The purpose of this study was to compare several diltiazem-based antihypertensive drug
combinations and assess the usefulness of home blood pressure monitoring in the evaluation
of the efficacy of combination pharmacotherapy. Sixteen general practitioners
recruited hypertensive subjects uncontrolled on diltiazem monotherapy, who were randomized
to receive eight weeks of add-on therapy with a diuretic (chlorthalidone), a
dihydropyridine calcium antagonist (felodipine), an ACE inhibitor (lisinopril), or an
angiotensin blocker (valsartan). Sitting office and home blood pressure was measured
using electronic devices A&D 767. A total of 211 patients were randomized, and 185
completed the study. Of 52 subjects randomized to felodipine, 15 were withdrawn due to
ankle edema. The additional antihypertensive effect of the second drug was smaller in
18 subjects with a white coat effect (p < 0.01). All combinations produced a significant
decline in office (21.2 ± 14.8 / 7.7 ± 9.7 mmHg) and home (17.1 ± 11.9 / 6.0 ± 7.0) blood
pressure (systolic / diastolic, p < 0.001). There were no differences in the efficacy of the
four combinations assessed using office or home blood pressure monitoring. These data
suggest that diuretics, dihydropyridines, ACE inhibitors, and angiotensin receptor
blockers provide significant additional antihypertensive effects in hypertensive patients
uncontrolled on diltiazem monotherapy. The diltiazem-dihydropyridine combination is
often intolerable because of ankle edema. Home blood pressure monitoring is useful in
the assessment of the efficacy of combination pharmacotherapy and also allows for the
detection of subjects who do not require treatment intensification.
Introduction
There is agreement among hypertension guidelines that diuretics, b-blockers, calcium
antagonists, ACE inhibitors, and angiotensin receptor antagonists are appropriate to be
used as first line treatment in hypertension (1–3). Moreover, it is recognized that in order
to achieve the recommended blood pressure (BP) goals, combination pharmacotherapy is
required in the majority of hypertensive patients (1,2). It is clear, however, that more clinical
research from randomized comparative trials on the efficacy and tolerability of antihypertensive
drug combinations is needed (1).
Non-dihydropyridine calcium antagonists are effective antihypertensive drugs and are
being widely used in clinical practice (4). Outcome trials have shown that these drugs
improve cardiovascular prognosis in hypertensive patients with or without coronary heart
disease (5,6). Some short-term studies have assessed the antihypertensive effects of
combined treatment of non-dihydropyridine calcium antagonists with thiazide diuretics
(7–9) or angiotensin-converting enzyme (ACE) inhibitors (10,11). However, the evidence
on the combination of these drugs with dihydropyridines or angiotensin blockers is very
limited (12,13). In addition, no direct comparison of these combinations in regard to their
antihypertensive efficacy has been reported.
Self-blood pressure monitoring at home is regarded as an important adjunct to office
measurements in hypertensive patients and is being increasingly used in clinical practice
(1,2,14,15). Accumulating evidence suggests that home BP is devoid of the white coat (16)
and the placebo effect (14) and provides highly reproducible BP values (17). Therefore,
home BP has been recently used in several trials to assess the efficacy of antihypertensive
drugs, and it has been suggested that the use of this method instead of the conventional
office measurements can improve the accuracy of antihypertensive drug trials (14,17).
The objectives of this study are to (1) assess the additional antihypertensive effect of a
thiazide diuretic versus a dihydropyridine calcium antagonist, an ACE inhibitor, and an
angiotensin receptor blocker in hypertensive patients uncontrolled on diltiazem monotherapy,
and (2) compare self-home BP measurements with office BP measurements in the
assessment of the antihypertensive effect of combination pharmacotherapy.
Subjects and Methods
Physicians and Patients
Trained general practitioners employed in primary care recruited subjects aged 25–79
years with uncontrolled hypertension after at least four weeks of open monotherapy with
diltiazem at 240 mg o.d. Uncontrolled hypertension was defined as average office BP
greater than 140/90 mmHg for all or 135/85 mmHg for diabetics or subjects under the age
of 65, confirmed on two office visits at least one week apart (3).
