American Journal Cardiovascular Drugs 2012;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
2 Department of Geriatric Cardiology, Provincial Hospital Affiliated to Shandong University, Jinan, Shandong Province, China
3 Department of Cardiology, Jinan Central Hospital Affiliated to Shandong University, Jinan, Shandong Province, China
4 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 combi-
nation 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 am-
lodipine 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 2.5–5mg plus amiloride/hydrochlorothiazide 1.25–2.5mg/12.5–25mg (Group A) or am-
lodipine 2.5–5mg plus telmisartan 40–80mg (Group T). If a target BP was not reached, other anti-
hypertensive agents would be added. The target BPwas <130/80mmHg for patients with diabetesmellitus or
chronic kidney disease and <140/90mmHg 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 27.4/14.3mmHg in Group A and 27.1/14.5mmHg 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 ami-
loride/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
for cardiovascular morbidity and mortality, and imposes a
major public health challenge on both developed and devel-
oping 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 200million 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.
ORIGINAL RESEARCH ARTICLE Am J Cardiovasc Drugs 2012; 12 (2): 137-142
1175-3277/12/0002-0137/$49.95/0
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 2million 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 cardio-
vascular events associated with hypertension. A BP reduction
of 10mmHg systolic or 5mmHg diastolic is associated with a
22% reduction in CHD events (17–27%) and a 41% (33–48%)
reduction in stroke.[7] Although the importance of antihyper-
tensive therapy has beenwidely 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 Trial-
Blood Pressure Lowering Arm),[11] and ACCOMPLISH (Avoid-
ing 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 Hyperten-
sion andEuropean Society of Cardiology (ESH/ESC) guidelines[13]
and the Seventh Report of the Joint National Committee on Pre-
vention,Detection, Evaluation andTreatment ofHighBloodPres-
sure (JNC 7)[2] recommend initial combination of two drugs with
different mechanisms of actions to treat patients with moderate to
severe hypertension or BP ‡20/10mmHg above goal.
Calcium channel blockers (CCBs) are widely used for treat-
ment 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 combi-
nation of a CCB and diuretics has been shown to be effective for
both BP control and outcomes in high-risk patients.[16,17] Telmi-
sartan 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 dem-
onstrated 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 cardio-
vascular 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
the 96-week efficacy and safety of two antihypertensive regi-
mens, 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 pro-
spective, randomized, open-label, blinded endpoint evaluation
(PROBE) design. It was approved by the Medical Ethics Com-
mittee of the Beijing Fuwai Hospital and started in 2007. The
rationale and design of this study have been described in detail
elsewhere.[21]
Hypertensive patients aged 50–79 years were eligible for
inclusion if they had at least one of the following cardiovas-
cular risk factors: a history of stroke, myocardial infarction
(MI), stable angina pectoris, coronary artery angioplasty more
than 3 months prior to trial commencement, transient ische-
mic attack, cardiac insufficiency (New York Heart Associa-
tion [NYHA] class II), peripheral vascular disease, controlled
type 2 diabetes mellitus, mild ormoderate chronic nephropathy
(urine albumin >300mg/24 h, or blood creatinine >1.5mg/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] >5.7mmol/L, high-density lipoprotein [HDL]
<1.0mmol/L, triglycerides >1.76mmol/L); family history of
premature cardiovascular disease (onset before 50 years of age),
age ‡65 years, current cigarette smoker, left ventricular hyper-
trophy (LVH), intimal thickening or atherosclerotic plaque in
the carotid arteries; hypertensive fundus oculi grade III–IV or
retinal atherosclerosis grade III–IV.
Patients with any of the following conditions were excluded:
secondary hypertension; cardiac or cerebral events less than
3 months before registration; severe cardiomyopathy or signif-
icant valvular heart disease; unstable angina; severe liver disease or
nephropathy (elevation of alanine aminotransferase [ALT] >2· upper level of normal [ULN] or serum creatinine >2.5mg/dL), malignant tumor; gout; pregnant or taking contraceptives; un-
controlled diabetes (fasting plasma glucose >10mmol/L, de- spite therapy); definite allergies or contraindication to the study
medications; or any clinical conditions unsuitable for this trial
according to the investigator’s opinion.
All participants provided written informed consent.
