J-CHF: Tailoring carvedilol dose to heart failure patients' response more effective

Tailoring the dose of a heart failure drug to a patient's response is better than the one-size-fits-all approach, according to research presented in a late-breaking clinical trial at the American Heart Association's Scientific Sessions 2009.

The Randomized Trial to Optimize the Dose and Efficacy of Beta-Blocker in Systolic Heart Failure: Japanese Chronic Heart Failure (J-CHF) Study involved 364 patients with mild to moderate heart failure assigned to one of three daily dosages of the beta blocker carvedilol (2.5 mg, 5 mg or 20 mg).

Researchers sought to determine the optimum minimal dose of the drug. They also investigated background factors that could predict the response to beta-blocker treatment, and established a method for individualized treatment with the drug.
During three years of follow-up, 20 percent of the patients reached the primary endpoint -- a composite of all-cause death or hospitalization for cardiovascular disease including heart failure. Researchers found no statistically significant difference between groups. However, 26 percent of the patients assigned to get 20 mg/day had to discontinue or change their dose due to adverse effects, compared to only 2 percent in the low-dose group and 7 percent in the moderate-dose group.

"Beta-blocker therapy has proved to be a very powerful tool in the treatment of patients with heart failure," said Masatsugu Hori, M.D., Ph.D., principal investigator of the study, president of the Osaka Medical Center for Cancer and Cardiovascular Diseases and professor emeritus at Osaka University in Osaka, Japan. "However, the optimum dose of beta-blockers in patients with chronic heart failure is unknown. We found that all three of the doses we tested were equally effective at reducing our primary endpoint."

The target dose is the maximum dose that has shown to be effective in randomized clinical trials. The clinical target dose in the United States and Europe is 50 mg of carvedilol greater than the highest dose of 20 mg used in this study.

In the previous study, MUCHA (Multi-center Carvedilol Heart Failure Dose Assessment trial) conducted in Japan in patients with mild to moderate heart failure, researchers found no significant difference in outcome between 5 mg and 20 mg daily dose of carvedilol, though it remains difficult to determine how individual patients will respond.

"The important point may not be dosage," said Hiroshi Okamoto, M.D., Ph.D., co-author of the study and director of cardiovascular medicine at Nishi Sapporo National Hospital (Hokkaido Medical Center) in Sapporo, Japan. "Our results do not simply indicate that 2.5 mg/day is the optimal dose. Rather, our results indicate that therapeutic response to carvedilol shows a high amount of variability between individuals, and we had better select the dose that can achieve reductions in heart rate and/or plasma BNP beyond dosage."

Change in a patient's heart rate and/or plasma BNP is "one of the very simple markers to predict mortality, and the optimal dose is the lowest one that reduces heart rate and BNP in an individual patient," Hori said.

"We are searching possible genes that may someday help predict individual response. It appears to be related to the responsiveness of heart rate and levels of plasma BNP, a biomarker for heart stress in response to the drug," Okamoto said.

The J-CHF researchers found that patients with a good response in heart rate reduction and plasma BNP decrease in the early period after initiation of the drug had a better outcome in the primary endpoint. The ethnic and individual differences in the dosage of beta-blocker deserve further studies for patients with different genetic backgrounds.

The study was funded by the Japan Heart Foundation.

Co-authors are: Tsutomu Yamazaki, M.D., Ph.D.; Tsutomu Yoshikawa, M.D., Ph.D.; Hiroyuki Tsutsui, M.D., Ph.D.; Junichi Azuma, M.D.; Masunori Matsuzaki, M.D., Ph.D.; Tohru Izumi, M.D., Ph.D.; Yasuo Ohashi, Ph.D.; and Akira Kitabatake, M.D., Ph.D.
Disclosures: None.