Abstract
BackgroundBlood pressure (BP) within pre-hypertensive levels confers higher cardiovascular risk and is an intermediate stage for full hypertension, which develops in an annual rate of 7 out of 100 individuals with 40 to 50 years of age. Non-drug interventions to prevent hypertension have had low effectiveness. In individuals with previous cardiovascular disease or diabetes, the use of BP-lowering agents reduces the incidence of major cardiovascular events. In the absence of higher baseline risk, the use of BP agents reduces the incidence of hypertension. The PREVER-prevention trial aims to investigate the efficacy, safety and feasibility of a population-based intervention to prevent the incidence of hypertension and the development of target-organ damage.MethodsThis is a randomized, double-blind, placebo-controlled clinical trial, with participants aged 30 to 70 years, with pre-hypertension. The trial arms will be chlorthalidone 12.5 mg plus amiloride 2.5 mg or identical placebo. The primary outcomes will be the incidence of hypertension, adverse events and development or worsening of microalbuminuria and of left ventricular hypertrophy in the EKG. The secondary outcomes will be fatal or non-fatal cardiovascular events: myocardial infarction, stroke, heart failure, evidence of new sub-clinical atherosclerosis, and sudden death. The study will last 18 months. The sample size was calculated on the basis of an incidence of hypertension of 14% in the control group, a size effect of 40%, power of 85% and P alpha of 5%, resulting in 625 participants per group. The project was approved by the Ethics committee of each participating institution.DiscussionThe early use of blood pressure-lowering drugs, particularly diuretics, which act on the main mechanism of blood pressure rising with age, may prevent cardiovascular events and the incidence of hypertension in individuals with hypertension. If this intervention shows to be effective and safe in a population-based perspective, it could be the basis for an innovative public health program to prevent hypertension in Brazil.Trial RegistrationClinical Trials NCT00970931.
Highlights
Blood pressure (BP) within pre-hypertensive levels confers higher cardiovascular risk and is an intermediate stage for full hypertension, which develops in an annual rate of 7 out of 100 individuals with 40 to 50 years of age
After a long period of high peripheral resistance and diastolic blood pressure, stiffness of large vessels arises, with consequent rise of systolic blood pressure. This deleterious natural history of blood pressure rising with ageing could be aborted in the very beginning by a low-salt diet or by increasing natriuresis, which could be accomplished by very low doses of diuretics or other drugs that enhance the renal capacity of excreting sodium
The very low absolute risk of pre-hypertension in young individuals free of diabetes or cardiovascular disease precludes the launching of clinical trials with the aim to prevent hard outcomes
Summary
Double-blind, clinical trial, controlled by placebo. Eligible participants individuals with 30 to 70 years of age with prehypertension. Trial rationale The early use of blood pressure-lowering drugs may prevent cardiovascular events and the incidence of hypertension. The blood pressure-lowering effect and the prevention of the incidence of full hypertension may be valid surrogate endpoints that could be investigated in feasible randomized clinical trials. The PREVER prevention trial study will test if a low dose of an association of chlorthalidone with amiloride prevents hypertension at an acceptable safety in a nationwide large sample of individuals with prehypertension (Clinical trials registration number: NCT00970931). Other intermediate outcomes, such as microalbuminuria and left ventricular hypertrophy, are going to be investigated. The organizational study chart will include an executive Committee, a safety committee, outcome committee, data, lab and EKG centers, and the research units
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