of Sacubitril/Valsartan on N-Terminal Pro-B-Type Natriuretic Peptide in Heart Failure With Preserved Ejection Fraction
AU - Cunningham, Jonathan W.
AU - Vaduganathan, Muthiah
AU - Claggett, Brian L.
AU - Zile, Michael R.
AU - Anand, Inder S.
AU - Packer, Milton
AU - Zannad, Faiez
AU - Lam, Carolyn S.P.
AU - Janssens, Stefan
AU - Jhund, Pardeep S.
AU - Kober, Lars
AU - Rouleau, Jean
AU - Shah, Sanjiv J.
AU - Chopra, Vijay K.
AU - Shi, Victor C.
AU - Lefkowitz, Martin P.
AU - Prescott, Margaret F.
AU - Pfeffer, Marc A.
AU - McMurray, John J.V.
AU - Solomon, Scott D.
N1 - Funding Information: The PARAGON-HF trial was sponsored by Novartis. Dr. Cunningham is supported by Heart, Lung, and Blood Institute (NHLBI) T32 postdoctoral training grant T32HL094301. Dr. Vaduganathan is supported by KL2/Catalyst Medical Research Investigator Training award from Harvard Catalyst (NIH/NCATS Award UL 1TR002541). Dr. Lam is supported by a Clinician Scientist Award from the National Medical Research Council of Singapore. Dr. Vaduganathan has been a consultant or served on advisory boards for Amgen, AstraZeneca, Baxter HealthCare, Bayer AG, Boehringer Ingelheim, Relypsa, Boehringer Ingelheim, and Cytokinetics. Dr. Claggett has been a consultant for Amgen, AO Biome, Biogen, Boehringer Ingelheim, Corvia, Gilead, MyoKardia, and Novartis. Dr. Zile has received research funding from Novartis; and has been a consultant for Novartis, Abbott, Boston Scientific, CVRx, EBR, Endotronics, Ironwood, Merck, Medtronic, and MyoKardia V Wave. Dr. Anand has been a consultant for AstraZeneca, ARCA, Amgen, Boston Scientific, Boehringer Ingelheim, Novartis, LivaNova, and Zensun. Dr. Packer has received personal fees from Akcea Therapeutics, AstraZeneca, Amgen, Actavis, AbbVie, Bayer, Boehringer Ingelheim, Cardiorentis, Daiichi Sankyo, Johnson & Johnson, Novo Nordisk, Pfizer, Relypsa, Sanofi, Synthetic Biologics, and Theravance. Dr. Zannad has received personal fees from Janssen, Novartis, Bayer, Boston Scientific, Amgen, CVRx, Boehringer Ingelheim, AstraZeneca, Vifor Fresenius, Cardior, Cereno Pharmaceutical, Applied Therapeutics, and Merck; has been a Novartis steering committee member; and has received other payments from CVCT and Cardiorenal. Dr. Lam has received research support from Boston Scientific, Bayer, Roche Diagnostics, AstraZeneca, Medtronic, and Vifor Pharma; has served as consultant or on advisory boards/steering committees/executive committees for Boston Scientific, Bayer, Roche Diagnostics, AstraZeneca, Medtronic, Vifor Pharma, Novartis, Amgen, Merck, Janssen Research & Development, Menarini, Boehringer Ingelheim, Novo Nordisk, Abbott Diagnostics, Corvia, Stealth BioTherapeutics, JanaCare, Biofourmis, Darma, Applied Therapeutics, MyoKardia, Cytokinetics, WebMD Global, Radcliffe Group Ltd., and Corpus; and serves as cofounder and nonexecutive director of eKo.ai. Dr. Janssens has received grants and consulting fees from Novartis through the University of Leuven, Belgium. Dr. Jhund has received personal fees and consulting from Novartis, Vifor Pharma, and Cytokinetics; other fees from AstraZeneca; and grants from Boehringer Ingelheim. Dr. Kober has received personal fees from AstraZeneca and Novartis; and speaker honoraria from Novartis, AstraZeneca, and Boehringer Ingelheim. Dr. Rouleau has received personal fees from Novartis and AstraZeneca. Dr. Shah has received grants from the National Institutes of Health (NIH) (R01 