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Corresponding author at: Department of Cardiovascular Medicine, Hokkaido Medical Center, Yamanote 5-7, Nishi-ku, Sapporo 063-0005, Japan. Tel./fax: +81 1 11 611 8111.
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.
2009 focused update: ACCF/AHA guidelines for the diagnosis and management of heart failure in adults: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines: developed in collaboration with the International Society for Heart and Lung Transplantation.
ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012. The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC.
]. In the clinical setting, dose-escalation therapy beginning at a low dose has been applied according to these key guidelines. The established target daily carvedilol dose is usually 50 mg, occasionally 100 mg, in the United States and Europe. Despite guideline recommendations, prescribed doses are often lower than those shown to reduce morbidity and mortality in clinical trials [
Dosing of beta-blocker therapy before, during, and after hospitalization for heart failure (from organized program to initiate lifesaving treatment in hospitalized patients with heart failure).
]. In the Multicenter Carvedilol Heart Failure Dose Assessment (MUCHA) study, morbidity improved even at carvedilol daily doses of 5 mg and 20 mg, as compared to a placebo [
Low-dose carvedilol improves left ventricular function and reduces cardiovascular hospitalization in Japanese patients with chronic heart failure: the Multicenter Carvedilol Heart Failure Dose Assessment (MUCHA) trial.
] found a dose-dependent decrease in mortality and cardiovascular hospitalization; however, the differences in the outcomes between doses were minimal during the six-month follow-up. Further, no report has been published comparing the efficacy of different doses for identifying the minimal effective dose. In a recent meta-analysis, the survival benefit of beta-blockade was demonstrated to be associated with the degree of heart rate reduction, while no significant relationship was observed between beta-blocker doses and the improvement of all-cause mortality [
Heart rate as a risk factor in chronic heart failure (SHIFT): the association between heart rate and outcomes in a randomized placebo-controlled trial.
]. However, whether the benefits of beta-blockade are related to the administered dose or the degree of heart rate reduction remains unclear. As well, the ethnic or individual genetic background likely determines the clinical outcome of beta-blocker drugs, as genetic variants have been shown to modify the responsiveness to beta-blockade [
]. For instance, the Beta-Blocker Evaluation of Survival (BEST) substudy revealed that beta1ARArg389 homozygotes treated with bucindolol had a lower mortality risk than those treated with the placebo [
In the present study, we prospectively examined whether the clinical outcome of carvedilol was related to the administered dose or the heart rate reduction, and whether the minimal dose of carvedilol provided a survival benefit. To accomplish this aim, we evaluated event-free survival by intention-to-treat analysis in response to carvedilol treatment by comparing the efficacy and safety of 3 doses of carvedilol in Japanese patients with CHF. In addition, we assessed different surrogate markers to determine which ones were predictive of drug efficacy, including heart rate, brain natriuretic peptide (BNP), ejection fraction (EF), New York Heart Association (NYHA) functional class, and other clinical parameters.
2. Methods
2.1 Study design and patient recruitment
The J-CHF study was approved by the Ethics Committee of Hokkaido University Graduate School of Medicine, Hokkaido, Japan, and complies with the Declaration of Helsinki. The institutional review board of each participating institution approved the J-CHF study protocol, including the pharmaco-genomic analyses. The authors have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology.
Between July 2003 and January 2008, 364 patients were registered at 130 clinical sites in Japan using an internet-based entry system. Using centralized, computer-generated randomization with an algorithm based on the underlying disease, severity, age, and sex, the 364 patients were randomly allocated using a 1:1:1 ratio to one of three carvedilol groups (2.5 mg, 5 mg, or 20 mg daily). Other beta-blockers were prohibited, as were α-blockers, αβ-blockers, and inotropic agents other than digitalis. Consent for this study was given by all patients enrolled in this study, while consent for the pharmaco-genomic study was obtained from 126 patients. Inclusion criteria were stable CHF (NYHA class II/III, EF≤40%), not currently taking carvedilol, and an age between 20 and 80 years. Exclusion criteria were the same as in the MUCHA study [
Low-dose carvedilol improves left ventricular function and reduces cardiovascular hospitalization in Japanese patients with chronic heart failure: the Multicenter Carvedilol Heart Failure Dose Assessment (MUCHA) trial.
