The PCSK9-LDL Receptor Axis and Outcomes in Heart Failure

BIOSTAT-CHF Subanalysis

Antoni Bayes-Genis (Lead / Corresponding author), Julio Núñez, Faiez Zannad, João Pedro Ferreira, Stefan D. Anker, John G. F. Cleland, Kenneth Dickstein, Gerasimos S. Filippatos, Chim C. Lang, Leong Ng, Piotr Ponikowski, Nilesh J. Samani, Dirk J. van Veldhuisen, Aeilko H. Zwinderman, Marco Metra, Josep Lupón, Adriaan A. Voors

Research output: Contribution to journalArticle

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Abstract

Background: Proprotein convertase subtilisin/kexin type 9 (PCSK9) binds low-density lipoprotein receptor (LDLR), preventing its recycling. PCSK9 is a risk predictor and a biotarget in atherosclerosis progression.

Objectives: The aim of this study was to determine whether the PCSK9-LDLR axis could predict risk in patients with heart failure (HF).

Methods: The BIOSTAT-CHF (Biology Study to Tailored Treatment in Chronic Heart Failure) is a multicenter, multinational, prospective, observational study that included patients with worsening HF signs and/or symptoms. The primary endpoints were all-cause mortality and the composite of mortality or unscheduled hospitalizations for HF. We implemented Cox proportional hazard regression to determine the simultaneously adjusted effect of PCSK9 and LDLR on both outcomes when added to the previously validated BIOSTAT-CHF risk scores.

Results: This study included 2,174 patients (mean age: 68 ± 12 years; 53.2% had a history of ischemic heart disease). Median (interquartile range) PCSK9 and LDLR levels were 1.81 U/ml (1.45 to 2.18) and 2.98 U/ml (2.45 to 3.53), respectively. During follow-up, 569 deaths (26.2%) and 896 (41.2%) composite endpoints were ascertained. A multivariable analysis, which included BIOSTAT-CHF risk scores, LDLR, and statin treatment as covariates, revealed a positive linear association between PCSK9 levels and the risk of mortality (hazard ratio [HR]: 1.24; 95% confidence interval [CI]: 1.04 to 1.49; p = 0.020) and the composite endpoint (HR: 1.21; 95% CI: 1.05 to 1.40; p = 0.010). A similar analysis for LDLR revealed a negative association with mortality (HR: 0.86; 95% CI: 0.76 to 0.98; p = 0.025) and the composite endpoint (HR: 0.92; 95% CI: 0.83 to 1.01; p = 0.087). Including PCSK9 and LDLR improved risk score performance.

Conclusions: The PCSK9-LDLR axis was associated with outcomes in patients with HF. Future studies must assess whether PCSK9 inhibition will result in better outcomes in HF.

Original languageEnglish
Pages (from-to)2128-2136
Number of pages9
JournalJournal of the American College of Cardiology
Volume70
Issue number17
Early online date16 Oct 2017
DOIs
Publication statusPublished - 24 Oct 2017

Fingerprint

LDL Receptors
Heart Failure
Confidence Intervals
Therapeutics
Mortality
Proprotein Convertase 9
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Recycling
Signs and Symptoms
Observational Studies
Myocardial Ischemia
Atherosclerosis
Hospitalization
Prospective Studies

Keywords

  • Heart failure
  • LDLR
  • Low-density lipoprotein receptor
  • PCSK9
  • Proprotein convertase subtilisin/kexin type 9

