American Heart Journal
Volume 147, Issue 2 , Pages 200-201, February 2004

Clinical trials in Japan and the United States

  • John H Alexander, MD, MS, FACC

      Affiliations

    • Duke University Medical Center, Duke Clinical Research Institute, Durham, NC, USA
    • Corresponding Author InformationReprint requests: John H. Alexander, MD, MS, Box 3300 Duke University Medical Center, Durham, NC, 27710, USA.

Article Outline

 

Heart failure, characterized by fatigue, shortness of breath, and peripheral edema, is a major public health problem facing the United States, Japan, and the rest of the industrialized world. Patients with this clinical syndrome have either impaired left ventricular systolic function (systolic heart failure) or normal left ventricular systolic function with impaired diastolic relaxation (diastolic heart failure). Although hypertension, thyroid disease, valvular heart disease, alcohol, and myocarditis are contributors, the most common cause of systolic heart failure in the industrialized world is atherosclerotic coronary artery disease. Because both atherosclerosis and heart failure are primarily diseases of the elderly, the incidence of heart failure is likely to increase over the foreseeable future.

Substantial progress has been made recently in the medical management of chronic systolic heart failure. Current treatment recommendations include a “cocktail” of ≥4 medications that typically include a diuretic, an angiotensin-converting enzyme (ACE) inhibitor, a β-adrenergic receptor blocker, and usually digitalis.1 The use of β-blockers in heart failure has been evaluated in >10,000 patients in >20 published, placebo-controlled, clinical trials.2, 3, 4, 5, 6 These trials typically enrolled patients with reduced left ventricular systolic function (ejection fraction 0.30–0.40) who were already being treated with both diuretics and an ACE inhibitor. In these trials, treatment with β-adrenergic blockers including carvedilol,3 bisoprolol,4 or metoprolol5 resulted in a consistent 30% to 40% reduction in mortality as well as need for rehospitalization. The beneficial effects of β-blockers on morbidity and mortality were seen in all subgroups, including women and the elderly, as well as in patients with a wide range of causes and severity of left ventricular dysfunction. A recent study in patients with NYHA class II to IV and a left ventricular ejection fraction <35% even suggested a difference among the β-blockers with carvedilol (25 mg twice daily) resulting in a lower mortality than short-acting metoprolol tartrate (50 mg twice daily).7 The totality of the evidence supporting the use of β-adrenergic receptor blockers in patients with heart failure and impaired left ventricular systolic function is overwhelming. Because of this compelling evidence of benefit from multiple randomized clinical trials, β-blockers have been given a Class IA recommendation in the American College of Cardiology/American Heart Association Practice Guidelines for the Evaluation and Management of Chronic Heart Failure.1

In this issue of the Journal, Hori et al report on the results of The Multicenter Carvedilol Heart Failure Dose Assessment (MUCHA) trial.8 In this small, randomized, multicenter, placebo-controlled, double-blind study, 174 patients with mild to moderate heart failure (NYHA class II or III) and a left ventricular ejection fraction of ≤40% were randomized 1:1:2 to placebo, 2.5 mg of carvedilol twice daily, or 10 mg of carvedilol twice daily. Patients were treated for 24 to 48 weeks and the primary end point was a global assessment of congestive heart failure (CHF) (signs and symptoms) by the patients' attending physician. Important secondary end points were all-cause mortality and hospitalization for cardiovascular disease or heart failure. The rate of improvement in global assessment of CHF score was 36.7% in the placebo group, 44.7% in the group taking 2.5 mg of carvedilol twice daily, and 59.7% in the group taking 10 mg of carvedilol twice daily (P = .01). The incident of the more conventional end point of death or cardiovascular disease hospitalization was 24.5% in the placebo group, 8.5% in the group taking 2.5 mg of carvedilol twice daily, and 5.2% in the group taking 10 mg of carvedilol twice daily (P = .002). These results confirm, once again, the beneficial effects of β-andrenergic blockade in patients with heart failure and left ventricular dysfunction.

The first question that arises from MUCHA is, so what? The results of MUCHA appear to simply confirm the results of multiple, large, prior trials of β-blockade in heart failure, albeit in a much smaller sample of patients. On closer examination, however, there are at least 2 important lessons that can be gleaned from this trial. Learning these lessons is critical if our goal as physicians and clinical researchers is to improve the health of patients with heart failure.

