AJH 2004; 17:495–501
Initial Angiotensin-Converting Enzyme
Inhibitor/Calcium Channel Blocker
Combination Therapy Achieves Superior
Blood Pressure Control Compared With
Calcium Channel Blocker Monotherapy
in Patients With Stage 2 Hypertension
Kenneth A. Jamerson, Oliseyenum Nwose, Lisa Jean-Louis,
Lesley Schofield, Das Purkayastha, and Michelle Baron
Background: The Seventh Report of the Joint Na-
tional Committee (JNC 7) on Prevention, Detection,
Evaluation, and Treatment of High Blood Pressure recom-
mends initial combination therapy for patients whose
blood pressure (BP) is ⬎20/10 mm Hg above goal. This
study evaluated the efficacy and safety of initial combina-
tion therapy versus that of monotherapy in patients with
stage 2 hypertension, who by definition meet the JNC 7
recommendation for initial combination antihypertensive
therapy.
Methods: This multicenter, double-blind, 12-week
study randomized 364 patients with stage 2 hypertension
to fixed-dose combination therapy with amlodipine
besylate/benazepril HCl (5/20 mg/d titrated to 10/20 mg/d)
or amlodipine besylate monotherapy (5 mg/d titrated to 10
mg/d).
Results: Significantly more patients randomized to
combination therapy (74.2%) compared with those ran-
domized to monotherapy (53.9%; P ⬍ .0001) achieved the
primary end point (reductions in systolic BP ⱖ25 mm Hg,
if baseline systolic BP was ⬍180 mm Hg, or ⱖ32 mm Hg,
if baseline systolic BP was ⱖ180 mm Hg). Significantly
A
confluence of data, treatment guidelines, and clin-
ical judgment is making the initial use of combi-
nation antihypertensive therapy increasingly
commonplace. There is a steep and graded relationship
between increasing blood pressure (BP) and increasing
Received August 12, 2003. First decision December 18, 2003. Accepted
February 3, 2004.
From the Division of Hypertension, Department of Internal Medicine,
University of Michigan Medical Center (KAJ), Ann Arbor, Michigan,
and Novartis Pharmaceuticals Corporation (ON, LJ-L, LS, DP, MB),
East Hanover, New Jersey.
© 2004 by the American Journal of Hypertension, Ltd.
Published
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more patients randomized to combination therapy com-
pared with monotherapy attained BP goals of ⬍140/90
mm Hg (61.0% v 43.3%; P ⫽ .0007) and ⱕ130/85 mm Hg
(35.7% v 19.1%; P ⫽ .0004). Among patients with base-
line systolic BP ⱖ180 mm Hg, combination therapy re-
sulted in significantly greater reductions in systolic BP
compared with monotherapy (⫺42.3 v ⫺30.4 mm Hg; P
⫽ .001). More than 90% of patients in each group were
titrated to the higher dose. Both treatments were well
tolerated.
Conclusions: Combination therapy was well tolerated
and resulted in significantly greater BP reductions and
attainment of BP goals compared with monotherapy in
patients with stage 2 hypertension. This evidence supports
the recommendation of combination therapy as first-line
treatment in stage 2 hypertension. Am J Hypertens 2004;
17:495–501 © 2004 American Journal of Hypertension,
Ltd.
Key Words: Amlodipine besylate/benazepril HCl, an-
tihypertensive therapy, fixed-dose combination therapy,
hypertension, JNC 7.
cardiovascular disease (CVD) morbidity and mortality,
with the risk of death from CVD doubling for each incre-
ment of 20/10 mm Hg across the BP range from 115/75
mm Hg to 185/115 mm Hg.1 Equally well documented is
that only slightly more than one-third of hypertensive
This work was supported by a grant from Novartis Pharmaceuticals
Corporation, East Hanover, New Jersey.
Address correspondence and reprint requests to Dr. Kenneth A.