Cite this

Bayes-Genis, A., Núñez, J., Zannad, F., Ferreira, J. P., Anker, S. D., Cleland, J. G. F., ... Voors, A. A. (2017). The PCSK9-LDL Receptor Axis and Outcomes in Heart Failure: BIOSTAT-CHF Subanalysis. Journal of the American College of Cardiology, 70(17), 2128-2136. https://doi.org/10.1016/j.jacc.2017.08.057
Bayes-Genis, Antoni ; Núñez, Julio ; Zannad, Faiez ; Ferreira, João Pedro ; Anker, Stefan D. ; Cleland, John G. F. ; Dickstein, Kenneth ; Filippatos, Gerasimos S. ; Lang, Chim C. ; Ng, Leong ; Ponikowski, Piotr ; Samani, Nilesh J. ; van Veldhuisen, Dirk J. ; Zwinderman, Aeilko H. ; Metra, Marco ; Lupón, Josep ; Voors, Adriaan A. / The PCSK9-LDL Receptor Axis and Outcomes in Heart Failure : BIOSTAT-CHF Subanalysis. In: Journal of the American College of Cardiology. 2017 ; Vol. 70, No. 17. pp. 2128-2136.
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title = "The PCSK9-LDL Receptor Axis and Outcomes in Heart Failure: BIOSTAT-CHF Subanalysis",
abstract = "Background: Proprotein convertase subtilisin/kexin type 9 (PCSK9) binds low-density lipoprotein receptor (LDLR), preventing its recycling. PCSK9 is a risk predictor and a biotarget in atherosclerosis progression.Objectives: The aim of this study was to determine whether the PCSK9-LDLR axis could predict risk in patients with heart failure (HF).Methods: The BIOSTAT-CHF (Biology Study to Tailored Treatment in Chronic Heart Failure) is a multicenter, multinational, prospective, observational study that included patients with worsening HF signs and/or symptoms. The primary endpoints were all-cause mortality and the composite of mortality or unscheduled hospitalizations for HF. We implemented Cox proportional hazard regression to determine the simultaneously adjusted effect of PCSK9 and LDLR on both outcomes when added to the previously validated BIOSTAT-CHF risk scores.Results: This study included 2,174 patients (mean age: 68 ± 12 years; 53.2{\%} had a history of ischemic heart disease). Median (interquartile range) PCSK9 and LDLR levels were 1.81 U/ml (1.45 to 2.18) and 2.98 U/ml (2.45 to 3.53), respectively. During follow-up, 569 deaths (26.2{\%}) and 896 (41.2{\%}) composite endpoints were ascertained. A multivariable analysis, which included BIOSTAT-CHF risk scores, LDLR, and statin treatment as covariates, revealed a positive linear association between PCSK9 levels and the risk of mortality (hazard ratio [HR]: 1.24; 95{\%} confidence interval [CI]: 1.04 to 1.49; p = 0.020) and the composite endpoint (HR: 1.21; 95{\%} CI: 1.05 to 1.40; p = 0.010). A similar analysis for LDLR revealed a negative association with mortality (HR: 0.86; 95{\%} CI: 0.76 to 0.98; p = 0.025) and the composite endpoint (HR: 0.92; 95{\%} CI: 0.83 to 1.01; p = 0.087). Including PCSK9 and LDLR improved risk score performance.Conclusions: The PCSK9-LDLR axis was associated with outcomes in patients with HF. Future studies must assess whether PCSK9 inhibition will result in better outcomes in HF.",
keywords = "Heart failure, LDLR, Low-density lipoprotein receptor, PCSK9, Proprotein convertase subtilisin/kexin type 9",
author = "Antoni Bayes-Genis and Julio N{\'u}{\~n}ez and Faiez Zannad and Ferreira, {Jo{\~a}o Pedro} and Anker, {Stefan D.} and Cleland, {John G. F.} and Kenneth Dickstein and Filippatos, {Gerasimos S.} and Lang, {Chim C.} and Leong Ng and Piotr Ponikowski and Samani, {Nilesh J.} and {van Veldhuisen}, {Dirk J.} and Zwinderman, {Aeilko H.} and Marco Metra and Josep Lup{\'o}n and Voors, {Adriaan A.}",
note = "This project was funded by a grant from the European Commission (FP7-242209-BIOSTAT-CHF; EudraCT 2010-020808-29). Dr. Bayes-Genis was supported by grants from the Ministerio de Educaci{\'o}n y Ciencia (SAF2014-59892), Fundaci{\'o} La MARAT{\'O} de TV3 (201502, 201516), CIBER Cardiovascular (CB16/11/00403), and AdvanceCat 2014-2020; and has received board membership fees and travel expenses from Novartis, Roche Diagnostics, and Critical Diagnostics. Dr. N{\'u}{\~n}ez has received board membership fees and travel expenses from Novartis, Roche Diagnostics, Abbott, Rovi and Vifor. Dr. Voors has received consultancy fees and/or research grants from Alere, Amgen, Bayer, Boehringer Ingelheim, Cardio3Biosciences, Celladon, GlaxoSmithKline, Merck/Merck Sharp & Dohme, Novartis, Servier, Stealth Peptides, Singulex, Sphingotec, Trevena, Vifor, and ZS Pharma. Dr. Anker has received grants from Vifor and Abbott Vascular; and fees for consultancy or speaking from Vifor, Bayer, Boehringer Ingelheim, Brahms, Janssen, Novartis, Servier, Stealth Peptides, and ASTRA. Dr. Filippatos has received committee fees and/or research grants from Novartis, Bayer, Vifor, and Servier. Dr. Lang has received consultancy fees and/or research grants from Amgen, Astra Zeneca, Merck Sharp & Dohme, Novartis, and Servier. Dr. van Veldhuisen has received board membership fees or travel expenses from Novartis, Johnson & Johnson, and Vifor. Dr. Metra has received consulting honoraria from Amgen, AstraZeneca, Bayer, Novartis, Relypsa, Servier, Stealth Therapeutics, and Trevena; and speaker fees from Abbott Vascular and Servier. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose",
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language = "English",
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pages = "2128--2136",
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Bayes-Genis, A, Núñez, J, Zannad, F, Ferreira, JP, Anker, SD, Cleland, JGF, Dickstein, K, Filippatos, GS, Lang, CC, Ng, L, Ponikowski, P, Samani, NJ, van Veldhuisen, DJ, Zwinderman, AH, Metra, M, Lupón, J & Voors, AA 2017, 'The PCSK9-LDL Receptor Axis and Outcomes in Heart Failure: BIOSTAT-CHF Subanalysis', Journal of the American College of Cardiology, vol. 70, no. 17, pp. 2128-2136. https://doi.org/10.1016/j.jacc.2017.08.057

