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Review
Diuretics: drugs of choice for
the initial management of
patients with hypertension
Flávio D Fuchs
CONTENTS
How everything began: the
pioneering trials
Second generation trials
Why were diuretics less
efficacious in preventing
coronary heart disease in
older trials?
Trials comparing new
antihypertensive agents
with placebo
Trials comparing drugs from
different antihypertensive
groups
The ALLHAT trial
Expert opinion
Five-year view
Key issues
References
Affiliation
Unit of Hypertension, Division of
Cardiology, Hospital de Clínicas de
Porto Alegre, Porto Alegre, RS,
Brazil
Tel./Fax: +55 51 3316 8420
[email protected]
KEYWORDS:
antihypertensive treatment,
diuretics
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The optimal first-line treatment of hypertension has been a contentious issue. Despite the
probable advantage of diuretics, which was demonstrated in early clinical trials, concern
about their metabolic effects meant that therapy was often commenced with drugs of
other types. The results of the Antihypertensive and Lipid-Lowering Treatment to Prevent
Heart Attack Trial, which compared agents of three groups of new antihypertensive drugs
with a diuretic, demonstrated the equivalence between these drugs and chlorthalidone
(Tenoretic™, AstraZeneca, London, UK) in the prevention of incident fatal coronary heart
disease and nonfatal myocardial infarction. The diuretic was superior to other drugs in
preventing some major secondary end-points, such as cerebrovascular disease and heart
failure. These findings, together with other very practical reasons, such as easy
administration, few side effects and low cost, demonstrate that diuretics are the first option
for drug management of hypertension.
Expert Rev. Cardiovasc. Ther. 1(1), (2003)
Hypertension, a highly prevalent condition
worldwide, is one of the risk factors for cardiovascular disease and has been studied by a wide
range of investigational models. In terms of
treatment, there are many studies of efficacy of
drug and nondrug therapies in reducing blood
pressure, a surrogate end-point of the goals of
treatment nowadays. In comparison to these
studies, there are fewer than 30 large clinical
trials looking at the effects of treatment on
hard outcomes. Until the recent publication of
the results of the Antihypertensive and LipidLowering Treatment to Prevent Heart Attack
(ALLHAT) Trial [1], however, the fundamental
therapeutic question was still subject to controversial opinions and guidelines, that is, which
drug should be used for first-line antihypertensive therapy. A review of these clinical trials,
together with the main results of ALLHAT,
supports the nomination of diuretics as the
first option for the treatment of hypertension.
How everything began: the pioneering trials
Thiazide diuretics were the first group of blood
pressure lowering drugs that were tolerable and
efficacious in reducing blood pressure.
© Future Drugs Ltd. All rights reserved. ISSN 1478-7210
Moreover, a therapy based on diuretics was the
first to be tested in a randomized, placebocontrolled trial, with hard end-points, in
patients with hypertension [2]. This study was
nominated as one of the classic clinical trials
[3]. The design and development of this trial
are superb. In the selection phase, all participants were hospitalized for 6 days and only
male patients whose diastolic blood pressures
averaged 90–129 mmHg without treatment
from the fourth to sixth day of their hospitalization were considered for admission to the
prerandomization period. Following their discharge from the hospital, potential trial participants entered a prerandomization trial period
of 2–4 months of duration, during which they
received placebo treatment with riboflavin, in
order to select those who were the most compliant pill takers (50% were excluded). The
active treatment consisted of a thiazide diuretic, reserpine and hydralazine. The terminating events defined by the investigators were
death or class ‘A’ events (mainly hemorrhage of
one or both optic fundi), or treatment failure
(primarily hospitalization with high blood
pressure or adverse effects of the study drugs).
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Fuchs
A second group of events (class ‘B’) were nonterminating but
included serious outcomes, such as cerebrovascular accidents,
congestive heart failure (CHF) and myocardial infarction (MI).
After 2 years, a strong treatment benefit emerged in patients
with a baseline diastolic blood pressure greater than or equal to
115 mmHg. In the reanalysis of this study according to a more
current definition of hard outcomes [3], it was demonstrated
that the treatment of only six patients with severe hypertension
per year prevented a major cardiovascular event (death, cerebrovascular incident, MI, CHF, retinal hemorrhage or doubling
of creatinine or urea).