HL140731, R01 HL120728, R01 HL107577, and R01 HL149423), American Heart Association, Actelion, AstraZeneca, Corvia, and Novartis; and consulting fees from Actelion, Amgen, AstraZeneca, Bayer, Boehringer-Ingelheim, Cardiora, Eisai, Ionis, Ironwood, Merck, Novartis, Pfizer, Sanofi, and United Therapeutics. Dr. Chopra has received consulting fees from Novartis. Drs. Shi, Lefkowitz, and Prescott are employees of Novartis; Dr. Prescott receives stock as part of her salary. Dr. Pfeffer has been a consultant for AstraZeneca, DalCor Pharmaceuticals, GlaxoSmithKline, Novo Nordisk, Sanofi, Jazz, MyoKardia, Servier, Takeda, and Corvidia. Dr. McMurray has received consulting payments through Glasgow University from Bayer, Cardiorentis, Amgen, Theracos, AbbVie, DalCor Pharmaceuticals, Pfizer, Merck, AstraZeneca, GlaxoSmithKline, Bristol-Myers Squibb, Vifor-Fresenius, Kidney Research UK, Novartis, and Theracos; all payments were made through a consultancy with Glasgow University and were not personal payments. Dr. Solomon has received research grants from Novartis, Alnylam, Amgen, AstraZeneca, Bristol-Myers Squibb, Gilead, GlaxoSmithKline, MyoKardia, Theracos, Cytokinetics, Celladon, Bellerophon, Bayer, Ionis, Lone Star Heart, Mesoblast, Eidos, MyoKardia; National Institutes of Health/NHLBI, and Sanofi Pasteur; and personal/consulting fees from Akros, Alnylam, Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Cardior, Corvia, Cytokinetics, Daiichi Sankyo, Gilead, GlaxoSmithKline, Ironwood, Merck, MyoKardia, Roche, Takeda, Quantum Genomics, Cardurion, AoBiome, Janssen, Cardiac Dimensions, Tenaya, Novartis, and Theracos. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Funding Information: The PARAGON-HF trial was sponsored by Novartis. Dr. Cunningham is supported by Heart, Lung, and Blood Institute (NHLBI) T32 postdoctoral training grant T32HL094301. Dr. Vaduganathan is supported by KL2/Catalyst Medical Research Investigator Training award from Harvard Catalyst (NIH/NCATS Award UL 1TR002541). Dr. Lam is supported by a Clinician Scientist Award from the National Medical Research Council of Singapore. Dr. Vaduganathan has been a consultant or served on advisory boards for Amgen, AstraZeneca, Baxter HealthCare, Bayer AG, Boehringer Ingelheim, Relypsa, Boehringer Ingelheim, and Cytokinetics. Dr. Claggett has been a consultant for Amgen, AO Biome, Biogen, Boehringer Ingelheim, Corvia, Gilead, MyoKardia, and Novartis. Dr. Zile has received research funding from Novartis; and has been a consultant for Novartis, Abbott, Boston Scientific, CVRx, EBR, Endotronics, Ironwood, Merck, Medtronic, and MyoKardia V Wave. Dr. Anand has been a consultant for AstraZeneca, ARCA, Amgen, Boston Scientific, Boehringer Ingelheim, Novartis, LivaNova, and Zensun. Dr. Packer has received personal fees from Akcea Therapeutics, AstraZeneca, Amgen, Actavis, AbbVie, Bayer, Boehringer Ingelheim, Cardiorentis, Daiichi Sankyo, Johnson & Johnson, Novo Nordisk, Pfizer, Relypsa, Sanofi, Synthetic Biologics, and Theravance. Dr. Zannad has received personal fees from Janssen, Novartis, Bayer, Boston Scientific, Amgen, CVRx, Boehringer Ingelheim, AstraZeneca, Vifor Fresenius, Cardior, Cereno Pharmaceutical, Applied Therapeutics, and Merck; has been a Novartis steering committee member; and has received other payments from CVCT and Cardiorenal. Dr. Lam has received research support from Boston Scientific, Bayer, Roche