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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- more patients randomized to combination therapy com-
tional Committee (JNC 7) on Prevention, Detection, pared with monotherapy attained BP goals of ⬍140/90
Evaluation, and Treatment of High Blood Pressure recom- mm Hg (61.0% v 43.3%; P ⫽ .0007) and ⱕ130/85 mm Hg
mends initial combination therapy for patients whose (35.7% v 19.1%; P ⫽ .0004). Among patients with base-
blood pressure (BP) is ⬎20/10 mm Hg above goal. This line systolic BP ⱖ180 mm Hg, combination therapy re-
study evaluated the efficacy and safety of initial combina- sulted in significantly greater reductions in systolic BP
tion therapy versus that of monotherapy in patients with compared with monotherapy (⫺42.3 v ⫺30.4 mm Hg; P
stage 2 hypertension, who by definition meet the JNC 7 ⫽ .001). More than 90% of patients in each group were
recommendation for initial combination antihypertensive titrated to the higher dose. Both treatments were well
therapy. tolerated.
Methods: This multicenter, double-blind, 12-week Conclusions: Combination therapy was well tolerated
study randomized 364 patients with stage 2 hypertension and resulted in significantly greater BP reductions and
to fixed-dose combination therapy with amlodipine attainment of BP goals compared with monotherapy in
besylate/benazepril HCl (5/20 mg/d titrated to 10/20 mg/d) patients with stage 2 hypertension. This evidence supports
or amlodipine besylate monotherapy (5 mg/d titrated to 10 the recommendation of combination therapy as first-line
mg/d). treatment in stage 2 hypertension. Am J Hypertens 2004;
Results: Significantly more patients randomized to 17:495–501 © 2004 American Journal of Hypertension,
combination therapy (74.2%) compared with those ran- Ltd.
domized to monotherapy (53.9%; P ⬍ .0001) achieved the
primary end point (reductions in systolic BP ⱖ25 mm Hg, Key Words: Amlodipine besylate/benazepril HCl, an-
if baseline systolic BP was ⬍180 mm Hg, or ⱖ32 mm Hg, tihypertensive therapy, fixed-dose combination therapy,
if baseline systolic BP was ⱖ180 mm Hg). Significantly hypertension, JNC 7.

A
confluence of data, treatment guidelines, and clin- cardiovascular disease (CVD) morbidity and mortality,
ical judgment is making the initial use of combi- with the risk of death from CVD doubling for each incre-
nation antihypertensive therapy increasingly ment of 20/10 mm Hg across the BP range from 115/75
commonplace. There is a steep and graded relationship mm Hg to 185/115 mm Hg.1 Equally well documented is
between increasing blood pressure (BP) and increasing that only slightly more than one-third of hypertensive

Received August 12, 2003. First decision December 18, 2003. Accepted This work was supported by a grant from Novartis Pharmaceuticals
February 3, 2004. Corporation, East Hanover, New Jersey.
From the Division of Hypertension, Department of Internal Medicine,
University of Michigan Medical Center (KAJ), Ann Arbor, Michigan, Address correspondence and reprint requests to Dr. Kenneth A.
and Novartis Pharmaceuticals Corporation (ON, LJ-L, LS, DP, MB), Jamerson, University of Michigan Medical Center, 3918 Taubman Cen-
East Hanover, New Jersey. ter, Ann Arbor, MI 48109; e-mail: jamerson@umich.edu

