Effects of combined renin-angiotensin-aldosterone system inhibitor and beta-blocker treatment on outcomes in heart failure with reduced ejection fraction: insights from BIOSTAT-CHF and ASIAN-HF registries

Wouter Ouwerkerk; Tiew-Hwa K. Teng; Jasper  Tromp; Wan Ting Tay; John G. Cleland; Dirk J. van Veldhuisen; Kenneth Dickstein; Leong L. Ng; Chim C. Lang; Stefan D. Anker; Faiez Zannad; Chung-Lieh Hung; Jitendra P. S. Sawhney; Ajay Naik; Wataru Shimizu; Nobuhisa Hagiwara; Gurpreet Singh Wander; Inder Anand; A. Mark Richards; Adriaan A. Voors; Carolyn S. P. Lam

doi:10.1002/ejhf.1869

Effects of combined renin-angiotensin-aldosterone system inhibitor and beta-blocker treatment on outcomes in heart failure with reduced ejection fraction: insights from BIOSTAT-CHF and ASIAN-HF registries

Wouter Ouwerkerk, Tiew-Hwa K. Teng, Jasper Tromp, Wan Ting Tay, John G. Cleland, Dirk J. van Veldhuisen, Kenneth Dickstein, Leong L. Ng, Chim C. Lang, Stefan D. Anker, Faiez Zannad, Chung-Lieh Hung, Jitendra P. S. Sawhney, Ajay Naik, Wataru Shimizu, Nobuhisa Hagiwara, Gurpreet Singh Wander, Inder Anand, A. Mark Richards, Adriaan A. VoorsCarolyn S. P. Lam (Lead / Corresponding author)

Research output: Contribution to journal › Article › peer-review

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Abstract

Background: Angiotensin-converting enzyme inhibitors (ACEi)/angiotensin receptor blockers (ARB) and β-blockers are guideline-recommended first-line therapies in heart failure (HF) with reduced ejection fraction (HFrEF). Previous studies showed that individual drug classes were under-dosed in many parts of Europe and Asia. In this study, we investigated the association of combined up-titration of ACEi/ARBs and β-blockers with all-cause mortality and its combination with hospitalization for HF.

Methods and results: A total of 6787 HFrEF patients (mean age 62.6 ± 13.2 years, 77.7% men, mean left ventricular ejection fraction 27.7 ± 7.2%) were enrolled in the prospective multinational European (BIOSTAT-CHF; n = 2100) and Asian (ASIAN-HF; n = 4687) studies. Outcomes were analysed according to achieved percentage of guideline-recommended target doses (GRTD) of combination ACEi/ARB and β-blocker therapy, adjusted for indication bias. Only 14% (n = 981) patients achieved ≥50% GRTD for both ACEi/ARB and β-blocker. The best outcomes were observed in patients who achieved 100% GRTD of both ACEi/ARB and β-blocker [hazard ratio (HR) 0.32, 95% confidence interval (CI) 0.26-0.39 vs. none]. Lower dose of combined therapy was associated with better outcomes than 100% GRTD of either monotherapy. Up-titrating β-blockers was associated with a consistent and greater reduction in hazards of all-cause mortality (HR for 100% GRTD: 0.40, 95% CI 0.25-0.63) than corresponding ACEi/ARB up-titration (HR 0.75, 95% CI 0.53-1.07).

Conclusion: This study shows that best outcomes were observed in patients attaining GRTD for both ACEi/ARB and β-blockers, unfortunately this was rarely achieved. Achieving >50% GRTD of both drug classes was associated with better outcome than target dose of monotherapy. Up-titrating β-blockers to target dose was associated with greater mortality reduction than up-titrating ACEi/ARB.

