Minimal dose for effective clinical outcome and predictive factors for responsiveness to carvedilol: Japanese chronic heart failure (J-CHF) study

Hiroshi Okamoto, Masatsugu Hori, Masunori Matsuzaki, Hiroyuki Tsutsui, Tsutomu Yamazaki, Ryozo Nagai, Tsutomu Yoshikawa, Yasushi Fujio, Shinpei Nonen, Junichi Azuma, Tohru Izumi, Yasuo Ohashi, Akira Kitabatake

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

AbstractBackground In chronic heart failure (CHF), it remains unclear whether the minimal dose of beta-blockade is related to survival benefits and which parameter predicts morbidity and mortality. We sought to determine the minimal dose related to survival benefits by comparing the efficacy and safety of three doses of carvedilol and the best predictive parameter for effective outcomes in Japanese patients with CHF. Methods In this prospective, randomized, stratified trial, 364 patients with mild to moderate CHF were assigned to a daily carvedilol dose of 2.5, 5, or 20 mg, plus optimal standard therapy. Findings During the mean 3-year follow-up, resting heart rate (HR) and BNP were significantly reduced with dose-response relations in the early period but without dose-response relations in the late period. The LVEF and the LVDd were increased and decreased, respectively, without a dose-response relation. No significant difference was seen in the composite primary endpoint of all-cause mortality and hospitalization for cardiovascular diseases and heart failure. Multivariate analysis indicated early decreases in HR and BNP predicted long-term outcomes. However, adverse events increased dose-dependently. Among 237 polymorphisms in 87 heart failure-related genes, the osteopontin G-156 del genotype was associated with an event-free survival rate (Wilcoxon test, P = 0.030). Conclusions A low carvedilol dose is effective if the HR and/or plasma BNP has been reduced. Carvedilol therapy should be guided by reductions in HR and/or BNP, especially by initial HR reduction, but not only by its dose. OPN might be a surrogate genetic marker for long-term event-free survival.

Original languageEnglish
Pages (from-to)238-244
Number of pages7
JournalInternational Journal of Cardiology
Volume164
Issue number2
DOIs
Publication statusPublished - Apr 5 2013
Externally publishedYes

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Heart Failure
Heart Rate
Disease-Free Survival
Osteopontin
Survival
Mortality
Genetic Markers
Hospitalization
Cardiovascular Diseases
Multivariate Analysis
Survival Rate
Biomarkers
Genotype
carvedilol
Morbidity
Safety
Therapeutics
Genes

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine

Cite this

Minimal dose for effective clinical outcome and predictive factors for responsiveness to carvedilol : Japanese chronic heart failure (J-CHF) study. / Okamoto, Hiroshi; Hori, Masatsugu; Matsuzaki, Masunori; Tsutsui, Hiroyuki; Yamazaki, Tsutomu; Nagai, Ryozo; Yoshikawa, Tsutomu; Fujio, Yasushi; Nonen, Shinpei; Azuma, Junichi; Izumi, Tohru; Ohashi, Yasuo; Kitabatake, Akira.

In: International Journal of Cardiology, Vol. 164, No. 2, 05.04.2013, p. 238-244.

Research output: Contribution to journalArticle

Okamoto, H, Hori, M, Matsuzaki, M, Tsutsui, H, Yamazaki, T, Nagai, R, Yoshikawa, T, Fujio, Y, Nonen, S, Azuma, J, Izumi, T, Ohashi, Y & Kitabatake, A 2013, 'Minimal dose for effective clinical outcome and predictive factors for responsiveness to carvedilol: Japanese chronic heart failure (J-CHF) study', International Journal of Cardiology, vol. 164, no. 2, pp. 238-244. https://doi.org/10.1016/j.ijcard.2012.11.051
Okamoto, Hiroshi ; Hori, Masatsugu ; Matsuzaki, Masunori ; Tsutsui, Hiroyuki ; Yamazaki, Tsutomu ; Nagai, Ryozo ; Yoshikawa, Tsutomu ; Fujio, Yasushi ; Nonen, Shinpei ; Azuma, Junichi ; Izumi, Tohru ; Ohashi, Yasuo ; Kitabatake, Akira. / Minimal dose for effective clinical outcome and predictive factors for responsiveness to carvedilol : Japanese chronic heart failure (J-CHF) study. In: International Journal of Cardiology. 2013 ; Vol. 164, No. 2. pp. 238-244.
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AU - Hori, Masatsugu