Design
Participants were randomized to receive one of the following open add-on therapies for
eight weeks:
1. thiazide diuretic chlorthalidone 12.5 mg o.d.,
2. dihydropyridine calcium antagonist felodipine 5 mg o.d.,
3. ACE inhibitor lisinopril 10 mg o.d., or
4. angiotensin receptor blocker valsartan 80 mg o.d.
Add-on treatment was doubled if office BP remained uncontrolled after four weeks of randomized
combination pharmacotherapy. All antihypertensive drugs were taken in the
morning just after rising from bed. The study protocol was approved by the Quality Assurance
Committee of the Greek Association of General Practitioners. Participants gave
informed consent for study participation.
Exclusion criteria included the following:
• contraindication or known intolerance of diuretics, calcium antagonists, ACE inhibitors,
or angiotensin blockers;
• compelling indication for treatment with a specific antihypertensive drug class;
• nephropathy, coronary heart disease, congestive heart failure, major cardiac, hematological,
or hepatic or pulmonary disease;
• cerebrovascular event in the three months prior to study entry;
• any other clinically significant illness based upon recent medical history, with the
exception of stable diabetes type-2 on diet alone and/or by oral hypoglycemic agents;
• evidence of secondary hypertension;
• systolic BP >200 mmHg and/or diastolic >110 mmHg at any time during the study;
• therapy with any drug likely to influence BP, including diuretics and NSAIDs
(excluding aspirin up to 300 mg per day); and
• clinically important abnormalities of baseline laboratory data.
Measurements
Office BP was measured by general practitioners at trough before randomization and after
four and eight weeks using validated electronic devices A&D 767 (18) (bladder size 12 × 23
cm or 14 × 2 8 cm, where appropriate). Triplicate measurements were taken at each visit
after 5 min sitting rest and 1 min between readings, and the average was used for decision
making (randomization and titration). Home BP was monitored by the patients themselves
on three routine workdays in the week before randomization and after four and eight weeks.
Self-measurements were taken by the patients at home using the same device and cuff as
office measurements (A&D 767). Participants were trained in the conditions of home BP
measurement and the use of the devices and were instructed to perform duplicate morning
(0600–1000 h, before morning drug intake) and evening (1800–2100 h) measurements after
5 min sitting rest and 1 min between recordings. A form was supplied to the patients to
report self-home BP values. The average of all home measurements was used in the analysis.
Physical examination, body weight measurement, and 12-lead ECG were performed
before randomization and after four and eight weeks. Routine hematology and biochemistry
and urine dipstick and microscopy were performed within four weeks prior to study
entry. Depending on the randomized regimen, selected tests were repeated after four and
eight weeks according to current hypertension recommendations (1–3). An assessment of
adverse reactions was performed at each office visit.
Analysis
Taking into account that home BP was used in a four-group parallel design, in order to
have a probability greater than 0.9 (study power) to detect between treatment groups differences
of 10/5 mmHg in systolic/diastolic home BP at p < 0.05, a total of at least 180
subjects with complete data should be studied (estimated standard deviation of differences
for home systolic/diastolic BP = 7/5 mmHg (17); clinically important between periods
difference ≥ 10/5 mmHg in home systolic/diastolic BP; corrected for multiple comparisons).
Paired t-tests were used to assess treatment-induced changes in clinic and home BP
and unpaired t-tests for between-groups comparisons of antihypertensive drug effects. A
Bonferroni’s correction for multiple comparisons was applied where appropriate.