A similar relative efficacy was demonstrated in patients with
diastolic blood pressure between 105 and 114 mmHg [4], albeit
the absolute benefit was lower (NNT = 35 patients per year). In
patients with blood pressure between 90 and 104 mmHg, recognized as mild hypertension at that time, the active treatment
was not superior to placebo. The lower risk conferred by these
levels of blood pressure and the insufficient statistical power of
this study to show small differences between treatment groups,
were responsible for such negative results.
Second generation trials
In an attempt to demonstrate the benefit of therapy in
patients with mild hypertension, more than 30,000 patients
were randomized in subsequent trials to an active treatment or
placebo. The first studies were conducted predominantly in
younger patients [5] and subsequently in the elderly [6–8]. In
most studies, the first drug was a thiazide diuretic and the second drug was a β-blocker, mainly propranolol. In a small
number of studies, the first option was a β-blocker and the
add-on drug was a diuretic. In only one study, with elderly
participants, an association of a thiazide diuretic with amiloride was compared with propranolol and to placebo as the first
option [7]. The mean 40% reduction in the incidence of cerebrovascular disease observed in these studies reached the levels
predicted by observational studies. The 16% reduction in the
incidence of coronary heart disease in the studies with
younger participants, however, was lower than the 25% anticipated by studies of risk [5]. This lower than expected efficacy
generated heated controversy surrounding possible causes.
Why were diuretics less efficacious in preventing coronary
heart disease in older trials?
The prevailing explanation for the lower efficacy of diuretics in
earlier studies was derived from the identification of adverse
effects of diuretics on the metabolism of carbohydrates and lipids. It was assumed that part of the beneficial effect on blood
pressure was negated by the deleterious effect on glucose tolerance and cholesterol levels – a finding of small studies with
short duration. The absence of and clinically relevant effects in
comparative trials of long duration [9,10], including a large trial
with hard end-points [11], was largely ignored. The metabolic
hypothesis was the reason for the launch of several clinical trials
to demonstrate the superiority of new antihypertensive drugs,
which were free of those adverse metabolic effects.
90
Another explanation for the lower than expected efficacy of
diuretics in the prevention of coronary heart disease was their
effect on the balance of potassium and uric acid. An elegant
case-control study demonstrated that the use of higher doses of
diuretics, without a potassium-sparing agent, was associated
with sudden death [12]. In a reanalysis of the Systolic Hypertension in the Elderly Program (SHEP) trial [13], participants who
had hypokalemia after 1 year of treatment with a low-dose diuretic did not experience the reduction in cardiovascular events
achieved among those who did not have hypokalemia. Those
with a serum uric acid increase of 0.06 mM or more in the
active treatment group in the SHEP trial had a similar risk of
coronary events as the placebo group [14].
In trials with participants older than 60 years, with a therapy based on lower doses of thiazide diuretics (in some
instances associated with a potassium-sparing agent), the
magnitude of prevention of coronary events came closer to
that predicted by cohort studies [6–8]. Taking together these
and older studies and re-classifying the participants by the
drug used as the first option, Psaty and associates confirmed
the superiority of low doses of thiazide diuretics [15]. Only
diuretics at lower doses were effective in preventing both cerebrovascular and coronary events. That lower doses have a better effect is a peculiar situation in terms of drug therapy. The
ineffectiveness of β-blockers was unexpected because they are
efficacious in the secondary prevention of MI. The lower efficacy in the elderly, in particular of atenolol, may be the reason
for this finding. In the Medical Research Council (MRC) trial
with old participants, only diuretics in lower doses, with a
potassium-sparing agent, prevented both coronary and cerebrovascular disease; atenolol was not superior to placebo in
any of the predefined end-points [7].
Trials comparing new antihypertensive agents with placebo
Only one agent of other antihypertensive groups, nitrendipine,
was previously shown to be superior to placebo in a large trial
with clinical end-points [16]. The effect size observed in that
study, with elderly participants with isolated systolic hypertension, was very similar to that observed in the American trial,
which had a similar design and used a thiazide-like diuretic as
the first option [6].
