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Journal of Human Hypertension (2003) 17, 367–372
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COMMENTARY
The Antihypertensive and Lipid-Lowering
Treatment to Prevent Heart Attack Trial
(ALLHAT): ALL predictable, and no big
surprise out of a HAT?
DG Beevers, KW Lee and GYH Lip
University Department of Medicine, City Hospital, Birmingham, UK
Journal of Human Hypertension (2003) 17, 367–372. doi:10.1038/sj.jhh.1001556
In May 2001, the following paragraph appeared in
the Journal of Human Hypertension:1 ‘All too few
clinicians are aware that possibly the most successful antihypertensive drugs are the thiazide diuretics.
They have been shown in many studies, particularly
in older patients, to be the best option for lowering
blood pressure (BP) as well as preventing heart
attacks and strokes. They are also much more cost
effective than other first-line agents’.
One could now argue that cynical clinical pharmacologists and die-hard diuretic enthusiasts have
(probably) been vindicated with the publication of
the results of the largest hypertension clinical trial
ever conductedFthe Antihypertensive and LipidLowering Treatment to Prevent Heart Attack Trial
(ALLHAT).2 This study reported that the incidence
of the primary end points of fatal coronary heart
disease (CHD) and nonfatal myocardial infarction
(MI) was identical with a thiazide diuretic, an
angiotensin-converting enzyme (ACE) inhibitor,
and a dihydropyridine calcium-channel blocker
(CCB).
In addition, the better results with chlorthalidone
in the prevention of other hypertension-related
cardiovascular complications in the secondary outcomes, and at a lower cost, means that the thiazide
diuretics can be considered to be ‘superior’ to ACE
inhibitors or CCBs. Results from the antihypertensive and lipid-lowering components of the study
were published in two papers in the 18 December
2002 issue of JAMA.2,3 ALLHAT was a randomised,
double-blind, active-controlled trial designed to
compare the rate of CHD events in ‘high-risk’
hypertensive patients initially randomised to a
Correspondence: Professor GYH Lip, University Department of
Medicine, City Hospital, Birmingham, B18 7QH, UK.
E-mail: [email protected]
diuretic (chlorthalidone) vs each of three ‘alternative’ antihypertensive drugs: an alpha-adrenergic
blocker (doxazosin), an ACE-inhibitor (lisinopril),
and a CCB (amlodipine).
Eligible patients were aged X55 years with stage 1
or 2 hypertension or who were already taking
antihypertensive medication, and with at least one
other CHD risk factor. These risk factors included
previous MI or stroke, left ventricular hypertrophy
(LVH) by electrocardiogram or echocardiogram, a
history of Type II diabetes mellitus, current cigarette
smoking, and low high-density lipoprotein cholesterol levels. Enrolment began in February 1994, and
follow-up was completed in March 2002 in 623
centres in Canada, Puerto Rico, the US, and the US
Virgin Islands.
The original trial population comprised 42 418
patients, but the doxazosin arm of the trial was
stopped prematurely in January 2000 because of a
25% higher rate of combined cardiovascular events
and a two-fold higher rate of admission for heart
failure compared with chlorthalidone.4 The remaining 33 357 patients stayed on their study drugs until
the end of the study. Of these, 15 255 were randomised to chlorthalidone (12.5–25.0 mg/day), 9048 to
amlodipine (2.5–10.0 mg/day), and 9054 to lisinopril (10–40 mg/day). If BP was not controlled to
below 140/90 mmHg with the step-1 drug (after dose
optimisation), open-label treatment drugs from other
classes (atenolol, clonidine, or reserpine as step-2
drugs, and hydralazine as step-3) could be added at
the physician’s discretion. However, low doses of
open-label step-1 drug classes were also allowed if
clinically indicated. The mean age of participants
was 67 years; while 47% were women, 35% were
black, 19% Hispanic, and 36% were diabetic.
After a mean follow-up of 4.9 years, the major
results provided no big surprises. Primary outcome
ALLHAT
DG Beevers et al
368
events occurred in 2956 patients, with virtually
identical frequencies in each of the three treatment
groups. Compared with chlorthalidone (6-year rate,
11.5%), the relative risks were 0.98 (95% confidence
interval (CI), 0.90–1.07) for amlodipine (6-year rate,
11.3%), and 0.99 (95% CI, 0.91–1.08) for lisinopril
(6-year rate, 11.4%). Likewise, all-cause mortality
was not different between the three groups.
