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Received: 20 February 2017    Revised: 17 May 2017    Accepted: 19 May 2017

DOI: 10.1111/jch.13053

O R I G I N A L PA P E R

Blood pressure–lowering efficacy of indapamide SR/

amlodipine combination in older patients with hypertension:
A post hoc analysis of the NESTOR trial (Natrilix SR vs Enalapril
in Hypertensive Type 2 Diabetics With Microalbuminuria)

Olivier Hanon MD1,2 | Laure Caillard MD1,2 | Edouard Chaussade MD1,2 | 

Intza Hernandorena MD1,2 | Clemence Boully MD1,2

1
Sorbonne Paris Cité, Université Paris
Descartes, Paris, France
2
APHP, Hôpital Broca, Paris, France
Correspondence
Olivier Hanon, Hôpital Broca, Paris, France.
Email: olivier.hanon@brc.aphp.fr
Funding information
The NESTOR trial and the current analysis
were funded by Servier. The authors
thank Dr Martine de Champvallins and the
biostatistician of the Institut de Recherches
Servier for their support.
To examine the antihypertensive efficacy and safety of indapamide sustained-release
(SR)/amlodipine compared with enalapril/amlodipine in patients 65 years and older
with uncontrolled blood pressure (BP) on monotherapy, a post hoc analysis of the
NESTOR trial (Natrilix SR vs Enalapril in Hypertensive Type 2 Diabetics With
Microalbuminuria) was conducted. NESTOR randomized 570 patients (n=197, aged
≥65 years) with hypertension (systolic BP 140–180/diastolic BP <110 mm Hg) to in-
dapamide SR 1.5 mg or enalapril 10 mg. If target BP (<140/85 mm Hg) was not
achieved at 6 weeks, amlodipine 5 mg was added with uptitration to 10 mg if required.
A total of 107 patients aged 65 years and older received dual therapy (53 indapamide
SR/amlodipine and 54 enalapril/amlodipine). Amlodipine uptitration occurred in 22
and 24 patients, respectively. At 52 weeks, mean systolic BP (±SE) reduction was sig-
nificantly greater with indapamide SR/amlodipine vs enalapril/amlodipine
6.2±2.7 mm Hg (P=.02). Indapamide SR/amlodipine was also associated with a greater
BP response rate (88% vs 75%, respectively). Both regimens were well tolerated.
Indapamide SR/amlodipine may be more effective than enalapril/amlodipine for low-
ering systolic BP in patients with hypertension aged 65 years and older.

1 |  INTRODUCTION hypertension.5 In the Framingham cohort, hypertension increased the

The prevalence of hypertension increases with age and is estimated
to affect up to 65% of the population aged 60 years and older.1 With
an aging population, this number is likely to increase in the years to
come. Arterial stiffness of large conduct arteries is common among
the elderly and is responsible for an increase in pulse wave velocity
as the arterial structure deteriorates.2,3 This, in turn, causes systolic
blood pressure (SBP) to rise and diastolic blood pressure (DBP) to fall,
leading to a distinct blood pressure (BP) profile in elderly patients with
hypertension. As a consequence, they present with especially elevated
SBP levels associated with lower DBP values when compared with
younger patients.4
The elderly population is at particularly high risk for stroke and
cognitive impairments, and this risk is amplified in the presence of
risk of stroke by twofold in the elderly.6 At aged 65 years, the lifetime
risk of having a stroke was estimated to be 15% in patients with hyper-
tension, vs 7% in patients without hypertension.7 As many hypertension
trials have upper age limits or do not present age-­specific results, data
on the efficacy of antihypertensive treatments in elderly patients remain
limited. However, there is now strong evidence that elderly patients
would benefit from antihypertensive treatment in terms of outcomes.8,9
They are a challenging population to treat, and control rates remain poor
(54% in patients ≥60 years), highlighting the need for efficient treatment
specific to this population.1 As the level of renin activity is lower in the
elderly, the use of a renin-­angiotensin system blocker may not be an effi-
cient antihypertensive treatment in this population,10 and antihyperten-
sive agents targeting alternative pathways, such as diuretics or calcium
channel blockers (CCBs), may represent a more effective strategy.