© 2004 by the American Journal of Hypertension, Ltd. 0895-7061/04/$30.00


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

adults have BP values controlled to ⬍140/90 mm Hg.2 It ative Efficacy Trial (SOLACE) was designed to compare
seems plausible that at least part of the reason for these the efficacy and safety of initial antihypertensive therapy
poor control rates is the repeated observation that the use with the fixed-dose combination of amlodipine besylate/
of any single antihypertensive agent normalizes BP in benazepril HCl with that of the most commonly prescribed
little more than 50% of hypertensive patients.2– 6 To antihypertensive monotherapy, amlodipine besylate, in pa-
achieve recommended BP goals, it is often necessary to tients with stage 2 hypertension. The SOLACE study
combine two or more antihypertensive agents.2,5–11 design tests the efficacy of combination therapy as sug-
Recognizing these data, the recently released Seventh gested by JNC 7.
Report of the Joint National Committee on Prevention,
Detection, Evaluation, and Treatment of High Blood Pres- Methods
sure (the JNC 7 report)2 recommends that patients whose
BP is ⬎20/10 mm Hg above goal be treated initially with The primary objective of the study was to compare the
combination antihypertensive therapy. The conventional percentage of patients achieving a reduction in systolic BP
wisdom of the JNC suggests that “[t]he initiation of drug of ⱖ25 mm Hg (if baseline systolic BP was ⬍180 mm Hg)
therapy with more than 1 agent may increase the like- or ⱖ32 mm Hg (if baseline systolic BP was ⱖ180 mm
lihood of achieving the BP goal in a more timely Hg), during 12 weeks of a daily treatment regimen with
fashion. . . .”2 The recommendation for initial use of com- amlodipine besylate/benazepril HCl, versus amlodipine
bination antihypertensive therapy was endorsed in another besylate monotherapy. Other objectives included compar-
recently released treatment guideline,12 which preceded ing the percentage of patients achieving a reduction in
the JNC 7 report. This guideline for treatment of hyper- diastolic BP of ⱖ15 mm Hg (if baseline diastolic BP was
tension in African Americans recommends initial combi- ⬍110 mm Hg) or ⱖ20 mm Hg (if baseline diastolic BP
nation therapy in patients whose BP levels are ⬎15/10 mm was ⱖ110 mm Hg); the percentage of patients achieving a
Hg above goal.12 BP goal of ⬍140/90 mm Hg; the percentage of patients
The recent release of these data and treatment guide- achieving a BP goal of ⱕ130/85 mm Hg; mean change
lines has put increasing focus on prescribers to control BP from baseline in systolic BP and diastolic BP at week 12;
to recommended goals and to consider initial combination time to achieving reductions in BP; and the incidence of
therapy when appropriate. From a clinician’s perspective, peripheral (ankle) edema.
appropriate combination antihypertensive therapy may This was a multicenter, randomized, double-blind, par-
have a number of advantages, including improved efficacy, allel-group study. Men and women aged 18 to 80 years
tolerability, and patient adherence.13 Fixed-dose combina- with a documented diagnosis of stage 2 hypertension,
tion therapy in particular may result in improved patient defined as systolic BP ⱖ160 and ⱕ210 mm Hg or diastolic
adherence through simplicity of use; also, data indicate BP ⱖ100 and ⱕ120 mm Hg, were eligible to participate in
that patients are more likely to remain on therapy if they the study. Written informed consent was obtained from
attain BP control with the initially prescribed agent.14 The each patient. Women of childbearing potential were re-
potential benefits of combination therapy notwithstanding, quired to practice an effective method of contraception.
clinicians are faced with a myriad of choices and little data The study excluded pregnant or nursing women, patients
on the efficacy and benefits of specific fixed-dose combi- with systolic BP ⬎210 mm Hg or diastolic BP ⬎120 mm
nation therapies. Hg, patients with medical conditions that would impair
Amlodipine besylate/benazepril hydrochloride (HCl) is their ability to participate to conclusion in a trial of anti-
a fixed-dose combination antihypertensive containing a hypertensive therapy, and those with any known allergy or
dihydropyridine calcium channel blocker (CCB) and an hypersensitivity to any of the study drugs.
angiotensin-converting enzyme (ACE) inhibitor. Calcium
Study Design
channel blockers are potent antihypertensive agents that
act directly on vascular smooth muscle to reduce periph- Previously treated patients were withdrawn from all anti-
eral vascular resistance and promote arterial vasodilata- hypertensive medication for a period ranging from 3 to 10
tion, which results in powerful BP-lowering effects. The days. Blood pressure was monitored on day 3, and patients
use of high doses of CCBs often results in adverse events, with systolic BP ⱖ200 mm Hg and ⱕ210 mm Hg or
most notably, peripheral (ankle) edema. When used in diastolic BP ⬎110 mm Hg and ⱕ120 mm Hg were ran-
combination with a CCB, ACE inhibitors have been domized, whereas those who had systolic BP ⬍200 mm
shown to ameliorate dose-related edema associated with Hg or diastolic BP ⬍110 mm Hg continued the washout
CCB monotherapy.15,16 Numerous studies have shown period for another 7 days. Patients who were naı̈ve to drug
that ACE inhibitors have protective effects on target or- therapy could be randomized on day 3 if they met the
gans beyond their ability to lower BP; these studies have protocol definition of stage 2 hypertension and fulfilled the
included patients with heart failure, diabetes, and renal inclusion criteria. Patients were randomized to active treat-
disease, as well as studies of the primary and secondary ment at dose level 1 with either fixed-dose combination
prevention of CVD.17–21 amlodipine besylate/benazepril HCl (5/20 mg) or mono-
The Safety of Lotrel versus Amlodipine in a Compar- therapy with amlodipine besylate (5 mg) for 2 weeks. At