There were, however, significant differences in
the secondary outcomes for both of the newer drugs
compared with the diuretic. Compared with those
taking chlorthalidone, patients on amlodipine had,
on average, 0.8 mmHg higher systolic BP, 38%
higher risk of developing heart failure (Po0.001)
(6-year absolute risk, 2.5%), and 35% higher risk of
hospitalisation or fatal heart failure (Po0.001).
Interestingly, the ACE inhibitor lisinopril appeared
to be worse than chlorthalidoneFthose taking
lisinopril had, on average, about a 2 mmHg higher
follow-up systolic BP (4 mmHg higher in black
patients), 15% higher risk of stroke (Po0.02, but
40% higher risk in blacks, P ¼ 0.01), and 10% higher
risk of combined cardiovascular disease (CVD)
(Po0.001) (6-year absolute risk, 2.4%, but 19%
higher risk in black patients, P ¼ 0.04) with 11%
higher risk of hospitalisation or treated angina
(P ¼ 0.01) as well as 10% higher risk of coronary
revascularisation (P ¼ 0.05). Rather surprisingly,
patients on lisinopril also had 19% higher risk of
developing heart failure (Po0.001) and 10% higher
risk of being hospitalised or fatal heart failure
(P ¼ 0.11).
Thiazide diuretics: growing superiority?
There are many reasons to believe that thiazide
diuretics are the most successful antihypertensive
drugs. In terms of cost-effectiveness, they are
certainly the superior agents, and have been recommended as first-line antihypertensive agents in all
international hypertension treatment guidelines.
They have been shown in many large clinical
studies, particularly in older patients, to be the best
option for lowering BP as well as preventing stroke
and heart attacks, and importantly, in all ethnic
groups. In a study by Klungel et al,5 antihypertensive treatment that did not include a thiazide
diuretic was associated with an 85% increased risk
of ischaemic stroke when compared with the use of
an antihypertensive drug regimen, which did include a thiazide. Patients taking a beta-blocker, CCB,
or ACE inhibitor in combination with a thiazide
diuretic seemed to have the same risk of stroke as
patients taking a diuretic alone. In contrast, patients
taking drugs other than a diuretic appeared to have
a 2.5-fold increase in the risk of stroke, when
compared to the use of a diuretic only. These data
are also in parallel to the PROGRESS trial,6 where a
significant reduction in second stroke was seen with
a perindopril–indapamide (ACE inhibitor–thiazide
Journal of Human Hypertension
diuretic) combination, whereas the stroke reduction
with perindopril monotherapy was not statistically
significant.
Furthermore, recent analyses from the Systolic
Hypertension in the Elderly Program (SHEP)7 also
showed that treatment of elderly patients with
isolated systolic hypertension using a diuretic-based
regimen (chlorthalidone 12.5 mg/day which could
be doubled, or stepped up with atenolol or reserpine) resulted in a significant reduction (vs placebo)
of all strokes (both ischaemic and haemorrhagic;
fatal and nonfatal) by 36%, particularly in patients
reaching certain target levels of systolic BP.8 Importantly, along with this reduction in stroke there
was a 71% reduction in fatal and nonfatal heart
attack, a reduction in all CHD of 27%, all CVD of
32% and total mortality by 13%. In addition, there
was also a 49% reduction of fatal and nonfatal heart
failure, with a dramatic 80% risk reduction observed
in patients with prior MI.9
ACE inhibitors and increased heart failureya big surprise from ALLHAT, or is it?