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966       HANON et al.

Indeed, the main randomized control trials performed in el-
derly patients with isolated systolic hypertension (SHEP [Systolic
Hypertension in the Elderly Program] and SYST-­EUR [Systolic
Hypertension in Europe])11,12 have been based on treatment that in-
cluded diuretics or CCBs, and these agents are recommended as first-­
line treatment for systolic hypertension in the elderly in the European
guidelines.13 Few studies have evaluated the effect of dual therapy
with a thiazide diuretic combined with CCB in elderly patients. The
objective of this study was to assess the antihypertensive efficacy and
safety of the indapamide SR/amlodipine combination in the elderly
population (≥65 years) in the NESTOR trial (Natrilix SR vs Enalapril in
Hypertensive Type 2 Diabetics With Microalbuminuria) in comparison
with enalapril/amlodipine.
2 |  METHODS
The population and methods for the NESTOR trial are described in de-
tail elsewhere.14 In brief, the NESTOR trial was a 1-­year randomized,
double-­blind, controlled study in 570 men and women aged 35 to
80 years with mild to moderate essential hypertension, controlled
type 2 diabetes mellitus (by diet with or without ≥1 oral antidiabetes
medications unchanged for at least 3 months), and persistent micro-
albuminuria that included 197 (35%) elderly patients.15 Mild to mod-
baseline in supine SBP ≥20 mm Hg, or a reduction from baseline in
supine DBP ≥10 mm Hg. Changes from baseline in laboratory data are
presented as estimates±SE. A Student two-­sided t test with P values
was used for between-­group comparisons.
3 | RESULTS
3.1 | Patients
A total of 107 patients 65 years and older received amlodipine as add-
­on therapy (53 patients in the indapamide SR group, and 54 patients
in the enalapril group). Of these, 49 patients were uptitrated to am-
lodipine 10 mg (23 in the indapamide SR group and 26 in the enalapril
group). Patient demographics and baseline characteristics were gener-
ally similar between groups, with a slightly longer duration of hyper-
tension in the indapamide SR/amlodipine group (Table 1).
During monotherapy, BP changes were similar in both groups
and did not lead to statistically significant differences in SBP or DBP
(−0.99±1.96 mm Hg for SBP [P=.615] and 0.21±1.47 mm Hg for
DBP [P=.885]) in the whole cohort. The two groups were therefore
T A B L E   1   Baseline characteristics of patients 65 years and older
receiving amlodipine 5 or 10 mg as add-­on therapy in the NESTOR
trial

erate hypertension was defined as an SBP of 140 to <180 mm Hg Indapamide Enalapril/

and DBP <110 mm Hg. The main exclusion criteria were a body mass SR amlodipine amlodipine
index >40 kg/m2, ventricular rhythm disorders, plasma creatinine (n=53) (n=54)