Jamerson, University of Michigan Medical Center, 3918 Taubman Cen-
ter, Ann Arbor, MI 48109; e-mail: jamerson@umich.edu
0895-7061/04/$30.00
doi:10.1016/j.amjhyper.2004.02.003
 496 INITIAL COMBINATION THERAPY ACHIEVES GREATER BP CONTROL
adults have BP values controlled to ⬍140/90 mm Hg.2 It
seems plausible that at least part of the reason for these
poor control rates is the repeated observation that the use
of any single antihypertensive agent normalizes BP in
little more than 50% of hypertensive patients.2– 6 To
achieve recommended BP goals, it is often necessary to
combine two or more antihypertensive agents.2,5–11
Recognizing these data, the recently released Seventh
Report of the Joint National Committee on Prevention,
Detection, Evaluation, and Treatment of High Blood Pres-
sure (the JNC 7 report)2 recommends that patients whose
BP is ⬎20/10 mm Hg above goal be treated initially with
combination antihypertensive therapy. The conventional
wisdom of the JNC suggests that “[t]he initiation of drug
therapy with more than 1 agent may increase the like-
lihood of achieving the BP goal in a more timely
fashion. . . .”2 The recommendation for initial use of com-
bination antihypertensive therapy was endorsed in another
recently released treatment guideline,12 which preceded
the JNC 7 report. This guideline for treatment of hyper-
tension in African Americans recommends initial combi-
nation therapy in patients whose BP levels are ⬎15/10 mm
Hg above goal.12
The recent release of these data and treatment guide-
lines has put increasing focus on prescribers to control BP
to recommended goals and to consider initial combination
therapy when appropriate. From a clinician’s perspective,
appropriate combination antihypertensive therapy may
have a number of advantages, including improved efficacy,
tolerability, and patient adherence.13 Fixed-dose combina-
tion therapy in particular may result in improved patient
adherence through simplicity of use; also, data indicate
that patients are more likely to remain on therapy if they
attain BP control with the initially prescribed agent.14 The
potential benefits of combination therapy notwithstanding,
clinicians are faced with a myriad of choices and little data
on the efficacy and benefits of specific fixed-dose combi-
nation therapies.
Amlodipine besylate/benazepril hydrochloride (HCl) is
a fixed-dose combination antihypertensive containing a
dihydropyridine calcium channel blocker (CCB) and an
angiotensin-converting enzyme (ACE) inhibitor. Calcium
channel blockers are potent antihypertensive agents that
act directly on vascular smooth muscle to reduce periph-
eral vascular resistance and promote arterial vasodilata-
tion, which results in powerful BP-lowering effects. The
use of high doses of CCBs often results in adverse events,
most notably, peripheral (ankle) edema. When used in
combination with a CCB, ACE inhibitors have been
shown to ameliorate dose-related edema associated with
CCB monotherapy.15,16 Numerous studies have shown
that ACE inhibitors have protective effects on target or-
gans beyond their ability to lower BP; these studies have
included patients with heart failure, diabetes, and renal
disease, as well as studies of the primary and secondary
prevention of CVD.17–21
The Safety of Lotrel versus Amlodipine in a Compar-
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AJH–June 2004 –VOL. 17, NO. 6
ative Efficacy Trial (SOLACE) was designed to compare
the efficacy and safety of initial antihypertensive therapy
with the fixed-dose combination of amlodipine besylate/
benazepril HCl with that of the most commonly prescribed
antihypertensive monotherapy, amlodipine besylate, in pa-
tients with stage 2 hypertension. The SOLACE study
design tests the efficacy of combination therapy as sug-
gested by JNC 7.
Methods
The primary objective of the study was to compare the
percentage of patients achieving a reduction in systolic BP
of ⱖ25 mm Hg (if baseline systolic BP was ⬍180 mm Hg)
or ⱖ32 mm Hg (if baseline systolic BP was ⱖ180 mm
Hg), during 12 weeks of a daily treatment regimen with
amlodipine besylate/benazepril HCl, versus amlodipine
besylate monotherapy. Other objectives included compar-
ing the percentage of patients achieving a reduction in
diastolic BP of ⱖ15 mm Hg (if baseline diastolic BP was
⬍110 mm Hg) or ⱖ20 mm Hg (if baseline diastolic BP
was ⱖ110 mm Hg); the percentage of patients achieving a
BP goal of ⬍140/90 mm Hg; the percentage of patients
achieving a BP goal of ⱕ130/85 mm Hg; mean change
from baseline in systolic BP and diastolic BP at week 12;
time to achieving reductions in BP; and the incidence of
peripheral (ankle) edema.