The study design is outlined in Fig. 1. Following an 8-week observation period, carvedilol was titrated upward over an 8-week period from 1.25 mg twice daily to the target dose of 10 mg twice daily based on tolerability. Thereafter, patients were seen every 2 to 8 weeks for the 3-year follow-up. Every 6 months, patients were evaluated for NYHA class and specific activity scale (SAS). In addition, an ECG, chest X-ray, echocardiography, and lab tests including BNP were conducted at weeks 0, 24, and 48 of the fixed-dose period. Of the 364 eligible patients, 4 withdrew informed consent, 8 were lost to follow-up, and 352 patients were maintained at the randomly assigned dose or the maximum tolerated dose below the target dose for the study duration and were available for analyses by treatment allocation (Fig. 2).
Fig. 1Study protocol. The mean up-titration period (from the initiation of carvedilol to a fixed-dose period week 0) was 52.9 days. NYHA, New York Heart Association, SAS, specific activity scale; SBP, systolic blood pressure; and BNP, brain natriuretic peptide.
The primary endpoint was the composite of all-cause mortality and hospitalization for cardiovascular diseases (CVD) and heart failure. All the clinical data were collected at an independent core lab of the Administration Office. Study endpoints and all outcomes were assessed by an independent and blinded Endpoints Committee and then statistically evaluated in an independent Monitoring Office. The secondary endpoints were all-cause mortality, hospitalization for CVD or heart failure, or worsening of symptoms (defined as a decrease ≥1 Mets in the questionnaire score or an increase ≥1 NYHA class for at least 3 months) or a need for modification of heart failure treatment (changes in oral medicine for at least one month or addition of intravenous inotropes for at least 4 h).
2.3 Genetic polymorphisms
Genomic DNA was extracted from peripheral blood leukocytes using the QIAamp DNA Blood Maxi Kit (QIAGEN, Hilden, Germany). Eighty-seven heart failure-related genes and 237 polymorphisms were selected as detailed in Appendix 3. The genotyping of each polymorphism was performed by PCR-based methods. The OPN gene polymorphisms were determined by sequencing with the ABI PRISM BigDye Terminator Cycle Sequencing Ready Reaction Kit (Applied Biosystems, Foster City, USA).
2.4 Sample size
The sample size was based on a significance level of α=0.04 for all-cause mortality and hospitalizations for CVD or heart failure (two-sided, by treatment allocation) with 80% power (β<0.20) to detect differences between treatment groups for the primary endpoint, we calculated that we needed to recruit 450 patients. Using the results from the MUCHA study in Japanese patients as a guide, we set the event incidence rate in the 5-mg and 20-mg groups at 9% and 6%, respectively. The event incidence rate for the 2.5-mg group was set at 15%, based on a separate hyperbolic graph. During the time frame of the J-CHF study, carvedilol became the standard treatment for heart failure. Consequently it became increasingly difficult to recruit patients who were not taking the drug. In March 2007, the Executive Committee extended the length of the fixed dose maintenance phase from 24 weeks to 48 weeks and the follow-up period from 26 weeks until a sufficient number of events had occurred, thereby reducing the number of patients required to 420. Two interim analyses were planned when the study length was extended. The predefined stopping rule for efficacy was based on the occurrence of primary outcome events, analyzed by treatment allocation, with predetermined interim analyses when 25%, 50%, and 75% of expected primary events had occurred. The study was designed to terminate after the accrual of 97 primary events and a minimum of 4.5 years of follow-up for all enrolled patients. The first interim analysis was performed in December 2006 after 298 patients were enrolled (median follow-up period; 1.56 years, person-time; 420.8 person-years). A primary event had occurred in 29 patients and the 2-year event-free survival rate was calculated to be 87.7% (95% CI; 82.6%–91.3%). The second interim analysis was performed in December 2008. A primary event had occurred in 74 patients. With 2 interim analyses, the study-wide type I error rate of 0.05 was maintained by allocating α=0.0113 to the analysis of all-cause mortality or hospitalization for CVD or CHF, and α=0.0008 to the short-term clinical status studies.