>150 μmol/L, potassium <3.5 or >5.5 mmol/L, uric acid >536 μmol/L, Age, y 70.8±4.2 70.1±3.8
and hematuria or leukocyturia. After a 4-­week placebo run-­in pe- Men, % 68 63
riod, patients were randomized to double-­blind treatment with in- Body mass index, kg/m2 28.3±3.6 29.3±4.1
dapamide SR 1.5 mg or enalapril 10 mg. Patients not at target BP Duration of diabetes 124 (51–202) 121 (40–177)
(<140/85 mm Hg) after 6 weeks of monotherapy were uptitrated with mellitus, month
the addition of amlodipine 5 mg, which could be followed 6 weeks Hypertension characteristics
later by a further uptitration to amlodipine 10 mg. Adjustment of an- Duration, month 119 (67–230) 81 (26–181)a
tidiabetes medication was permitted from week 6 of the study. This Previous antihyper- 81 78
post hoc analysis of the NESTOR trial included all patients with un- tensive treatment, %
controlled BP on initial monotherapy who received add-­on amlodipine SBP, mm Hg 168.0±8.5 166.3±7.9
and who were 65 years and older. A subanalysis was also performed DBP, mm Hg 93.1±7.5 92.1±6.4
in the subset of patients whose therapy combination was uptitrated to
Grade of hypertension, %
amlodipine 10 mg. The study was performed in accordance with Good
Grade 1 11 17
Clinical Practice and approved by the ethics committees in each coun-
Grade 2 83 81
try (Argentina, Belgium, Brazil, Denmark, Finland, France, Hungary,
Grade 3 6 2
Israel, Mexico, Poland, Portugal, Romania, Russian Federation, Spain,
Isolated systolic 25 26
The Netherlands, United Kingdom, and Venezuela). Each patient gave
hypertension
written informed consent before enrollment.
All statistical analyses were performed in the intent-­to-­treat popu- Values are mean±SD, median (quartile 1–quartile 3), or percentage of
patients.
lation (patients who received at least one dose of the combination with
Abbreviations: NESTOR, Natrilix SR vs Enalapril in Hypertensive Type 2
amlodipine) using SAS/PC Software version 9.2 (SAS Institute). For BP Diabetics With Microalbuminuria; SR, sustained-­release.
a
data, between-­group comparisons for changes (mean±SD) from base- Statistical difference between groups (P=.087). Grade of hypertension
line were performed using a linear model for analysis of covariance was defined according to the highest level of blood pressure value, whether
systolic blood pressure (SBP) or diastolic blood pressure (DBP): for grade 1,
with treatment as a factor and baseline as a covariate. BP control was
SBP=140 to 159 mm Hg and/or DBP=90 to 99 mm Hg; for grade 2,
defined as a supine SBP <140 mm Hg and a supine DBP <90 mm Hg. SBP=160 to 179 mm Hg and/or DBP=100 to 109 mm Hg; and for grade 3,
Response to treatment was defined as BP control, a reduction from SBP ≥180 mm Hg and/or DBP ≥110 mm Hg.
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similar in terms of BP at the end of monotherapy, with mean SBP

values of 157.3±10.6 mm Hg vs 157.1±12.1 mm Hg for indapamide
and enalapril, respectively, and mean DBP values of 88.9±8.3 vs
88.1±9.0 mm Hg, respectively. The same applied to the subgroup up-
titrated to amlodipine 10 mg.

3.2 | Patients receiving amlodipine (5 or 10 mg)

At the end of treatment, SBP/DBP decreased significantly from
baseline in both treatment groups (by 30±12/14±9 mm Hg in the
indapamide SR/amlodipine group and by 22±16/11±9 mm Hg in the
enalapril/amlodipine group). The decrease in SBP was significantly
greater in patients treated with the combination indapamide SR/am-
lodipine as compared with enalapril/amlodipine (intergroup compari-
son: −6.2 mm Hg; 95% CI, −11.4 to −0.9 [P=.022] (Figure 1).
DBP reduction was not statistically different in both groups (inter-
group comparisons: −2.1 mm Hg; 95% CI, −5.0 to 0.9 [P=.173]). Pulse
pressure (PP) reduction, although even more pronounced in the in-
dapamide SR/amlodipine group, was not statistically different in both
groups (intergroup comparisons: −4.0; 95% CI, −8.3 to 0.2 [P=.064]).
F I G U R E   1   Reduction in systolic blood pressure from baseline
At the end of treatment, mean SBP/DBP fell below the BP tar-
to the end of treatment in patients 65 years and older receiving
get level of 140/85 mm Hg in the indapamide SR/amlodipine group amlodipine 5 or 10 mg as add-­on therapy in the indapamide
(138.4±10.1/79.2±7.5 mm Hg) but not in the enalapril/amlodipine SR group (n=53) vs the enalapril group (n=54). Changes from
group (143.9±16.4/81.0±8.2 mm Hg). BP control was achieved by baseline within group are presented as means±SD, and differences
59% of patients in the indapamide SR/amlodipine group and by 48% between groups as an estimate of the changes adjusted for baseline,
95% CI
of patients in the enalapril/amlodipine group (not significant [NS]). A
majority (88%) of patients in the indapamide SR/amlodipine group
were responders to treatment, vs 75% in the enalapril/amlodipine
group (NS).