This was a multicenter, randomized, double-blind, par-
allel-group study. Men and women aged 18 to 80 years
with a documented diagnosis of stage 2 hypertension,
defined as systolic BP ⱖ160 and ⱕ210 mm Hg or diastolic
BP ⱖ100 and ⱕ120 mm Hg, were eligible to participate in
the study. Written informed consent was obtained from
each patient. Women of childbearing potential were re-
quired to practice an effective method of contraception.
The study excluded pregnant or nursing women, patients
with systolic BP ⬎210 mm Hg or diastolic BP ⬎120 mm
Hg, patients with medical conditions that would impair
their ability to participate to conclusion in a trial of anti-
hypertensive therapy, and those with any known allergy or
hypersensitivity to any of the study drugs.
Study Design
Previously treated patients were withdrawn from all anti-
hypertensive medication for a period ranging from 3 to 10
days. Blood pressure was monitored on day 3, and patients
with systolic BP ⱖ200 mm Hg and ⱕ210 mm Hg or
diastolic BP ⬎110 mm Hg and ⱕ120 mm Hg were ran-
domized, whereas those who had systolic BP ⬍200 mm
Hg or diastolic BP ⬍110 mm Hg continued the washout
period for another 7 days. Patients who were naı̈ve to drug
therapy could be randomized on day 3 if they met the
protocol definition of stage 2 hypertension and fulfilled the
inclusion criteria. Patients were randomized to active treat-
ment at dose level 1 with either fixed-dose combination
amlodipine besylate/benazepril HCl (5/20 mg) or mono-
therapy with amlodipine besylate (5 mg) for 2 weeks. At
 AJH–June 2004 –VOL. 17, NO. 6 INITIAL COMBINATION THERAPY ACHIEVES GREATER BP CONTROL 497

week 2 or any time thereafter, patients with BP ⬎130/85
mm Hg were titrated to dose level 2 (amlodipine besylate/
benazepril HCl 10/20 mg or amlodipine besylate 10 mg)
for the remainder of the treatment period. After 3 weeks at
dose level 2, patients with systolic BP ⱖ180 and ⱕ210
mm Hg or diastolic BP ⱖ110 and ⱕ120 mm Hg could
receive adjunctive open-label hydrochlorothiazide
(HCTZ) 12.5 mg. Downward dose adjustment to the pre-
vious dose level was not permitted. Patients who had
systolic BP ⬎210 mm Hg or diastolic BP ⬎120 mm Hg at
any time during the study were discontinued. The total
duration of double-blind treatment was 12 weeks.
Efficacy and Safety Assessments
Vital signs (seated BP and heart rate) were assessed at
each visit. Height and weight were measured at the screen-
ing visit. Blood pressure was measured using a calibrated
automatic sphygmomanometer and appropriately sized
cuff. Three separate seated BP measurements were taken 2
min apart, and the mean of three readings was calculated
and recorded. A physical examination was performed at
randomization (week 0) and at week 12. The presence of
peripheral (ankle) edema was assessed at each visit. Pa-
tients were required to stand for at least 5 min, after which
the circumference of each ankle was measured, and the
presence of edema was assessed by the examiner. In
addition, the presence of edema, whether noted by the
investigator or reported by the patient, was collected as an
adverse event.
Fasting insulin and glucose levels were measured at
randomization and at week 12 and used to calculate
changes in insulin resistance as assessed by the homeosta-
sis model (HOMA).22 Blood chemistry (including potas-
sium) and lipid profiles were also measured at
randomization and at week 12.
Insulin levels were measured by a two-site chemilumi-
nescent assay (Diagnostic Products Corp., Los Angeles,
CA). All other analyses were performed at a central lab-
oratory (Clinical Reference Laboratory, Lenexa, KS) us-
ing standard methods.
Statistical Analysis
Background and demographic variables were summarized
using descriptive statistics. The ␹2 test was used for cate-
gorical variables and the two-sample t test was used for
continuous variables to test for homogeneity between the
two treatment groups. All efficacy analyses were per-
formed using the intent-to-treat (ITT) population, consist-
ing of all randomized patients who received study drug
and from whom at least one postbaseline efficacy assess-
ment was obtained, using the last observation carried
forward approach. The safety analysis included all ran-
domized patients who took at least one dose of study
medication. Efficacy variables were assessed with an anal-
ysis of covariance using baseline assessment as a covari-
ate, and treatment and center as factors in the model. To
analyze the time to achieve the first BP target, Kaplan-
Meier estimates were obtained. The log-rank test was used
to test for the survival curve difference between the two
treatment groups. The sample size was determined to
provide ⬎90% power at the two-sided significance level
of .05, to detect a 15% difference between the two groups.
