Valsartan Amlodipine Randomized Trial (VART): Design, Methods, and Preliminary Results

21 Hypertens Res Vol.31 (2008) No.1 p.19-26 Original Article Valsartan Amlodipine Randomized Trial (VART): Design, Methods, and Preliminary Results Keiko NAKAYAMA1), Yoichi KUWABARA1), Masao DAIMON1), Satoshi SHINDO1), Miwa FUJITA1), Hiroya NARUMI1), Hiroshi MIZUMA1), and Issei KOMURO1) Antihypertensive therapy has been well established to reduce hypertension-related morbidity and mortality, but the optimal therapy for Japanese patients remains unknown. The Valsartan Amlodipine Randomized Trial (VART), a prospective randomized open-label trial, was designed to determine whether treatment with an angiotensin II type 1 receptor blocker (valsartan) or a calcium channel blocker (amlodipine) lowers cardiovascular disease events in essential hypertensives in Japan. Registration, randomization and data entry were performed over the Internet. The minimization method (to control for age, gender, blood pressure level and history) was used at random assignment to ensure that the background factors were equivalent between the groups at baseline. After the registration, patients were followed-up for cardiovascular events (primary endpoints), echocardiography, 123I-metaiodobenzylguanidine (MIBG) imaging, laboratory tests and blood pressure for 3 years. Currently, 797 patients have been enrolled and assigned to two groups: a valsartan (n = 399) and an amlodipine (n = 398) group. At baseline, controlled factors (age, gender, blood pressure level, and left ventricular hypertrophy) and the proportions of patients with diabetes and hyperlipidemia were equally allocated. At 12 months, both drugs evenly and significantly lowered blood pressure to the target level (valsartan: 133/79 mmHg; amlodipine: 132/79 mmHg). In conclusion, by combining the data on cardiovascular events with the results of echocardiographic, radionuclide imaging, and blood/urine studies, the VART study will provide mechanistic insights into the clinical outcomes and treatment effects of the trial. (Hypertens Res 2008; 31: 21–28) Key Words: hypertension, randomized trial, valsartan, amlodipine Introduction Hypertension is the most common disease in the Japanese population, and many large randomized clinical trials using antihypertensive drugs have established that reduction of blood pressure reduces hypertension-related morbidity and mortality (1). Several basic and clinical studies suggest that antihypertensive drugs which inhibit the renin-angiotensin system (RAS) have cardiovascular and renal benefits beyond their reduction of blood pressure (2–8), and thus these drugs are now being widely used as a first-choice therapy. However, since most of the clinical trials have been performed in Western countries, it remains to be determined whether RAS inhibitors also have beneficial effects in the Japanese population. Since angiotensin II receptor blockers (ARBs) directly block angiotensin II type 1 (AT1) receptors, which are involved in hypertension, myocyte hypertrophy and fibrosis, they are expected to have beneficial effects in protecting major organs, such as the heart, kidney and arteries (9–14). Valsartan is a highly selective AT1 subtype blocker with potent blood pressure reduction ability. Several clinical trials have revealed the cardio-protective effects of valsartan in patients with heart failure and acute myocardial infarction (13–16). From the 1)Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine, Chiba, Japan. Address for Reprints: Issei Komuro, M.D. Ph.D., Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine, 1–8–1 Inohana, Chuo-ku, Chiba 260–8670, Japan. E-mail: Received February 8, 2006; Accepted in revised form August 3, 2007. 22 Hypertens Res Vol. 31, No. 1 (2008) In the Valsartan Heart Failure Trial (Val-HeFT) (13, 14), patients who had already received heart failure treatment were assigned to receive valsartan or placebo. The results of this trial showed a significant decrease in symptoms, combined mortality, and morbidity from heart failure, and a significant improvement of cardiac function in those who received valsartan. The Valsartan in Acute Myocardial Infarction Trial (VALIANT) (16) enrolled patients with heart failure or left ventricular dysfunction during the immediate postinfarction period, and compared the incidence of hard cardiac events among the patients treated with captopril alone (angiotensin converting enzyme [ACE] inhibitor), valsartan alone (ARB) or their combination. Valsartan was found to be as effective as captopril. On the other hand, calcium channel blockers (CCBs) have long been established as a first-line treatment for hypertension due to their clear blood pressure–lowering effects and the evidence of their efficacy provided by several large clinical trials (17–20). Among CCBs, amlodipine, which is a longacting, third-generation calcium channel blocker, has been widely used in Japan (21, 22). Recently, the results of the Valsartan Antihypertensive Long-term Use Evaluation (VALUE) (16) trial were released. This study directly compared amlodipine and valsartan in terms of incidence of cardiac events in high-risk patients with hypertension. In this study, no significant difference was shown for the primary endpoint, although the incidence of myocardial infarction and stroke was lower in those with amlodipine, and the incidence of heart failure was lower in those with valsartan. Because comparable blood pressure reduction was not obtained between the groups in this study, further comparison of the effects of these drugs is warranted. Furthermore, because most of the patients were recruited in Europe and the United Sates, it is unknown whether the results of these studies are extensible to a Japanese population. Both valsartan and amlodipine are good representatives of their drug classes (ARBs and CCBs, respectively), with effective blood pressure–lowering effects and wide use among Japanese hypertensive patients. Thus, to determine which of these drugs is optimal for Japanese hypertensives, we designed and are conducting a prospective randomized openlabel clinical trial, the Valsartan Amlodipine Randomized Trial (VART). Study Design Overview The VART, a prospective, multicenter, randomized, openlabel trial, was designed to measure the effects of treatment with the ARB valsartan and the CCB amlodipine on cardiovascular disease events in essential hypertensives. Eligible patients have been enrolled since July 2002. Follow-up data will be collected every 6 months for at least 3 years in each subject. Table 1. Patient Eligibility Criteria Inclusion criteria 1. 30 years old or older 2. Patients newly diagnosed hypertension (SBP≥140 mmHg or DBP≥90 mmHg in a sitting position at clinic) or treated with hypertensive drugs Exclusion criteria 1. Secondary hypertension 2. Severe valvular disease or congenital heart disease requiring operative treatment 3. Hypertrophic or dilated cardiomyopathy 4 (...truncated)