3.3 | Subgroup of patients uptitrated to amlodipine

10 mg
At the end of treatment, SBP/DBP/PP significantly (P<.001 for all pa-
rameters) decreased from baseline in both treatment groups (by −2
9.5±12.8/−12.6±8.8/−16.9±12.1 mm Hg in the indapamide SR/am-
lodipine 10-­mg group and by −24.2±13.1/−11.8±7.0/−12.4±11.3 m
m Hg in the enalapril/amlodipine 10-­mg group). The decrease in SBP
was greater in patients treated with the combination indapamide SR/
amlodipine 10 mg vs enalapril/amlodipine 10 mg, although this did
not reach significance in view of the limited number of patients per
group (Figure 2). Similarly, between-­group difference in PP reduc-
tion was 5.5 mm Hg (95% CI, −11.6 to 0.7; P=.080). The uptitration
from amlodipine 5 to 10 mg was associated with a greater reduction
in mean (±SD) SBP and PP in the indapamide SR/amlodipine 10-­mg
group (−12.7±11.1 mm Hg, P<.001/−4.8±11.1, P=.055, respec-
tively), vs the enalapril/amlodipine 10-­mg group (−7.1±18.6 mm Hg,
P=.07/−1.7±15.6, P=.598, respectively). In the same way, DBP de- F I G U R E   2   Reduction in systolic blood pressure from baseline
creased by −12.6±8.8 in the indapamide SR/amlodipine 10-­mg group to the end of treatment in patients 65 years and older uptitrated
to amlodipine 10 mg as add-­on therapy in the indapamide
(P<.001) and by −11.85±7.0 in the enalapril/amlodipine 10-­mg group
SR group (n=22) vs the enalapril group (n=24). Changes from
(P<.001). DBP reduction from baseline to end of treatment was similar baseline within group are presented as means±SD, and difference
in both groups (intergroup comparison: 0.3 mm Hg; 95% CI, −3.5 to between groups as an estimate of the changes adjusted for baseline,
−4.0 [NS]). 95% CI
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968       HANON et al.

T A B L E   2   Laboratory parameters in
Indapamide Enalapril/ P value
patients 65 years and older receiving
SR/amlodipine amlodipine (intergroup
amlodipine 5 or 10 mg as add-­on therapy
(n=53) (n=54) comparison)

Fasting glucose, mmol/L

Baseline 8.7±3.7 9.7±3.4
Change from baseline 0.9±3.5 −0.1±3.0 NS
Uric acid, μmol/L
Baseline 346±80 331±79
a
Change from baseline 26±73 8±60 NS
Total cholesterol, mmol/L
Baseline 5.2±0.8 5.1±0.9
Change from baseline 0.1±0.6 −0.1±0.6 NS
HDL cholesterol, mmol/L
Baseline 1.1±0.3 1.2±0.4
Change from baseline 0.0±0.1 −0.0±0.2 NS
LDL cholesterol, mmol/L
Baseline 3.4±0.6 3.1±0.8
Change from baseline −0.0±0.5 −0.1±0.4 NS
Triglycerides, mmol/L
Baseline 1.6±0.7 1.6±0.8
Change from baseline 0.1±0.7 0.1±0.7 NS

Creatinine clearance, mL/min

Baseline 73.1±17.6 72.8±19.9
a
Change from baseline −5.3±6.8 −2.0±6.4a 0.015
Potassium, mmol/L
Baseline 4.4±0.4 4.5±0.4
Change from baseline −0.3±0.5a 0.1±0.4 <0.0001
Sodium, mmol/L
Baseline 140.8±2.3 140.0±2.4
a
Change from baseline −1.5±2.8 −1.0±2.3a NS
ASAT, IU/L
Baseline 14.6±4.9 14.4±5.8
Change from baseline −0.5±3.3 −1.0±4.3 NS
ALAT, IU/L
Baseline 17.5±6.4 18.9±11.0
Change from baseline −0.9±5.2 −1.1±8.1 NS
Alkaline phosphatase, UI/L
Baseline 150±53 128±40
Change from baseline −0.1±29.2 7.0±26.5 NS

Baseline and changes from baseline values are mean±SD.