Results
Demographics
The baseline demographic characteristics and vital signs
of the ITT population are presented in Table 1. Of 364
patients randomized, 182 were in both the combination
and the monotherapy groups. The safety population com-

Table 1. Patient demographics and vital signs

Amlodipine Besylate/ Amlodipine All

Variable Benazepril HCl Besylate Patients
Study population
Safety 182 182 364
Intent-to-treat 182 178 360
Completers 157 145 302
Age (y) 55.0 ⫾ 12.1 55.1 ⫾ 11.5 55.0 ⫾ 11.8
Sex (M/F) 96/86 71/107 167/193
Race (%)
White 114 (63) 104 (58) 218 (61)
Black 39 (21) 44 (25) 83 (23)
Asian 0 (0.0) 1 (0.6) 1 (0.3)
Other 29 (16) 29 (16) 58 (16)
BMI (kg/m2) 32.1 ⫾ 6.2 32.6 ⫾ 7.6 32.4 ⫾ 6.9
Pulse rate (beats/min) 73.0 ⫾ 10.2 74.6 ⫾ 10.9 73.8 ⫾ 10.6
SBP (mm Hg) 167.3 ⫾ 13.4 167.5 ⫾ 14.2 167.4 ⫾ 13.7
DBP (mm Hg) 100.0 ⫾ 9.6 99.2 ⫾ 10.2 99.6 ⫾ 9.9

Values are represented as mean ⫾ SD. The safety population includes all randomized patients who took at least one dose of study drug. The
intent-to-treat population includes all randomized patients who received study drug and had at least one postbaseline efficacy assessment.
BMI ⫽ body mass index; SBP ⫽ systolic blood pressure; DBP ⫽ diastolic blood pressure.

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 498 INITIAL COMBINATION THERAPY ACHIEVES GREATER BP CONTROL AJH–June 2004 –VOL. 17, NO. 6

prised all 364 randomized patients, and the ITT population

comprised 360 patients, 182 in the combination group and
178 in the monotherapy group. A total of 62 (17.0%)
patients discontinued the study: 25 patients in the combi-
nation group and 37 patients in the monotherapy group.
The most common reason for discontinuation from the
study was an adverse event, reported in 30 (48.4%) pa-
tients (11 in the combination group and 19 in the mono-
therapy group). It is noteworthy that the patient population
had many of the characteristics of the metabolic syndrome.
In general, patients were obese (body mass index ⬎30),
had elevated total cholesterol and triglyceride levels, and
had mean fasting insulin and fasting glucose in the upper
limit of normal. FIG. 1. A) Cumulative proportion of patients in the intent-to-treat
population achieving reductions in systolic blood pressure ⱖ25/32
mm Hg during the 12-week study (amlodipine besylate/benazepril
BP HCl versus amlodipine besylate, P ⬍ .0001). B) Cumulative propor-
tion of patients in the intent-to-treat population achieving reduc-
The baseline mean (⫾ SD) systolic BP and diastolic BP tions in diastolic blood pressure ⱖ15/20 mm Hg during the 12-week
were 167.3 ⫾ 13.4 and 100.0 ⫾ 9.6 mm Hg, respectively, study (amlodipine besylate/benazepril HCl versus amlodipine besy-
late, P ⫽ .0003). The analyses were performed using the patient
s
in the fixed-dose combination group and 167.5 ⫾ 14.2 and last nonmissing postbaseline assessment (last observation carried
99.2 ⫾ 10.2 mm Hg, respectively, in the monotherapy forward).
group. A group of 56 patients (28 from each treatment
group) had high baseline systolic BP of ⱖ180 mm Hg. To
achieve the aggressive BP target of ⱕ130/85 mm Hg,
Hg (n ⫽ 28 per group), reductions in systolic BP/diastolic
more than 90% of patients in both groups were titrated to
BP were significantly greater in the group randomized to
dose level 2, and thus received the highest recommended
receive combination therapy (⫺42.3 ⫾ 12.2/⫺17.9 ⫾ 9.7
dose of each study drug by the end of the study. Adjunc-
mm Hg) compared with those randomized to monotherapy
tive HCTZ was administered to 10 of 182 (5.5%) patients
(⫺30.4 ⫾ 16.9/⫺12.1 ⫾ 11.1 mm Hg; P ⫽ .0014 for
in the fixed-dose combination group and to 11 of 182
systolic BP and .0038 for diastolic BP).
