Diuretics and Angiotensin-Receptor Blocker Agents in Patients With Stage I Hypertension

Study Overview
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Brief Summary
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High blood pressure is the major risk factor for Cardiovascular disease (CVD). The prevalence of hypertension in Brazil was established in population-based studies conducted in different cities and States, varying from 22.3 to 44% of adults. The benefit of drug treatment of hypertension to prevent major cardiovascular events was consistently demonstrated in a large series of clinical trials controlled by placebo. Diuretics are at least as efficacious as other blood pressure-lowering drugs, are well tolerated, have longer duration of action and the advantage of very low cost to be used in a population intervention. Chlorthalidone is the more efficacious agent. Its main limitation is to induce hypokalemia in a proportion of patients, an adverse effect that can be antagonized by a potassium-sparing diuretic, as amiloride. A study comparing diuretic with an ARB agent is therefore recommendable in Brazil, in order to support the decisions of the Health Secretary in regard to blood pressure agents supply for the Brazilian population. Such a study was demanded and funded by the Health and Technology Ministries in Brazil.

Detailed Description
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Cardiovascular disease (CVD) is already the leading cause of death in Brazil. The superiority of any particular agent among the groups of blood pressure-lowering drugs was investigated in various clinical trials. ALLHAT, the largest and better designed trial showed that chlorthalidone had similar efficacy to prevent fatal and non-fatal coronary events as an ACE inhibitor (lisinopril) and a calcium channel blocker agent (amlodipine). Chlorthalidone was superior to the other agents in the prevention of other cardiovascular outcomes, particularly heart failure. Amlodipine was superior to valsartan, an angiotensin-receptor blocker (ARB) agent, in the prevention of CHD and stroke. There is no head-to-head comparison between diuretics and ARB agents in the prevention of hard cardiovascular outcomes, and even the comparison of their blood pressure-lowering effects is scarcely described in the literature. Despite this, ARB agents are the leading brands in terms of profits in various countries in the world, including Brazil. This leadership is based on a strong commercial strategy, which includes the distortion of the evidences of clinical trials in favor of these drugs. The idea that they have blood pressure-independent effects is accepted by most, despite the evidences of better designed trials. The option by an ARB agent instead of a diuretic as the first line option in the public health system in Brazil would result in a large expenditure of resources, and there is a pressure to include them in the list of essential drugs provided by the government. This is a nation-based trial, with 24 clinical centers distributed in 9 States. A Coordinating Committee is responsible for the elaboration of this proposal and for the main decisions of the trial. The organizational chart of the study will include an executive Committee, a safety committee, outcome committee, lab and EKG centers, and the research units. Research questions Is losartan more efficacious and safe than the association of chlorthalidone with amiloride as the first option to control blood pressure in patients with stage I hypertension? Is losartan more efficacious than the association of chlorthalidone with amiloride as the first option to prevent the development of target-organ damage in patients with stage I hypertension? Is losartan more efficacious than the association of chlorthalidone with amiloride as the first option to prevent the occurrence of major cardiovascular events in patients with stage I hypertension? Methods Design: randomized, double-blind, clinical trial, controlled by an active treatment. Eligible participants: patients older than 40 years of age with Stage I hypertension. Exclusion criteria: low life expectancy, other indications for the use of diuretics, such as cardiovascular disease, intolerance to the study drugs, pregnancy. Random allocation: by a computer generated list, stratified by center. Interventions: Chlorthalidone plus amiloride up to 25 e 5 mg daily, versus losartan up to 100 mg daily. Amlodipine up to 10 mg daily and propranolol up to 160 mg/dia, in an open fashion, will be added if blood pressure is not controlled. Outcomes: Primary: Blood pressure variation and proportion of use of add-on drugs. Adverse events. Development or worsening of microalbuminuria and of left ventricular hypertrophy in the EKG. Secondary: fatal or major cardiovascular events: myocardial infarction, stroke, coronary interventions, heart failure, duplication of creatinine. Follow-up and duration of the study: consultations for evaluation and enrollment and thereafter consultations at the 3th., 6th., 9th, 12th. and 18th. months.

Official Title
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A Comparison Between Diuretics and Angiotensin-receptor Blocker Agents in Patients With Stage I Hypertension: PREVER-treatment Study

Conditions
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Hypertension, Cardiovascular Disease

Intervention / Treatment
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* Drug: losartan
* Drug: Chlorthalidone plus amiloride


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: patients older than 40 years of age with stage I hypertension Exclusion Criteria: low life expectancy other indications for the use of diuretics, such as cardiovascular disease intolerance to the study drugs pregnancy

Ages Eligible for Study
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Minimum Age: 40 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Chlorthalidone plus amiloride<br>Oral Chlorthalidone plus amiloride up to 25 e 5 mg daily for 18 months | Drug: Chlorthalidone plus amiloride<br>* Oral Chlorthalidone plus amiloride up to 25 e 5 mg daily, once a day for 18 months<br>* Other names: diuretics;|
| Experimental: losartan<br>Oral losartan up to 100 mg daily, once a day, for 18 month | Drug: losartan<br>* Oral losartan up to 100 mg daily fo 18 months<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Blood pressure variation and proportion of use of add-on drugs |  | 18 months | 
| Adverse events |  | 18 months | 
| Development or worsening of microalbuminuria and of left ventricular hypertrophy in the EKG. |  | 18 monyhs | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| fatal or major cardiovascular events: myocardial infarction, stroke, coronary interventions, heart failure, duplication of creatinine |  | 18 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hypertension, Chlorthalidone, Amiloride, Losartan, treatment