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Efficacy of Different Drug Classes Used to Initiate Antihypertensive Treatment in Black Subjects
Results of a Randomized Trial in Johannesburg, South Africa
Pinhas Sareli, MD;
Ivelin V. Radevski, MD;
Zdravka P. Valtchanova, MD;
Elena Libhaber, MSc;
Geoffrey P. Candy, MSc;
Elly Den Hond, DSc;
Carlos Libhaber, MD;
Daniel Skudicky, MD;
Ji G. Wang, MD;
Jan A. Staessen, MD
Arch Intern Med. 2001;161:965-971.
ABSTRACT
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Background Thiazides are recommended to initiate antihypertensive drug treatment
in black subjects.
Objective To test the efficacy of this recommendation in a South African black
cohort.
Methods Men and women (N = 409), aged 18 to 70 years, with a mean ambulatory
daytime diastolic blood pressure between 90 and 114 mm Hg, were randomized
to 13 months of open-label treatment starting with the nifedipine gastrointestinal
therapeutic system (30 mg/d, n = 233), sustained-release verapamil hydrochloride
(240 mg/d, n = 58), hydrochlorothiazide (12.5 mg/d, n = 58), or enalapril
maleate (10 mg/d, n = 60). If the target of reducing daytime diastolic blood
pressure below 90 mm Hg was not attained, the first-line drugs were titrated
up and after 2 months other medications were added to the regimen.
Results While receiving monotherapy (2 months, n = 366), the patients' systolic
and diastolic decreases in daytime blood pressure averaged 22/14 mm Hg for
nifedipine, 17/11 mm Hg for verapamil, 12/8 mm Hg for hydrochlorothiazide,
and 5/3 mm Hg for enalapril. At 2 months the blood pressure of more patients
treated with nifedipine was controlled: 133 (63.3%, P .03)
vs 20 (39.9%) receiving verapamil, 21 (40.4%) receiving hydrochlorothiazide,
and 11 (20.8%) receiving enalapril. At 13 months (n = 257), more patients
(P<.001) continued receiving monotherapy with
nifedipine (94/154 [61.0%]) or verapamil (22/35 [62.9%]) than hydrochlorothiazide
(10/39 [25.6%]) or enalapril (1/29 [3.4%]). A sustained decrease of left ventricular
mass (P<.001) with no between-group differences
was achieved at 4 and 13 months.
Conclusions In contrast to current recommendations, calcium channel blockers are
more effective than thiazides as initial treatment in black subjects with
hypertension. If treatment is started with thiazides or converting-enzyme
inhibitors, combination therapy is more likely to be required to control blood
pressure and reduce left ventricular mass.
INTRODUCTION
SIMILAR TO the recommendations of the Joint National Committee on Prevention,
Detection, Evaluation, and Treatment of High Blood Pressure,1
the South African guidelines for antihypertensive therapy2
recommend the use of low-dose thiazides as the preferred first-line drug,
to which calcium channel blockers, angiotensin-converting enzyme (ACE) inhibitors, ß-blockers,
or reserpine may be added to achieve blood pressure (BP) control. Although
many patients with mild to moderate hypertension require more than 1 drug
to reach normal BP,3 it remains unclear what
proportion of black patients with hypertension can be controlled in the long-term
if thiazides or other drug classes are used to initiate treatment.
The Baragwanath Hypertension Ambulatory Monitoring Study was a randomized
open-label trial conducted in black patients with hypertension. Its objective
was to compare the BP-lowering effect of a thiazide, the recommended first-line
treatment,1-2 with those of calcium
channel blockers and an ACE inhibitor. To exclude patients with white-coat
hypertension and to avoid observer bias4 in
an open-label trial, ambulatory BP monitoring was used for the selection of
patients and the adjustment of treatment. The patients were followed up for
13 months, so that the long-term efficacy of monotherapy could be evaluated
as well as the need for additional medications to achieve lasting BP control.
We also assessed echocardiographic left ventricular mass as an index of the
efficacy of antihypertensive treatment.