(6.0%) patients in the monotherapy group. Significantly
more patients randomized to amlodipine besylate/benaz-
epril HCl fixed-dose combination therapy compared with Attaining Goal BP
patients randomized to amlodipine besylate monotherapy
attained the primary end point of a reduction in systolic BP The proportion of patients in each treatment group who
of ⱖ25 mm Hg (if baseline systolic BP was ⬍180 mm Hg) attained the treatment goals of ⬍140/90 mm Hg and
or ⱖ32 mm Hg (if baseline systolic BP was ⱖ180 mm ⱕ130/85 mm Hg were evaluated (Fig. 2). Significantly
Hg). Reductions in systolic BP of this magnitude were more patients in the combination group (61.0%) compared
achieved in 135 of 182 patients (74.2%) in the fixed-dose with patients in the monotherapy group (43.3%) achieved
combination group compared with 96 of 178 patients a BP goal of ⬍140/90 mm Hg during the treatment period
(53.9%) in the monotherapy group (P ⬍ .0001). The (P ⫽ .0007). Significantly more patients attained the more
proportion of patients who attained reductions in diastolic
BP ⱖ15 mm Hg (if baseline diastolic BP was ⬍110 mm
Hg) or ⱖ20 mm Hg (if baseline diastolic BP was ⱖ110
mm Hg) was significantly greater for those randomized to
fixed-dose combination therapy compared with patients
randomized to monotherapy (67.0% v 48.3%, respectively;
P ⫽ .0003). A greater percentage of patients in the fixed-
dose combination group achieving target reductions in
systolic BP and diastolic BP were seen at every study visit
(Fig. 1). Similarly, patients receiving combination therapy
had significantly greater overall mean changes from base-
line compared with those receiving monotherapy in both
systolic BP (⫺25.5 ⫾ 15.2 mm Hg v ⫺20.5 ⫾ 15.6 mm
Hg, respectively; P ⫽ .0003) and diastolic BP (⫺14.3 ⫾
9.8 mm Hg v ⫺10.4 ⫾ 9.6 mm Hg, respectively; P ⫽ FIG. 2. Proportion of patients attaining blood pressure targets of
⬍140/90 mm Hg (amlodipine besylate/benazepril HCl versus amlo-
.0001). dipine besylate, P ⫽ .0007) and ⱕ130/85 mm Hg (amlodipine be-
Among patients with a baseline systolic BP ⱖ180 mm sylate/benazepril HCl versus amlodipine besylate, P ⫽ .0004).

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 AJH–June 2004 –VOL. 17, NO. 6 INITIAL COMBINATION THERAPY ACHIEVES GREATER BP CONTROL
stringent goal of ⱕ130/85 mm Hg with combination ther-
apy (35.7%) than with monotherapy (19.1%; P ⫽ .0004).
The time to achieving the treatment and BP goals was
significantly shorter with combination therapy compared
with monotherapy. The time by which 50% of patients
attained the primary end point (reduction in systolic BP of
ⱖ25 mm Hg or ⱖ32 mm Hg) was 4 weeks shorter among
patients randomized to combination therapy compared
with those randomized to monotherapy (systolic BP goal
attained by study weeks 5 and 9, respectively; P ⬍ .0001).
Similarly, the time by which 50% of patients attained the
diastolic BP goal (reduction ⱖ15 mm Hg or ⱖ20 mm Hg)
was 6 weeks shorter among patients randomized to com-
bination therapy compared with those randomized to
monotherapy (diastolic BP goal attained by study weeks 6
and 12, respectively; P ⫽ .0004). By week 6, 50% of
patients in the combination group achieved the BP goal of
⬍140/90 mm Hg; less than 50% of patients in the mono-
therapy group achieved this goal by week 12 (P ⬍ .0001).