2.5 Statistical analysis
Based on survival in the MUCHA trial, event-free survival was assumed to be 85.3% in the second year of the 2.5-mg/d group. For an 80% power to detect a hazard ratio of 2.0 in the 5-mg or 20-mg groups using the log-rank test and a significance level of 2.5% (one-sided), a sample size of 417 (139 per treatment group) was required. For the main analyses, we used the log-rank test to compare the three groups, and the Cox hazards model to calculate hazard ratios and 95% confidence intervals (CI). Cumulative survival curves were constructed as time-to-first-event plots by the Kaplan–Meier method. For estimating effect size, hazard ratios with 95% CI were calculated using the Cox regression model. Continuous variables are reported as mean±standard deviation (SD). An α-level of 0.02168 (one-sided) was used to indicate statistical significance for the primary endpoint; an α-level of 0.05 (two-sided), all secondary endpoints. All analyses were conducted by treatment allocation in accordance with the intention-to-treat principle. Data were analyzed with the SAS version 9.1 statistical program (SAS Institute Inc., Cary, NC, USA).
2.6 Role of the funding source
The sponsors of this study played no role in the study design, data collection, data analysis, data interpretation, the writing of the report, or in the decision to submit the paper for publication. HO had full access to all the data in the study and had final responsibility for the decision to submit for publication.
3. Results
In March 2009, based on data from two interim analyses, the study was terminated because of a statistically equivalent improvement in survival with carvedilol, exceeding the pre-specified interim monitoring boundaries for all three treatment groups. The safety parameters were similar among the groups. Furthermore, the Data and Safety Monitoring Committee deemed this finding clinically important, since it was the first demonstration that low-dose carvedilol is safe and effectively reduces all-cause mortality or hospitalization, and thus could not be denied to patients outside the study.
3.1 Demographics and patient characteristics
The patient demographics and baseline characteristics are shown in Table 1. CHF was due to ischemia and cardiomyopathy in 29% and 62% of the patients, respectively. The mean LVEF was 30.2±0.7%. Meanwhile, 83% of patients had NYHA class II heart failure. Chronic atrial fibrillation was found in 20.6%, while 12% had a prior coronary artery bypass graft or a percutaneous coronary intervention. No significant differences in the key parameters shown in Table 1 were observed between groups; the drugs used for treating heart failure were similar.
Table 1Demographics and baseline characteristics of the patients. BMI, body mass index; IHD, ischemic heart disease; LVEF, left ventricular ejection fraction; SAS, specific activity scale; SBP, systolic blood pressure; BNP, brain natriuretic peptide; ACEI, angiotensin-converting enzyme inhibitor; and ARB, angiotensin II receptor blocker. Data are represented as the mean±SD or the number of patients (%).
At the completion of the 8-week up-titration, the average daily doses of carvedilol were 2.4 mg, 4.8 mg, and 16.7 mg in the three treatment groups. One patient died during this period. Table 2 shows discontinuation or changes in the treatment doses. Gradual dose escalation resulted in a higher tolerable dose of carvedilol. Only 0.7% of patients in the 2.5-mg group did not tolerate carvedilol, as compared to 4.2% in the 5-mg group (P<0.05) and 23% in the 20-mg group (P<0.05). Drug discontinuation occurred in only 1.7%, 2.6%, and 3.4% of the patients in the 2.5-mg, 5-mg, and 20-mg groups, respectively. In the 20-mg group, discontinuation rate was significantly higher due to hypotension or bradycardia compared with the 2.5-mg group. More adverse effects related to hypotension and bradycardia and fewer tachycardia and tachyarrhythmia events occurred in the 20-mg group than in the other two groups.