When the doxazosin arm was withdrawn from the
trial because of 25% greater risk of combined CVD,
which was largely driven by increased incidence of
hospitalisation for congestive heart failure, many
questioned the validity of reported heart failure end
points that were based only on clinical symptoms
and signs. Indeed, the ALLHAT Data and Safety
Monitoring Board set up an ad hoc endpoints
subcommittee (even prior to the termination of the
doxazosin arm) in order to address the reliability
and validity of reported heart failure events.10 It is of
note that the ALLHAT definition of heart failure was
used previously in the SHEP study.9
While there is little surprise that patients taking
amlodipine had a higher rate of heart failure than
chlorthalidone in ALLHAT, it may seem rather
surprise at first glance of its data that the relative
risk (RR) of heart failure (fatal, hospitalised, or
treated nonhospitalised) was significantly higher in
patients on lisonopril (RR 1.19, 95% CI 1.07–1.31,
Po0.001). Given the solid evidence available from
several large-scale randomised trials for ACE inhibitors in the reduction of heart failure morbidity
and mortality, the observed higher risk of heart
failure with lisinopril in the high-risk hypertensive
patients in ALLHAT is difficult to reconcile (surely,
some of these patients must have had left ventricular
dysfunction). However, when only hospitalised or
fatal heart failure is considered, the observed excess
RR was not significant (RR 1.1, 95% CI 0.98–1.23,
P ¼ 0.11). It is of note that the heart failure diagnosis
validation process was confined only to hospitalised
or fatal heart failure events, while the diagnosis of
treated but nonhospitalised heart failure events in
the community were not evaluated.10 Furthermore,
it is possible that chlorthalidone, as a diuretic could
ALLHAT
DG Beevers et al
mask or prevent the clinical signs of fluid retentionFperipheral oedema and pulmonary crackles in
some patients, and thus may have underestimated
the true incidence of heart failure.
Despite these considerations, however, chlorthalidone still appears to be superior to lisinopril as a
means to lower BP and prevent stroke and combined
CVD. Given the strong evidence of chlorthalidone in
preventing stroke in the SHEP study, one would not
argue too vigorously against its effectiveness in
preventing stroke better than an ACE inhibitor.
However, it still seems difficult to conceive that a
diuretic prevents CVD better than an ACE inhibitor
in ALLHAT.
Although there is no strong clinical evidence that
ACE inhibitor therapy alone leads to a decrease of
hospitalisation for angina or coronary revascularisation, there have been many pathophysiological
reports of beneficial effects in preventing atherosclerosis by blocking the renin–angiotensin system.
The Heart Outcomes Prevention Evaluation
(HOPE)11 study reported significant benefits in
terms of cardiovascular event reduction by targeting
‘high risk’ patients rather than hypertensives per se.
It should be noted that although the baseline BP in
the HOPE study was ‘normal’F139/79 mmHgFin
the overall population, a history of hypertension
was present in almost 50% of patients, suggesting
that their background cardiovascular risk was
probably similar to, if not higher than, the patients
in ALLHAT. In HOPE, however, the cardioprotective
or vascular protective effect of the ACE inhibitor
ramipril is very clear; this was particularly true with
the stroke protection that was touted in HOPE to
be independent of ‘clinic’ BP, although ambulatory blood pressure monitoring may have told us
otherwise.
In contrast, there is no clear pathophysiological
link between the prevention of atherothrombosis
and the diuresis induced by a diuretic, besides
lowering of BP. Further counteracting the anticipation of more benefits with lisinopril over chlorthalidone is the fact that diuretics are known to
stimulate the renin–angiotensin system, worsen
glucose tolerance, and the lipid profile.
As the achieved BP reduction was similar with
chlorthalidone and amlodipine, the superiority of
the diuretic in that comparison is clear. What
complicates the issue with the interpretation of
ALLHAT is that the achieved average BP reduction
with lisinopril was 2 mmHg (4 mmHg in black
patients) less than chlorthalidone, and there were
more secondary end points reported in the lisinopril
group. Could a 2-mmHg systolic BP difference in
favour of the thiazide explain this? Were some of the
patients in ALLHAT ‘resistant’ to the ACE inhibitors? Was the increased trend for heart failure and
other CVD events in the lisinopril group mainly
driven by African-American patients on ACE inhibitors? Was chlorthalidone doing more than just a
diuretic that ‘simply’ depletes plasma volume?
ACE inhibitors on the ‘black list’ for
hypertensive black patients
369
In ALLHAT, 35% of the participants were black
African Americans. When one examines the ALLHAT results carefully, it is not difficult to spot that
much of the differences or so-called ‘surprise
findings’ of the chlorthalidone/lisinopril comparison in secondary end points could possibly be
driven by the differences between black and white
patients, as evidenced by the overall poorer BP
control among black participants on lisinopril.