PATIENTS AND METHODS
This trial was a randomized, open-label study conducted at the Chris
Hani-Baragwanath Hospital, Johannesburg, South Africa from September 1, 1994,
through November 30, 1997. The protocol was approved by the Committee for
Research on Human Subjects of the University of the Witwatersrand. Black men
and women could be enrolled, if they were between the ages of 18 and 70 years
and were free of clinically significant cardiovascular or noncardiovascular
disorders. Women of reproductive age had to use adequate contraception. All
patients gave informed written consent.
To screen patients for hypertension, we measured their sitting diastolic
BP 10 times consecutively at 3-minute intervals, using calibrated oscillometric
monitors5 (Dinamap 1846 SX; Critikon Inc, Tampa,
Fla). If the mean diastolic BP was 90 mm Hg or higher, the patients underwent
24-hour ambulatory BP monitoring. Oscillometric devices6
(SpaceLabs 90207; SpaceLabs Inc, Redmond, Wash) were programmed to obtain
readings every 15 minutes from 6 AM to 6 PM. Patients whose mean daytime diastolic
BP was 90 mm Hg or higher then proceeded to a 2-week placebo run-in period,
after which the ambulatory recording was repeated. If on the second set of
measurements the mean daytime diastolic BP ranged from 90 to 114 mm Hg and
if the count of the returned placebo tablets was within 80% to 120% of the
expected number, the patients qualified for enrollment in the study.
Eligible patients were randomized to the nifedipine gastrointestinal
therapeutic system (GITS), 30 mg/d, or 1 of 3 available reference treatments
starting with verapamil hydrochloride sustained release (SR), 240 mg/d; hydrochlorothiazide,
12.5 mg/d; or enalapril maleate, 10 mg/d; as indicated in the current guidelines.1 Patients were followed up at monthly intervals for
13 months with the goal being to lower the daytime diastolic BP below 90 mm
Hg. The ambulatory BP recordings were systematically repeated at monthly intervals
for 4 months and at the final 13-month visit. From the 4-month visit onward,
only the patients whose BP remained uncontrolled at a previous visit underwent
ambulatory BP monitoring. At baseline and at 4 and 13 months, M-mode and 2-dimensional
echcardiograms (Sonos 2500; Hewlett Packard, Andover, Mass) were obtained
using a 2.5-MHz transducer. The echocardiograms were analyzed according to
the American Society of Echocardiography convention.7
Left ventricular mass index was derived according to an anatomically validated
regression method that corrects left ventricular mass estimates obtained from
the recommended measurements.8
If at the first monthly follow-up visit the target BP was not attained,
the daily dose of the first-line drug was increased as follows: nifedipine
GITS to 60 mg/d, verapamil hydrochloride SR to 360 mg/d, hydrochlorothiazide
to 25 mg/d, and enalapril maleate to 20 mg/d. If at 2 months the target BP
was not attained, the patients in the nifedipine GITS group were randomized
to 1 of the following 4 treatment strategies: the addition of enalapril maleate
(10-20 mg/d), carvedilol (25 mg/d), or verapamil hydrochloride SR (120-240
mg/d), or the increase of the daily dose of nifedipine GITS to 90 mg. In the
uncontrolled patients of the verapamil SR group, the daily dose of the calcium
channel blocker could be increased to 480 mg, and subsequently hydrochlorothiazide,
12.5 mg/d, could be added to the regimen. Patients whose BP was uncontrolled
while taking hydrochlorothiazide, 25 mg/d, received reserpine, 0.125 mg/d,
and those whose BP was uncontrolled while taking enalapril maleate, 20 mg/d,
received hydrochlorothiazide, 12.5 mg/d. Patients whose BP was still uncontrolled
at 4 months could receive any study drug in combination with the treatment
already instituted. Patients were withdrawn from the study if at any follow-up
visit after 4 months while receiving combination therapy, the mean 24-hour
systolic BP exceeded 200 mm Hg, or the mean daytime diastolic BP exceeded
114 mm Hg, or they experienced any serious adverse event.
