Clinical Trial: ADVANCE Trial

Effects of Combination of Perindopril, Indapamide,

and Calcium Channel Blockers in Patients With Type 2
Diabetes Mellitus
Results From the Action in Diabetes and Vascular Disease: Preterax and
Diamicron Controlled Evaluation (ADVANCE) Trial
John Chalmers, Hisatomi Arima, Mark Woodward, Giuseppe Mancia, Neil Poulter,
Yoichiro Hirakawa, Sophia Zoungas, Anushka Patel, Bryan Williams, Stephen Harrap

See Editorial Commentary, pp 220221

AbstractThe objective of the present analysis was to determine the effects of a fixed combination of perindopril and
indapamide in combination with calcium channel blockers (CCBs) in patients with type 2 diabetes mellitus. The Action in
Diabetes and Vascular Disease: Preterax and Diamicron Controlled Evaluation (ADVANCE) trial was a factorial randomized
controlled trial. A total of 11140 patients with type 2 diabetes mellitus were randomly assigned to fixed combination of
perindoprilindapamide (4/1.25 mg) or placebo. Effects of randomized treatment on mortality and major cardiovascular
outcomes were examined in subgroups defined by baseline use of CCBs. Patients on CCB at baseline (n=3427) constituted
a higher risk group compared with those not on CCB (n=7713), with more extensive use of antihypertensive and other
protective therapies. Active treatment reduced the relative risk of death by 28% (95% confidence interval, 10%43%)
among patients with CCB at baseline compared with 5% (12% to 20%) among those without CCB (P homogeneity=0.02)
and 14% (2%25%) for the whole population. Similarly, the relative risk reduction for major cardiovascular events was
12% (8% to 28%) versus 6% (10% to 19%) for those with and without CCB at baseline although the difference was
not statistically significant (P homogeneity=0.38). There was no detectable increase in adverse effects in those receiving
CCB. The combination of perindopril and indapamide with CCBs seems to provide further protection against mortality in

patients with type 2 diabetes mellitus.(Hypertension. 2014;63:259-264.) Online Data Supplement
Key Words: angiotensin-converting enzyme inhibitors blood pressure calcium channel blockers
diabetes mellitus diuretics drug therapy, combination randomized controlled trial

I t is a sad reflection of our collective failure to deal effectively

with the growing burden of blood pressurerelated diseases1
that control rates among patients known to be hypertensive
remain poor in most regions of the world.27 Thus, national,
regional, and international guidelines uniformly stress the impor-
tance and the frequent need of combination therapy for effective
control of hypertension and of suboptimal blood pressure in high-
risk groups.813 Despite this, control rates remain poor with <15%
well controlled in 17 countries participating in the Prospective
Urban Rural Epidemiology (PURE) study.4 This is partly attrib-
utable to the continuing reliance on monotherapy and partly to
the inadequacy of control rates achieved with combinations of 2
drugs.4,14,15 There is also a considerable resistance on the part of
community doctors to the use of fixed-dose (single-pill) combina-
tions,16,17 although there is considerable evidence to support their
effectiveness in improving adherence to therapy and achievement
of effective blood pressure control.211,13,1821 Among several pos-
sible combinations recommended by current guidelines,813 some
of the most favored combinations supported by evidence from
randomized trials include angiotensin-converting enzyme (ACE)
inhibitors and diuretics, as in the Perindopril Protection Against
Recurrent Stroke Study (PROGRESS),22 Action in Diabetes
and Vascular Disease: Preterax and Diamicron Controlled
Evaluation (ADVANCE),19 and Hypertension in the Very Elderly

Received August 16, 2013; first decision August 28, 2013; revision accepted October 28, 2013.
From The George Institute for Global Health, Sydney, Australia (J.C., H.A., M.W., Y.H., S.Z., A.P.); The University of Sydney, Sydney, Australia (J.C.,
H.A., M.W., Y.H., A.P.); Royal Prince Alfred Hospital, Sydney, Australia (J.C., H.A., M.W., Y.H., A.P.); IRCCS Istituto Auxologico Italiano and University
of Milan-Bicocca, Milan, Italy (G.M.); Imperial College London, London, United Kingdom (N.P.); School of Public Health, Monash University, Clayton,
Australia (S.Z.); University College London and The National Institute for Health Research University College London Hospitals Biomedical Research
Centre, London, United Kingdom (B.W.); and Department of Physiology, University of Melbourne, Melbourne, Victoria, Australia (S.H.).
This paper was sent to Takayoshi Ohkubo, Guest editor, for review by expert referees, editorial decision, and final disposition.
The online-only Data Supplement is available with this article at http://hyper.ahajournals.org/lookup/suppl/doi:10.1161/HYPERTENSIONAHA.
113.02252/-/DC1.
Correspondence to John Chalmers, The George Institute for Global Health, PO Box M201, Camperdown, NSW 2050, Australia. E-mail chalmers@
georgeinstitute.org.au
2013 American Heart Association, Inc.
Hypertension is available at http://hyper.ahajournals.org DOI: 10.1161/HYPERTENSIONAHA.113.02252