Indeed, the RRs (lisinopril vs chlorthalidone) were
1.40 (95% CI 1.17–1.68) and 1.00 (95% CI 0.85–1.17)
for stroke and 1.19 (95% CI 1.09–1.30) and 1.06
(95% CI 1.00–1.13) for combined CVD in black and
nonblack participants, respectively. In contrast,
there was less of a difference in the chlorthalidone/amlodipine comparison, and the treatment
effects were consistent across all subgroups by sex
and diabetic and baseline CHD status.
African Americans are known to have a higher
prevalence of hypertension, diabetes, CVD, stroke,
and renal disease than white Americans. Indeed, for
many years, there have been concerns that ACE
inhibitors may be less efficacious in black patients
with hypertension, heart failure, or nondiabetic
kidney disease. However, in the recently published
African-American Study of Kidney Disease and
Hypertension (AASK) study,12 an ACE inhibitor
(ramipril) was superior to both a CCB (amlodipine)
and a beta-blocker (metoprolol) in preventing the
progression of renal disease in nondiabetic black
hypertensives with mild-to-moderate renal disease.
Furthermore, recent data from the reanalysis of the
Studies of Left Ventricular Dysfunction (SOLVD)
Prevention trial13 demonstrated that ACE inhibitor
(enalapril) was equally efficacious in reducing the
risk of development of heart failure in both black
and white people in spite of the increased absolute
risk in black patients compared with white patients
for the progression of asymptomatic left ventricular
systolic dysfunction. In contrast, other studies have
shown contradictory results.14
Given the fact that black hypertensives on lisinopril clearly had higher absolute BPs (4 mmHg
systolic BP) than white participants on chlorthalidone in ALLHAT, the question of whether black
hypertensives were less ACE responsive is not an
important issue to discuss further here. The more
important issue is whether the difference in systolic
BP could explain the higher relative risk of stroke,
combined CVD and heart failure in black hypertensives on lisinopril. Indeed, after adjustment for
follow-up BP as time-dependent covariates, the
authors reported that the 2-mmHg systolic BP
difference overall between the lisinopril and
chlorthalidone groups only partially accounts for
the observed CVD event differenceFthe RRs for
stroke reduced from 1.15 to 1.12 and heart failure
from 1.20 to 1.17 overall and in the black subgroup
Journal of Human Hypertension
ALLHAT
DG Beevers et al
370
(stroke, from 1.40 to 1.35; and heart failure, from
1.32 to 1.26), and these differences remained
statistically significant. The discrepancy is particularly obvious in black patients for stroke, as the
data suggested a staggering 40% higher risk of stroke
in black patients, while only 13–16% of such risk
was predicted using an external standard of pooled
results of long-term hypertension treatment trials
and observational studies (10–12 mmHg systolic BP
difference associated with 38% stroke reduction).
Clearly, the black hypertensives were more at risk
of stroke and this could not be explained by a few
mmHg of BP difference alone. It is, however, unclear
to what extent biological, dietary, and/or social
inequality factors contribute to these differences.
Black hypertensives tend to have more saltsensitive, low-renin hypertension coupled with
high peripheral vascular resistance, and have more
hypertension-related target-organ damage for a given
level of BP compared with white hypertensives.
Indeed, left ventricular mass (LVM) and the prevalence of LVH are greater among hypertensive black
than among white patients. In ALLHAT, the baseline
rate of echocardiographic LVH were similar in all
three treatment groups (B4.5%), but no follow-up
echocardiographic data on LVM reported. In the
Treatment of Mild Hypertension Study (TOMHS),15
chlorthalidone led to a greater reduction in LVM
than doxazosin, amlodipine, enalapril, and acebutolol in 844 stage 1 hypertensive participants
(20% were black) at each follow-up visit for 4 years,
despite equivalent BP reduction. Interestingly, in
the participants with chlorthalidone added as a
second agent, the demonstration of an additional
decrease in LVM further suggests an independent
effect of chlorthalidone on reduction of LVM.
Interestingly, this was not the case when the ACE
inhibitor enalapril was added as a second agent to
the chlorthalidone group. Furthermore, patients
who received chlorthalidone also had the highest
pretreatment LVM, raising the possibility that they
were the only group with any residual LVH on
which a drug could act after the impressive effects of
the nutritional–hygienic regimen in the TOMHS
study.