Assessment of Peripheral Edema
The assessment of peripheral edema was included as a
secondary efficacy variable in the ITT population. The
incidence of peripheral edema was significantly higher in
the monotherapy group compared with that in the combi-
nation group (23.0% v 12.6%, respectively; P ⫽ .0102).
No statistically significant differences were noted between
the two treatment groups in the change from baseline in
ankle circumference.
Adverse Events
The majority of adverse events reported were mild to
moderate in severity. The incidence of adverse events was
slightly higher in the monotherapy group than in the
combination group (64.3% v 54.9%); however, this differ-
ence did not reach statistical significance. The most fre-
quent adverse events, reported for all patients in the safety
population at an incidence of ⱖ5% for either treatment
group, are shown in Table 2. Cough was more commonly
reported with combination therapy than with monotherapy
(6.0% v 2.7%). The incidence of fatigue was low in both
groups, reported in 5 (2.7%) patients in the combination
group and in 3 (1.6%) in the monotherapy group. Dizzi-
ness was reported at an incidence of 1.6% in the combi-
nation group and 1.1% in the monotherapy group.
Adverse events causing discontinuation from the study
were slightly more frequent in the monotherapy group
(10.4%) than in the combination group (6.0%). The most
frequent adverse event causing study discontinuation was
peripheral edema, reported in 3 patients on combination
therapy (1.6%) and 9 patients on monotherapy (4.9%).
Aggravated edema (edema that worsened during the
course of the study) resulting in discontinuation was re-
ported in 1 patient on combination therapy (0.5%) and 7
patients on monotherapy (3.8%).
Chemistry, hematology, insulin, and lipid profiles were
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499
Table 2. Adverse events reported at an incidence
of ⱖ5% for either treatment group: safety popula-
tion
Amlodipine
Besylate/ Amlodipine
Benazepril HCl Besylate
(n ⴝ 182) (n ⴝ 182)
Adverse Event No. (%) No. (%)
Peripheral edema 23 (12.6) 49 (26.9)*
Aggravated edema 11 (6.0) 19 (10.4)
Upper respiratory
tract infection 11 (6.0) 7 (3.8)
Cough 11 (6.0) 5 (2.7)
Headache 6 (3.3) 20 (11.0)
* P ⫽ .0102, amlodipine besylate/benazepril HCl v amlodipine be-
sylate.
similar for both treatment groups at baseline. No relevant
differences were noted between groups or in changes from
baseline to week 12. There were no significant changes
from baseline or between treatment groups for insulin
resistance as measured by HOMA.
There were no deaths during the study. One patient (0.5%)
in each group experienced a serious adverse event (dehydra-
tion in the combination group and myocardial infarction in
the monotherapy group). These adverse events were consid-
ered to be unrelated to the study medications.
Discussion
This study evaluated patients with stage 2 hypertension,
who by definition fit the JNC 7 recommendation for the
initial use of combination antihypertensive therapy.2 The
study population is representative of the larger nationwide
hypertensive population at highest risk of CVD and mor-
tality due to concomitant conditions including components
of the metabolic syndrome, such as obesity, dyslipidemia,
and insulin resistance.
The main objectives of this study were the achievement
of target reductions in systolic BP and diastolic BP and
evaluation of the incidence of usual treatment-related ad-
verse events. The results of this study support the recom-
mendation in the JNC 7 report for the initial use of
combination therapy in patients with stage 2 hypertension2
in that the use of this strategy resulted in a greater per-
centage of patients achieving target reductions in systolic
BP and diastolic BP and in a significantly shorter time to
achieve these target reductions compared with mono-
therapy. Of note, target reductions were achieved in pa-
tients with the highest baseline BP levels, a population
known to be difficult to treat.
The greater efficacy seen with combination therapy was
observed in tandem with a lower incidence of peripheral
edema, and an overall adverse event profile similar to that
of monotherapy. The majority of adverse events were not
suspected by the investigators to be related to the study
 500 INITIAL COMBINATION THERAPY ACHIEVES GREATER BP CONTROL
medications; in fact, the incidence of adverse events that
were considered treatment related were lower in the com-
bination group than in the monotherapy group. Both treat-
ment regimens were well tolerated and had no adverse
effects on blood chemistry or laboratory parameters in-
cluding potassium, glucose, and insulin resistance. The
JNC 7 report notes when therapy is initiated with more
than one agent, caution is advised in patients at risk for
orthostatic hypotension.2 Our data indicate that initial ther-
apy with two agents was associated with similar risk of
dizziness as with one agent (⬍2% in both groups), and
there were no reported instances of hypotension or light-
headedness in either group. These results highlight the
safety of initial combination therapy, as starting therapy
with two agents did not significantly increase the inci-
dence or severity of adverse events compared with a single
agent.
