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.
UR - http://www.scopus.com/inward/record.url?scp=85058909982&partnerID=8YFLogxK
U2 - 10.1093/eurheartj/ehy712
DO - 10.1093/eurheartj/ehy712
M3 - Article
C2 - 30551207
SN - 0195-668X
VL - 39
SP - 4269
EP - 4276
JO - European Heart Journal
JF - European Heart Journal
IS - 48
M1 - ehy712
ER -
