Novel Endotypes in Heart Failure: Effects on Guideline-Directed Medical Therapy

Jasper Tromp, Wouter Ouwerkerk, Biniyam Demissei, Stefan D. Anker, John G. F. Cleland, K. Dickstein, Gerasimos S. Filippatos, Pim van der Harst, Hans L. Hillege, Chim C. Lang, Marco Metra, Leong Loke Ng, Piotr Ponikowski, Nilesh J. Samani, Dirk Jan van Veldhuisen, Faiez Zannad, Aelko H. Zwinderman, Adriaan A. Voors, Peter van der Meer (Lead / Corresponding author)

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Aims: We sought to determine subtypes of patients with heart failure (HF) with a distinct clinical profile and treatment response, using a wide range of biomarkers from various pathophysiological domains. Methods and results: We performed unsupervised cluster analysis using 92 established cardiovascular biomarkers to identify mutually exclusive subgroups (endotypes) of 1802 patients with HF and reduced ejection fraction (HFrEF) from the BIOSTAT-CHF project. We validated our findings in an independent cohort of 813 patients. Based on their biomarker profile, six endotypes were identified. Patients with endotype 1 were youngest, less symptomatic, had the lowest N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels and lowest risk for all-cause mortality or hospitalization for HF. Patients with endotype 4 had more severe symptoms and signs of HF, higher NT-proBNP levels and were at highest risk for all-cause mortality or hospitalization for HF [hazard ratio (HR) 1.4; 95% confidence interval (CI) 1.1-1.8]. Patients with endotypes 2, 3, and 5 were better uptitrated to target doses of beta-blockers (P < 0.02 for all). In contrast to other endotypes, patients with endotype 5 derived no potential survival benefit from uptitration of angiotensin-converting enzyme-inhibitor/angiotensin-II receptor blocker and beta-blockers (Pinteraction <0.001). Patients with endotype 2 (HR 1.29; 95% CI 1.10-1.42) experienced possible harm from uptitration of beta-blockers in contrast to patients with endotype 4 and 6 that experienced benefit (Pinteraction for all <0.001). Results were strikingly similar in the independent validation cohort. Conclusion: Using unsupervised cluster analysis, solely based on biomarker profiles, six distinct endotypes were identified with remarkable differences in characteristics, clinical outcome, and response to uptitration of guideline directed medical therapy.

Original languageEnglish
Article numberehy712
Pages (from-to)4269-4276
Number of pages8
JournalEuropean Heart Journal
Volume39
Issue number48
Early online date13 Dec 2018
DOIs
Publication statusPublished - 21 Dec 2018

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Heart Failure
Guidelines
Biomarkers
Therapeutics
Brain Natriuretic Peptide
Cluster Analysis
Hospitalization
Confidence Intervals
Mortality
Angiotensin Receptor Antagonists
Angiotensin-Converting Enzyme Inhibitors
Signs and Symptoms
Survival