AU - Matsuzaki, Masunori

AU - Tsutsui, Hiroyuki

AU - Yamazaki, Tsutomu

AU - Nagai, Ryozo

AU - Yoshikawa, Tsutomu

AU - Fujio, Yasushi

AU - Nonen, Shinpei

AU - Azuma, Junichi

AU - Izumi, Tohru

AU - Ohashi, Yasuo

AU - Kitabatake, Akira

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N2 - AbstractBackground In chronic heart failure (CHF), it remains unclear whether the minimal dose of beta-blockade is related to survival benefits and which parameter predicts morbidity and mortality. We sought to determine the minimal dose related to survival benefits by comparing the efficacy and safety of three doses of carvedilol and the best predictive parameter for effective outcomes in Japanese patients with CHF. Methods In this prospective, randomized, stratified trial, 364 patients with mild to moderate CHF were assigned to a daily carvedilol dose of 2.5, 5, or 20 mg, plus optimal standard therapy. Findings During the mean 3-year follow-up, resting heart rate (HR) and BNP were significantly reduced with dose-response relations in the early period but without dose-response relations in the late period. The LVEF and the LVDd were increased and decreased, respectively, without a dose-response relation. No significant difference was seen in the composite primary endpoint of all-cause mortality and hospitalization for cardiovascular diseases and heart failure. Multivariate analysis indicated early decreases in HR and BNP predicted long-term outcomes. However, adverse events increased dose-dependently. Among 237 polymorphisms in 87 heart failure-related genes, the osteopontin G-156 del genotype was associated with an event-free survival rate (Wilcoxon test, P = 0.030). Conclusions A low carvedilol dose is effective if the HR and/or plasma BNP has been reduced. Carvedilol therapy should be guided by reductions in HR and/or BNP, especially by initial HR reduction, but not only by its dose. OPN might be a surrogate genetic marker for long-term event-free survival.

AB - AbstractBackground In chronic heart failure (CHF), it remains unclear whether the minimal dose of beta-blockade is related to survival benefits and which parameter predicts morbidity and mortality. We sought to determine the minimal dose related to survival benefits by comparing the efficacy and safety of three doses of carvedilol and the best predictive parameter for effective outcomes in Japanese patients with CHF. Methods In this prospective, randomized, stratified trial, 364 patients with mild to moderate CHF were assigned to a daily carvedilol dose of 2.5, 5, or 20 mg, plus optimal standard therapy. Findings During the mean 3-year follow-up, resting heart rate (HR) and BNP were significantly reduced with dose-response relations in the early period but without dose-response relations in the late period. The LVEF and the LVDd were increased and decreased, respectively, without a dose-response relation. No significant difference was seen in the composite primary endpoint of all-cause mortality and hospitalization for cardiovascular diseases and heart failure. Multivariate analysis indicated early decreases in HR and BNP predicted long-term outcomes. However, adverse events increased dose-dependently. Among 237 polymorphisms in 87 heart failure-related genes, the osteopontin G-156 del genotype was associated with an event-free survival rate (Wilcoxon test, P = 0.030). Conclusions A low carvedilol dose is effective if the HR and/or plasma BNP has been reduced. Carvedilol therapy should be guided by reductions in HR and/or BNP, especially by initial HR reduction, but not only by its dose. OPN might be a surrogate genetic marker for long-term event-free survival.

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