ORIGINAL RESEARCH ARTICLE

Am J Cardiovasc Drugs 2012; 12 (2): 137-142

1175-3277/12/0002-0137/$49.95/0

2012 Adis Data Information BV. All rights reserved.

Combination of Amlodipine plus Angiotensin

Receptor Blocker or Diuretics in High-Risk
Hypertensive Patients
A 96-Week Efficacy and Safety Study
Liyuan Ma,1 Wen Wang,1 Yong Zhao,2 Yuqing Zhang,1 Qing Deng,1 Mingbo Liu,1 Hui Sun,3 Jianchun Wang2
and Lisheng Liu1,4
1
2
3
4

Department of Evidence-Based Medicine, Cardiovascular Institute and Fuwai Hospital, Beijing, China
Department of Geriatric Cardiology, Provincial Hospital Affiliated to Shandong University, Jinan, Shandong Province, China
Department of Cardiology, Jinan Central Hospital Affiliated to Shandong University, Jinan, Shandong Province, China
Clinical Trial and Research Center, Beijing Hypertension League Institute, Chinese Hypertension League, Beijing, China

Abstract

Background and Objectives: Antihypertensive therapy is effective in reducing the risk of major adverse
cardiovascular events. However, blood pressure (BP) control rate remains poor and the optimal combination therapy against hypertension is not established in China. The objective of this study was to evaluate
the long-term efficacy and safety of two antihypertensive regimens, amlodipine plus telmisartan and amlodipine plus amiloride/hydrochlorothiazide, in patients with essential hypertension and at least one
cardiovascular risk factor.
Methods: In a multicenter open-label clinical trial, eligible patients were randomized to receive treatment
with amlodipine 2.55 mg plus amiloride/hydrochlorothiazide 1.252.5 mg/12.525 mg (Group A) or amlodipine 2.55 mg plus telmisartan 4080 mg (Group T). If a target BP was not reached, other antihypertensive agents would be added. The target BP was <130/80 mmHg for patients with diabetes mellitus or
chronic kidney disease and <140/90 mmHg for others. Efficacy variables were changes from baseline in
systolic BP and diastolic BP at the endpoint of 96 weeks. Safety evaluations included monitoring of any
adverse events (AEs).
Results: Of 13 542 patients randomized, 13 080 (96.6%) completed the study: 6529 in Group A and 6551 in
Group T. At endpoint, the BP levels were reduced by 27.4/14.3 mmHg in Group A and 27.1/14.5 mmHg in
Group T. The BP control rates were similar for the two therapeutic regimens (87.5% vs 86.1%). Less than 4%
of patients in each group discontinued their drugs during follow-up. Peripheral edema was one of the most
common AEs, and occurred in only 24 patients in Group A and 19 in Group T.
Conclusions: Long-term combination therapy with amlodipine plus telmisartan or amlodipine plus amiloride/hydrochlorothiazide was not only well tolerated but also efficacious in reducing BP levels with
acceptable control rates in the majority of hypertensive patients.
Clinical Trials Registration: ClinicalTrials.gov number NCT01011660.

Introduction
Hypertension is one of the most important risk factors
for cardiovascular morbidity and mortality, and imposes a
major public health challenge on both developed and developing countries. The prevalence of hypertension in Chinese
people 18 years of age was 18.8% according to the 2002 Na-

tional Nutritional Survey, which means the number of adult

patients with hypertension was greater than 200 million in
China.[1] Long-term untreated hypertension is likely to result in
life-threatening events, such as myocardial infarction, stroke,
congestive heart failure, and renal disease.[2,3] Coronary heart
disease (CHD) and stroke are the most prevalent forms of
cardiovascular disease (CVD) in the East Asian-Pacific region.

Ma et al.