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week 2 or any time thereafter, patients with BP ⬎130/85 Insulin levels were measured by a two-site chemilumi-
mm Hg were titrated to dose level 2 (amlodipine besylate/ nescent assay (Diagnostic Products Corp., Los Angeles,
benazepril HCl 10/20 mg or amlodipine besylate 10 mg) CA). All other analyses were performed at a central lab-
for the remainder of the treatment period. After 3 weeks at oratory (Clinical Reference Laboratory, Lenexa, KS) us-
dose level 2, patients with systolic BP ⱖ180 and ⱕ210 ing standard methods.
mm Hg or diastolic BP ⱖ110 and ⱕ120 mm Hg could
receive adjunctive open-label hydrochlorothiazide Statistical Analysis
(HCTZ) 12.5 mg. Downward dose adjustment to the pre- Background and demographic variables were summarized
vious dose level was not permitted. Patients who had using descriptive statistics. The ␹2 test was used for cate-
systolic BP ⬎210 mm Hg or diastolic BP ⬎120 mm Hg at gorical variables and the two-sample t test was used for
any time during the study were discontinued. The total continuous variables to test for homogeneity between the
duration of double-blind treatment was 12 weeks. two treatment groups. All efficacy analyses were per-
formed using the intent-to-treat (ITT) population, consist-
Efficacy and Safety Assessments
ing of all randomized patients who received study drug
Vital signs (seated BP and heart rate) were assessed at and from whom at least one postbaseline efficacy assess-
each visit. Height and weight were measured at the screen- ment was obtained, using the last observation carried
ing visit. Blood pressure was measured using a calibrated forward approach. The safety analysis included all ran-
automatic sphygmomanometer and appropriately sized domized patients who took at least one dose of study
cuff. Three separate seated BP measurements were taken 2 medication. Efficacy variables were assessed with an anal-
min apart, and the mean of three readings was calculated ysis of covariance using baseline assessment as a covari-
and recorded. A physical examination was performed at ate, and treatment and center as factors in the model. To
randomization (week 0) and at week 12. The presence of analyze the time to achieve the first BP target, Kaplan-
peripheral (ankle) edema was assessed at each visit. Pa- Meier estimates were obtained. The log-rank test was used
tients were required to stand for at least 5 min, after which to test for the survival curve difference between the two
the circumference of each ankle was measured, and the treatment groups. The sample size was determined to
presence of edema was assessed by the examiner. In provide ⬎90% power at the two-sided significance level
addition, the presence of edema, whether noted by the of .05, to detect a 15% difference between the two groups.
investigator or reported by the patient, was collected as an
adverse event. Results
Fasting insulin and glucose levels were measured at
Demographics
randomization and at week 12 and used to calculate
changes in insulin resistance as assessed by the homeosta- The baseline demographic characteristics and vital signs
sis model (HOMA).22 Blood chemistry (including potas- of the ITT population are presented in Table 1. Of 364
sium) and lipid profiles were also measured at patients randomized, 182 were in both the combination
randomization and at week 12. 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 patients
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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stringent goal of ⱕ130/85 mm Hg with combination ther- Table 2. Adverse events reported at an incidence
apy (35.7%) than with monotherapy (19.1%; P ⫽ .0004). of ⱖ5% for either treatment group: safety popula-
The time to achieving the treatment and BP goals was tion
significantly shorter with combination therapy compared
Amlodipine
with monotherapy. The time by which 50% of patients
Besylate/ Amlodipine
attained the primary end point (reduction in systolic BP of Benazepril HCl Besylate
ⱖ25 mm Hg or ⱖ32 mm Hg) was 4 weeks shorter among (n ⴝ 182) (n ⴝ 182)
patients randomized to combination therapy compared Adverse Event No. (%) No. (%)
with those randomized to monotherapy (systolic BP goal Peripheral edema 23 (12.6) 49 (26.9)*
attained by study weeks 5 and 9, respectively; P ⬍ .0001). Aggravated edema 11 (6.0) 19 (10.4)
Similarly, the time by which 50% of patients attained the Upper respiratory
diastolic BP goal (reduction ⱖ15 mm Hg or ⱖ20 mm Hg) tract infection 11 (6.0) 7 (3.8)
Cough 11 (6.0) 5 (2.7)
was 6 weeks shorter among patients randomized to com- Headache 6 (3.3) 20 (11.0)
bination therapy compared with those randomized to
monotherapy (diastolic BP goal attained by study weeks 6 * P ⫽ .0102, amlodipine besylate/benazepril HCl v amlodipine be-
sylate.
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). similar for both treatment groups at baseline. No relevant
differences were noted between groups or in changes from
Assessment of Peripheral Edema baseline to week 12. There were no significant changes
from baseline or between treatment groups for insulin
The assessment of peripheral edema was included as a resistance as measured by HOMA.
secondary efficacy variable in the ITT population. The There were no deaths during the study. One patient (0.5%)
incidence of peripheral edema was significantly higher in in each group experienced a serious adverse event (dehydra-
the monotherapy group compared with that in the combi- tion in the combination group and myocardial infarction in
nation group (23.0% v 12.6%, respectively; P ⫽ .0102). the monotherapy group). These adverse events were consid-
No statistically significant differences were noted between ered to be unrelated to the study medications.
the two treatment groups in the change from baseline in
ankle circumference.
Discussion
Adverse Events
This study evaluated patients with stage 2 hypertension,
The majority of adverse events reported were mild to who by definition fit the JNC 7 recommendation for the
moderate in severity. The incidence of adverse events was initial use of combination antihypertensive therapy.2 The
slightly higher in the monotherapy group than in the study population is representative of the larger nationwide
combination group (64.3% v 54.9%); however, this differ- hypertensive population at highest risk of CVD and mor-
ence did not reach statistical significance. The most fre- tality due to concomitant conditions including components
quent adverse events, reported for all patients in the safety of the metabolic syndrome, such as obesity, dyslipidemia,
population at an incidence of ⱖ5% for either treatment and insulin resistance.
group, are shown in Table 2. Cough was more commonly The main objectives of this study were the achievement
reported with combination therapy than with monotherapy of target reductions in systolic BP and diastolic BP and
(6.0% v 2.7%). The incidence of fatigue was low in both evaluation of the incidence of usual treatment-related ad-
groups, reported in 5 (2.7%) patients in the combination verse events. The results of this study support the recom-
group and in 3 (1.6%) in the monotherapy group. Dizzi- mendation in the JNC 7 report for the initial use of
ness was reported at an incidence of 1.6% in the combi- combination therapy in patients with stage 2 hypertension2
nation group and 1.1% in the monotherapy group. in that the use of this strategy resulted in a greater per-
Adverse events causing discontinuation from the study centage of patients achieving target reductions in systolic
were slightly more frequent in the monotherapy group BP and diastolic BP and in a significantly shorter time to
(10.4%) than in the combination group (6.0%). The most achieve these target reductions compared with mono-
frequent adverse event causing study discontinuation was therapy. Of note, target reductions were achieved in pa-
peripheral edema, reported in 3 patients on combination tients with the highest baseline BP levels, a population
therapy (1.6%) and 9 patients on monotherapy (4.9%). known to be difficult to treat.
Aggravated edema (edema that worsened during the The greater efficacy seen with combination therapy was
course of the study) resulting in discontinuation was re- observed in tandem with a lower incidence of peripheral
ported in 1 patient on combination therapy (0.5%) and 7 edema, and an overall adverse event profile similar to that
patients on monotherapy (3.8%). of monotherapy. The majority of adverse events were not
Chemistry, hematology, insulin, and lipid profiles were suspected by the investigators to be related to the study

