Valsartan Antihypertensive Long-Term Use Evaluation - VALUE
The goal of the trial was to evaluate valsartan compared with amlodipine at the same blood pressure (BP) control for cardiac morbidity and mortality in hypertensive patients at high cardiovascular risk.
Contribution to the Literature: The VALUE trial demonstrated that among high cardiovascular risk patients, treatment with valsartan did not reduce cardiac morbidity and mortality compared with amlodipine.
Patients Screened: 18,124
Patients Enrolled: 15,313
Mean Follow-Up: Mean 4.2 years
Mean Patient Age: Mean 67 years
Age ≥50 years, treated or untreated hypertension at baseline, predefined combinations of cardiovascular risk factors, and cardiovascular disease according to an algorithm based on age and sex
Renal artery stenosis, pregnancy, acute MI, PTCA, or CABG within 3 months; clinically relevant valvular disease; cerebrovascular accident in prior three months; severe hepatic disease; severe chronic renal failure; congestive heart failure requiring ACE inhibitor therapy; or patients on monotherapy with beta-blockers for both coronary artery disease and hypertension
Composite of sudden cardiac death, fatal MI, death during or after percutaneous coronary intervention or coronary artery bypass graft, death due to heart failure, and death associated with recent MI on autopsy, heart failure requiring hospital management, nonfatal MI, or emergency procedures to prevent MI
Fatal and nonfatal MI, fatal and nonfatal heart failure, and fatal and nonfatal stroke
Patients were randomized in a double-blind manner to valsartan (n=7,649) or amlodipine (n=7,596). Medication was titrated upward to reach a target BP of <140/90 mm Hg. Valsartan was started at 80 mg per day and uptitrated to 160 mg (step 2), 160 mg plus hydrochlorothiazide (HCTZ) 12.5 mg (step 3), 160 mg plus HCTZ 25 mg (step 4), or other hypertensive drugs (step 5). Amlodipine was started at 5 mg and uptitrated to 10 mg (step 2), 10 mg plus HCTZ 12.5 mg (step 3), 10 mg plus HCTZ 25 mg (step 4), or other hypertensive drugs (step 5).
With the exception of angiotensin-receptor blockers (ARBs), antihypertensive medications could be given to achieve BP control. Angiotensin-converting enzyme inhibitors or calcium antagonists were allowed only when clinically indicated for reasons other than hypertension.
At the time of the primary endpoint, more patients in the amlodipine arm than the valsartan arm were at steps 1-3 (39.6% vs. 29.1%) and fewer were at step 4 (16.8% vs. 23.0%) or step 5, other combinations, or drugs (23.9% vs. 25.5%). The median daily dose for valsartan was 151.7 mg and for amlodipine was 8.5 mg. BP was lower from baseline in both treatment arms, but BP reduction was greater in the amlodipine-based regimen versus valsartan (17.3/9.9 mm Hg vs. 15.2/8.2 mm Hg at study end in the amlodipine and valsartan arms, respectively; p<0.0001).
There was no difference between treatment groups in the primary composite endpoint: in the amlodipine group, 10.4%, n=789, 24.7 per 1,000 patient-years; in the valsartan group 10.6%, n=810, 25.5 per 1,000 patient-years; hazard ratio (HR) 1.04, 95% confidence interval 0.94-1.15, p=0.49. There was also no difference in cardiac mortality (4.0% each, HR 1.01, p=0.90) or cardiac morbidity (7.6% vs. 7.7%, HR 1.02, p=0.71). However, myocardial infarction (MI) occurred less frequently in the amlodipine group (4.1% vs. 4.8%, HR 1.19, p=0.02), and stroke trended lower (3.7% vs. 4.2%, HR 1.15, p=0.08). Conversely, new onset diabetes was higher in the amlodipine group (16.4% vs. 13.1%, HR 0.77, p<0.0001) and heart failure trended higher (5.3% vs. 4.2%, HR 0.89, p=0.12). Among individual outcomes, stroke tended to be reduced with on-treatment systolic BP <130 mm Hg.
Severe adverse events were infrequent in both arms. Dizziness, headache, and diarrhea were reported more frequently in the valsartan group while edema was more frequent in the amlodipine group.
Among hypertensive patients at high cardiovascular risk, treatment with the ARB valsartan was not associated with a reduction in the primary composite endpoint of cardiac morbidity and mortality compared with the calcium channel blocker amlodipine. The lack of benefit may be due to the fact that the BP reduction was greater in the amlodipine-based regimen, albeit relatively small, particularly early during treatment. Given the lack of similarity in BP reduction between groups, the true hypothesis of the trial—that for the same BP control, valsartan will reduce cardiac morbidity and mortality more than amlodipine—could not be fully evaluated. One important benefit observed with valsartan was the reduction in new-onset diabetes, a finding that has been observed in other trials with ARBs.
It was noted that the dosing regimen for the valsartan arm, which was standard practice at the time of the study design, may not have been adequate.
Mancia G, Kjeldsen SE, Zappe DH, et al. Cardiovascular outcomes at different on-treatment blood pressures in the hypertensive patients of the VALUE trial. Eur Heart J 2015;Nov 20:[Epub ahead of print].
Julius S, 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.
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