Abbreviations: ALAT, alanine aminotransferase; ASAT, aspartate aminotransferase; HDL, high-­density
lipoprotein; LDL, low-­density lipoprotein; NS, not significant; SR, sustained-­release.
a
Significant changes within group.

BP control was achieved in 64% of patients in the indapamide SR/

amlodipine 10-­mg group and by 50% of patients in the enalapril/am-
lodipine 10-­mg group (NS). Response rate was 91% in the indapamide
SR/amlodipine 10-­mg group and 75% in the enalapril/amlodipine 10-­
mg group (NS).
3.4 | Laboratory parameters
Results of laboratory parameters are presented in Table 2. Slight
changes that were expected were observed for some parameters.
Sodium levels decreased in both treatment groups but remained
HANON et al.
within the normal range. A decrease in creatinine clearance was
also noted with both treatments over 1 year, which was more pro-
nounced in the indapamide SR/amlodipine group. Uric acid increased
and potassium decreased in the indapamide SR/amlodipine group, a
common feature of diuretics. Of note, only two patients experienced
hypokalemia (<3.4 mmol/L) in the indapamide SR/amlodipine group,
and there were no cases of hypokalemia in the subgroup of patients
uptitrated to amlodipine 10 mg. Both treatment regimens were meta-
bolically neutral with no observed effects on lipid or glucose metabo-
lism. No relevant changes were observed for other parameters in any
group.
3.5 | Safety
Treatment was well tolerated in both groups. Three patients in each
group withdrew from the study. Adverse events were the cause of
these withdrawals in two patients in the indapamide SR/amlodipine
group and in one patient in the enalapril/amlodipine group. Lack of
efficacy was the cause of one withdrawal in the enalapril/amlodipine
group. In all, six (11%) and eight (15%) patients experienced treatment-­
related adverse events in the indapamide SR/amlodipine group and in
the enalapril/amlodipine group, respectively. Noteworthy, treatment-­
related adverse events included coughing (two patients per group
[4%]) and hypokalemia (one patient per group [2%]). Edema, a com-
mon adverse effect of amlodipine, was reported in one patient (2%)
in the indapamide SR/amlodipine group and three (6%) patients in the
enalapril/amlodipine group.
There were no cases of orthostatic hypotension reported in this
subpopulation. However, orthostatic hypotension (decline of SBP
≥20 mm Hg or decline of DBP 10 mm Hg after 1 and 3 minutes of
standing) occurred during dynamic tests in 25% of the indapamide/
amlodipine group vs 17% of the enalapril/amlodipine group (P=NS),
with no increase observed with the highest dose of indapamide/am-
lodipine 10 mg (22% vs 24% with enalapril/amlodipine 10 mg).
4 | DISCUSSION
In elderly patients with concomitant hypertension and type 2 diabe-
tes mellitus, the indapamide SR/amlodipine combination was more
effective in reducing SBP than the enalapril/amlodipine combination.
Treatment with indapamide SR/amlodipine was generally well toler-
ated in elderly patients, with a safety profile comparable to that of the
enalapril/amlodipine combination. The greater efficacy of the indapa-
mide SR/amlodipine combination on SBP reduction in elderly patients
with hypertension makes it an attractive therapeutic option for this
age class.
The greater reduction in SBP achieved with the indapamide SR/
amlodipine combination is particularly important in the elderly given
that arterial stiffness increases with age and is a major determinant
of SBP in central vessels in this population.2 In contrast, reductions
in DBP were not statistically significant between the two groups.
Moreover, indapamide SR/amlodipine resulted in a more potent SBP
|
      969
reduction in patients 65 years and older (30 mm Hg) than the SBP re-
duction previously reported in the overall population of the NESTOR
trial (26 mm Hg).16
The activity of the renin-­angiotensin system in elderly patients
with hypertension is reduced compared with younger patients, as re-
flected by a lower level of plasma renin activity, and may in part explain
their lesser response to agents targeting this pathway.10 Several stud-
ies have shown that the use of agents that target alternative pathways
to the renin-­angiotensin system may be more effective in reducing BP
in elderly patients.17–19
Sodium sensitivity has been shown to increase with age, which
makes the class of diuretic an obvious strategy in elderly patients be-