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Tromp, J., Ouwerkerk, W., Demissei, B., Anker, S. D., Cleland, J. G. F., Dickstein, K., ... van der Meer, P. (2018). Novel Endotypes in Heart Failure: Effects on Guideline-Directed Medical Therapy. European Heart Journal, 39(48), 4269-4276. [ehy712]. https://doi.org/10.1093/eurheartj/ehy712
Tromp, Jasper ; Ouwerkerk, Wouter ; Demissei, Biniyam ; Anker, Stefan D. ; Cleland, John G. F. ; Dickstein, K. ; Filippatos, Gerasimos S. ; van der Harst, Pim ; Hillege, Hans L. ; Lang, Chim C. ; Metra, Marco ; Ng, Leong Loke ; Ponikowski, Piotr ; Samani, Nilesh J. ; van Veldhuisen, Dirk Jan ; Zannad, Faiez ; Zwinderman, Aelko H. ; Voors, Adriaan A. ; van der Meer, Peter. / Novel Endotypes in Heart Failure : Effects on Guideline-Directed Medical Therapy. In: European Heart Journal. 2018 ; Vol. 39, No. 48. pp. 4269-4276.
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abstract = "Aims: We sought to determine subtypes of patients with heart failure (HF) with a distinct clinical profile and treatment response, using a wide range of biomarkers from various pathophysiological domains. Methods and results: We performed unsupervised cluster analysis using 92 established cardiovascular biomarkers to identify mutually exclusive subgroups (endotypes) of 1802 patients with HF and reduced ejection fraction (HFrEF) from the BIOSTAT-CHF project. We validated our findings in an independent cohort of 813 patients. Based on their biomarker profile, six endotypes were identified. Patients with endotype 1 were youngest, less symptomatic, had the lowest N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels and lowest risk for all-cause mortality or hospitalization for HF. Patients with endotype 4 had more severe symptoms and signs of HF, higher NT-proBNP levels and were at highest risk for all-cause mortality or hospitalization for HF [hazard ratio (HR) 1.4; 95{\%} confidence interval (CI) 1.1-1.8]. Patients with endotypes 2, 3, and 5 were better uptitrated to target doses of beta-blockers (P < 0.02 for all). In contrast to other endotypes, patients with endotype 5 derived no potential survival benefit from uptitration of angiotensin-converting enzyme-inhibitor/angiotensin-II receptor blocker and beta-blockers (Pinteraction <0.001). Patients with endotype 2 (HR 1.29; 95{\%} CI 1.10-1.42) experienced possible harm from uptitration of beta-blockers in contrast to patients with endotype 4 and 6 that experienced benefit (Pinteraction for all <0.001). Results were strikingly similar in the independent validation cohort. Conclusion: Using unsupervised cluster analysis, solely based on biomarker profiles, six distinct endotypes were identified with remarkable differences in characteristics, clinical outcome, and response to uptitration of guideline directed medical therapy.",
author = "Jasper Tromp and Wouter Ouwerkerk and Biniyam Demissei and Anker, {Stefan D.} and Cleland, {John G. F.} and K. Dickstein and Filippatos, {Gerasimos S.} and {van der Harst}, Pim and Hillege, {Hans L.} and Lang, {Chim C.} and Marco Metra and Ng, {Leong Loke} and Piotr Ponikowski and Samani, {Nilesh J.} and {van Veldhuisen}, {Dirk Jan} and Faiez Zannad and Zwinderman, {Aelko H.} and Voors, {Adriaan A.} and {van der Meer}, Peter",
note = "BIOSTAT-CHF was funded by the European Commission [FP7-242209-BIOSTAT-CHF; EudraCT 2010-020808-29]. Conflict of interest: S.D.A. received grants from Vifor, Abbott Vascular, consultancy, or speaking from Vifor, Bayer, Boehringer Ingelheim, Brahms, Janssen, Novartis, Servier, and Stealth Peptides, and ASTRA. M.M. received consulting or speaker fees from Amgen, Astra-Zeneca, Bayer, Novartis, Relypsa, Servier, Stealth therapeutics, Trevena, Abbott Vascular. G.F. has received committee fees and/or research grants from Novartis, Bayer, Vifor, Servier. A.A.V. received consultancy fees and/or research grants from Alere, Amgen, Bayer, Boehringer Ingelheim, Cardio3Biosciences, Celladon, GSK, Merck, Novartis, Servier, Stealth Peptides, Singulex, Sphingotec, Trevena, Vifor, and ZS Pharma. C.C.L. received fees and/or research grants from Novartis, Astra Zenenca and MSD.",
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Tromp, J, Ouwerkerk, W, Demissei, B, Anker, SD, Cleland, JGF, Dickstein, K, Filippatos, GS, van der Harst, P, Hillege, HL, Lang, CC, Metra, M, Ng, LL, Ponikowski, P, Samani, NJ, van Veldhuisen, DJ, Zannad, F, Zwinderman, AH, Voors, AA & van der Meer, P 2018, 'Novel Endotypes in Heart Failure: Effects on Guideline-Directed Medical Therapy', European Heart Journal, vol. 39, no. 48, ehy712, pp. 4269-4276. https://doi.org/10.1093/eurheartj/ehy712

Novel Endotypes in Heart Failure : Effects on Guideline-Directed Medical Therapy. / Tromp, Jasper ; Ouwerkerk, Wouter; Demissei, Biniyam; Anker, Stefan D.; Cleland, John G. F.; Dickstein, K.; Filippatos, Gerasimos S.; van der Harst, Pim; Hillege, Hans L.; Lang, Chim C.; Metra, Marco; Ng, Leong Loke; Ponikowski, Piotr; Samani, Nilesh J.; van Veldhuisen, Dirk Jan; Zannad, Faiez; Zwinderman, Aelko H.; Voors, Adriaan A.; van der Meer, Peter (Lead / Corresponding author).

In: European Heart Journal, Vol. 39, No. 48, ehy712, 21.12.2018, p. 4269-4276.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Novel Endotypes in Heart Failure

T2 - Effects on Guideline-Directed Medical Therapy

AU - Tromp, Jasper

AU - Ouwerkerk, Wouter

AU - Demissei, Biniyam

AU - Anker, Stefan D.

AU - Cleland, John G. F.

AU - Dickstein, K.

AU - Filippatos, Gerasimos S.

AU - van der Harst, Pim

AU - Hillege, Hans L.

AU - Lang, Chim C.

AU - Metra, Marco

AU - Ng, Leong Loke

AU - Ponikowski, Piotr

AU - Samani, Nilesh J.

AU - van Veldhuisen, Dirk Jan

AU - Zannad, Faiez

AU - Zwinderman, Aelko H.

AU - Voors, Adriaan A.