138

CHD is the second leading cause of cardiovascular death in

China, and accounts for 22% of cardiovascular deaths in urban
areas and 13% in rural areas.[4] Liu et al.[5,6] showed that stroke
occurred in approximately 2 million Chinese people each year,
accounting for over 40% of deaths.
Optimal blood pressure (BP) control with pharmacological
therapy is very effective in reducing major adverse cardiovascular events associated with hypertension. A BP reduction
of 10 mmHg systolic or 5 mmHg diastolic is associated with a
22% reduction in CHD events (1727%) and a 41% (3348%)
reduction in stroke.[7] Although the importance of antihypertensive therapy has been widely recognized, only around 10% of
patients in Europe, 5% in China, and 30% in North America
have their BP adequately controlled.[8,9] Many large clinical
randomized trials, including ALLHAT (Antihypertensive and
Lipid-Lowering Treatment to Prevent Heart Attack Trial),[10]
ASCOT-BPLA (Anglo-Scandinavian Cardiac Outcomes TrialBlood Pressure Lowering Arm),[11] and ACCOMPLISH (Avoiding Cardiovascular Events through Combination Therapy in
Patients Living with Systolic Hypertension),[12] indicated that
the majority of patients require two or more antihypertensive
agents to achieve BP targets. The European Society of Hypertension and European Society of Cardiology (ESH/ESC) guidelines[13]
and the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure (JNC 7)[2] recommend initial combination of two drugs with
different mechanisms of actions to treat patients with moderate to
severe hypertension or BP 20/10 mmHg above goal.
Calcium channel blockers (CCBs) are widely used for treatment of hypertension in China. Their efficacy and tolerability
have been well documented in a number of Chinese clinical trials,
such as STONE (Shanghai Trial Of Nifedipine in the Elderly),[14]
Syst-China (Systolic Hypertension in China Trial),[15] and
FEVER (Felodipine Event Reduction).[16] Diuretics are also a
first-line class of antihypertensive agents in China. The combination of a CCB and diuretics has been shown to be effective for
both BP control and outcomes in high-risk patients.[16,17] Telmisartan is a long-acting angiotensin II type 1 receptor antagonist
(angiotensin receptor blocker [ARB]) and has an outstanding
BP-lowering effect. The efficacy and tolerability of telmisartan in
combination with the CCB amlodipine have already been demonstrated in multinational, randomized, controlled clinical trials
in patients with hypertension ranging from mild to severe.[18-20]
To define the relative benefits in terms of reducing cardiovascular events from the combination of a CCB and an ARB in
comparison with those from the combination of a CCB and
diuretics, we conducted a clinical trial entitled CHIEF (Chinese
Hypertension Intervention Efficacy study). Here, we reported
2012 Adis Data Information BV. All rights reserved.

the 96-week efficacy and safety of two antihypertensive regimens, amlodipine plus telmisartan and amlodipine plus amiloride/
hydrochlorothiazide, in the treatment of patients with essential
hypertension and at least one cardiovascular risk factor.

Materials and Methods

The CHIEF study is a multicenter clinical trial with a prospective, randomized, open-label, blinded endpoint evaluation
(PROBE) design. It was approved by the Medical Ethics Committee of the Beijing Fuwai Hospital and started in 2007. The
rationale and design of this study have been described in detail
elsewhere.[21]
Subjects

Hypertensive patients aged 5079 years were eligible for

inclusion if they had at least one of the following cardiovascular risk factors: a history of stroke, myocardial infarction
(MI), stable angina pectoris, coronary artery angioplasty more
than 3 months prior to trial commencement, transient ischemic attack, cardiac insufficiency (New York Heart Association [NYHA] class II), peripheral vascular disease, controlled
type 2 diabetes mellitus, mild or moderate chronic nephropathy
(urine albumin >300 mg/24 h, or blood creatinine >1.5 mg/dL
or >133 mmol/L), overweight (body mass index >25 kg/m2),
or obese or having abdominal obesity (waist circumference:
male >85 cm, female >80 cm); abnormal blood lipid levels (total
cholesterol [TC] >5.7 mmol/L, high-density lipoprotein [HDL]
<1.0 mmol/L, triglycerides >1.76 mmol/L); family history of
premature cardiovascular disease (onset before 50 years of age),
age 65 years, current cigarette smoker, left ventricular hypertrophy (LVH), intimal thickening or atherosclerotic plaque in
the carotid arteries; hypertensive fundus oculi grade IIIIV or
retinal atherosclerosis grade IIIIV.
Patients with any of the following conditions were excluded:
secondary hypertension; cardiac or cerebral events less than
3 months before registration; severe cardiomyopathy or significant valvular heart disease; unstable angina; severe liver disease or
nephropathy (elevation of alanine aminotransferase [ALT] >2
upper level of normal [ULN] or serum creatinine >2.5 mg/dL),
malignant tumor; gout; pregnant or taking contraceptives; uncontrolled diabetes (fasting plasma glucose >10 mmol/L, despite therapy); definite allergies or contraindication to the study
medications; or any clinical conditions unsuitable for this trial
according to the investigators opinion.
All participants provided written informed consent.
Am J Cardiovasc Drugs 2012; 12 (2)