cause of its well-­established natriuretic effect.20 Indapamide SR is a
thiazide-­like diuretic with both a mild natriuretic and vasodilating ef-
fect.21 This dual effect is believed to be especially effective in elderly
patients with hypertension, in whom a rise in BP is linked both to salt
retention and increased vascular stiffness. In addition to amlodipine’s
well-­known vasorelaxant effects, it has been suggested that long-­term
treatment might have an effect on total body sodium.22,23
The safety and BP-­lowering efficacy of indapamide SR in the el-
derly was demonstrated in a randomized, double-­blind trial of patients
with hypertension 65 years and older (mean age 72.4 years).24 In this
3-­month study, indapamide SR was as efficient as amlodipine or hydro-
chlorothiazide in reducing BP and was superior to hydrochlorothiazide
in the subgroup of elderly patients with isolated systolic hypertension.
The long-­term efficacy and safety of indapamide SR in elderly patients
with hypertension was further confirmed in a 12-­month follow-­up of
the study.25 In a trial that examined an indapamide-­containing combi-
nation in older patients with type 2 diabetes, treatment benefits were
proven and not offset by any increased risk of side effects.26
Diuretics may cause hypokalemia and hyponatremia and increase
hyperuricemia, which can be problematic in the elderly. However,
there is evidence that indapamide 1.5 mg SR may have minimal
long-­term effects on metabolic profile,27 a finding confirmed in the
long-­term HYVET trial (Hypertension in the Very Elderly Trial) in oc-
togenarians.9 There is consensus that the cardiovascular benefit of
treating elderly patients with hypertension with a diuretic largely
outweighs any side effects related to treatment.9,26,28 Among the
diuretic agents, the thiazide-­like drugs indapamide and chlorthali-
done have the highest levels of evidence for cardiovascular protec-
tion in patients with hypertension.29 Moreover, several randomized
trials have demonstrated the benefit of thiazide-­like diuretics in
terms of outcomes in elderly patients with hypertension.9,11,17 One
of the landmark trials in the treatment of hypertension in elderly
patients was the HYVET trial, which included patients 80 years and
older.9 In HYVET, treatment with indapamide SR±perindopril con-
sistently reduced the risk of cardiovascular end points as compared
with placebo, including a 39% reduction of risk for fatal stroke,
21% reduction of risk for total mortality, and a 64% reduction of
risk for total heart failure. Thiazide-­like diuretics have been shown
to reduce clinical outcomes, particularly stroke and heart failure, in
other morbidity-­mortality trials in older patients with hypertension
(≥55 years).11,17
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970       HANON et al.
Rates of orthostatic hypotension observed in both groups were
in line with the 20% observed in the ACCORD (Action to Control
Cardiovascular Risk in Diabetes) BP trial.30 Due to the high risk for falls
and the frequent use of antihypertensive drugs in older adults, it is
important that there is no increase in fracture risk with prescribed an-
tihypertensive agents. In the HYVET trial, which randomized patients
80 years and older to indapamide SR±perindopril or placebo, fracture
rate was a secondary end point.31 The authors found no increase in
fracture risk and a significant 42% reduction in risk of incident fracture
with indapamide SR±perindopril compared with placebo. Two meta-­
analyses have also reported a statistically significant reduction in frac-
ture risk with treatment regimens that included a thiazide diuretic.32,33
It has been suggested that the lower rates of calcium excretion ob-
served with the use of thiazide diuretics may help preserve bone min-
eral density and thereby decrease the risk of fracture.31
While it is now commonly accepted that antihypertensive treat-
ment is beneficial in elderly patients for reducing outcomes, there is
34
still a lack of consensus on the SBP target to achieve in these patients.
In a recent secondary analysis of SPRINT (Systolic Blood Pressure
Intervention Trial), intensive therapy (SBP target <120 mm Hg) in the
subgroup of patients 75 years and older treated with antihypertensive
therapy was associated with a significant reduction in cardiovascular
events and mortality as compared with those treated with standard
