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

 1. 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?

 2. 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?

 3. 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:

 1. Blood pressure variation and proportion of use of add-on drugs.

 2. Adverse events.

 3. 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.
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