Amlodipine + Angiotensin Receptor Blocker or Diuretics in High-Risk Hypertensives

Antihypertensive Interventions

After registration, potentially eligible patients entered a

2-week run-in period and discontinued any antihypertensive
medications. Patients with a systolic BP (SBP) of 140179 mmHg
and/or a diastolic BP (DBP) of 90109 mmHg were randomized
to combination therapy once daily with amlodipine 2.5 mg plus
amiloride/hydrochlorothiazide 1.25 mg/12.5 mg (Group A) or
amlodipine 2.5 mg plus telmisartan 40 mg (Group T). If the
target BP was not reached at the end of the second week after
randomization, the dose of diuretics was titrated to amiloride/
hydrochlorothiazide 2.5 mg/25 mg in Group A and telmisartan to
80 mg in Group T, once daily. Thereafter, the dosage of amlodipine in both groups could be increased to 5 mg/day after 4 weeks of
treatment, if necessary, to attain a target BP. The addition of other
antihypertensive agents, including an angiotensin-converting enzyme (ACE) inhibitor, a b-adrenoceptor blocker or an a-adrenergic
antagonist, was permitted at the discretion of the investigator if BP
remained uncontrolled 23 months after randomization.
Assessment of Efficacy and Safety

After randomization, patients returned at 2, 4, 8, and

12 weeks and 12-weekly thereafter. Seated BP levels were measured three times at 1-minute intervals with a calibrated mercury sphygmomanometer. The appearance and disappearance
of Korotkoff sounds were taken as SBP and DBP, respectively.
The average of the last two BP records was used for analysis.
The target BP was <130/80 mmHg for patients with diabetes or
chronic kidney disease (CKD), and <140/90 mmHg for others.
Safety data were collected by inquiry into the discomfort of
patients, physical examination, and clinical laboratory tests,
including occurrence of any adverse events (AEs).
Data Analysis and Statistics

SAS software (SAS Institute Inc., Cary, NC, USA) was used
for data analysis. The two-tailed unpaired t-test was performed
to examine the continuous data, and the chi-squared (w2) test
was used to compare categorical data. Differences were considered significant at p < 0.05.

Results
By the end of the recruitment in October 2008, a total of
13 542 patients from 180 clinical centers in China had been
randomized to either Group A (n = 6776) treated with amlodipine plus amiloride/hydrochlorothiazide or Group T (n = 6766)
2012 Adis Data Information BV. All rights reserved.

139

treated with amlodipine plus telmisartan. The baseline characteristics of the randomized patients have been delineated
previously. No significant difference was found between the
two groups.[21]
Changes in BP Levels

At randomization, the BP levels were 157.3 10.8/93.1

8.0 mmHg in Group A and 157.0 10.7/93.2 8.0 mmHg in
Group T. In comparison with the readings at randomization,
the BP levels at 2, 4, 8, 12, 48, and 96 weeks after treatment were
reduced by 17.0/8.2, 21.4/10.5, 24.0/12.1, 25.6/12.7, 27.0/14.0,
and 27.4/14.3 mmHg, respectively, in Group A, and 17.1/9.0,
21.1/10.9, 24.1/12.6, 25.5/13.4, 26.9/14.3, and 27.1/14.5 mmHg,
respectively, in Group T. Figure 1 lists the BP levels at each visit
for patients in Group A or Group T.
BP Target Achievements

The overall BP control rates (target BP <140/90 mmHg) at 2,

4, 8, and 12 weeks after treatment were 42.7%, 57.9%, 72.1%, and
78.1%, respectively, in Group A, and 45.2%, 58.5%, 72.6%, and
78.9%, respectively, in Group T. At the 96-week visit, these rates
reached 87.5% in Group A and 86.1% in Group T (figure 2). However, for the patients with diabetes or CKD, the BP control rates
were strikingly low, with 31.7% in Group A and 32.9% in Group T.
Safety