259
260HypertensionFebruary 2014

Trial (HYVET) trials,23 and ACE inhibitors and calcium chan- 5569 assigned to active treatment with the fixed combination of
nel blockers (CCBs), as in the Anglo-Scandinavian Cardiac perindopril and indapamide and 5571 to matching placebo.19 Of
Outcomes Trial (ASCOT)24 and Avoiding Cardiovascular Events these, 3427 (1669 in active group and 1758 in placebo group) were
through Combination Therapy in Patients Living with Systolic taking a CCB and 7713 (3900 in active group and 3813 in pla-
Hypertension (ACCOMPLISH)20 trial. cebo group) were not at baseline. The mean duration of follow-up
In this context, the ADVANCE trial provides us with an was 4.3 years. The characteristics of these patients at baseline are
opportunity to examine the possible advantages of a triple shown in Table1. Those on CCB represent a higher risk group with
combination for which there are as yet no randomized data longer duration of diabetes mellitus, higher systolic and diastolic
from cardiovascular outcome trials. In this trial, the study blood pressures despite higher rates of treatment with antihyper-
drugs were the ACE inhibitor perindopril and the diuretic tensive drugs, and higher rates of previous cardiovascular disease.
indapamide, used in fixed combination.19 The mean difference in systolic blood pressure between those
In this article, we compare the effects of randomized treat- on active treatment and those on placebo, across the whole period
ment with the combination of perindopril and indapamide in of randomized treatment, was 4.7 mmHg (95% confidence inter-
subgroups defined by use of CCBs at baseline. Specifically, val, 3.85.6) in those on CCB and 6.2 mmHg (5.56.8) in those
we examine the effects on major cardiovascular events (the
primary outcome), cardiovascular death, and all-cause mor-
Table 1. Baseline Characteristics by Baseline Use of CCBs
tality. We also report observational analyses comparing the
effects of randomized treatment, with the fixed combination No Baseline CCB Baseline CCB
of perindopril and indapamide, in subgroups defined by use Characteristic (n=7713) (n=3427)
of CCBs at any time, whether before or after randomization. Demographic
Age, y (SD) 66 (6) 66 (6)
Methods
ADVANCE trial was a factorial randomized controlled trial of blood Women, % 42 44
pressure lowering and intensive blood glucose control in patients with Asian,* % 28 33
type 2 diabetes mellitus. Details of the design and procedures have been Medical history
described previously.19,25 Patients were potentially eligible if they had
been diagnosed with type 2 diabetes mellitus at the age of 30 years and Duration of diabetes mellitus, y (IQR) 6 (311) 7 (312)
were aged 55 years at entry to the study. Potentially eligible patients History of macrovascular disease, % 29 40
also needed to have 1 of the following: a history of major cardiovascu-
History of microvascular disease, % 9 12
lar disease (stroke, myocardial infarction, hospital admission for transient
ischemic attack, hospital admission for unstable angina, coronary revas- Current smoking, % 16 12
cularization, peripheral revascularization, or amputation secondary to Blood pressure
vascular disease) or 1 other risk factor for cardiovascular disease. There
were no blood pressure criteria for entry. Prior blood pressurelowering Systolic blood pressure, mmHg (SD) 144 (22) 148 (21)
medications were not required to be stopped at the start of the run-in Diastolic blood pressure, mmHg (SD) 80 (11) 81 (11)
period. Approval for the trial was obtained from each centers institutional Blood test
review board, and all participants provided written informed consent.
Participants who tolerated 6 weeks of run-in therapy with fixed HbA1c, % (SD) 7.5 (1.5) 7.5 (1.6)
combination tablet consisting of perindopril (2 mg) and indapamide LDL cholesterol, mmol/L (SD) 3.1 (1.0) 3.1 (1.0)
(0.625 mg) were randomly assigned, in a double-blind fashion, to
HDL cholesterol, mmol/L (SD) 1.3 (0.4) 1.3 (0.4)
fixed combination of perindopril and indapamide (2/0.625 mg for the
first 3 months and 4/1.25 mg thereafter) or matching placebo. Medication, %
Information on use of CCBs (any dihydropyridine or nondihydro- Antihypertensive therapy 58 93
pyridine) was collected at baseline and follow-up visits.
The outcomes for the present analysis were major cardiovascular Angiotensin-converting enzyme inhibitor 40 49
events (nonfatal myocardial infarction, nonfatal stroke, or cardiovas- Angiotensin receptor blocker 5 6
cular death), cardiovascular death, and death from any cause. -Blocker 22 30
Diuretic 21 29
Statistical Analysis
The effects of randomized treatment on events were calculated Others 12 14
using univariate Cox proportional hazards models, according to Glucose-lowering therapy
the principle of intention-to-treat. The effects of randomized treat- Gliclazide (modified release) 7 8
ment on blood pressure were estimated using linear mixed models.
Comparisons of treatment effects between subgroups were examined Other sulfonylurea 64 63
by adding an interaction term to the statistical models. Drug effects Metformin 61 61
were also estimated from observational analyses that used Cox pro-
Other oral drugs 13 13
portional hazards models after adjustment for wide variety of covari-
ates as described in the legends of Figures and Tables. Percentage risk Insulin 1 2
reductions were calculated as ([1hazard ratio]100). All P values Antiplatelet therapy 43 55
were calculated from 2-tailed tests of statistical significance.
Oral anticoagulants 3 4