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

medications; in fact, the incidence of adverse events that 2. Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA,
were considered treatment related were lower in the com- Izzo JL Jr, Jones DW, Materson BJ, Oparil S, Wright JT Jr, Rocella
EJ, and the National High Blood Pressure Education Program Co-
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cluding potassium, glucose, and insulin resistance. The 2572.
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These results support those of SHIELD (The Study of
6. Cushman WC, Ford CE, Cutler JA, Margolis KL, Davis BR, Grimm
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(ALLHAT). J Clin Hypertens 2002;4:393–404.
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Severe uncontrolled hypertension is a risk factor for 8. Elliott WJ: Average number of drugs and mean change in blood
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are far from adequate; only about 31% of individuals with 9. Lewis EJ, Hunsicker LG, Clarke WR, Berl T, Pohl MA, Lewis JB,
high BP are controlled to levels ⬍140/90 mm Hg.2 The Ritz E, Atkins RC, Rohde R, Raz I: Renoprotective effect of the
more stringent goal of ⬍130/85 mm Hg is achieved in angiotensin receptor antagonist irbesartan in patients with nephrop-
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10. Agodoa LY, Appel LJ, Bakris GL, Beck G, Bourgoignie J, Briggs
reductions in BP ultimately may translate into better long- JP, Charleston J, Cheek D, Cleveland W, Douglas JG, Douglas M,
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tension and its devastating consequences. Hebert L, Hiremath L, Jamerson K, Johnson CJ, Kopple J, Kusek J,
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initial treatment regimen with an ACE inhibitor/CCB Miller ER III, Norris K, O’Connor D, Ojo A, Phillips RA, Pogue V,
Rahman M, Randall OS, Rosand S, Schulman G, Smith W, Thorn-
fixed-dose combination provided significantly greater ef-
ley-Brown D, Tisher CC, Toto RD, Wright JT Jr, Xu S, for the
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