The first controlled large-scale intervention trial of angiotensin receptor blockade in Japanese patients has confirmed that the cardiovascular protective effects of the drug valsartan is greater than to those seen with other therapies giving the same level of blood pressure control.
The trial, conducted by the Jikei University School of Medicine in Tokyo, Japan, examined over 3,000 patients with high blood pressure, coronary heart disease and/or heart failure who were currently treated with recommended therapies. Patients were assigned either treatment with the angiotensin receptor blocker (ARB) valsartan or a non-ARB therapy, taken in addition to their current therapy. The aim of the JIKEI HEART Study was to achieve the same blood pressure (remaining under the goal of 140/90 mmHg) in both treatment groups, and compare benefit in cardiovascular outcomes, including angina, stroke and heart failure.
The trial was halted early for ethical reasons, due to unequivocal benefit from valsartan. There were 39%
fewer cardiovascular events in the valsartan group than in the non-ARB therapy group (92 vs 149, p=0.0002) according to analysis of the primary endpoint of the trial. This difference was mainly attributable to
significantly reduced incidences of stroke (40% relative reduction; 29 vs 48, p=0.028), angina pectoris (65% relative reduction; 19 vs 53, p<0.0001), and heart failure (46% relative reduction; 19 vs 36, p=0.029). Hospitalizations for cardiovascular events were also significantly reduced by 33% in the valsartan group compared to added non-ARB therapy.
Cardiovascular disorders are the leading cause of mortality worldwide [i] . While many cutting-edge trials have investigated the cardioprotective effects of angiotensin receptor blockade in other populations, the clinical benefits have not been demonstrated widely in the Asian population. For the first time, these results extend the established benefits of valsartan to an Asian population, increasing the relevance of the results from past major mortality-morbidity studies such as Val-HeFT [ii] , VALIANT [iii] and VALUE [iv] in the Japanese population.
Professor Björn Dahlöf, a member of the Executive Committee of the JIKEI HEART study said "there is a higher prevalence of stroke in the Japanese population than in Western society, so the significantly reduced incidence of stroke shown in the trial with valsartan will be of interest to Japanese clinicians." High blood pressure is the most common cause of stroke and heart disease in Japan [v] . The Japanese population has 4-fold higher mortality and morbidity rates from stroke than from cardiovascular disease [vi] .
More detail on the trial
The JIKEI HEART study was a multi-center controlled clinical trial with a prospective randomized open-label blinded endpoint (PROBE) design. It was conducted in 3,081 patients (one third female) 20 to 79 years of age (mean 65+/-10 years). The Executive Committee was Seibu Mochizuki (Chair, the Jikei University School of Medicine, Tokyo, Japan) and Björn Dahlöf (Co-chair, Sahlgrenska University Hospital/Östra, Göteborg, Sweden).
At randomization 67% of patients were receiving a calcium channel blocker, 35% an ACE-inhibitor, 32% a beta-blocker, 10% a diuretic and 31% a statin. Physicians could give variable doses of valsartan (40-160 mg/day) starting at 80 mg. The average dose of valsartan given was 75 mg. Other therapy added in the other treatment group could be any conventional therapy apart from an ARB. The other therapies in both groups were mainly calcium channel blockers, ACE-inhibitors and beta-blockers. Blood pressure dropped from 139/81 mmHg at baseline to 132/78 mmHg in the group with added non-ARB therapy and to 131/77 mmHg in the group with added valsartan. There were no significant differences in blood pressure or heart rate between the valsartan group and the non-ARB group throughout the trial. There was no significant difference in tolerability between groups. The cardiovascular events counted in the primary endpoint were: stroke or transient ischemic attack, heart attack, hospitalization for heart failure, hospitalization for angina pectoris, dissecting aneurysm of the aorta, lower limb arterial obstruction, doubling of serum creatinine and transition to dialysis.
Angiotensin receptor blockade
Angiotensin receptor blockers, a blood pressure lowering drug class, have been shown to have cardiovascular benefits beyond blood pressure lowering – reducing stroke, providing renal benefits in diabetes post heart attack and providing benefits in heart failure. Valsartan is indicated for the treatment of high blood pressure in Japan. In many other countries, as well as the blood pressure indication, valsartan is also indicated for people with heart failure and in people at high cardiovascular risk who have had a heart attack.
The JIKEI Heart Study was conceived, designed, and coordinated by an investigator-led, independent steering committee, members of which represented the executive committee and all the hospitals where the trial was undertaken. It was supported by an unrestricted grant from Novartis. The sponsor had no role in study design, data collection, data analysis, data interpretation
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[iii] Pfeffer MA, McMurray JJ, Velazques EJ et al. Valsartan, captopril or both in myocardial infarction complicated by heart failure, left ventricular dysfunction or both. N Engl J Med 2003;349:1893-1906.
[iv] Julius, Kjeldsen SE, Weber M et al. Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: the VALUE randomised trial. Lancet 2004;363:2022-31.
[v] National Integrated Project for the Prospective Observation of Non-communicable Disease and its Trends in the Aged (NIPPON DATA).
[vi] Kimura Y, Takishita S, Muratani H, Kinjo K, Shinzato Y, Muratani A, Fukiyama K. Demographic study of first-ever stroke and acute myocardial infarction in Okinawa, Japan. Intern Med 1998;37:736-745.