Results Lipid-lowering therapy 34 37

CCB indicates calcium channel blocker; HbA1c, hemoglobin A1c; HDL, high-
Analyses of Randomized Data density lipoprotein; IQR, interquartile range; and LDL, low-density lipoprotein.
A total of 11140 patients with type 2 diabetes mellitus were ran- *Participants recruited from Peoples Republic of China.
domized into the blood pressure arm of ADVANCE trial, with Currently treated hypertension.
 Chalmers et al Combination Therapy in ADVANCE Trial 261
Table 2. Effects of Baseline CCB (Nonstudy Drug) on Major
Cardiovascular Events and Death, in the Whole Cohort,
Independent of Randomized Treatment
No. of Events
(Annual Rate)
No CCB CCB Hazard Ratio
Outcome (n=7713) (n=3427) (95% CI)
Major cardiovascular 628 (1.9) 372 (2.6) 1.24 (1.081.42)
event
Cardiovascular death 286 (0.9) 182 (1.3) 1.22 (1.001.49)
Total death 573 (1.7) 306 (2.1) 1.07 (0.921.24)
Hazard ratios and P values were adjusted for age, sex, duration of diabetes
mellitus, systolic blood pressure, hemoglobin A1c, low-density lipoprotein
cholesterol, high-density lipoprotein cholesterol, log-transformed triglyceride,
estimated glomerular filtration rate, urinary albumincreatinine ratio, body
mass index, smoking, ECG abnormalities, and randomized treatments. 95% CI
indicates 95% confidence interval; and CCB, calcium channel blocker.
not on CCB, reflecting the greater difficulty of lowering blood
pressure in a higher risk group of patients that was receiving more
extensive antihypertensive therapy (Tables1 and 2).
Figure1 shows the effects of randomized treatment in sub-
groups defined by use of CCBs at baseline. Active treatment
with the fixed combination of perindopril and indapamide
reduced the relative risk of death by 28% (10%43%) among
patients with CCB compared with 5% (12% to 20%) among
those without CCB (P homogeneity=0.02) and 14% (2%
25%) for the whole population (Figure1). There were also
trends, although not significant, for greater reductions in major
cardiovascular events and cardiovascular mortality (Figure1).
Analyses of Observational Data
We compared the effects of blood pressure lowering in the
group assigned to randomized treatment with the fixed com-
bination of perindopril and indapamide who received CCBs at
any time point (whether at baseline or during follow-up) with
effects in the group assigned to placebo who did not receive
CCBs at any time, whether before or after randomization. The
baseline characteristics of those 2 groups are shown in Table
S1 in the online-only Data Supplement. Once again, the group
receiving CCBs was a higher risk group. As can be seen in
Figure2, after adjustment, those receiving active treatment
plus CCBs had substantial and significant reductions in both
all-cause mortality and cardiovascular death.
We also compared the effects of blood pressure lowering
in the group assigned to randomized treatment with the fixed
combination of perindopril and indapamide who also received
CCBs at baseline with effects in the group assigned to placebo
P Value who also received open-label perindopril and a CCB. The base-
line characteristics of those 2 groups are shown in Table S2. As
0.002
can be seen in Figure3, after adjustment, the group receiving
the triple therapy with ACE inhibitor, diuretic, and CCB had a
0.04
significant reduction in all-cause mortality compared with the
0.40
patients on dual therapy with CCB and ACE inhibitor. There
was a nonsignificant trend to greater reduction in major cardio-
vascular events and cardiovascular death (Figure3).
Permanent Discontinuation and Adverse Effects of
Study Treatment
The frequency of permanent discontinuation and key adverse
effects among patients assigned active treatment and those
assigned placebo are reported by baseline use of CCBs in Table
S3. Compared with participants who did not receive CCBs at
baseline, there was no clear increase in the frequency of total
permanent discontinuation or of discontinuation attributable
to adverse effects such as hypotension and cough among those
on CCBs at baseline for both active and placebo groups.
Discussion
The present analyses in patients with type 2 diabetes mel-
litus indicate that adding a CCB to the combination of an
ACE inhibitor and a diuretic produces additional tangible
benefits. Thus, being on a CCB as well as the fixed combi-
nation of perindopril and indapamide in patients participat-
ing in ADVANCE trial led to significantly greater reductions
in all-cause mortality, with nonsignificant trends to greater
reduction in cardiovascular mortality and major cardiovas-
cular events, than being on the fixed combination alone.
Furthermore, these benefits seemed to be independent of the
degree of blood pressure reduction and were observed despite
the greater risk profile of the patients receiving CCB, either at
baseline or during follow-up.
The best combinations of blood pressurelowering drugs
combine different primary actions so as to achieve fully
Figure 1. Effects of randomized
treatment with the fixed combination of
perindopril and indapamide on major
cardiovascular (CV) events and death
by baseline use of calcium channel
blockers (CCBs). Solid boxes represent
estimates of treatment effect on the
risk of clinical outcomes. Centers of
the boxes are placed at the estimates
of effect; areas of the boxes are
proportional to the reciprocal of the
variance of the estimates. Horizontal
lines represent 95% confidence interval
(CI). Diamonds represent estimates and
95% CI for overall effects in both groups.
The P value for homogeneity tested
the consistency of the treatment effect
between subgroups.
262HypertensionFebruary 2014