138 Ma et al.
ª 2012 Adis Data Information BV. All rights reserved. Am J Cardiovasc Drugs 2012; 12 (2)
Antihypertensive Interventions
medications. Patients with a systolic BP (SBP) of 140–179mmHg
and/or a diastolic BP (DBP) of 90–109mmHgwere randomized
to combination therapy once daily with amlodipine 2.5mg plus
amiloride/hydrochlorothiazide 1.25mg/12.5mg (Group A) or
amlodipine 2.5mg plus telmisartan 40mg (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 2.5mg/25mg in Group A and telmisartan to
80mg in Group T, once daily. Thereafter, the dosage of amlodi-
pine in both groups could be increased to 5mg/day after 4weeks of treatment, if necessary, to attain a target BP. The addition of other
antihypertensive agents, including an angiotensin-converting en-
zyme (ACE) inhibitor, ab-adrenoceptor blocker or ana-adrenergic antagonist, was permitted at the discretion of the investigator if BP
remained uncontrolled 2–3 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 mea-
sured three times at 1-minute intervals with a calibrated mer-
cury 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 <130/80mmHg for patients with diabetes or
chronic kidney disease (CKD), and <140/90mmHg 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 con-
sidered 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 amlodi-
pine plus amiloride/hydrochlorothiazide or Group T (n = 6766)
treated with amlodipine plus telmisartan. The baseline char-
acteristics 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 – 8.0mmHg in Group A and 157.0 – 10.7/93.2 – 8.0mmHg 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 27.4/14.3mmHg, 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 27.1/14.5mmHg,
respectively, inGroup 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 <140/90mmHg) 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 GroupA and 86.1% in Group T (figure 2). How-
ever, for the patients with diabetes or CKD, the BP control rates
were strikingly low,with 31.7% inGroupAand 32.9% inGroupT.
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 studymedications was slightly greater in
Group T than that in Group A. Table I lists the reasons for
patients withdrawing from this trial.
Discussion
apeutic 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
Amlodipine + Angiotensin Receptor Blocker or Diuretics in High-Risk Hypertensives 139
ª 2012 Adis Data Information BV. All rights reserved. Am J Cardiovasc Drugs 2012; 12 (2)
extra benefit of this combination for CCBs is the alleviation of
peripheral edema by ARBs through the enhancement of in-
terstitial fluid absorption. The combinations of CCBs with di-
uretics 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 1–2 hypertension, combination of amlodipine 5mg
with telmisartan 80mg resulted in a seated cuff BP reduction of
21.9/17.8mmHg[18] and an ambulatory BP reduction of 19.5/ 12.8mmHg.[20] For moderate or severe hypertension, combi-
nation therapy with amlodipine 5mg and hydrochlorothiazide
12.5mg was associated with a mean sitting BP reduction of
32.6/14.6mmHg.[23] In this clinical trial, BP levels were reduced
by 24.0/12.1mmHg in Group A and by 24.1/12.6mmHg in
Group T at the 8-week visit when combination of amlodipine
5mg with telmisartan 80mg or amlodipine 5mg with amiloride
2.5mg/hydrochlorothiazide 25mg was used. Significant and per-
sistent reductions in BP levels were achieved after 96-week anti-
hypertensive treatment (approximately -27/-14mmHg for both
regimens). The open-label design with up-titration of medications
reflected a common approach to controllingBP in clinical practice.
The findings of this study may represent real-world conditions.
In well designed randomized clinical trials with add-on ther-
apy, BP target achievements were up to 60–75%.[10,12,24] How-
ever, 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
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
<130/80mmHg. In contrast, more than 85% of patients without
these diseases had their BP levels controlled to <140/90mmHg
(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]
0
20
40
60
80
100
2 4 8 12 24 36 48 60 72 84 96
Time (wk)
B P
c on
tr ol
r at
Group A Group T
Fig. 2. BP control rates (defined as BP <140/90 mmHg) in patients with hy-
pertension receiving treatment with amlodipine plus amiloride/hydrochlorothizide
(Group A) or amlodipine plus telmisartan (Group T). BP = blood pressure.
78.879.078.879.179.680.3 78.6 93.1 84.9 82.6 81.0 80.4
78.778.978.578.979.379.9 78.5
60.0
70.0
80.0
90.0
100.0
110.0
120.0
130.0
140.0
150.0
160.0
0 2 4 8 12 24 36 48 60 72 84 96
Time (wk)
B P
130.0 130.6 130.6
Group A (SBP) Group T (SBP) Group A (DBP) Group T (DBP)
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.
140 Ma et al.
ª 2012 Adis Data Information BV. All rights reserved. Am J Cardiovasc Drugs 2012; 12 (2)
ARB commonly used in practice. In an open-label extension
study,[29] which followed a multinational, multicenter, ran-
domized, double-blind, placebo-controlled, parallel-group core
trial,[30] patients with mild to moderate hypertension were
randomized to once-daily therapy with amlodipine and val-
sartan. By the end of 52 weeks, 84.5% of patients on the high-
dose regimen (amlodipine 5mg/valsartan 80mg) and 88.0% of
patients on the low-dose regimen (amlodipine 2.5mg/valsartan 80mg) 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 pre-
tibial subcutaneous tissue pressure, two objective measures
of ankle edema, in hypertensive patients treated with amlodi-
pine. They demonstrated that peripheral edema due to ad-
ministration of amlodipine could be mitigated by 60–70% 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 com-
pliance. Peripheral edema was one of the most common rea-
sons for discontinuing therapy, with 24 cases in Group A and
19 cases in Group T. Relatively few patients discontinued fol-
low-up because of dizziness or headache. The safety profile
was consistent with the known pharmacology of the respective
study medication.
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 re-
cently in themanagement of hypertension. Similar to this study,
an investigator-initiated trial named COLM (Combination of
OLMesartan and calcium channel blocker or diuretic in high-
risk 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.
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 telmisartanor 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 People’s 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
142 Ma et al.
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