Results
A total of 211 subjects were recruited by 16 general practitioners and randomized. Fifty-four
subjects were randomized to receive add-on chlorthalidone; 52, felodipine; 54, lisinopril; and
51, valsartan. Twenty-six subjects were withdrawn after randomization, of whom 22 (10.4%)
due to adverse drug effects (17 due to ankle edema) and 4 (1.8%) due to missing follow-up
data. Ankle edema was observed in 15 subjects on felodipine (29%), 1 on valsartan (0.5%), 1
on chlorthalidone (0.5%), and none on lisinopril (p < 0.001). Data from the remaining 185 subjects
with complete follow-up were included in the final analysis, of whom 51 (27.6%) were on
chlorthalidone, 36 (19.5%) on felodipine, 50 (27.03%) on lisinopril, and 48 (25.9%) on valsartan.
The mean age of the 185 subjects was 63.9 ± 10.6 years, 80 (43%) were men, the mean
body mass index (BMI) was 28.7 ± 4.6 kg/m2, and 41 (22%) had type-2 diabetes.
Average office BP at randomization was 158.6 ± 13.1 / 86.1 ± 9.4 mmHg (mean ±
SD, systolic / diastolic), whereas average home BP was significantly lower (150.3 ± 13.3 /
83.0 ± 8.6 mmHg; p < 0.001). There was no significant difference among randomized
groups in regard to patients' age, sex, BMI, proportion of diabetics, and baseline office or
home BP (see Table 1). Eighteen subjects (10%) had average home BP <135/85 mmHg at
randomization and where classified as having a white coat effect. After four weeks of
combination pharmacotherapy, the dose of the second drug was doubled in 113 subjects
(61%) because of an uncontrolled office BP. There was no difference among randomized
groups in the proportion of subjects in whom randomized treatment was doubled.
Table 1
Baseline characteristics of participants in the four randomized treatment
groups (mean ± SD)
Thiazide
diuretic
Dihydropyridine
ACE
inhibitor
Angiotensin
blocker All drugs
Subjects 51 36 50 48 181
Age (years) 63.5 ± 9.9 64.7 ± 9.8 62.6 ± 12.9 65.2 ± 8.6 63.9 ± 10.5
BMI (kg/m2) 28.7 ± 4.2 28.2 ± 4.7 28.1 ± 4.7 29.3 ± 4.3 28.6 ± 4.6
Men (%) 24 (47) 15 (42) 20 (40) 21 (44) 80 (44)
Diabetes (%) 16 (31) 5 (15) 8 (49) 12 (47) 41 (22)
Office BP (mmHg)
Systolic 159.6 ± 13.6 160.2 ± 16.0 157.7 ± 11.4 157.7 ± 12.2 158.6 ± 13.1
Diastolic 86.5 ± 9.3 87.1 ± 8.1 86.1 ± 10.5 85.0 ± 9.7 86.1 ± 9.4
Pulse rate 75.2 ± 8.3 77.8 ± 7.9 77.1 ± 10.7 73.2 ± 9.5 75.7 ± 9.4
Home BP (mmHg)
Systolic 148.6 ± 14.1 152.4 ± 14.0 151.2 ± 14.2 149.7 ± 10.9 150.3 ± 13.3
Diastolic 82.7 ± 8.5 83.6 ± 8.6 83.5 ± 8.8 82.0 ± 8.3 83.0 ± 8.6
Pulse rate 72.1 ± 8.1 74.2 ± 7.5 72.4 ± 6.9 70.5 ± 8.9 2.2 ± 7.9
BMI: body mass index; BP: blood pressure.
Significant decline in both office and home BP was achieved during the study (see
Table 2). The additional antihypertensive effect obtained by the second drug was significantly
greater in subjects without compared to those with a white coat effect (Table 2).
This difference in the antihypertensive effect was more pronounced and reached statistical
significance when home BP monitoring was used (average home BP decline 8.0 / 2.8
mmHg systolic / diastolic in subjects with a white coat effect versus 17.1 / 6.0 mmHg in
the others; see Table 2). All drug combinations induced a significant decline (p < 0.001) in
both office and home BP during the study (see Table 3). There were no significant differences
in the additional antihypertensive effects of the four drugs assessed using either
office or home BP monitoring.