Other recent evidence also points towards beneficial effects of diuretics in hypertension with LVH.
In the VA Cooperative Study Group on Antihypertensive Agents (VAC),16 in 587 patients with definite
hypertension (58% were black and 45% had LVH at
study entry), the decrease over time in LVM in the
diuretic-treated (hydrochlorothiazide) and ACE inhibitor-treated (captopril) groups were statistically
greater than those in the groups treated with the CCB
(diltiazem), alpha-adrenergic receptor blocker (prazosin), and central sympatholytic agent (clonidine).
The LIVE study17 also demonstrated a greater
efficacy of indapamide SR (a thiazide-like diuretic)
over enalapril (ACE inhibitor) in the reduction of
LVM in hypertensive patients with LVH, despite
equal BP reductions.
Journal of Human Hypertension
As there were no echocardiographic data on LVM
reported in ALLHAT, comparisons between treatment groups in the changes of LVM between black
and white patients could not be made. One cannot
therefore exclude the possibility that black patients
on chlorthalidone had a greater reduction in LVM in
addition to a greater reduction of BP than black
patients on lisinopril.
Finally, the risk of hypertensive end-stage renal
disease (ESRD) for African Americans is 20-fold
greater than in white patients. In the AASK study,
ramipril was more effective than both amlodipine
and metoprolol in preventing the progression of
renal disease. ALLHAT demonstrated no substantial
differences in incidence of ESRD, glomerular filtration rate, or reciprocal creatinine slopes for the
lisinopril vs chlorthalidone, as well as the lisinopril
vs amlodipine comparisons. Nevertheless, the ALLHAT study population was selected for high CVD
risk and had a baseline mean creatinine of only
1.0 mg/dl (88.4 mmol/l). More detailed analyses of
high renal risk subgroups (ie diabetic, renal-impaired, and black patients) will be expected.
End of the CCB saga after ALLHAT?
The international consensus for thiazide diuretics as
the first-line antihypertensive agent is unchanged
through years, although guidelines for treatment of
hypertension have changed significantly in the last
decade, especially regarding the role of ACE inhibitors and CCBs as first-line agents.
Current guidelines, including the JNC VI18 have
renewed emphasis on the use of CCBs as first-line
antihypertensive agents for treating isolated systolic
hypertension in older patients or those with angina
or diabetes. However, the use of CCBs as first-line
agents have again been subjected to heavy debate as
another meta-analysis by Pahor et al19 found CCBs to
be less effective in preventing cardiovascular events
(with the exception of stroke) compared to other
first-line antihypertensives.
It should be noted that CCBs, are a very heterogeneous group of drugs with properties differing
significantly from one drug to another. Even different formulations of the same molecule have significantly different effects on cardiovascular
pathophysiology, besides lowering BP. The data
from the various meta-analyses of the use of CCBs
in preventing hard end points was largely fragmented because of many possible subgroupings across
the class (eg dihydropyridine vs nondihydropyridine CCBs), patients (diabetics vs nondiabetics) and
end points (cardiovascular vs renal). Such metaanalyses have limited statistical power to really
determine whether the small, but often significant,
differences detected can be generalised to all CCBs.
The clinical effectiveness of every formulation must
be evaluated separately in well-designed clinical
studies.
ALLHAT
DG Beevers et al
However, CCBs do fail to prevent heart failure, an
observation that has been consistently reported in
many studies. For example, in the INSIGHT trial,20
heart failure was approximately twice as frequent in
the CCB, compared to the diuretic arm. Not
unexpectedly, chlorthalidone was superior to
amlodipine in preventing heart failure in ALLHAT.
The BP differences between amlodipine and
chlorthalidone were small (o1 mmHg) and balanced
(lower systolic BP in chlorthalidone but lower
diastolic BP for amlodipine), and cannot account
for the observed different in heart failure incidence.
Perhaps, it is some relief that there were no
significant differences in both CHD and stroke rates
found between amlodipine and chlorthalidonebased therapy in ALLHAT. Given the fact that CCBs
clearly fail to protect patients with hypertension
from heart failure in ALLHAT and elsewhere, their
place when used purely as an antihypertensive
agent would remain at the ‘middle’ if not at the
‘bottom’ on the list of the current array of antihypertensive drugs available. Importantly, there
was no increase risk of cancer, gastrointestinal
bleeding, or noncardiovascular deaths in patients
on amlodipine.