Original language	English
Pages (from-to)	1472-1482
Number of pages	11
Journal	European Journal of Heart Failure
Volume	22
Issue number	8
Early online date	25 Jun 2020
DOIs	https://doi.org/10.1002/ejhf.1869
Publication status	Published - 1 Aug 2020

Keywords

Evidence-based pharmacotherapy
Heart failure
Outcomes
Reduced ejection fraction
Up-titration

ASJC Scopus subject areas

Cardiology and Cardiovascular Medicine

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10.1002/ejhf.1869

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Ouwerkerk, W., Teng, T.-H. K., Tromp, J., Tay, W. T., Cleland, J. G., van Veldhuisen, D. J., Dickstein, K., Ng, L. L., Lang, C. C., Anker, S. D., Zannad, F., Hung, C.-L., Sawhney, J. P. S., Naik, A., Shimizu, W., Hagiwara, N., Wander, G. S., Anand, I., Richards, A. M., ... Lam, C. S. P. (2020). Effects of combined renin-angiotensin-aldosterone system inhibitor and beta-blocker treatment on outcomes in heart failure with reduced ejection fraction: insights from BIOSTAT-CHF and ASIAN-HF registries. European Journal of Heart Failure, 22(8), 1472-1482. https://doi.org/10.1002/ejhf.1869

@article{0a0694a2eda54cbd816d3680b267321b,

title = "Effects of combined renin-angiotensin-aldosterone system inhibitor and beta-blocker treatment on outcomes in heart failure with reduced ejection fraction: insights from BIOSTAT-CHF and ASIAN-HF registries",

abstract = "Background: Angiotensin-converting enzyme inhibitors (ACEi)/angiotensin receptor blockers (ARB) and β-blockers are guideline-recommended first-line therapies in heart failure (HF) with reduced ejection fraction (HFrEF). Previous studies showed that individual drug classes were under-dosed in many parts of Europe and Asia. In this study, we investigated the association of combined up-titration of ACEi/ARBs and β-blockers with all-cause mortality and its combination with hospitalization for HF.Methods and results: A total of 6787 HFrEF patients (mean age 62.6 ± 13.2 years, 77.7% men, mean left ventricular ejection fraction 27.7 ± 7.2%) were enrolled in the prospective multinational European (BIOSTAT-CHF; n = 2100) and Asian (ASIAN-HF; n = 4687) studies. Outcomes were analysed according to achieved percentage of guideline-recommended target doses (GRTD) of combination ACEi/ARB and β-blocker therapy, adjusted for indication bias. Only 14% (n = 981) patients achieved ≥50% GRTD for both ACEi/ARB and β-blocker. The best outcomes were observed in patients who achieved 100% GRTD of both ACEi/ARB and β-blocker [hazard ratio (HR) 0.32, 95% confidence interval (CI) 0.26-0.39 vs. none]. Lower dose of combined therapy was associated with better outcomes than 100% GRTD of either monotherapy. Up-titrating β-blockers was associated with a consistent and greater reduction in hazards of all-cause mortality (HR for 100% GRTD: 0.40, 95% CI 0.25-0.63) than corresponding ACEi/ARB up-titration (HR 0.75, 95% CI 0.53-1.07).Conclusion: This study shows that best outcomes were observed in patients attaining GRTD for both ACEi/ARB and β-blockers, unfortunately this was rarely achieved. Achieving >50% GRTD of both drug classes was associated with better outcome than target dose of monotherapy. Up-titrating β-blockers to target dose was associated with greater mortality reduction than up-titrating ACEi/ARB.",

keywords = "Evidence-based pharmacotherapy, Heart failure, Outcomes, Reduced ejection fraction, Up-titration",

author = "Wouter Ouwerkerk and Teng, {Tiew-Hwa K.} and Jasper Tromp and Tay, {Wan Ting} and Cleland, {John G.} and {van Veldhuisen}, {Dirk J.} and Kenneth Dickstein and Ng, {Leong L.} and Lang, {Chim C.} and Anker, {Stefan D.} and Faiez Zannad and Chung-Lieh Hung and Sawhney, {Jitendra P. S.} and Ajay Naik and Wataru Shimizu and Nobuhisa Hagiwara and Wander, {Gurpreet Singh} and Inder Anand and Richards, {A. Mark} and Voors, {Adriaan A.} and Lam, {Carolyn S. P.}",

note = "Funding Information Biomedical Research Council Asian neTwork for Translational Research and Cardiovascular Trials (ATTRaCT). Grant Numbers: SPF2014/005, SPF2014/004, SPF2014/003 Boston Scientific Investigator Sponsored Research Program, National Medical Research Council of Singapore. Grant Number: R‐172‐003‐219‐511 European Commission. Grant Numbers: EudraCT 2010‐020808‐29, FP7‐242209‐BIOSTAT‐CHF {\textcopyright} 2020 European Society of Cardiology.",