The incidence of drug-related AEs in this study was low, and

no new tolerability concerns were identified in association with
either therapeutic regimen. Less than 4% of patients in each
group discontinued their drugs during follow-up. The number
of patients adhering to study medications was slightly greater in
Group T than that in Group A. Table I lists the reasons for
patients withdrawing from this trial.
Discussion
The ideal antihypertensive strategy is to maximize the therapeutic efficacy and minimize the intolerability. Combination
of different medications with complementary mechanisms of
action is beneficial for attaining a greater BP reduction through
synergism and avoiding serious clinical or metabolic AEs at a
lower dosage. With respect to the complementary mechanisms
in relation to ARBs, the BP-lowering effects produced by CCBs
or diuretics may stimulate the renin-angiotensin-aldosterone
system, which in turn is blunted by the addition of ARBs. An
Am J Cardiovasc Drugs 2012; 12 (2)

Ma et al.

140

Group A (SBP)
Group T (SBP)
Group A (DBP)
Group T (DBP)
160.0
150.0

157.3
157.0

139.9

130.0
BP (mmHg)

SBP

140.3

140.0

135.9 133.0
131.7 132.1 131.3 130.4 130.0 130.6 130.6 130.4
135.9
132.9 131.5 132.0
131.2 130.3 130.0 130.2 130.2 130.0

120.0
110.0
100.0
90.0

93.2
93.1

DBP
84.9

84.2

80.0

82.6

81.0

80.4

82.3

80.6

79.8

12

80.3
79.9

79.6
79.3

79.1

79.0

78.8

78.8

78.6

78.9

78.5

78.9

78.7

78.5

48

60

72

84

96

70.0
60.0
0

24
36
Time (wk)

Fig. 1. BP levels at each visit for patients in either Group A or Group T. BP = blood pressure; DBP = diastolic BP; SBP = systolic BP.

2012 Adis Data Information BV. All rights reserved.

this study were similarly higher, hypertension is more difficult

to treat when stringent BP controls are required. In the patients
with diabetes or CKD, only 30% achieved a BP goal of
<130/80 mmHg. In contrast, more than 85% of patients without
these diseases had their BP levels controlled to <140/90 mmHg
(data not shown). However, recent clinical trials provided no
evidence that the strategy of intensive BP control would reduce
the rate of a composite of major adverse cardiovascular events
in patients with type 2 diabetes at high risk for cardiovascular
events.[27,28]
Safety is an important factor affecting the compliance
of patients during long-term treatment. Valsartan is another
Group A
Group T
100

80
BP control rates (%)

extra benefit of this combination for CCBs is the alleviation of

peripheral edema by ARBs through the enhancement of interstitial fluid absorption. The combinations of CCBs with diuretics or CCBs with ARBs were recommended recently for
priority use by ESH, because the former regimen has been
supported by trial evidence of outcome reduction and the latter
is considered rational and effective.[22]
Previous short-term studies demonstrated that for patients
with stage 12 hypertension, combination of amlodipine 5 mg
with telmisartan 80 mg resulted in a seated cuff BP reduction of
21.9/17.8 mmHg[18] and an ambulatory BP reduction of 19.5/
12.8 mmHg.[20] For moderate or severe hypertension, combination therapy with amlodipine 5 mg and hydrochlorothiazide
12.5 mg was associated with a mean sitting BP reduction of
32.6/14.6 mmHg.[23] In this clinical trial, BP levels were reduced
by 24.0/12.1 mmHg in Group A and by 24.1/12.6 mmHg in
Group T at the 8-week visit when combination of amlodipine
5 mg with telmisartan 80 mg or amlodipine 5 mg with amiloride
2.5 mg/hydrochlorothiazide 25 mg was used. Significant and persistent reductions in BP levels were achieved after 96-week antihypertensive treatment (approximately -27/-14 mmHg for both
regimens). The open-label design with up-titration of medications
reflected a common approach to controlling BP in clinical practice.
The findings of this study may represent real-world conditions.
In well designed randomized clinical trials with add-on therapy, BP target achievements were up to 6075%.[10,12,24] However, in epidemiological investigations, the control rate of BP
was only approximately 4% in rural China[25] and 30% in the
US.[26] Although the overall success rates for both regimens in

60

40

20

0
2

12

24

36
48
Time (wk)