The Heart Outcomes Prevention Evaluation (HOPE) study
compared ramipril (Altace™, Wyeth, NJ, USA) with placebo
in patients at higher risk of presenting a cardiovascular event
but was not originally included among the clinical trials with
hypertensive patients [17]. Since almost 50% of the participants
had hypertension, their results may also apply to these patients.
The 22% reduction in the incidence of the primary end-point
was originally attributed to other effects of the ACE inhibitor
because the reduction of office blood pressure in patients
treated with ramipril was slight. A small substudy, however,
with ambulatory blood pressure monitoring, demonstrated a
large fall in blood pressure, especially at night, in patients
treated actively, suggesting that the effect of ramipril could be
ascribed mainly to the reduction in blood pressure [18].
Expert Rev. Cardiovasc. Ther. 1(1), (2003)
Use of diuretics in hypertension
The Perindopril Protection Against Recurrent Stroke study
(PROGRESS) allocated patients with a previous episode of cerebrovascular disease to an active treatment (perindopril alone or
combined with indapamide, a diuretic) or placebo [19]. There
was a 40% reduction in the recurrence of strokes in patients
treated with the combination but not with perindopril alone.
This beneficial effect was independent of the baseline blood
pressure, as it was observed in hypertensive and normotensive
participants. These findings, together with the results of HOPE
trial, may lead to change in the paradigm in terms of hypertension diagnosis and blood pressure goals to be reached with
treatment. In patients at higher risk of a cardiovascular event,
such as patients with Type 2 diabetes or with a previous cardiovascular event, it is probably worthwhile to reduce blood pressure, independently of a formal diagnosis of hypertension. The
absence of effect of perindopril alone for this purpose, and the
beneficial effect of indapamide, suggests that a diuretic may
have the preference in this context also.
Trials comparing drugs from different antihypertensive groups
The foundation for such trials was the idea that old therapies
(i.e., diuretics and β-blockers) were not sufficiently efficacious
in preventing coronary heart disease. Besides the scientific reasoning, the pharmaceutical companies have pushed research on
new antihypertensive drugs, sometimes more towards conducting placebo-controlled trials than to comparing a new drug
with an old drug. National drug agencies, such as the FDA, also
requested that comparative, drug-controlled trials be undertaken, which conversely seems ethically and clinically appropriate. Even before the results of these new trials were released,
physicians around the world were already convinced about the
potential advantages of new drugs, and the newer classes of
antihypertensive drugs surpassed diuretics and β-blockers in
preference for antihypertensive treatment.
In the Captopril Prevention Project (CAPPP) trial [20], the
open design without a centralized randomization of patients
involved a systematic allocation of an unknown proportion of
participants to captopril (Capoten®, Bristol-Myers Squibb) or
to the control group, a fact that raises questions about the
inclusion of this study in the category of randomized trials.
Nevertheless, this trial showed that similar effects on a combined cardiovascular end-point could be achieved with a therapy based on either captopril, diuretics or β-blockers. Among
the predefined secondary end-points, the only statistically significant supremacy was of conventional therapy over captopril
in terms of the prevention of cerebrovascular events, which
occurred at a frequency approximately 25% higher in participants
randomized to captopril.
The Swedish Trial in Old Patients with Hypertension
(STOP)-2 trial compared new therapies (a calcium channel
blocker or an ACE inhibitor) with older therapies (one of the
old β-blockers or a diuretic [21]) in patients aged 70–84 years.
The incidence of clinical end-points did not differ between
the two general strategies and the incidence of adverse effects
was higher in patients treated with a calcium-channel blocker
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or an ACE inhibitor. Since this trial was not designed to compare individual drugs, some important differences may have
been concealed [22]. β-blockers are known to be less effective
than diuretics, particularly in this age group [7], and the proportion of patients treated with one of these heterogeneous
groups was not reported in the publication. Moreover, pindolol, a β-blocker implicated in coronary risk [23] and not only
due to the absence of a protective effect, was one of the
β-blockers employed by an unknown proportion of patients.