Figure 2. Effects of the combination of perindopril and indapamide (randomized study drugs) with calcium channel blockers (CCBs) at
any visit (nonstudy drug) on major cardiovascular (CV) events and death compared with participants on placebo who never received
CCBs. Solid boxes represent estimates of treatment effect on the risk of clinical outcomes. Centers of the boxes are placed at the
estimates of effect; areas of the boxes are proportional to the reciprocal of the variance of the estimates. Horizontal lines represent 95%
confidence interval (CI). Hazard ratios and P values were adjusted for age, sex, duration of diabetes mellitus, systolic blood pressure,
hemoglobin A1c, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, log-transformed triglyceride, estimated
glomerular filtration rate, urinary albumincreatinine ratio, body mass index, smoking, ECG abnormalities, and randomized glucose-
lowering treatment.

additive effects on blood pressure reduction. At the same
time, the combination of 2 drugs enables the use of each
drug either in standard dose or even in low dose, thus reduc-
ing the frequency of side effects and enhancing acceptabil-
ity and adherence to therapy.811,13,26 Two of the most favored
combinations in the modern era are the use of ACE inhibi-
tors with diuretics and the use of ACE inhibitors with CCBs.
The former has the advantage of opposing effects on potas-
sium secretion by the kidneys, thus minimizing the risks of
hyper- or hypokalemia. This combination has been shown to
have outstanding effects on mortality and hard cardiovascular
outcomes in the PROGRESS,22 ADVANCE,19 and HYVET
trials23 in which the ACE inhibitor was perindopril and the
diuretic was indapamide. The combination of ACE inhibitors
with CCBs also has additive effects on blood pressure low-
ering and has been amply vindicated by the ASCOT which
achieved excellent results on hard outcomes, using perin-
dopril and amlodipine24 and the ACCOMPLISH trial using
benazepril and amlodipine, on a range of cardiovascular out-
comes.20 The present analyses indicate that when a third drug
is necessary, the combination of an ACE inhibitor, a diuretic,
and a CCB provides an excellent 3-fold option to reduce the
risk of death and major cardiovascular events with low rates
of adverse events. Furthermore, the triple combination of per-
indopril, indapamide, and a CCB seems superior to the dou-
ble combination of either perindopril and indapamide alone
(Figure1) or perindopril and a CCB (Figure3).
Many guidelines for management of hypertension recom-
mend combination antihypertensive therapy for patients with
hypertension and also for patients with high cardiovascular
risk, whether hypertensive or not.811,13 However, one of the
biggest dilemmas in our field continues to be the great gap
between evidence and practice, with low levels of achieve-
ment of recommended blood pressure targets worldwide.27
One possible reason for the resistance of both patients and
community physicians against combination therapy is likely
to be the increase in the number of antihypertensive agents.
There is considerable evidence that use of fixed-dose (single-
pill) combinations of 2, 3, or even more blood pressurelow-
ering agents may result in better adherence to medications and
subsequent better blood pressure control.1416,18,21,27
In the present analysis, the effects of active treatment with
the fixed combination of perindopril and indapamide on total
mortality were larger among patients with CCB compared with
those without CCB, with nonsignificant trend for the outcome
of cardiovascular death. It is difficult to explain the reasons
for this finding clearly, but it should be noted that the main
results of ADVANCE trial reported major reductions in all-
cause mortality (14%) and cardiovascular mortality (18%).19
In addition, possible imbalance in unknown confounding fac-
tors may have contributed to these findings.
The analyses reported here have the advantage of being based
on a large-scale clinical trial with sufficient power to examine
the effects of randomized treatment in a variety of subgroups