60

72

84

96

Fig. 2. BP control rates (defined as BP <140/90 mmHg) in patients with hypertension receiving treatment with amlodipine plus amiloride/hydrochlorothizide
(Group A) or amlodipine plus telmisartan (Group T). BP = blood pressure.
Am J Cardiovasc Drugs 2012; 12 (2)

Amlodipine + Angiotensin Receptor Blocker or Diuretics in High-Risk Hypertensives

Limitations

Table I. Reasons for discontinuation of antihypertensive agents

Reason
Dizziness or headache

Group A
(n = 6529)
9

Group T
(n = 6551)
13

Cough

Hypokalemia

24

19

Peripheral edema
SBP >200 mmHg or DBP >120 mmHg
Severe AEs

Lost to follow-up

24

22

Participant withdrew consent

45

43

Discontinuation by investigator

22

15

Others

112

95

Total

247 (3.65%)

Limitations of this study include an open-label design and

the patient selection criteria. These results are only applicable
to patients with similar characteristics to those enrolled in the
trial, and extrapolation to a broad clinical practice population
is not prudent. Initial combination therapy was advocated recently in the management of hypertension. Similar to this study,
an investigator-initiated trial named COLM (Combination of
OLMesartan and calcium channel blocker or diuretic in highrisk elderly hypertensive patients) is ongoing in Japan.[34] It will
compare combination therapy using an ARB, olmesartan, and
a CCB with that using an ARB and a diuretic in high-risk
elderly hypertensive patients.

215 (3.18%)

AE = adverse event; DBP = diastolic blood pressure; SBP = systolic blood

pressure.

ARB commonly used in practice. In an open-label extension

study,[29] which followed a multinational, multicenter, randomized, double-blind, placebo-controlled, parallel-group core
trial,[30] patients with mild to moderate hypertension were
randomized to once-daily therapy with amlodipine and valsartan. By the end of 52 weeks, 84.5% of patients on the highdose regimen (amlodipine 5 mg/valsartan 80 mg) and 88.0% of
patients on the low-dose regimen (amlodipine 2.5 mg/valsartan
80 mg) completed follow-up. Peripheral edema was the most
common AE, leading to discontinuation of 2.1% of patients
in the high-dose regimen and 0.3% of patients in the low-dose
regimen.[29] In a 54-week extension study following the same
core trial above,[30] the incidence of peripheral edema was
1.2%, and no patient discontinued due to edema.[31] Fogari
and colleagues[32,33] analyzed the ankle-foot volume and pretibial subcutaneous tissue pressure, two objective measures
of ankle edema, in hypertensive patients treated with amlodipine. They demonstrated that peripheral edema due to administration of amlodipine could be mitigated by 6070%
when an ACE inhibitor[32] or an ARB[33] was added. In the
present study, the combination regimens of amlodipine plus
telmisartan or amlodipine plus amiloride/hydrochlorothiazide
were both well tolerated, with more than 96% of the total
participants completing the trial, indicating a favorable compliance. Peripheral edema was one of the most common reasons for discontinuing therapy, with 24 cases in Group A and
19 cases in Group T. Relatively few patients discontinued follow-up because of dizziness or headache. The safety profile
was consistent with the known pharmacology of the respective
study medication.
2012 Adis Data Information BV. All rights reserved.

141

Conclusion
Up to now, the effects of combination therapy with CCBs
and ARBs on the long-term cardiovascular outcomes have not
been established in a randomized clinical trial. The findings in
this study demonstrated that combination regimens of amlodipine
plus telmisartan or amlodipine plus amiloride/hydrochlorothiazide
provided statistically significant and substantial BP reductions
over 96 weeks with a favorable tolerability profile.
Acknowledgments
This study was supported by the Ministry of Sciences and Technology
of the Peoples Republic of China (Grant No. 2006BAI01A03). We would
like to express our gratitude to the doctors participating in the CHIEF
study and thank Dawnrays Pharmaceutical (Holdings) Limited Company
for providing the study drugs for free.
Liyuan Ma and Yong Zhao are co-first authors, and contributed
equally to this work.
Conflicts of interest: The authors have no conflicts of interest directly
relevant to the content of this study.

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Correspondence: Dr Wen Wang, Department of Evidence-Based Medicine,

Cardiovascular Institute and Fuwai Hospital, 167 Beilishi Road, Beijing
100037, China.
E-mail: wangwen5588@vip.sina.com

Am J Cardiovasc Drugs 2012; 12 (2)

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