Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT06395194 |
| Other study ID # |
OsloUHtheValueTrial |
| Secondary ID |
|
| Status |
Completed |
| Phase |
Phase 3
|
| First received |
|
| Last updated |
|
| Start date |
September 27, 1997 |
| Est. completion date |
December 5, 2003 |
Study information
| Verified date |
April 2024 |
| Source |
Oslo University Hospital |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
The Valsartan Antihypertensive Long-term Use Evaluation (VALUE) trial tested the hypothesis
that for the same blood-pressure control, valsartan would reduce cardiac morbidity and
mortality more than amlodipine in hypertensive patients at high cardiovascular risk. The
present study investigates effects of valsartan and amlodipine on pre-specified secondary
kidney outcomes.
Description:
VALUE was a multicenter, prospective, double-blinded randomized clinical trial initiated and
led by the investigators. The study took place from 1997 to 2004. The sponsor was Novartis,
who had an interactive role with the investigators for the study design, and Novartis
monitored study sites and provided source data verifications. In 2011, Ullevaal University
Hospital, Oslo, Norway, took over the database with conditions detailed in a written
agreement with the funder. One author (S.E.K.) had from then full access to all the data and
took responsibility for its integrity and the data analysis. Thus, the data file resides in
the hands of the authors, and Novartis had no role in the present study.
The trial was approved by ethics committees and written informed consent collected from all
the participants in 31 countries.
The study compared, in a prospective, randomized double-blinded design, the effects of two
different antihypertensive treatment regimens on cardiac morbidity and mortality in
hypertensive patients aged 50 years or older. One regimen was based on the ARB valsartan, and
the other on the CCB amlodipine.
VALUE participants were selected based on predefined combinations of risk factors, including
age, male gender, and the presence of certain conditions such as electrocardiographic left
ventricular hypertrophy (ECG-LVH), determined by Cornell voltage-duration product or
Sokolow-Lyon voltage criteria with or without a strain pattern, serum creatinine ≥150 μmol/l,
proteinuria (positive dipstick in morning urine at two different visits), diabetes mellitus
(DM), or verified coronary, cerebrovascular, or peripheral artery disease.
Exclusion criteria included pregnancy, renal artery stenosis, either myocardial infarction,
percutaneous coronary intervention, or coronary artery bypass surgery during last three
months, medically relevant valvular disease, cerebrovascular events last 3 months, severe
hepatic disease, severe chronic kidney failure (serum creatinine >3.0 mg/dl, >265 µmol/L),
congestive heart failure requiring angiotensin converting enzyme inhibitor and patients using
beta-blocker for both coronary artery disease and hypertension.
Participants were followed for 4-6 years, until a minimum of 1450 primary cardiac events
("endpoint driven") with monthly visits during the initial six months after randomization and
later at six-month intervals. BP was measured at each visit using a calibrated
sphygmomanometer or a validated digital device with an appropriate size cuff. Patients were
seated quietly for 5 minutes before the measurement of BP. Blood samples were collected and
analyzed at central labs in each continent. Serum creatinine was measured yearly.
The primary goal of the study was to determine the time to the occurrence of the first
cardiac event, which included a combination of fatal or non-fatal myocardial infarction,
sudden cardiac death, death from revascularization procedures or heart failure,
hospitalization for heart failure, and emergency procedures to prevent myocardial infarction.
The secondary endpoints were all cardiovascular events, fatal and non-fatal stroke,
myocardial infarction, hospitalized heart failure, cardiovascular-, non-cardiovascular-, and
all-cause mortality.
Pre-specified secondary kidney endpoints were end-stage kidney disease (ESKD) in patients
with need for dialysis or kidney transplantation and worsened kidney function (WKF) with at
least 50% increase in serum creatinine from baseline. To ensure impartiality, the endpoint
committee was not informed of the treatment assignments when assessing events.
Patients who were previously treated for hypertension (92%) were eligible if SBP was <210
mmHg and diastolic(D) BP was <115 mmHg. Untreated hypertensive patients were eligible if SBP
was between 160 and 210 mmHg, and DBP was <115 mmHg. Patients who already were on treatment,
discontinued their previous antihypertensive medications when randomized to one of the
trial's masked study arms (valsartan or amlodipine) without a run-in phase ("rolled over").
Valsartan treatment started at a dosage of 80 mg daily, and amlodipine treatment started at 5
mg daily. If BP did not reach <140/90 mmHg, the dose of either drug was doubled to 160 mg or
10 mg, respectively, and hydrochlorothiazide (12.5 mg and 25 mg daily) and other
antihypertensive drugs were added in sequential steps.
Age, the presence of coronary heart disease, and the presence of ECG-LVH at baseline were
used in the randomized study as à priori covariates to account for the effects of key risk
predictors at baseline.
To minimize the influence of potential confounding factors, hazard ratios (HRs) in the
observational analysis of different achieved BP levels were adjusted for treatment allocation
and baseline covariates including age, sex, SBP, diastolic blood pressure, body mass index,
smoking status, high serum total cholesterol (>6.2 mmol/L or >240 mg/dL), presence of
diabetes mellitus, proteinuria, ECG-LVH, previous stroke, previous myocardial infarction, and
previous peripheral artery disease.
Statistical power was calculated for the original comparison of valsartan vs amlodipine on
the primary endpoint.15 The trial was endpoint driven, needed 1450 primary events to close,
and showed no difference between valsartan and amlodipine on the primary endpoint, which
allowed consolidation of data from both treatment arms for other studies of this hypertensive
population like investigation BP variability and the influence of achieved BPs on certain
endpoints. Of the 15,245 hypertensive patients enrolled by 969 investigators, 13,803 patients
did not experience any cardiovascular event during the initial six months of treatment after
randomization and had attended a minimum of three study visits after that period. A minimum
of three visits was decided à priori to ensure meaningful follow up of representative
achieved BPs. Patients with cardiovascular events during the first six months after
randomization were excluded because of the uncontrolled BP following discontinuation of
previous antihypertensive drugs and concomitant up-titration of the randomized medications;
these early BPs were neither included as they were not representative for the later achieved
average BPs.
Treatment effects on kidney endpoints in the RCT were measured by hazard ratios and their 95%
CIs based on Cox regression models and analyzed as intention-to-treat. Event rates over time
are presented as Kaplan-Meier curves. Similar multivariate adjusted Cox models were used to
analyze the kidney endpoints for patients who achieved average SBP <135 mmHg vs SBP ≥135 mmHg
up to the occurrence of a prespecified endpoint, or throughout the treatment period if no
event occurred. Similar comparisons were done for patients who achieved average DBP <85 mmHg
vs ≥85 mmHg and for groups with SBP ≥135 and/or DBP ≥85 mmHg vs patients with SBP <135 and
DBP <85 mmHg.
Statistical significance was determined with a two-sided p-value of <0.05. Data analysis was
carried out using SPSS (IBM SPSS Statistics: Version: 28.0.1.0, Armonk, NY, USA). Data are
presented as means with standard deviations (SDs), absolute numbers with percentages in
parentheses, or point estimates with 95% confidence intervals (CIs).