Diagnostics, AstraZeneca, Medtronic, and Vifor Pharma; has served as consultant or on advisory boards/steering committees/executive committees for Boston Scientific, Bayer, Roche Diagnostics, AstraZeneca, Medtronic, Vifor Pharma, Novartis, Amgen, Merck, Janssen Research & Development, Menarini, Boehringer Ingelheim, Novo Nordisk, Abbott Diagnostics, Corvia, Stealth BioTherapeutics, JanaCare, Biofourmis, Darma, Applied Therapeutics, MyoKardia, Cytokinetics, WebMD Global, Radcliffe Group Ltd., and Corpus; and serves as cofounder and nonexecutive director of eKo.ai. Dr. Janssens has received grants and consulting fees from Novartis through the University of Leuven, Belgium. Dr. Jhund has received personal fees and consulting from Novartis, Vifor Pharma, and Cytokinetics; other fees from AstraZeneca; and grants from Boehringer Ingelheim. Dr. Kober has received personal fees from AstraZeneca and Novartis; and speaker honoraria from Novartis, AstraZeneca, and Boehringer Ingelheim. Dr. Rouleau has received personal fees from Novartis and AstraZeneca. Dr. Shah has received grants from the National Institutes of Health (NIH) (R01 HL140731, R01 HL120728, R01 HL107577, and R01 HL149423), American Heart Association, Actelion, AstraZeneca, Corvia, and Novartis; and consulting fees from Actelion, Amgen, AstraZeneca, Bayer, Boehringer-Ingelheim, Cardiora, Eisai, Ionis, Ironwood, Merck, Novartis, Pfizer, Sanofi, and United Therapeutics. Dr. Chopra has received consulting fees from Novartis. Drs. Shi, Lefkowitz, and Prescott are employees of Novartis; Dr. Prescott receives stock as part of her salary. Dr. Pfeffer has been a consultant for AstraZeneca, DalCor Pharmaceuticals, GlaxoSmithKline, Novo Nordisk, Sanofi, Jazz, MyoKardia, Servier, Takeda, and Corvidia. Dr. McMurray has received consulting payments through Glasgow University from Bayer, Cardiorentis, Amgen, Theracos, AbbVie, DalCor Pharmaceuticals, Pfizer, Merck, AstraZeneca, GlaxoSmithKline, Bristol-Myers Squibb, Vifor-Fresenius, Kidney Research UK, Novartis, and Theracos; all payments were made through a consultancy with Glasgow University and were not personal payments. Dr. Solomon has received research grants from Novartis, Alnylam, Amgen, AstraZeneca, Bristol-Myers Squibb, Gilead, GlaxoSmithKline, MyoKardia, Theracos, Cytokinetics, Celladon, Bellerophon, Bayer, Ionis, Lone Star Heart, Mesoblast, Eidos, MyoKardia; National Institutes of Health/NHLBI, and Sanofi Pasteur; and personal/consulting fees from Akros, Alnylam, Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Cardior, Corvia, Cytokinetics, Daiichi Sankyo, Gilead, GlaxoSmithKline, Ironwood, Merck, MyoKardia, Roche, Takeda, Quantum Genomics, Cardurion, AoBiome, Janssen, Cardiac Dimensions, Tenaya, Novartis, and Theracos. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Publisher Copyright: © 2020 The Authors
PY - 2020/5
Y1 - 2020/5
N2 - 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)
AB - 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)
KW - clinical outcomes
KW - heart failure with preserved ejection fraction
KW - natriuretic peptides
UR - http://www.scopus.com/inward/record.url?scp=85083339037&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85083339037&partnerID=8YFLogxK
U2 - 10.1016/j.jchf.2020.03.002
DO - 10.1016/j.jchf.2020.03.002
M3 - Article
C2 - 32241619
AN - SCOPUS:85083339037
VL - 8
SP - 372
EP - 381
JO - JACC: Heart Failure
JF - JACC: Heart Failure
SN - 2213-1779
IS - 5
ER -