82th AHA Meeting Nov 17, 2009 Orlando, USA

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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

Tachycardia Treatment Hypotension Heart failure Tachy- Others Group Bradycardia related arrhythmias

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

0.90 0.80

2.5 mg /day 0.70 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 Log-rank test P Group (n) (n) (95%CI)

2.5 mg/day 118 27 reference

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

2.5 mg 5 mg 20 mg HR (95% CI) HR(95% CI) Daily dose

P P (N=118) (N=116) (N=118) 2.5 mg vs. 5 mg 2.5 mg vs. 20mg

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 2 2 1 1.105 0.921 0.590 0.67 Failure

Hospitalization for Cardiovascular 8 10 5 1.336 0.542 0.656 0.46

Diseases

Hospitalization for 21 14 18 0.671 0.248 0.880 0.69 Heart Failure

Primary Endpoint Multivariate analyses related to the primary endpoint (Cox Hazard Model)

Parameter Chi-square Parameters Hazard ratio(95%CI) estimate P Value

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 -0.031 0.052 0.969 (0.939-1.000)

（Fixed 24W－OP）

∆BNP log 2.807 <.0001 16.56 (4.759-57.61) （Fixed 0 W－OP)

∆HR 0.054 0.002 1.055 (1.020-1.091) （Fixed 0 W－OP) ∆: change OP: observation period

Changes in LVEF (mean ±95%CI.) 60

2.5 mg/day ΔLVEF

1.6 5 mg/day

20 mg/day 50 1.4

NS 40 1.2

30 1.0

20 OP 24 W 48 W OP 24 W

Fixed Dose Period Treatment Observation 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.) Δ Heart Rate

100

5 mg/day 90 1.0 20 mg/day

80 P<0.01 0.9

70

0.8 60

50 OP 0 W 24 W 48 W OP 0 W

Fixed Dose Period Treatment Observation 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

2.5 mg/day 1.1

Changes in BNP log (mean ±95％CI.) 3 2.5 mg/day

5 mg/day ΔBNP log

1.2 20 mg/day

1.0

2 0.8

P<0.05

0.6

1 OP 0 W OP 0 W 24 W 48 W

Fixed Dose Period Treatment Observation Period Group (OP) 0 W 24 W 48 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

2.5 mg/day

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 2nd T 3rd T 3rd T

2nd T 2nd T 3rd T 3rd T 2.5 mg/day

2nd T 5 mg/day * 2nd T 3rd T

20 mg/day 3rd T * 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 -2.0 -1.5 -1.0 -0.5 0.0 0.5 1.0 1.5 Data are expressed as mean ± 95％CI.

*P<0.05 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 dose-dependently.

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 periodcould 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.