82th AHA Meeting Nov 17, 2009 Orlando, USA Presenter Disclosure Information Randomized Trial to Optimize the Dose and Efficacy of Beta-Blocker in Systolic Heart Failure: Japanese Chronic Heart Failure (J-CHF) Study Masatsugu Hori, Hiroshi Okamoto Masunori Matsuzaki, Tohru Izumi, Tsutomu Yamazaki, Tsutomu Yoshikawa, Hiroyuki Tsutsui, Yasushi Fujio, Jyunichi Azuma, Yasuo Ohashi, Akira Kitabatake On behalf of the J-CHF Investigators and Patients Disclosures Research funding from Japanese Heart Foundation Consulting Fees & Honorarium: None
Rationale & Objectives of J-CHF Trial Rationale: Beta blocker therapy has become a standard treatment for chronic heart failure (CHF). Dose-escalation of carvedilol from a small dose to a target dose of 50-100 mg/day is recommended in most Western countries. Based on the MUCHA trial conducted in Japan, however, a small dose of 5-20 mg of carvedilol is recommended as the maintenance dose. The optimal minimal dose of beta blockers for CHF remains to be determined based on ethnic differences. Objectives: To determine the optimal minimal dose of the beta blocker carvedilol for CHF in Japan. To determine the predictors of responders to beta blocker
Inclusion/Exclusion Criteria Chronic stable heart failure 20-80 years, NYHA II or III, EF<40% Key Exclusions: cardiogenic shock, SBP < 80 mmhg severe arrhythmia (e.g. sustained VT, VF) bradycardia (<50 beats/min), II degree or advanced AV block recent MI, CABG or PCI
Study Design multi-center, prospective, randomized, open-labeled, blinded endpoint (PROBE)
Primary endpoint Composite of all cause death and hospitalization for cardiovascular diseases and heart failure Secondary endpoints All cause death Hospitalization for Cardiovascular Diseases Hospitalization for heart failure and need to modify treatment due to worsening of heart failure Death from heart failure Sudden death (including death from arrhythmia) Aggravation of SAS or NYHA class Left ventricular ejection fraction (LVEF) Plasma BNP
Baseline characteristics of the three treatment groups
Discontinuation or change in treatment dose Treatment Achieved No change in Change in Discon- Group dose treatment dose treatment dose tinuation 2.5 mg 2.4 mg 93 % 0.7 % 1.7 % 5 mg 4.8 mg 90 % 4.2 % 2.6 % 20 mg 16.7 mg 73 %* 23 %* 3.4 % Total 85 % 9.4 % 2.6 % Adverse events by treatment group *p<0.05 Treatment Hypotension Group Bradycardia Tachycardia Tachyarrhythmias Heart failure related Others 2.5 mg 3.4 % 10.3 % 19.7 % 15.4 % 5 mg 6.0 % 5.1 %* 9.4 % 15.4 % 20 mg 11.2 %* 3.2 %* 14.7 % 27.6 %* Total 6.9 % 6 % 14.6 % 19.4 %
Kaplan-Meier Estimate for Primary Endpoint Follow-up: 3.0±1.3 years 1.00 0.70 0.90 0.80 2.5 mg /day 5 mg /day 0.60 20 mg /day 0.50 0 1 2 3 4 5 6 Time after randomization (yrs) Treatment Patients Events Hazard ratio Group (n) (n) (95%CI) 2.5 mg/day 118 27 reference Log-rank test P 0.862 2.5mg vs. 5mg 5 mg/day 116 22 P=0.625 (0.491-1.514) x2= 0.2383 1.004 2.5mg vs. 20mg 20 mg/day 118 25 P=0.990 (0.583-1.731) x2= 0.0002
Primary and Secondary Endpoints Daily dose 2.5 mg 5 mg 20 mg HR (95% CI) HR(95% CI) (N=118) (N=116) (N=118) 2.5 mg vs. 5 mg P 2.5 mg vs. 20mg P Primary Endpoint- n 27 22 25 0.862 1.004 0.606 0.99 (%) (22.9) (19.0) (21.2) (0.491-1.514) (0.583-1.731) Secondary Endpoints All-Cause Death 9 7 8 0.832 0.715 0.988 0.98 Sudden Death 5 3 6 0.632 0.530 1.310 0.66 Death from Heart Failure 2 2 1 1.105 0.921 0.590 0.67 Hospitalization for Cardiovascular 8 10 5 1.336 0.542 0.656 0.46 Diseases Hospitalization for Heart Failure 21 14 18 0.671 0.248 0.880 0.69