Database management and statistical analysis were performed with SAS
software, version 6.12 (SAS Institute Inc, Cary, NC). Between-group and within-group
differences in continuous measurements were tested with repeated measures
analysis of variance and the Scheffé test for multiple comparisons.
Proportions were compared using the Fisher exact test with Bonferroni correction
for multiple comparisons. Longitudinal changes in treatment status were evaluated
by Kaplan-Meier survival function estimates9
and the log rank test.
RESULTS
As shown in Figure 1, of 591
patients enrolled in the placebo run-in phase, 409 patients were randomized.
At baseline no statistically significant differences were noted between the
patients in the 4 treatment groups (Table
1). The analysis included 366 patients at 2 months, 344 at 4 months,
and 257 at 13 months (Table 2).
The women in particular had high body mass indices (BMIs) (32.4 [SE, 0.4]
kg/m2) compared with the men (26.9 [SE, 0.5] kg/m2, P<.001).
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Figure 1. Trial profile. BP indicates blood
pressure; GITS, gastrointestinal therapeutic system; and SR, sustained release.
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Table 1. Characteristics of 409 Patients at Randomization*
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Table 2. Study Drugs Administered During the Trial
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At 2 months, monotherapy with nifedipine GITS had lowered the daytime
BP more than monotherapy with hydrochlorothiazide or enalapril (Figure 2). The mean systolic and diastolic decreases in the daytime
BP at 2 months for the various treatment groups were as follows: 22/14 mm
Hg for nifedipine GITS, 17/11 mm Hg for verapamil SR, 12/8 mm Hg for hydrochlorothiazide,
and 5/3 mm Hg for enalapril. At 2 months (Figure 3) the BP of significantly more patients treated with nifedipine
GITS was controlled: 133 (63.3%, P.03) vs 20
(39.2%) receiving verapamil SR, vs 21 (40.4%) receiving hydrochlorothiazide,
and vs 11 (20.8%) receiving enalapril; BP control while receiving monotherapy
was not different among patients randomized to verapamil SR, hydrochlorothiazide,
or enalapril (Figure 3). At 2 months
the decrease in the mean (SE) daytime heart rate in the verapamil SR–treated
group (-5.6 [1.3] /min) was significantly different (P = .02) from the heart rate changes for those receiving nifedipine
GITS (+2.7 [0.6] /min), hydrochlorothiazide (-0.5 [1.0] /min), or enalapril
(+0.8 [1.2] /min). The heart rate changes among the latter 3 groups were not
significantly different. There was no difference in control rates while receiving
monotherapy between patients with a higher BMI (>25 kg/m2) and
those with a BMI of 25 kg/m2 or less throughout the trial period.
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Figure 2. Mean daytime (6 AM-6 PM) systolic
(A) and diastolic (B) blood pressure at randomization and during follow-up.
At 2 months all patients were still receiving monotherapy with the randomized
first-line medications; thereafter 1 or more additional drugs could be added
to the regimen (see Table 2).
n refers to the total number of patients in follow-up. GITS indicates gastrointestinal
therapeutic system; SR, sustained release.
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Figure 3. Proportion of patients whose blood
pressure was controlled (mean daytime diastolic blood pressure [DBP] <90
mm Hg) at various stages of follow-up. For further explanation, see Figure
2. n refers to the total number of patients in follow-up. GITS indicates gastrointestinal
therapeutic system; SR, sustained release.
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At 4 months fewer patients (P<.004) in the
nifedipine GITS–treated and verapamil SR–treated groups had required
the addition of second-line medication than did those in the hydrochlorothiazide-treated
and enalapril-treated groups (Table 2).
Similarly, at 13 months (Table 2
and Figure 4), more patients (P<.001) continued to receive monotherapy with nifedipine
GITS (94/154 [61.0%]) or verapamil SR (22/35 [62.9%]) than with hydrochlorothiazide
(10/39 [25.6%]) or enalapril (1/29 [3.4%]). Because many patients proceeded
to combination therapy (Table 2),
the BP differences observed on monotherapy at 2 months disappeared at 13 months
(Figure 2).