Table 2Discontinuation or changes in the treatment dose. The study protocol defined a serious adverse event as a fatal or life-threatening event that required or prolonged hospitalization or resulted in a persistent or significant disability or incapacity.
During the follow-up period, symptoms (NYHA and SAS) improved equivalently in each group. LV diastolic diameter (LVDd) was decreased by a significant 7.4% at week 24 and 8.7% at week 48, without a dose–response relationship. There was a significant 37.7% and 41.7% relative increase in LVEF at weeks 24 (41.6±1.3) and 48 (42.8±1.4) of the fixed-dose period from baseline (30.2±0.7), respectively, without a dose–response relationship. The delta changes in the LVEF between the observation period and week 24 were equivalent in each group (Fig. 3). The BNP levels were dose-dependently reduced at week 0 (217.8±247.2 pg/ml). Although BNP levels gradually and relatively decreased by 60% from baseline (388.8±444.5 pg/ml) at week 48 (156.4±307.9 pg/ml), no differences between doses were observed. Resting heart rate, based on 12-lead ECG data, was significantly reduced in each group during the fixed-dose period at week 0 (5.4 bpm, 7.3 bpm, and 11.0 bpm) with a clear dose–response relationship, at weeks 24 (8.3 bpm, 8.2 bpm, and 12.1 bpm) and 48 (8.7 bpm, 9.7 bpm, and 10.9 bpm) without any significant dose–response relationship. Chronic AF was present in 20.6% of all the patients. There were no significant differences in age, sex, NYHA class, EF, dose of carvedilol and resting HR between patients with AF or sinus rhythm (SR). Resting mean heart rates at baseline were 78.5 and 81.1 bpm, and reduced to 71.4 and 70.7 bpm at week 48 in the AF and SR patients, respectively. No significant differences for the primary endpoint were found in both AF and SR patients. There were significant 41.9% and 43.6% relative increases in LVEF at week 48 of the fixed-dose period from baseline in both AF and SR patients, respectively. Patients with CHF and AF derive comparable clinical benefits from carvedilol titration as those in SR.
Fig. 3Changes in LVEF. The mean LVEF (left ventricular ejection fraction) from the initiation of carvedilol to the fixed-dose period of weeks 24 and 48 increased without a dose–response relationship. *P<0.05 versus the observation period (OP). Values represent the mean±CI.
The primary endpoint occurred in 74 patients (20%) during the mean 3-year follow-up period (Table 3). The occurrence of the primary endpoint was 14% lower in the 2.5-mg group than that in the 5-mg group (P=0.31). No significant between-group differences for the primary endpoint were found, as shown by the Kaplan–Meier curve (Fig. 4). In total, 24 patients died; all cause-death was a secondary endpoint. NYHA was not related to an increased risk for the primary endpoint, whereas SAS was weakly correlated. At week 0 of the fixed-dose period, as compared to the observation period, the BNP and heart rate were significantly related to a decreased risk for the primary endpoint. In fact, a decrease in BNP was associated with a statistically significant 17% relative risk reduction for the primary endpoint. Change in EF did not correlate significantly, whereas changes in heart rate and BNP did (P<0.001). There was a significant 12% relative decrease in resting HR (from 80.6 to 71.2 bpm) at week 48 of the fixed-dose period from baseline without a dose–response relationship. Resting heart rates reached below 75 bpm in 66.3% of all patients. Patients with reduced HR below 75 bpm showed better clinical outcomes as shown in Fig. 5B . For evaluating the risk of the primary endpoint in relation to changes in the distribution of heart rate and BNP between the observation and fixed-dose periods, a change in trimester distribution was associated with a reduction in risk at week 0 (Fig. 5A and B). Thus, BNP and heart rate at week 0 seem to be predictors for the risk of death or hospitalization in these patients.