Another finding of this study was the observation that ACE
inhibitors were superior to calcium-channel blockers in terms
of prevention of coronary events and heart failure. In this
respect, their results confirm indirect evidence, from a casecontrol study [24] and in secondary analysis of clinical trials
[25,26] that has implicated short-acting calcium antagonists in
an increased risk of MI. Similarly, a trial with African-American patients with hypertensive renal disease showed that those
allocated to ramipril had 48% fewer clinical end-points
(reduction in glomerular filtration rate of more than 50% or
25 ml/min per 1.73 m2, end stage renal disease or death) than
the patients treated with amlodipine [27].
The Nordic Diltiazem trial (NORDIL) was another trial that
compared the calcium-channel blocker diltiazem with an oldstrategy treatment (a diuretic or β-blocker) [28]. The incidence
of a composite end-point was virtually identical in both groups.
Patients treated with diltiazem had a lower incidence of stroke
whilst patients on an old treatment strategy showed a trend
towards a lower incidence of MI. Similarly to the STOP-2 trial,
patients in the control group were mainly treated with one
β-blocker, which is not the most effective antihypertensive
agent. More patients stopped taking diltiazem than patients in
the control group stopped one of their drugs.
International Nifedipine-GITS Study: Intervention as a Goal
in Hypertension Treatment (INSIGHT), a well-designed double-blind clinical trial, compared the effect of co-amilozide (a
thiazide and a potassium-sparing diuretic) with a gastrointestinal slow-release preparation of nifedipine (Adalat®, Bayer) [29].
There was a non-significant 12% higher incidence of the composite end-point in patients treated with nifedipine, as a result
of a higher and statistically significant incidence of fatal MI and
nonfatal heart failure. More patients stopped taking nifedipine
than diuretics because of intolerable adverse effects, mainly
ankle edema. Among those who tolerated the antihypertensives, some metabolic effects were more common in patients
treated with diuretics.
Curiously, two reviews of almost the same trials have reached
opposite conclusions. Pahor and colleagues demonstrated that
the calcium channel blockers may be inferior to other antihypertensive drugs [30]. The Trialists Collaboration concluded
that any drug with the capacity to lower blood pressure might
be regarded as an efficacious antihypertensive drug, regardless
of small differences between classes of drugs observed in some
studies [31]. The quality of some studies included in the metaanalysis and the inclusion of a few different trials may explain
the variability of estimates presented in these reviews. Despite
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the large number of patients included in these overviews, there
were few studies looking at comparisons. The direct comparison of new options with diuretics was scarce and was mainly
represented by the INSIGHT trial. The CAPPP, STOP-2 and
NORDIL trials had the probe design and the comparison of
new and old strategies, one of them represented by diuretics.
The probe design, a new denomination for an open (not
blinded) clinical trial, generated serious problems in the
CAPPP trial due the noncentral allocation of patients, a problem that was resolved in the other two trials. The old strategy
group, however, mixed up drugs with different efficacy, especially in the elderly. β-blockers were the preferred drugs in the
conservative strategy and may have concealed a higher efficacy
of diuretics.
The LIFE trial compared the effects of losartan (Cozaar®,
Merck) with atenolol (Tenormin®, AstraZeneca, London UK)
in patients aged 55–80 years with hypertension and left ventricular hypertrophy ascertained by ECG [32]. The primary
composite end-point – death, MI or stroke – occurred in 23.8
per 1000 patient-years treated with losartan and in 27.9 per
1000 patient-years treated with atenolol (p = 0.021). This difference was ascribed to the reduction of strokes in participants
allocated to losartan and was more intense in patients with diabetes [33]. The large majority of patients in both trial arms used
diuretics to reach the blood pressure goal. This study was heavily criticized, mainly for choosing atenolol as the control drug.
Besides the overall restriction to β-blockers as the primary
option for treating elderly patients with hypertension [34], atenolol may be particularly ineffective, which was suggested in
older trials that compared atenolol and metoprolol (Toprol®,
AstraZeneca, London, UK) with diuretics [35,36].
