Ignite Creation Date:
2024-05-06 @ 8:28 PM
Last Modification Date:
2024-10-26 @ 3:28 PM
Study NCT ID:
NCT06395194
Status:
COMPLETED
Last Update Posted:
2024-05-02
First Post:
2024-04-10
Brief Title:
Effects of Valsartan vs Amlodipine and Low BP on Kidney Outcomes in Essential Hypertension
Sponsor:
Oslo University Hospital
Organization:
Oslo University Hospital
Study Overview
Official Title:
The Valsartan Antihypertensive Long-term Use Evaluation Trial
Status:
COMPLETED
Status Verified Date:
2024-04
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
VALUE
Brief 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
Detailed 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 SEK 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 μmoll 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 30 mgdl 265 µmolL 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 diastolicD 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 trials 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 14090 mmHg the dose of either drug was doubled to 160 mg or 10 mg respectively and hydrochlorothiazide 125 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 62 mmolL or 240 mgdL 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 endpoint15 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 15245 hypertensive patients enrolled by 969 investigators 13803 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 andor DBP 85 mmHg vs patients with SBP 135 and DBP 85 mmHg
Statistical significance was determined with a two-sided p-value of 005 Data analysis was carried out using SPSS IBM SPSS Statistics Version 28010 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
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 μmoll 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 30 mgdl 265 µmolL 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 diastolicD 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 trials 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 14090 mmHg the dose of either drug was doubled to 160 mg or 10 mg respectively and hydrochlorothiazide 125 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 62 mmolL or 240 mgdL 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 endpoint15 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 15245 hypertensive patients enrolled by 969 investigators 13803 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 andor DBP 85 mmHg vs patients with SBP 135 and DBP 85 mmHg
Statistical significance was determined with a two-sided p-value of 005 Data analysis was carried out using SPSS IBM SPSS Statistics Version 28010 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
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
False
Is an FDA AA801 Violation?:
None