Table 3Multivariate analyses related to the primary endpoint. Compared to the 5-mg group, the occurrence of the primary endpoint was 14% lower in the 2.5-mg group (P=0.31). A total of 24 patients died. All cause-death was a secondary endpoint.
Fig. 4Kaplan–Meier estimate for primary endpoint. The primary endpoint occurred in 74 patients during the mean 3-year follow-up period. No significant between-group differences for the primary endpoint were found.
Fig. 5A and B. Kaplan–Meier estimates for the primary endpoints ∆BNP log and ∆HR. The Kaplan–Meier plots for the primary endpoints by tertiles of ∆BNP log and ∆HR. ∆, change; BNP, brain natriuretic peptide; and HR, heart rate.
In a Wilcoxon analysis of 237 polymorphisms in 87 genes, only the OPN G-156 del genotype showed a significant relation with the event-free survival rate (P=0.030) (Fig. 6). Patients with the OPN del/del genotype showed survival benefits, indicating the OPN del allele is a genetic risk factor for responsiveness to carvedilol. The beta1AR Arg389Gly, Ser49Gly, and alpha (2C) Del genotypes were not associated with event-free survival or heart rate (data not shown), and no significant results were observed for these three genotypes for the low-dose and high-dose groups.
Fig. 6Association between OPN G-156del polymorphism and event-free survival. Solid line, del homozygote and broken line, G allele carrier. The two curves were significantly different according to the Wilcoxon test (P=0.030).
The J-CHF study with blinded efficacy adjudication revealed no significant differences in the primary endpoint of all-cause mortality or hospitalization for CVD or heart failure among the three evaluated carvedilol doses (2.5 mg, 5 mg, and 20 mg). LVEF increased by 41.7% from the baseline of the fixed-dose period from baseline (from 30.2±0.7 to 42.8±1.4). Plasma BNP, heart rate, and LVDd were significantly decreased initially in a dose-dependent manner and later in a non-dose-dependent manner. Notably, a small dose of carvedilol (2.5 mg/d) provided a similar long-term outcome relative to the higher doses, with concomitant heart rate reduction and improved LVEF, plasma BNP, NYHA functional class, and SAS. Multivariate analysis indicated early decreases in plasma BNP and heart rate to be clinical predictors of long-term outcomes. In contrast to dose-independent outcomes, drug discontinuation and adverse events were dose-dependent. The study was stratified with underlying disease, severity, age, and sex and we used Cox's proportional hazards regression analyses of total mortality or hospitalization to explore any unfavorable outcome in prespecified risk groups, defined by entry characteristics.
Several studies have reported that the mortality benefits of beta-blockers are dose-dependent, but only the MOCHA study prospectively examined dose-related efficacy, in which carvedilol produced a linear improvement in LVEF in the 12-mg, 25-mg, and 50-mg groups and showed reductions in mortality and hospitalization rates compared with the placebo. However, the median follow-up was only 6 months. Further, the trial was designed to evaluate the sub-maximal exercise capacity as a primary parameter and was not examined for the influence of heart rate. Even now, no reports have been published comparing the efficacy of different doses of carvedilol to identify the minimal effective dose for heart failure.
Recently, in a post hoc analysis, a higher dose of beta-blockade was associated with significantly lower rates of all-cause death and all-cause hospitalization [
]. However, there is as yet no definitive evidence of a dose–response relationship in a randomized, controlled trial. It has been demonstrated in the meta-analysis of randomized heart failure trials that the survival benefit of beta-blockers to be associated with the magnitude of heart rate reduction but not with the dose; a commensurate 18% reduction in the risk of death was obtained with every heart rate reduction of 5 bpm, while no significant relationship was found between all-cause mortality and the beta-blocker dose [
]. Is there any additional benefit to up-titrating beta-blockers to trial doses if substantial heart rate reduction has already been achieved even with a lower dose? In the MERIT-HF trial [
Dose of metoprolol CR/XL and clinical outcomes in patients with heart failure. Analysis of the experience in metoprolol CR/XL randomized intervention trial in chronic heart failure (MERIT-HF).