The results of the second Australian National Blood Pressure (ANBP-2) study were published recently [37]. In an openlabel trial (probe design), 6083 subjects with hypertension
who were between 65 and 84 years of age and predominantly
white, the majority free of cardiovascular disease or diabetes
were randomized, in 1594 family practices, to the recommendation to start treating hypertension with enalapril (Vasotec®,
Merck, NJ, USA) or with a thiazide diuretic. The combined
primary outcome – any cardiovascular event or death from
any cause – occurred in 56.1 per 1000 patient-years in the
ACE-inhibitor group and in 59.8 per 1000 patient-years in
the diuretic group; the hazard ratio for a cardiovascular event
or death with ACE-inhibitor treatment was 0.89 (95% CI:
0.79–1.00; p = 0.05). The advantage of enalapril over diuretics was restricted to male subjects. The results of this study
contradicted part of the results of the Antihypertensive and
Lipid Lowering Treatment to Prevent Heart Attack trial
(ALLHAT) (see below) and originated an immediate questioning of their reasons [38]. These reasons may be among the
differences between the studies in terms of statistical power,
blind allocation of treatment, treatments actually used, age
and race of participants, presence of co-morbidities and differences between the diuretics and ACE inhibitors employed
in these trials.
92
Table 1. Difference in frequency of end-point occurrence
between lisinopril- and chlortalidone-treated patients.
End-point
Difference in
frequency§ (%)
Stroke
15
CVD
10
Overall heart failure
19
Hospitalized/fatal heart failure
10
Hospitalized/treated angin
11
Coronary revascularization
10
§
Difference expressed as end-point frequency for lisinopril - frequency for
chlortalidone. CVD: Cardiovascular disease.
ALLHAT trial
ALLHAT was designed to compare the efficacy of drugs from
four major classes of antihypertensive drugs in the prevention
of cardiovascular events [1]. The primary outcome was the
combination of fatal coronary heart disease (CHD) or nonfatal
MI. The study was planned with enough statistical power to
test the effects of treatment on four major prespecified secondary outcomes – all-cause mortality, fatal and nonfatal stroke,
combined CHD events and combined cardiovascular (CVD)
events – in different gender, race and age strata, and in patients
with and without diabetes. More than 40,000 participants
were randomized to chlorthalidone (12.5–25 mg/day),
amlodipine (2.5–10 mg/day), lisinopril (10–40 mg/day) or
doxazosin (2–8 mg/day), in a double-blind fashion, with a
mean follow-up of 4.9 years. To maximize statistical power,
1.7 times as many participants were assigned to the diuretic
group as to each of the other 3 groups. Open-label step 2
drugs were atenolol, reserpine or clonidine and step 3 was
hydralazine, since the participants could not cross over to
drugs from the other groups.
The doxazosin arm was terminated prematurely because
patients treated with this α-blocker had a higher incidence of
stroke (RR: 1.19; 95% CI: 1.01–1.40), cardiovascular events
(RR: 1.25; 95% CI: 1.17–1.33) and heart failure (RR: 2.04;
95% CI: 1.79–2.32) than patients treated with chlorthalidone [39].
The incidence of the primary outcome was not different
in patients assigned to chlorthalidone, amlodipine or lisinopril. The incidence of overall and hospitalized/fatal heart
failure were 38 and 35% higher, respectively, in patients
treated with amlodipine in comparison to those allocated to
chlorthalidone. Several secondary end-points were statistically significantly more frequent among patients treated
with lisinopril than in patients treated with chortalidone
(TABLE 1). The incidence of end-stage renal disease was not
different among the three groups. The treatment effects for
all outcomes were consistent across subgroups by sex and
diabetic status in both comparisons with the diuretic. Some
differences emerged in other subgroup analyses; it is worth
Expert Rev. Cardiovasc. Ther. 1(1), (2003)
Use of diuretics in hypertension
noting that there was an interaction of drug treatment by
race: stroke and combined CVD were more frequent in
black participants than nonblack participants assigned to
lisinopril in comparison to chlorthalidone.
Five-year systolic blood pressures were significantly higher in
the amlodipine (0.8 mmHg) and lisinopril (2 mmHg) groups
compared with chlorthalidone; 5-year diastolic blood pressure
was significantly lower with amlodipine (0.8 mmHg). Given
the large sample, small differences in some biochemical measurements were statistically significant after 4 years of follow-up,
such as cholesterol (197.2, 195.6 and 195.0 mg/dl for chlorthalidone, amlodipine and lisinopril, respectively), potassium (4.1,
4.4 and 4.5 mEq/l, respectively) and fasting glucose (126.3,
123.7 and 121.5 mg/dl for chlorthalidone, amlodipine and lisinopril, respectively). New diagnoses of diabetes occurred in
11.6, 9.8 and 8.1% of the participants allocated to chlorthalidone, amlodipine and lisinopril, respectively. The only difference in the incidence of serious adverse outcomes was a higher
frequency of angioedema in patients treated with lisinopril
(0.4 versus 0.1% in the other groups, one case in the lisinopril
group being fatal).