Figure 3. Effects of the combination of perindopril and indapamide (randomized study drugs) with calcium channel blockers (CCBs)
at baseline (nonstudy drug) on major cardiovascular (CV) events and death compared with participants on placebo who received
nonrandomized perindopril and CCBs at baseline (nonstudy drugs). Solid boxes represent estimates of treatment effect on the risk of
clinical outcomes. Centers of the boxes are placed at the estimates of effect; areas of the boxes are proportional to the reciprocal of
the variance of the estimates. Horizontal lines represent 95% confidence interval (CI). Hazard ratios and P values were adjusted for age,
sex, duration of diabetes mellitus, systolic blood pressure, hemoglobin A1c, low-density lipoprotein cholesterol, high-density lipoprotein
cholesterol, log-transformed triglyceride, estimated glomerular filtration rate, urinary albumincreatinine ratio, body mass index, smoking,
ECG abnormalities, and randomized glucose-lowering treatment.
 Chalmers et al Combination Therapy in ADVANCE Trial 263
defined by baseline characteristics, in this instance the use of
CCBs or not. The analyses also have several limitations. They
are all post hoc, and none were prespecified at the time the
ADVANCE trial was designed. Because the use of CCB was
not randomly assigned, there was significant heterogeneity
in baseline characteristics and in the risks of cardiovascular
events and deaths between patients with and without CCB.
Furthermore, some analyses are based on observational data
and lose the advantage of unbiased randomized comparison.
Perspectives
The addition of CCBs to the combination of the ACE inhibitor
perindopril with the diuretic indapamide seems to enhance the
reduction of all-cause mortality and hard cardiovascular out-
comes in patients with type 2 diabetes mellitus in ADVANCE
trial. These potential benefits were seen without any detect-
able increase in adverse events.
Sources of Funding
The ADVANCE trial was funded by grants from the National Health
and Medical Research Council (NHMRC) of Australia and Servier
International.
Disclosures
J. Chalmers and N. Poulter have received research grants and lecture
fees from Servier International. H. Arima holds Future Fellowship
from Australian Research Council (ARC). M. Woodward, G. Mancia,
and S. Zoungas have received lecture fees from Servier International.
M. Woodward holds a Senior Research Fellowship from the NHMRC.
Y. Hirakawa holds a fellowship from the Uehara Memorial Foundation.
B. Williams has received lecture fees from Servier, Novartis, and
Boehringer Ingelheim and is a National Institutes for Health Research
(NIHR) Senior Investigator. The other authors report no conflicts.
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Novelty and Significance
What Is New?
These analyses present the first evidence from randomized data that
the use of a triple combination of antihypertensive agents (angiotensin-
converting enzyme inhibitor+diuretic+calcium channel blocker) is more
effective than a double combination (angiotensin-converting enzyme
inhibitor+diuretic) in reducing mortality.
What Is Relevant?
Combination therapy is recommended by most guidelines to improve
control of hypertension worldwide, but there is so far little evidence of
the benefits of triple combinations on hard end points.
27. The Indian Polycap Study (TIPS). Effects of a polypill (Polycap) on risk
factors in middle-aged individuals without cardiovascular disease (TIPS):
a phase II, double-blind, randomised trial. Lancet. 2009;373:13411351.
Summary
The combination of perindopril and indapamide with calcium chan-
nel blockers seems to provide further protection against mortality
in patients with type 2 diabetes mellitus. This article provides the
first report of improvement in hard end points in patients receiving
the combination of 3 antihypertensive drugs compared with those
on 2 drugs.