year = "2020",

month = aug,

day = "1",

doi = "10.1002/ejhf.1869",

language = "English",

volume = "22",

pages = "1472--1482",

journal = "European Journal of Heart Failure",

issn = "1388-9842",

publisher = "Wiley",

number = "8",

}

Ouwerkerk, W, Teng, T-HK, Tromp, J, Tay, WT, Cleland, JG, van Veldhuisen, DJ, Dickstein, K, Ng, LL, Lang, CC, Anker, SD, Zannad, F, Hung, C-L, Sawhney, JPS, Naik, A, Shimizu, W, Hagiwara, N, Wander, GS, Anand, I, Richards, AM, Voors, AA & Lam, CSP 2020, 'Effects of combined renin-angiotensin-aldosterone system inhibitor and beta-blocker treatment on outcomes in heart failure with reduced ejection fraction: insights from BIOSTAT-CHF and ASIAN-HF registries', European Journal of Heart Failure, vol. 22, no. 8, pp. 1472-1482. https://doi.org/10.1002/ejhf.1869

Effects of combined renin-angiotensin-aldosterone system inhibitor and beta-blocker treatment on outcomes in heart failure with reduced ejection fraction: insights from BIOSTAT-CHF and ASIAN-HF registries. / Ouwerkerk, Wouter; Teng, Tiew-Hwa K.; Tromp, Jasper et al.
In: European Journal of Heart Failure, Vol. 22, No. 8, 01.08.2020, p. 1472-1482.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Effects of combined renin-angiotensin-aldosterone system inhibitor and beta-blocker treatment on outcomes in heart failure with reduced ejection fraction

T2 - insights from BIOSTAT-CHF and ASIAN-HF registries

AU - Ouwerkerk, Wouter

AU - Teng, Tiew-Hwa K.

AU - Tromp, Jasper

AU - Tay, Wan Ting

AU - Cleland, John G.

AU - van Veldhuisen, Dirk J.

AU - Dickstein, Kenneth

AU - Ng, Leong L.

AU - Lang, Chim C.

AU - Anker, Stefan D.

AU - Zannad, Faiez

AU - Hung, Chung-Lieh

AU - Sawhney, Jitendra P. S.

AU - Naik, Ajay

AU - Shimizu, Wataru

AU - Hagiwara, Nobuhisa

AU - Wander, Gurpreet Singh

AU - Anand, Inder

AU - Richards, A. Mark

AU - Voors, Adriaan A.

AU - Lam, Carolyn S. P.

N1 - Funding Information Biomedical Research Council Asian neTwork for Translational Research and Cardiovascular Trials (ATTRaCT). Grant Numbers: SPF2014/005, SPF2014/004, SPF2014/003 Boston Scientific Investigator Sponsored Research Program, National Medical Research Council of Singapore. Grant Number: R‐172‐003‐219‐511 European Commission. Grant Numbers: EudraCT 2010‐020808‐29, FP7‐242209‐BIOSTAT‐CHF © 2020 European Society of Cardiology.