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Figure 4. Proportion of patients who continued
receiving monotherapy with randomized first-line medication. The curves represent
Kaplan-Meier estimates9 in which the denominator
is the number of patients available for analysis at each time point. GITS
indicates gastrointestinal therapeutic system; SR, sustained release.
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Within 4 months of randomization (Figure
5), left ventricular mass index had decreased by 15% (P<.001) from 118 (34) g/m2 (mean [SD]) to 100 (25) g/m2 with no further decline between 4 and 13 months when the proportions
of patients receiving combination therapy were 131 (38.1%) of the 344 patients
and 130 (50.5%) of the 257 patients, respectively. There were no between-group
differences in the changes in echocardiographic left ventricular mass (Figure 5, P>.43).
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Figure 5. Mean echocardiographic left ventricular
mass index at baseline and during follow-up. At 4 and 13 months 131 (38.1%)
of the 344 patients and 130 (50.6%) of the 257 patients, respectively, were
receiving combination therapy. n refers to the number of patients in follow-up.
GITS indicates gastrointestinal therapeutic system; and SR, sustained release.
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Uncontrolled BP lead to the withdrawal of 6 patients in the enalapril-treated
group (11.3%), 2 patients in the nifedipine GITS–treated group (0.95%, P<.001 vs enalapril), and no patients in either of the
other 2 groups. The major adverse events were myocardial infarction (1 patient)
and unstable angina pectoris (1 patient) in the nifedipine GITS–treated
group; fatal pneumonia (1 patient) and second-degree atrioventricular block
complicated with left ventricular failure (1 patient) in the verapamil SR–treated
group; fatal bowel obstruction (1 patient) and grand mal epilepsy (1 patient)
in the hydrochlorothiazide-treated group; and angioneurotic edema (5 patients)
in the enalapril-treated group. No patient experienced gastrointestinal bleeding.
COMMENT
At 2 months the rate of BP control was higher for the patients receiving
nifedipine GITS treatment than for those patients receiving verapamil SR,
hydrochlorothiazide, or enalapril. Monotherapy with nifedipine GITS reduced
BP significantly more than hydrochlorothiazide and enalapril. At 13 months
more patients continued receiving monotherapy with nifedipine GITS or verapamil
SR than hydrochlorothiazide or enalapril.
This study must be interpreted within the context of its limitations.
Of 409 randomized patients, the numbers lost to follow-up were 32 (7.8%) at
2 months, 45 (11.0%) at 4 months, and 115 (28.1%) at 13 months. The patients
enrolled in the trial were recruited from the Soweto district, an urban black
community burdened by unemployment (52.9%), shortage of housing, deprivation,
social divide, and broken households. These conditions explain why people
frequently relocated to find new jobs and why many of our patients withdrew
their consent or dropped out of the study. However, the black inhabitants
of Soweto are representative of many modern African cities, characterized
by a high prevalence and incidence of hypertension.10-11
The patients characteristically also had a high BMI that may be explained
by inactivity or by their high-energy, low-protein maize-based diet. Our study
had an open-label design, but we used 24-hour ambulatory BP monitoring to
determine objectively the eligibility of the patients and to evaluate the
effects of treatment. Indeed, ambulatory BP measurements are characterized
by high reproducibility, are not subject to digit preference and observer
bias, and avoid the transient rise of a patient's BP in response to the clinic
surroundings or the presence of the observer, the so-called white-coat effect.4
To the best of our knowledge, no other study used ambulatory BP monitoring
on a large scale in black African patients with hypertension. In a previous
single-blind randomized trial (n = 41), we demonstrated that over a 12-week
period treatment twice with nifedipine (20-40 mg twice daily) reduced the