Where do we go from here?
The ALLHAT authors did acknowledge that because
of the trial design, the agents available for step-up
led to a somewhat artificial regimen with the use of
beta blockers rather than diuretics and CCBs as stepup drugs in the ACE inhibitor group.
Nevertheless, the message from ALLHAT is loud
and clear: ‘use thiazide diuretic as first-line agents
in the treatment of hypertension’. However, all
authoritative hypertension treatment guidelines
(and many cynical clinical pharmacologists) have
been saying this for years. Unfortunately, our oldest
friends the thiazides have been seriously underused
over the past 20 years despite abundant literature
documenting their cost-effectiveness in the management of mild-to-moderate hypertension. Perhaps
one obvious reason is because of the lack of
aggressive marketing for thiazide diuretics and
overzealous pharmaceutical marketing for other
newer agents. Other reasons include poor physicians’ adherence to treatment guidelines, physicians’ ‘belief’ that other agents (eg ACE inhibitors,
beta blockers) may be ‘more cardioprotective’ or the
fear of the many ‘adverse’ metabolic effects that been
associated with thiazide diuretics. These largely
theoretical disadvantages have traditionally been
overemphasised in medical schools. These fears
may now be laid to rest by ALLHAT as chlorthalidone prevented total as well as cardiovascular death
despite slightly more hypokalaemia, higher mean
serum cholesterol and glucose levels, and a slightly
high incidence of new cases of diabetes at 4 years’
follow-up.
The North Americans spent $120 million to
conduct ALLHAT simply to find out for sure which
BP lowering agent to choose to begin therapy.
Whichever agent is used to ‘start’ therapy in new
hypertensive patients, the fact remains that most
patients would end up on a combination of
therapies from different drug classes with time.
The answer for this question is more likely financially related than a biological one. So, was this
money well spent? Given the fact that 50–60
million Americans (one in four adults) with hypertension have spent an estimated $15.5 billion/year
on antihypertensive drugs, the cost savings from
using more thiazide diuretics would be substantial.
If diuretics are included in all multidrug regimens,
the annual savings in direct costs have been
estimated between $250 and $600 per patient per
year. There would also be other savings from a
reduced need for hospitalisation. The current UK
price for chlorthalidone 25 mg is d0.03 per tablet,
compared to d 0.42 for amlodipine 5 mg and d 0.40
for lisinopril 20 mg.
There will therefore be little change in any future
hypertension guidelines after ALLHAT, except for a
heavier emphasis on thiazide diuretics as first-line
agent for nearly all newly diagnosed hypertension
(except those with gout). As in ‘real life’, most
patients (63% of patients in ALLHAT) would
require more than one agent to reach their target
BP goal. A diuretic should always be included in the
multidrug regimen. The question is what agents
constitute second-line, does it still matter which
antihypertensive agents to use as long as you lower
the BP? Can the results from ALLHAT be generalised
to other agents of the same class and where would
beta blockers and other newer agents such as the
angiotensin II receptor blockers (ARBs) and new
centrally acting agents (moxonidine) fit into the
equation?
In addition, there would probably be little change
in future guidelines for using a specific class of
agent as initial therapy in the presence of compelling indications. Given the substantial positive
evidence available for ACE inhibitors in the treatment of heart failure, they are still the drugs of
choice together with a diuretic in all hypertensive
patients with known left ventricular dysfunction or
signs of heart failure, regardless of ethnic group.
Thiazide diuretics should only be used at low doses
and fixed dose formulations of thiazide diuretic/
ACE inhibitor may be used to improve compliance.
In patients with hypertension and diabetes (Type I
or Type II), with or without renal disease or
proteinuria, current guidelines recommend the use
of ACE inhibitors (and is likely to include ARBs) as
first choice.
Perhaps, the new guidelines need to be even more
firm, stating that every patient with hypertension
‘must be on a thiazide diuretic unless contraindicated’. Even the most cynical of clinical pharmacologists will be silenced.
371
Journal of Human Hypertension
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DG Beevers et al
372
Conflict of interest statement
GYHL and DGB have received funding for research,
educational symposia, and lecturing from different
manufacturers of antihypertensive drugs.
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