First, MUCHA gives direct support to the idea of a dose response for carvedilol in patients with heart failure and systolic dysfunction. It is critical to recognize that most clinical trials investigate not only a drug but a particular dose of a drug. When applying trial results to practice, a similar dosing strategy must be applied if one expects the same results. In MUCHA, although both the lower-dose (2.5 mg twice daily) and higher-dose (10 mg twice daily) carvedilol groups showed substantial benefit over placebo, a clear dose response was observed. Whether the still higher dose, targeted in most Western carvedilol trials, would have produced still greater benefits in this Japanese population is unknown. The hypothesis that seems to be favored by the authors is that Japanese patients with heart failure are different and require a lower dose of carvedilol than their Western counterparts. One striking difference is the smaller size of Japanese patients (median weight 60 kg). A second, and more likely, possibility is that the dose-response relationship is similar for Western and Japanese patients and that higher doses of carvedilol would produce still greater benefits in Japanese (and non-Japanese) patients. Unfortunately, sorting these dosing questions out will require additional clinical trials, ideally enrolling patients with heart failure from both Western countries and Japan. In the meantime, clinicians can feel good about the fact that these lower doses of carvedilol will likely provide some benefit for the substantial number of patients who are unable to tolerate higher target doses.

The second and most critical lesson from MUCHA is that patients with heart failure from around the world are similar, at least in their response to β-blockade. The bulk of the published experience on β-blockade in heart failure comes from trials that enrolled patients in the United States, Canada, Western Europe, and Australia. Are patients with heart failure from Japan, or other countries, sufficiently different from their Western counterparts that the results of these major trials can not safely be extrapolated to other populations?

There are numerous theoretical reasons why Japanese patients with heart failure might respond differently to β-blockade with carvedilol; however, most have not been substantiated in actual clinical trials. The report on MUCHA in this issue of the Journal fails to even speculate as to why Japanese patients with heart failure might be different from patients with heart failure from other countries. Concerns about different disease pathophysiology, different drug absorption and metabolism, different receptor biology, just distribution of clinical research risks and benefits, and national pride have all contributed to an unwillingness to accept the results of trials conducted in other countries. But is it really plausible that Japanese patients with heart failure will respond differently to β-adrenergic blockade? The beneficial effects of β-blockers in major trials in Western populations have been consistent across age, sex, etiology of heart failure, left ventricular ejection fraction, and other important subgroups, including, for those that enrolled patients in multiple countries, nationality. In fact, most efficacious (and ineffective) therapies show quantitative but not qualitative differences in efficacy across major subgroups. Requiring the replication of important research findings in each of the world's 190 countries would be a ridiculous exercise that would deprive most of the world's population therapies that have been proven to be beneficial. In the era of globalization, can the world community really afford to ignore important medical findings from other countries and require repetition of the same experiments locally? These are questions that the world's medical and clinical research communities, as well as national regulatory bodies, must address if we are to provide the best available care to our patients. The best solution would be global clinical research and drug development programs with inclusion of patients from all countries where a disease is prevalent. Appropriate exploratory subgroup analyses can then be performed to assess whether there is a differential effect based on region or enrollment, race, or ethnicity. In this case, it is fortunate for Japanese patients with heart failure that the results of MUCHA, an underpowered trial utilizing soft clinical end points, were consistent with the already extensive literature on β-adrenergic blockade in patients with heart failure from other countries.

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References 

  1. Hunt SA, Baker DW, Chin MH, et al. ACC/AHA guidelines for the evaluation and management of chronic heart failure in the adult: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1995 Guidelines for the Evaluation and Management of Heart Failure). 2001. American College of Cardiology Web site. Available at: http://www.acc.org/clinical/guidelines/failure/hf_index.htm
  2. Lechat P, Packer M, Chalon S, et al.  Clinical effects of beta-adrenergic blockade in chronic heart failure (a meta-analysis of double-blind, placebo-controlled, randomized trials). Circulation. 1998;98:1184–1191
  3. Packer M, Bristow MR, Cohn JN, et al.  The effect of carvedilol on morbidity and mortality in patients with chronic heart failure (US Carvedilol Heart Failure Study Group). N Engl J Med. 1996;334:1349–1355
  4. The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomized trial. Lancet 1999;353:9–13
  5. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet 1999;353:2001–7
  6. Packer M, Coats AJ, Fowler MB, et al.  Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med. 2001;344:1651–1658
  7. Poole-Wilson PA, Swedberg K, Cleland JGF, et al.  Comparison of carvedilol and metoprolol on clinical outcomes in patients with chronic heart failure in the Carvedilol or metoprolol european trial (COMET) (randomised controlled trial). Lancet. 2003;262:7–13
  8. Hori M, Sasayama S, Kitabatake A, et al. 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. Am Heart J 2004;147:324–30

PII: S0002-8703(03)00785-3

doi:10.1016/j.ahj.2003.11.004

American Heart Journal
Volume 147, Issue 2 , Pages 200-201, February 2004

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