], the heart rate showed a dose-related decrease in the early period, but after 3 months no significant difference was observed between the low- and high-dose groups. Total mortality was also similar in these 2 groups. In the J-CHF trial, the mean heart rate reduction was 8.0, 9.6, and 9.8 bpm at weeks 0, 24, and 48, respectively, which was compatible with the CIBIS II trial [
]. As well, a reduction in risk was reflected by early changes in the mean heart rate reduction. The linear dose-dependency of the heart rate reduction disappeared at weeks 24 and 48. Thus, initial changes in heart rate might predict the clinical outcome after long-term treatment with carvedilol, and it is suggested that even at 2.5 mg/d of carvedilol, if the heart rate has been reduced, the clinical outcome is improved. Still, the J-CHF trial is the only one to compare the effect of the dose from the perspective of heart rate reduction, which may correspond to the results of the meta-analysis.
At the completion of the COPERNICUS trial, the NT-proBNP levels in the carvedilol group were decreased by 15%, with a heart rate reduction of 12.5 bpm [
Prognostic impact of plasma N-terminal pro-brain natriuretic peptide in severe chronic congestive heart failure: a substudy of the Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) trial.
], both NT-proBNP and BNP were significantly reduced after 6 months of carvedilol treatment (NT-proBNP, −22% and BNP, −20%), which might reflect reversed cardiac remodeling. In the J-CHF study, the BNP was relatively decreased as much as 60% from baseline with no differences between doses of carvedilol, showing an essential effect on reverse remodeling even at a low dose of carvedilol.
Genetic variations cause differences in individual responses and may also serve as genetic predictors for long-term outcomes [
No positive association between adrenergic receptor variants of alpha2cDel322-325, beta1Ser49, beta1Arg389 and the risk for heart failure in the Japanese population.
]. In the J-CHF study, the OPN polymorphism, but not the beta1AR polymorphisms (Ser49Gly and Arg389Gly) and alpha (2C) Del, was significantly associated with event-free survival with carvedilol treatment among 237 heart failure-associated polymorphisms. Osteopontin plays a major role in regulating extracellular matrix proteins, including collagen and fibronectin. Increased OPN expression parallels cardiac remodeling and heart failure [
]. Myocardial biopsies from patients with advanced heart failure show higher expression of myocardial OPN than those of healthy subjects with concomitant cardiac fibrosis [
]. The OPN G-156 del polymorphism is located in the RUNX2 binding site, and an in vitro promoter assay revealed that the −156G allele shows higher promoter activity than the −156del allele in the presence of the Runt-related transcription factor 2 (RUNX2) expression vector [
]. Taking these observations together, we assume that patients with the OPN-156 G allele have a higher OPN expression, more myocardial fibrosis, and are less responsive to carvedilol than OPN-del homozygous patients. Besides J-CHF study, pharmaco-genomic analyses were performed in different cohorts to examine beforehand polymorphisms associated with responsiveness to beta-blocker in patients with heart failure. In other cohorts having similar sample size, OPN G-156 del genotype was significantly associated with responsiveness to carvedilol (Data not shown). In J-CHF, about one-third of patients had the −156G allele. OPN may be a genetic marker that predicts the morbidity and mortality of CHF patients, although our present findings are hypothesis-generating, and a large-scale trial is needed to confirm this hypothesis.