AU - van der Meer, Peter

N1 - BIOSTAT-CHF was funded by the European Commission [FP7-242209-BIOSTAT-CHF; EudraCT 2010-020808-29]. Conflict of interest: S.D.A. received grants from Vifor, Abbott Vascular, consultancy, or speaking from Vifor, Bayer, Boehringer Ingelheim, Brahms, Janssen, Novartis, Servier, and Stealth Peptides, and ASTRA. M.M. received consulting or speaker fees from Amgen, Astra-Zeneca, Bayer, Novartis, Relypsa, Servier, Stealth therapeutics, Trevena, Abbott Vascular. G.F. has received committee fees and/or research grants from Novartis, Bayer, Vifor, Servier. A.A.V. received consultancy fees and/or research grants from Alere, Amgen, Bayer, Boehringer Ingelheim, Cardio3Biosciences, Celladon, GSK, Merck, Novartis, Servier, Stealth Peptides, Singulex, Sphingotec, Trevena, Vifor, and ZS Pharma. C.C.L. received fees and/or research grants from Novartis, Astra Zenenca and MSD.

PY - 2018/12/21

Y1 - 2018/12/21

N2 - Aims: We sought to determine subtypes of patients with heart failure (HF) with a distinct clinical profile and treatment response, using a wide range of biomarkers from various pathophysiological domains. Methods and results: We performed unsupervised cluster analysis using 92 established cardiovascular biomarkers to identify mutually exclusive subgroups (endotypes) of 1802 patients with HF and reduced ejection fraction (HFrEF) from the BIOSTAT-CHF project. We validated our findings in an independent cohort of 813 patients. Based on their biomarker profile, six endotypes were identified. Patients with endotype 1 were youngest, less symptomatic, had the lowest N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels and lowest risk for all-cause mortality or hospitalization for HF. Patients with endotype 4 had more severe symptoms and signs of HF, higher NT-proBNP levels and were at highest risk for all-cause mortality or hospitalization for HF [hazard ratio (HR) 1.4; 95% confidence interval (CI) 1.1-1.8]. Patients with endotypes 2, 3, and 5 were better uptitrated to target doses of beta-blockers (P < 0.02 for all). In contrast to other endotypes, patients with endotype 5 derived no potential survival benefit from uptitration of angiotensin-converting enzyme-inhibitor/angiotensin-II receptor blocker and beta-blockers (Pinteraction <0.001). Patients with endotype 2 (HR 1.29; 95% CI 1.10-1.42) experienced possible harm from uptitration of beta-blockers in contrast to patients with endotype 4 and 6 that experienced benefit (Pinteraction for all <0.001). Results were strikingly similar in the independent validation cohort. Conclusion: Using unsupervised cluster analysis, solely based on biomarker profiles, six distinct endotypes were identified with remarkable differences in characteristics, clinical outcome, and response to uptitration of guideline directed medical therapy.

AB - Aims: We sought to determine subtypes of patients with heart failure (HF) with a distinct clinical profile and treatment response, using a wide range of biomarkers from various pathophysiological domains. Methods and results: We performed unsupervised cluster analysis using 92 established cardiovascular biomarkers to identify mutually exclusive subgroups (endotypes) of 1802 patients with HF and reduced ejection fraction (HFrEF) from the BIOSTAT-CHF project. We validated our findings in an independent cohort of 813 patients. Based on their biomarker profile, six endotypes were identified. Patients with endotype 1 were youngest, less symptomatic, had the lowest N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels and lowest risk for all-cause mortality or hospitalization for HF. Patients with endotype 4 had more severe symptoms and signs of HF, higher NT-proBNP levels and were at highest risk for all-cause mortality or hospitalization for HF [hazard ratio (HR) 1.4; 95% confidence interval (CI) 1.1-1.8]. Patients with endotypes 2, 3, and 5 were better uptitrated to target doses of beta-blockers (P < 0.02 for all). In contrast to other endotypes, patients with endotype 5 derived no potential survival benefit from uptitration of angiotensin-converting enzyme-inhibitor/angiotensin-II receptor blocker and beta-blockers (Pinteraction <0.001). Patients with endotype 2 (HR 1.29; 95% CI 1.10-1.42) experienced possible harm from uptitration of beta-blockers in contrast to patients with endotype 4 and 6 that experienced benefit (Pinteraction for all <0.001). Results were strikingly similar in the independent validation cohort. Conclusion: Using unsupervised cluster analysis, solely based on biomarker profiles, six distinct endotypes were identified with remarkable differences in characteristics, clinical outcome, and response to uptitration of guideline directed medical therapy.

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Tromp J, Ouwerkerk W, Demissei B, Anker SD, Cleland JGF, Dickstein K et al. Novel Endotypes in Heart Failure: Effects on Guideline-Directed Medical Therapy. European Heart Journal. 2018 Dec 21;39(48):4269-4276. ehy712. https://doi.org/10.1093/eurheartj/ehy712