Candesartan for cardiovascular prevention in Japanese hypertensive patients with coronary heart disease.

In the Heart Institute of Japan Candesartan Randomized Trial for Evaluation in Coronary Heart Disease (HIJ-CREATE), Kasanuki and colleagues randomized hypertensive patients with angiographically proven coronary heart disease either to candesartan or to blood pressure-lowering treatment not based on an angiotensin II type-1 receptor blocker (ARB), but possibly including an angiotensin-converting enzyme inhibitor (ACEI). The primary endpoint was the incidence of major cardiovascular events, a composite of cardiovascular death, non-fatal myocardial infarction, heart failure, stroke, and other cardiovascular events requiring hospitalization. During a median follow-up of 4.2 years, 264 patients of the candesartan group (25.8%) and 288 of the non-ARB group (28.1%) experienced an event. Neither for the composite primary endpoint [hazard ratio 0.89, 95% confidence interval (CI) 0.76–1.06) nor for any of its components did the hazard ratios comparing candesartan with non-ARB treatment approach statistical significance (P . 0.19) Setting up a clinical trial in Japan is not an easy enterprise. The Japanese Pharmaceutical Affairs Law restricts the use of placebo in investigator-initiated studies. A double-blind design goes against local perceptions of clinical experimentation. The HIJ-CREATE investigators have therefore to be congratulated for having randomized .2000 patients into an open-label actively controlled trial. Nonetheless, several features make the interpretation of the HIJ-CREATE results difficult and weaken their external validity. The HIJ-CREATE investigators recruited among selected hospitalized patients undergoing coronary angiography. Patients without stenotic coronary lesions were eligible for randomization in the presence of a history of coronary revascularization or coronary spasm. Of those screened, only 40.9% were enrolled. The trial was powered to detect a 20% reduction in the primary endpoint at a rate in the control group of 100 events per 1000 patientyears. The observed rate was only 67 events per 1000 patientyears and explains why the trial was underpowered. The primary endpoint included weak events, such as a clinically defined diagnosis of heart failure or growing aortic aneurysm without dissection. The daily dose of candesartan used in the HIJ-CREATE trial (range 4–12 mg) was lower than in most other countries (8–16 mg in hypertensive patients, and up to 32 mg in patients with heart failure). By the end of the trial, 23.0% of patients of the non-ARB group had crossed over to treatment with ARBs. Furthermore, the HIJ-CREATE trial had a prospective randomized open blinded endpoint (PROBE) design. An independent and blinded endpoint committee adjudicated the endpoints. However, such a PROBE design does not protect against observer bias in the assessment and reporting of endpoints or side effects. Only reported endpoints and symptoms qualify for blinded validation. HIJ-CREATE was not a trial of differential cardiovascular outcomes on ARB vs. non-ARB treatment, but a comparison of candesartan with a number of unspecified ACEIs. In the non-ARB group, the use of ACEIs increased from 38.0% at randomization to 70.5%. About half of the patients in both treatment groups were on treatment with calcium channel blockers or b-blockers. Only 10% of patients were on treatment with diuretics. The investigators reported that the incidence of side effects leading to discontinuation of medications was 5.7% on candesartan and 12.2% on non-ARB treatment. Not unexpectedly, cough