The PCSK9-LDL Receptor Axis and Outcomes in Heart Failure : BIOSTAT-CHF Subanalysis. / Bayes-Genis, Antoni (Lead / Corresponding author); Núñez, Julio; Zannad, Faiez; Ferreira, João Pedro; Anker, Stefan D.; Cleland, John G. F.; Dickstein, Kenneth; Filippatos, Gerasimos S.; Lang, Chim C.; Ng, Leong; Ponikowski, Piotr; Samani, Nilesh J.; van Veldhuisen, Dirk J.; Zwinderman, Aeilko H.; Metra, Marco; Lupón, Josep; Voors, Adriaan A.

In: Journal of the American College of Cardiology, Vol. 70, No. 17, 24.10.2017, p. 2128-2136.

Research output: Contribution to journalArticle

TY - JOUR

T1 - The PCSK9-LDL Receptor Axis and Outcomes in Heart Failure

T2 - BIOSTAT-CHF Subanalysis

AU - Bayes-Genis, Antoni

AU - Núñez, Julio

AU - Zannad, Faiez

AU - Ferreira, João Pedro

AU - Anker, Stefan D.

AU - Cleland, John G. F.

AU - Dickstein, Kenneth

AU - Filippatos, Gerasimos S.

AU - Lang, Chim C.

AU - Ng, Leong

AU - Ponikowski, Piotr

AU - Samani, Nilesh J.

AU - van Veldhuisen, Dirk J.

AU - Zwinderman, Aeilko H.

AU - Metra, Marco

AU - Lupón, Josep

AU - Voors, Adriaan A.

N1 - This project was funded by a grant from the European Commission (FP7-242209-BIOSTAT-CHF; EudraCT 2010-020808-29). Dr. Bayes-Genis was supported by grants from the Ministerio de Educación y Ciencia (SAF2014-59892), Fundació La MARATÓ de TV3 (201502, 201516), CIBER Cardiovascular (CB16/11/00403), and AdvanceCat 2014-2020; and has received board membership fees and travel expenses from Novartis, Roche Diagnostics, and Critical Diagnostics. Dr. Núñez has received board membership fees and travel expenses from Novartis, Roche Diagnostics, Abbott, Rovi and Vifor. Dr. Voors has received consultancy fees and/or research grants from Alere, Amgen, Bayer, Boehringer Ingelheim, Cardio3Biosciences, Celladon, GlaxoSmithKline, Merck/Merck Sharp & Dohme, Novartis, Servier, Stealth Peptides, Singulex, Sphingotec, Trevena, Vifor, and ZS Pharma. Dr. Anker has received grants from Vifor and Abbott Vascular; and fees for consultancy or speaking from Vifor, Bayer, Boehringer Ingelheim, Brahms, Janssen, Novartis, Servier, Stealth Peptides, and ASTRA. Dr. Filippatos has received committee fees and/or research grants from Novartis, Bayer, Vifor, and Servier. Dr. Lang has received consultancy fees and/or research grants from Amgen, Astra Zeneca, Merck Sharp & Dohme, Novartis, and Servier. Dr. van Veldhuisen has received board membership fees or travel expenses from Novartis, Johnson & Johnson, and Vifor. Dr. Metra has received consulting honoraria from Amgen, AstraZeneca, Bayer, Novartis, Relypsa, Servier, Stealth Therapeutics, and Trevena; and speaker fees from Abbott Vascular and Servier. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose

PY - 2017/10/24

Y1 - 2017/10/24

N2 - Background: Proprotein convertase subtilisin/kexin type 9 (PCSK9) binds low-density lipoprotein receptor (LDLR), preventing its recycling. PCSK9 is a risk predictor and a biotarget in atherosclerosis progression.Objectives: The aim of this study was to determine whether the PCSK9-LDLR axis could predict risk in patients with heart failure (HF).Methods: The BIOSTAT-CHF (Biology Study to Tailored Treatment in Chronic Heart Failure) is a multicenter, multinational, prospective, observational study that included patients with worsening HF signs and/or symptoms. The primary endpoints were all-cause mortality and the composite of mortality or unscheduled hospitalizations for HF. We implemented Cox proportional hazard regression to determine the simultaneously adjusted effect of PCSK9 and LDLR on both outcomes when added to the previously validated BIOSTAT-CHF risk scores.Results: This study included 2,174 patients (mean age: 68 ± 12 years; 53.2% had a history of ischemic heart disease). Median (interquartile range) PCSK9 and LDLR levels were 1.81 U/ml (1.45 to 2.18) and 2.98 U/ml (2.45 to 3.53), respectively. During follow-up, 569 deaths (26.2%) and 896 (41.2%) composite endpoints were ascertained. A multivariable analysis, which included BIOSTAT-CHF risk scores, LDLR, and statin treatment as covariates, revealed a positive linear association between PCSK9 levels and the risk of mortality (hazard ratio [HR]: 1.24; 95% confidence interval [CI]: 1.04 to 1.49; p = 0.020) and the composite endpoint (HR: 1.21; 95% CI: 1.05 to 1.40; p = 0.010). A similar analysis for LDLR revealed a negative association with mortality (HR: 0.86; 95% CI: 0.76 to 0.98; p = 0.025) and the composite endpoint (HR: 0.92; 95% CI: 0.83 to 1.01; p = 0.087). Including PCSK9 and LDLR improved risk score performance.Conclusions: The PCSK9-LDLR axis was associated with outcomes in patients with HF. Future studies must assess whether PCSK9 inhibition will result in better outcomes in HF.

AB - Background: Proprotein convertase subtilisin/kexin type 9 (PCSK9) binds low-density lipoprotein receptor (LDLR), preventing its recycling. PCSK9 is a risk predictor and a biotarget in atherosclerosis progression.Objectives: The aim of this study was to determine whether the PCSK9-LDLR axis could predict risk in patients with heart failure (HF).Methods: The BIOSTAT-CHF (Biology Study to Tailored Treatment in Chronic Heart Failure) is a multicenter, multinational, prospective, observational study that included patients with worsening HF signs and/or symptoms. The primary endpoints were all-cause mortality and the composite of mortality or unscheduled hospitalizations for HF. We implemented Cox proportional hazard regression to determine the simultaneously adjusted effect of PCSK9 and LDLR on both outcomes when added to the previously validated BIOSTAT-CHF risk scores.Results: This study included 2,174 patients (mean age: 68 ± 12 years; 53.2% had a history of ischemic heart disease). Median (interquartile range) PCSK9 and LDLR levels were 1.81 U/ml (1.45 to 2.18) and 2.98 U/ml (2.45 to 3.53), respectively. During follow-up, 569 deaths (26.2%) and 896 (41.2%) composite endpoints were ascertained. A multivariable analysis, which included BIOSTAT-CHF risk scores, LDLR, and statin treatment as covariates, revealed a positive linear association between PCSK9 levels and the risk of mortality (hazard ratio [HR]: 1.24; 95% confidence interval [CI]: 1.04 to 1.49; p = 0.020) and the composite endpoint (HR: 1.21; 95% CI: 1.05 to 1.40; p = 0.010). A similar analysis for LDLR revealed a negative association with mortality (HR: 0.86; 95% CI: 0.76 to 0.98; p = 0.025) and the composite endpoint (HR: 0.92; 95% CI: 0.83 to 1.01; p = 0.087). Including PCSK9 and LDLR improved risk score performance.Conclusions: The PCSK9-LDLR axis was associated with outcomes in patients with HF. Future studies must assess whether PCSK9 inhibition will result in better outcomes in HF.

KW - Heart failure

KW - LDLR

KW - Low-density lipoprotein receptor

KW - PCSK9

KW - Proprotein convertase subtilisin/kexin type 9

U2 - 10.1016/j.jacc.2017.08.057

DO - 10.1016/j.jacc.2017.08.057

M3 - Article

VL - 70

SP - 2128

EP - 2136

JO - Journal of the American College of Cardiology

JF - Journal of the American College of Cardiology

SN - 0735-1097

IS - 17

ER -