Primary Endpoint Multivariate analyses related to the primary endpoint (Cox Hazard Model) Parameters Parameter Chi-square estimate P Value Hazard ratio(95%ci) Treatment (2.5mg vs. 5mg) 0.612 0.183 1.844 (0.749-4.536) Treatment (2.5mg vs. 20mg) 0.868 0.056 2.383 (0.977-5.810) Sex (M/F) 0.518 0.216 1.679 (0.738-3.817) Age (Yr) -0.012 0.482 0.988 (0.957-1.021) LVEF(OP) -0.023 0.422 0.977 (0.925-1.033) BNP log (OP) 1.397 0.004 4.044 (1.563-10.46) HR (OP) 0.015 0.344 1.015 (0.984-1.047) NYHA Class 0.199 0.658 1.220 (0.507-2.938) SAS Score (Mets) -0.278 0.030 0.757 (0.589-0.974) Δ LVEF (Fixed 24W-OP) -0.031 0.052 0.969 (0.939-1.000) BNP log (Fixed 0 W-OP) 2.807 <.0001 16.56 (4.759-57.61) HR (Fixed 0 W-OP) 0.054 0.002 1.055 (1.020-1.091) : change OP: observation period
Changes in LVEF (mean ±95%CI.) 60 2.5 mg/day ΔLVEF 1.6 5 mg/day 50 20 mg/day 1.4 40 1.2 NS 30 1.0 20 OP 24 W 48 W OP 24 W Treatment Observation Period Fixed Dose Period Group (OP) 24 W 48 W 2.5 mg/day 30.4±7.9 (%) 41.2±12.2* (%) 42.6±14.5* (%) 5 mg/day 29.8±6.5 41.3±12.8* 42.6±13.6* 20 mg/day 30.4±7.0 42.4±13.0* 43.2±12.8* *p<0.05 vs. OP
Changes in Heart Rate (mean ± 95%CI.) 100 2.5 mg/day 1.1 5 mg/day 90 1.0 20 mg/day Δ Heart Rate 80 70 60 0.9 0.8 P<0.01 50 OP 0 W 24 W 48 W OP 0 W Treatment Observation Period Fixed Dose Period Group (OP) 0 W 24 W 48 W 2.5 mg/day 82.5±15.9 bpm 77.1±14.5* bpm 74.3±13.4* bpm 73.9±12.2* bpm 5 mg/day 79.0±15.9 72.0±13.1* 70.8±12.4* 69.3±10.3* 20 mg/day 79.8±17.6 68.8±13.6* 68.0±12.4* 68.9±14.0* *p<0.05 vs. OP
Changes in BNP log (mean ±95%CI.) 3 2.5 mg/day 2.5 mg/day 5 mg/day ΔBNP log 1.2 20 mg/day 1.0 2 0.8 0.6 P<0.05 1 OP 0 W 24 W 48 W OP Treatment Observation Period Fixed Dose Period Group (OP) 0 W 24 W 48 W 0 W 2.5 mg/day 335.1±348.0 pg/ml 216.2±215.4* pg/ml 260.5±203.8* pg/ml 148.6±219.7* pg/ml 5 mg/day 378.0±414.9 217.0±261.2* 186.5±378.9* 165.4±412.1* 20 mg/day 453.1±547.7 220.4±264.3* 162.2±238.9* 155.8±270.6* *p<0.05 vs. OP
Hazard ratio based on 1st trimester of distribution for difference between observation period and fixed dose period Changes of distribution in LVEF Changes of distribution in HR 2nd T 3rd T 2nd T 3rd T 2nd T 2nd T 3rd T 3rd T 2nd T 3rd T 2nd T 3rd T * * 2.5 mg/day 5 mg/day 20 mg/day 0 1 2 3 0 1 2 3 Hazard ratio Changes of distribution in BNP log Correlation of HR with BNP 80 60 2nd T 40 3rd T 20 0 2nd T 3rd T -20-40 2nd T -60 r=0.246 3rd T -80-100 0 1 2 3 Data are expressed as mean ± 95%CI. *P<0.05-2.0-1.5-1.0-0.5 0.0 0.5 1.0 1.5 ΔBNP log (Fixed 0W - OP)
Summary No significant difference in the primary endpoint of all-cause death and hospitalization for CVD and heart failure was seen between the three doses of carvedilol (2.5 mg, 5 mg, 20 mg). In all groups, LVEF was increased and plasma BNP and heart rate were significantly decreased with carvedilol. An increase in LVEF was not dose-dependent, whereas decreases in BNP and heart rate were dose-dependent. Multivariate analysis revealed that changes in BNP and heart rate in the observation period are predictors of long-term outcomes. Drug discontinuation and adverse events were increased dosedependently.
Conclusions Even a small dose of carvedilol, 2.5 mg/day, exhibits a beneficial effect on long-term outcomes in Japanese patients with mild to moderate chronic heart failure (CHF) with reduced LVEF. Larger decreases in BNP and heart rate in the observation period could be a predictor of responders to long-term beta blocker therapy that is beyond the dose itself. J-CHF suggests initiating carvedilol at the lowest dose and increasing the dose incrementally until the desired reductions in heart rate and/or plasma BNP are achieved. Further study is warranted to understand optimal dosing in different ethnic populations with different genetic backgrounds.