Based on the J-CHF results, the long-term effect of carvedilol in patients with CHF does not depend strictly on the target dose, and the relation between effect and dose, if any, is small. A higher dose can result in better outcomes, which may be offset by more adverse events. The optimal dose in terms of safety and efficacy should be determined by individual responsiveness, balanced by the impact on quality of life. Decreases in heart rate and/or BNP are effective as surrogate and predictive variables of improvement. In particular, initial heart rate reduction is an easily measured clinical parameter to evaluate the responsiveness to carvedilol.
4.1 Limitations
The present study had several limitations. First, because of the PROBE design and ethical considerations, the J-CHF study did not have a placebo group, although the MUCHA study revealed that 5 mg and 20 mg of carvedilol showed beneficial effects on morbidity relative to the placebo. Considering the magnitude of the increases in EF and the decreases in heart rate and BNP, each dose could exert beneficial responses in patients with systolic dysfunction. Second, the J-CHF study might be too small and of insufficient duration to determine the optimal carvedilol dose. In clinical practice, beta-blocker doses are substantially lower than the doses in clinical trials and those recommended by guidelines in Japan and Western countries. Thus, a large study is warranted to elucidate the optimal doses for populations with different ethnic/genetic backgrounds. Despite these limitations, the present study provides clinically important findings regarding the relationship between carvedilol use and outcomes in a large, representative dataset of CHF patients.
5. Conclusions
In conclusion, a low carvedilol dose is effective if the heart rate has been reduced and the J-CHF study suggests that carvedilol therapy should be guided by reductions in plasma BNP and/or heart rate, i.e. initial heart rate reduction, to obtain optimal safety and efficacy. An OPN polymorphism is a surrogate genetic marker for long-term event-free survival. Further research is needed to determine ethnic and racial differences in response to beta-blocker therapy.
Contributors
All authors participated in the design of the study, interpretation of the data, and writing of the article. The statistical analysis was done by StatCom Co., Ltd. Japan, and was verified by an independent statistician, Hideki Orikasa (Toyama Med. and Pharm. Univ.).
Acknowledgments
The J-CHF study was done auspices of the Japanese Circulation Society (JCS) and the Japanese Heart Failure Society (JHFS). The authors gratefully acknowledge the support of the JCS, JHFS, Japan Clinical Research Assist Center and the Data Management Center in Tokyo, Japan. We also benefited from the secretarial assistance of Tamami Cervantes and the technical assistance of Drs. Masatoshi Akino, Daisuke Goto and Naoki Ishizuka. Clinical data of the MUCHA trial and detailed information about carvedilol were kindly provided by Daiichi-Sankyo Pharmaceutical Co. Ltd.
2009 focused update: ACCF/AHA guidelines for the diagnosis and management of heart failure in adults: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines: developed in collaboration with the International Society for Heart and Lung Transplantation.
ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012. The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC.
Dosing of beta-blocker therapy before, during, and after hospitalization for heart failure (from organized program to initiate lifesaving treatment in hospitalized patients with heart failure).
Low-dose carvedilol improves left ventricular function and reduces cardiovascular hospitalization in Japanese patients with chronic heart failure: the Multicenter Carvedilol Heart Failure Dose Assessment (MUCHA) trial.
Heart rate as a risk factor in chronic heart failure (SHIFT): the association between heart rate and outcomes in a randomized placebo-controlled trial.
Dose of metoprolol CR/XL and clinical outcomes in patients with heart failure. Analysis of the experience in metoprolol CR/XL randomized intervention trial in chronic heart failure (MERIT-HF).
Prognostic impact of plasma N-terminal pro-brain natriuretic peptide in severe chronic congestive heart failure: a substudy of the Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) trial.
No positive association between adrenergic receptor variants of alpha2cDel322-325, beta1Ser49, beta1Arg389 and the risk for heart failure in the Japanese population.
☆☆Funding: The J-CHF study was funded by a Research Grant for Cardiovascular Diseases (14C-2) from the Ministry of Health, Labor, and Welfare of Japan, and the Japan Heart Foundation.
P<0.05 versus 2.5 mg/d dose.
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