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.