24-hour systolic and diastolic BP by 28/17 mm Hg, whereas treatment with captopril
(50 mg twice daily) did not change BP (+2/+1 mm Hg).12
Materson and coworkers13-14 randomized
1292 American men with a clinic diastolic BP of 95 to 109 mm Hg to placebo
or 1 of the following 6 drugs: hydrochlorothiazide (12.5-50 mg/d), diltiazem
SR (120-360 mg/d), atenolol (25-100 mg/d), clonidine (0.2-0.6 mg/d), captopril
(25-100 mg/d), or prazosin (4-20 mg/d). This trial included 291 black patients,13-14 aged 21 to 60 years, in whom the
nondihydropyridine calcium channel blocker diltiazem after 1 year achieved
the best control rate (56.8%),13 defined as
a clinic diastolic BP of less than 90 mm Hg. In agreement with our 2 months'
observations, hydrochlorothiazide treatment titrated up from 12.5 to 50 mg/d
controlled BP in 41.7% of the black patients.14
In keeping with other studies,3, 15
most of our black patients with mild to moderate hypertension required multiple
drug treatment to achieve adequate control, especially if treatment was initiated
with a thiazide or an ACE inhibitor. Low rates of BP control have been previously
documented in black patients with hypertension who were receiving treatment
with captopril,12 enalapril,16-17
or hydrochlorothiazide.18 On balance, the evidence
available suggests that ACE inhibitors should not be used as monotherapy in
black patients with hypertension, but only in combination with other medications.14 At 13 months, the addition of hydrochlorothiazide
and/or other drugs (nifedipine GITS in 15 of 29 patients) achieved BP control
in 79.3% of patients randomized to enalapril treatment. Furthermore, at the
end of the study, the addition of reserpine and/or enalapril to hydrochlorothiazide
treatment resulted in a control of 66.7%.
Two research groups19-20
have suggested that to reduce left ventricular hypertrophy ACE inhibitors
would be most efficient. However, a third meta-analyst21
considered only prospective, randomized, and properly controlled comparative
studies. This analysis revealed that thiazides, ß-blockers, calcium channel
blockers,and ACE inhibitors reduced left ventricular mass to the same degree
as the 3 other classes statistically combined, and that ACE inhibitors were
not superior to calcium channel blockers.21
Our study showed a significant decrease in left ventricular mass index at
4 months paralleling the decline in BP, with no differences between the treatment
groups. This observation suggests that BP control rather than drug class is
the predominant factor determining left ventricular mass regression.
CONCLUSIONS
In contrast with the modified South African guidelines,1-2
long-acting calcium channel blockers are more effective than thiazides as
initial treatment in African blacks with hypertension. Outcome trials in hypertension
were largely conducted in white22-23
and Asian subjects.24-26
Because such information is not yet available for African blacks, the present
findings should be subject to further investigation in prospective morbidity
and mortality trials in African blacks.
AUTHOR INFORMATION
Accepted for publication November 7, 2000.
The Baragwanath Hypertension Ambulatory Monitoring Study was supported
by Bayer (Pty) Ltd, Johannesburg.
We gratefully acknowledge the expert assistance of Elizabeth Tshele,
RN, and Margaret Hlatswayo, RN. William H. Birkenhäger, MD, Erasmus University,
Rotterdam, the Netherlands, provided helpful comments on the manuscript.
Corresponding author: Pinhas Sareli, MD, Department of Cardiology,
Chris Hani-Baragwanath Hospital, University of the Witwatersrand, PO Bertsham,
Johannesburg 2013, South Africa (e-mail: psareli{at}iafrica.com).
From the Department of Cardiology, Chris Hani-Baragwanath Hospital,
University of the Witwatersrand, Johannesburg, South Africa (Drs Sareli, Radevski,
Valtchanova, C. Libhaber, and Skudicky, and Mr Candy and Ms E. Libhaber);
and the Study Coordinating Centre, Hypertension and Cardiovascular Rehabilitation
Unit, Department of Molecular and Cardiovascular Research, University of Leuven,
Leuven, Belgium (Drs Den Hond, Wang, and Staessen).
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