Some results of the ALLHAT trial will be debated but their
main findings are robust and definitive. The similar incidence of the primary end-point occurrence among participants allocated to the four treatments and the higher incidence of some secondary, but clinically relevant, outcomes in
participants assigned to doxazosin, amlodipine and lisinopril, together with the consistency of these results among
most age, sex, race and diabetes strata, suggest that diuretics
are superior to other antihypertensive drugs in preventing
cardiovascular events.
The advantage of chlorthalidone on some outcomes may
be secondary to better blood pressure control, especially
systolic blood pressure. In this regard, these findings are in
accordance with the view that the blood pressure lowering
effect is the main mechanism responsible for the prevention
of cardiovascular events in patients with hypertension [40]
and, maybe, in patients without hypertension at higher risk
of presenting a cardiovascular event. The postulated antagonism of new drugs on potential cardiovascular toxic effects
of angiotensin or calcium and the advantages of these drugs
in terms of metabolic effects, did not overcome the real and
efficient blood pressure lowering effect of diuretics. The
poorest control of blood pressure in patients treated with
doxazosin, amlodipine and lisinopril in the ALLHAT may
be exactly secondary to the prohibition, by protocol, to use
diuretic as the second drug.
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Expert opinion
Diuretics are at least as efficacious as other antihypertensive
drugs in preventing combined cardiovascular outcomes in a
wide range of hypertension severity, age, gender, race and presence of other comorbidities, such as diabetes mellitus. Probably due to their more efficacious blood pressure lowering
effect, they are superior to other drugs in preventing some outcomes, such as cerebrovascular disease and heart failure. In the
case of heart failure, their unique preload reducing effect
among the antihypertensive drugs may be another reason to
explain their superiority. The consistent findings of some of
the previous clinical trials [41] and now of the ALLHAT trial,
together with their easiness of administration, infrequent side
effects and low price, recommend diuretics as the first option
in the management of hypertension. New clinical trials should
focus on drugs to be added to them as the second step in the
management of hypertension, which may also be a diuretic
(i.e., a potassium-sparing agent).
Five-year view
The next few years will see a modification in the paradigm for
hypertension diagnosis and management. The concept of highrisk individuals, such as patients with diabetes, or with a previous cardiovascular event, and the elderly, will probably demand
the use of blood pressure-lowering drugs independently of a
formal diagnosis of hypertension. The second drug to be added
to diuretics to reach such goals in the primary or secondary prevention should be established in newer clinical trials. Ideally,
these trials should focus on hard outcomes, but the constraint
of costs may justify the use of surrogate endpoints, such as
blood pressure and quality-of-life.
Key issues
• The benefit of blood pressure-lowering treatments in
preventing cardiovascular disease is fully established.
• Thiazide diuretics are the first-line agents to treat
hypertension in a wide range of age, gender and race strata,
and in patients with and without diabetes.
• The blood pressure-lowering effect of drugs to be added to
diuretics as the second option in the management of
hypertension may be an acceptable surrogate (mediator)
endpoint, as it correctly anticipates the effects of most
drugs on hard outcomes.
• There is compelling evidence for the use of blood pressurelowering drugs in patients at higher cardiovascular risk,
such as patients with Type 2 diabetes and patients recovered
from a myocardial infarction or stroke, independently of
their basal blood pressure levels.
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Fuchs
References
Papers of special note have been highlighted as:
• of interest
•• of considerable interest
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Affiliation
•
Flávio D Fuchs, MD, PhD, Serviço de
Cardiologia, Hospital de Clínicas de Porto
Alegre, Ramiro Barcelos, 2350, 90.035-003,
Porto Alegre, RS, Brazil
Tel./Fax: +55 51 3316 8420
[email protected]
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