PY - 2020/8/1

Y1 - 2020/8/1

N2 - Background: Angiotensin-converting enzyme inhibitors (ACEi)/angiotensin receptor blockers (ARB) and β-blockers are guideline-recommended first-line therapies in heart failure (HF) with reduced ejection fraction (HFrEF). Previous studies showed that individual drug classes were under-dosed in many parts of Europe and Asia. In this study, we investigated the association of combined up-titration of ACEi/ARBs and β-blockers with all-cause mortality and its combination with hospitalization for HF.Methods and results: A total of 6787 HFrEF patients (mean age 62.6 ± 13.2 years, 77.7% men, mean left ventricular ejection fraction 27.7 ± 7.2%) were enrolled in the prospective multinational European (BIOSTAT-CHF; n = 2100) and Asian (ASIAN-HF; n = 4687) studies. Outcomes were analysed according to achieved percentage of guideline-recommended target doses (GRTD) of combination ACEi/ARB and β-blocker therapy, adjusted for indication bias. Only 14% (n = 981) patients achieved ≥50% GRTD for both ACEi/ARB and β-blocker. The best outcomes were observed in patients who achieved 100% GRTD of both ACEi/ARB and β-blocker [hazard ratio (HR) 0.32, 95% confidence interval (CI) 0.26-0.39 vs. none]. Lower dose of combined therapy was associated with better outcomes than 100% GRTD of either monotherapy. Up-titrating β-blockers was associated with a consistent and greater reduction in hazards of all-cause mortality (HR for 100% GRTD: 0.40, 95% CI 0.25-0.63) than corresponding ACEi/ARB up-titration (HR 0.75, 95% CI 0.53-1.07).Conclusion: This study shows that best outcomes were observed in patients attaining GRTD for both ACEi/ARB and β-blockers, unfortunately this was rarely achieved. Achieving >50% GRTD of both drug classes was associated with better outcome than target dose of monotherapy. Up-titrating β-blockers to target dose was associated with greater mortality reduction than up-titrating ACEi/ARB.

AB - Background: Angiotensin-converting enzyme inhibitors (ACEi)/angiotensin receptor blockers (ARB) and β-blockers are guideline-recommended first-line therapies in heart failure (HF) with reduced ejection fraction (HFrEF). Previous studies showed that individual drug classes were under-dosed in many parts of Europe and Asia. In this study, we investigated the association of combined up-titration of ACEi/ARBs and β-blockers with all-cause mortality and its combination with hospitalization for HF.Methods and results: A total of 6787 HFrEF patients (mean age 62.6 ± 13.2 years, 77.7% men, mean left ventricular ejection fraction 27.7 ± 7.2%) were enrolled in the prospective multinational European (BIOSTAT-CHF; n = 2100) and Asian (ASIAN-HF; n = 4687) studies. Outcomes were analysed according to achieved percentage of guideline-recommended target doses (GRTD) of combination ACEi/ARB and β-blocker therapy, adjusted for indication bias. Only 14% (n = 981) patients achieved ≥50% GRTD for both ACEi/ARB and β-blocker. The best outcomes were observed in patients who achieved 100% GRTD of both ACEi/ARB and β-blocker [hazard ratio (HR) 0.32, 95% confidence interval (CI) 0.26-0.39 vs. none]. Lower dose of combined therapy was associated with better outcomes than 100% GRTD of either monotherapy. Up-titrating β-blockers was associated with a consistent and greater reduction in hazards of all-cause mortality (HR for 100% GRTD: 0.40, 95% CI 0.25-0.63) than corresponding ACEi/ARB up-titration (HR 0.75, 95% CI 0.53-1.07).Conclusion: This study shows that best outcomes were observed in patients attaining GRTD for both ACEi/ARB and β-blockers, unfortunately this was rarely achieved. Achieving >50% GRTD of both drug classes was associated with better outcome than target dose of monotherapy. Up-titrating β-blockers to target dose was associated with greater mortality reduction than up-titrating ACEi/ARB.

KW - Evidence-based pharmacotherapy

KW - Heart failure

KW - Outcomes

KW - Reduced ejection fraction

KW - Up-titration

UR - http://www.scopus.com/inward/record.url?scp=85087178957&partnerID=8YFLogxK

U2 - 10.1002/ejhf.1869

DO - 10.1002/ejhf.1869

M3 - Article

C2 - 32583922

SN - 1388-9842

VL - 22

SP - 1472

EP - 1482

JO - European Journal of Heart Failure

JF - European Journal of Heart Failure

IS - 8

ER -

Ouwerkerk W, Teng THK, Tromp J, Tay WT, Cleland JG, van Veldhuisen DJ et al. Effects of combined renin-angiotensin-aldosterone system inhibitor and beta-blocker treatment on outcomes in heart failure with reduced ejection fraction: insights from BIOSTAT-CHF and ASIAN-HF registries. European Journal of Heart Failure. 2020 Aug 1;22(8):1472-1482. Epub 2020 Jun 25. doi: 10.1002/ejhf.1869

Effects of combined renin-angiotensin-aldosterone system inhibitor and beta-blocker treatment on outcomes in heart failure with reduced ejection fraction: insights from BIOSTAT-CHF and ASIAN-HF registries

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