Discussion
This study compared the efficacy of four diltiazem-based antihypertensive drug combinations
using office and home BP monitoring. The study showed that a thiazide diuretic, a
dihydropyridine calcium antagonist, an ACE inhibitor, and an angiotensin receptor
blocker provide significant additional antihypertensive effects in hypertensive patients
uncontrolled on diltiazem monotherapy. However, the diltiazem-dihydropyridine combination
was often intolerable because of significant ankle edema. In addition, the study
showed that home BP monitoring is at least as effective as the conventional office measurements
in the assessment of the efficacy of antihypertensive drug combinations and
also allows for the detection of subjects who do not benefit from treatment intensification.
Studies have shown additional antihypertensive effects of diltiazem combined
with hydrochlorthiazide (7–9). Furthermore, several hypertension trials have investigated
the efficacy of combining non-dihydropyridine calcium antagonists with ACE
inhibitors, and fixed dose combinations of these drug classes have been developed
(10,11). However, in regard to the angiotensin blockers, there are no published studies
of the antihypertensive efficacy of these drugs in combination with non-dihydropyridine
calcium antagonists.
The combination of non-dihydropyridine calcium antagonists with dihydropyridines
remains controversial. Receptor binding studies have suggested that this combination
might result in either enhanced or diminished pharmacological effects (12). However, the
evidence from clinical trials on the antihypertensive efficacy and the tolerability of this
combination is very limited (12,13). A small randomized study in hypertensive patients
uncontrolled on nifedipine monotherapy showed significant additional antihypertensive
effects with either diltiazem or verapamil (12). That study provided evidence that the additional
antihypertensive effect is due to a pharmacokinetic interaction between diltiazem
and nifedipine (12). In another randomized comparative study of diltiazem versus nitrendipine
in patients with hypertension and stable angina, an additional antihypertensive
effect without additional side effects was observed in a subgroup of 16 subjects who
received both drugs because of uncontrolled BP on monotherapies (13). In contrast, the
present study showed that the diltiazem-felodipine combination is associated with intolerable
ankle edema in 30% of subjects. This adverse effect might be attributed to the high
dose of calcium antagonist rather than to a drug interaction, given that the incidence of the
calcium antagonist-induced vasodilatory ankle edema is the most common side adverse
effect of these drugs that leads to withdrawal and is clearly dose-dependent (19). It should
be noted that the abovementioned studies that assessed the efficacy of the combination of
non-dihydropyridine calcium antagonists with other antihypertensive drugs have compared
combination therapy with monotherapies, whereas the present study provided a
direct head-to-head comparison of the antihypertensive effect of four non-dihydropyridine
calcium antagonist-based combinations.
In this study, both office and home BP measurements were taken using validated
automated devices. This approach increases the reliability of measurements by preventing
observer bias and the terminal digit preference, which are known to be present using conventional
auscultatory BP measurements (14). Significant additional antihypertensive
effects were detected in this study using either office or home BP measurements (Table 3).
However, the use of home BP monitoring allowed for the detection of a significant white
coat effect in 10% of study participants (16). Recent recommendations suggest that subjects
with the white coat phenomenon do not benefit from treatment intensification
(1,2,14). In line with these recommendations, this study showed that in subjects with a
white coat effect, the magnitude of the decline in home BP was less than half of that
achieved in the rest of study participants (Table 2). It is clear that the implementation of
home BP monitoring in clinical trials aiming to assess the efficacy of antihypertensive
drugs allows for the exclusion of subjects with the white coat effect, thereby increasing the
study power or reducing the number of subjects required (16,17). On the other hand, the
use of home BP in clinical practice is essential for the detection of treated hypertensives
with a white coat effect in order to prevent unnecessary, costly, and potentially harmful
additional pharmacotherapy. These benefits of home BP monitoring are attributed to the
facts that measurements are taken away from the office setting and to the larger number of
readings obtained (14–16).
Подписаться на:
Комментарии к сообщению (Atom)
Комментариев нет:
Отправить комментарий