These results support those of SHIELD (The Study of
Hypertension and the Efficacy of Lotrel in Diabetes), a
study of combination therapy in diabetic patients with
hypertension.23 In contrast to SHIELD, the present work
provides data supporting the use of initial combination
antihypertensive therapy in a larger nondiabetic patient
population with higher mean BP at baseline. In this cohort
with severe hypertension, combination therapy resulted in
superior efficacy compared with the maximum dose of
monotherapy with a similar overall adverse event profile.
Severe uncontrolled hypertension is a risk factor for
CVD morbidity and mortality. National BP control rates
are far from adequate; only about 31% of individuals with
high BP are controlled to levels ⬍140/90 mm Hg.2 The
more stringent goal of ⬍130/85 mm Hg is achieved in
only 11% of patients.24 The early achievement of target
reductions in BP ultimately may translate into better long-
term control rates, thereby reducing the burden of hyper-
tension and its devastating consequences.
In conclusion, in patients with stage 2 hypertension, an
initial treatment regimen with an ACE inhibitor/CCB
fixed-dose combination provided significantly greater ef-
ficacy compared with high-dose CCB monotherapy. Max-
imum reductions in systolic BP were seen in the group of
patients with the highest systolic BP at baseline (ⱖ180
mm Hg). Combination therapy was associated with sig-
nificantly greater reductions in BP and a shorter time to BP
control without increasing the overall rate of untoward
events. This study supports the JNC 7 recommendation for
initial use of combination therapy in patients with stage 2
hypertension and further demonstrates that fixed-dose
ACE inhibitor/CCB combination therapy is an effective
and well tolerated therapeutic option for initial treatment
in these high-risk patients.
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Appendix
List of Investigators
D. Banish, Covington, LA; G. Boynton, Corpus Christi,
TX; R.L. Brazg, Renton, WA; F. Candal, Slidell, LA; F.
Civitarese, Carnegie, PA; J. Clark, Charlottesville, VA; G.
Collins, Charlotte, NC; W. Cox, Cincinnati, OH; W.L.
Crump, Meridian, ID; R.G. DeGarmo, Greer, SC; B. De
La Guardia, Houston, TX; E. DeNoia, San Antonio, TX;
W. Drummond, Dallas, TX; R. Egan, Pittsburgh, PA; J.
Fidelholtz, Cincinnati, OH; L. Gilderman, Pembroke
Pines, FL; J. Goldman, Pittsburgh, PA; R. Grenfell, Jr.,
Jackson, MS; C.B. Herring, Wilmington, NC; R.K. Hip-
pert, Fleetwood, PA; S.B. Jones, Salt Lake City, UT; J.
Kang, Reading, PA; D. Kereiakes, Cincinnati, OH; D.
Kushner, Pittsburgh, PA; M. Lamet, Hollywood, FL; A.
Lewin, Los Angeles, CA; R. Lipetz, San Diego, CA; T.
Littlejohn, Winston-Salem, NC; M.R. Mitchell, Bellevue,
WA; A.J. Mollen, Phoenix, AZ; J. Moreci, Pittsburgh, PA;
D. Morin, Bristol, TN; D. Morris, Tulsa, OK; S.T. Ong,
Oxon Hill, MD; G.F. Peterson, Des Moines, IA; T. Poling,
Wichita, KS; K.D. Roberts, Little Rock, AR; J. Rubino,
Raleigh, NC; Z. Salem, Margate, NJ; J. Sandoval, Corpus
Christi, TX; R. Sanzone, Chula Vista, CA; L. Schmidt,
Tucson, AZ; S. Schwartz, San Antonio, TX; S. Sharp,
Nashville, TN; B. Short, Overlook Park, KS; L. Smith,
Lewisburg, WV; M.J. Vargas, Riverside, CA; A. Vitelli,
McMurray, PA; C. Wattman, Bellevue, WA; R. Weiss,
Auburn, ME; P. Weissman, Miami, FL; K. Wiley, Kenner,
LA.