therapy (SBP target <140 mm Hg).35 This new evidence suggests that
aiming at lower SBP values could be beneficial in elderly patients and
highlights the need for antihypertensive drugs that efficiently reduce
SBP in these patients.
This analysis of elderly patients in SPRINT was part of a recent
meta-­analysis of four large randomized controlled trials that assessed
the efficacy and safety of intensive BP-­lowering strategies vs standard
BP control in older patients (≥65 years) with hypertension.36 Older pa-
tients receiving more intensive BP control (systolic BP <140 mm Hg)
had a significantly lower incidence of major adverse cardiovascular
events, including cardiovascular mortality and heart failure. Overall,
there was no significant difference in the incidence of serious adverse
events between the two groups, with the exception of an increased
risk for renal failure in the intensive BP-­lowering group. This finding
was largely driven by the results of the SPRINT elderly analysis, where
there was a higher incidence of composite renal outcomes (reduction
in estimated glomerular filtration rate, dialysis, or renal transplant)
with intensive therapy in patients without chronic kidney disease at
35
baseline. It is important to note that type 2 diabetes mellitus was an
exclusion criterion in SPRINT, so the population is different to that of
the NESTOR trial. Interestingly, there was no significant difference for
composite renal outcome between the intensive and standard treat-
ment groups in patients with chronic kidney disease at baseline, and
no significant difference in incident albuminuria among participants
with or without chronic kidney disease at baseline.36 Bavishi and col-
leagues36 suggested that greater use of diuretic agents in combination
with angiotensin-­converting enzyme inhibitors and angiotensin recep-
tor blockers in the intensive group of SPRINT may have resulted in
more pronounced alterations in intrarenal hemodynamics and a sub-
sequent rise in serum creatinine.
While all antihypertensive drugs can theoretically be used in the
elderly, European guidelines cite diuretics and CCBs as preferred
agents for elderly patients with isolated systolic hypertension.13
Similarly, National Institute for Health and Care Excellence guidelines
recommend initiating treatment with a CCB or a thiazide-­like diuretic
in patients 55 years and older.37 Here, we show that the indapamide/
amlodipine combination with one agent from each recommended
drug class is efficient and well tolerated in elderly patients with hy-
pertension. The benefit of such a combination is further supported
by the results of a recent meta-­analysis including 30 791 patients
with a mean age of 64 years, in which combination of a CCB and
thiazide-­like diuretic was associated with a 23% reduction in the risk
of stroke compared with other combination strategies.38 Combining
antihypertensive drugs allows for better BP control, and this strategy
is now recommended in all patients with hypertension, including the
elderly.5
Use of single-­pill combinations has a favorable effect on treat-
ment adherence, one of the major problems in the management of
hypertension. This adherence issue is usually amplified in elderly pa-
tients who have multiple comorbidities and receive a large number of
medications. In the EFFICIENT trial (Effects of a Fixed Combination
of Indapamide Sustained-­Release With Amlodipine on Blood Pressure
in Hypertension), a single-­pill combination of indapamide SR/am-
lodipine was shown to efficiently reduce BP and was associated with
almost maximal (99%) treatment adherence and good tolerability in
the general hypertensive population.39 Our findings suggest that the
benefits of such a single-­pill combination are likely to extend to el-
derly patients with hypertension in terms of SBP lowering and opti-
mal adherence.
In summary, the results of the current analysis confirmed the pri-
mary findings of the main study in the subgroup of patients older than
65 years. Although the analysis was based on a study that specifically
included patients with hypertension, diabetes mellitus, and microal-
buminuria, it is likely that the findings of this study will extend to all
elderly patients with hypertension, with or without diabetes mellitus,
as diabetes mellitus in patients is generally more challenging to treat
than other patients with hypertension.
4.1 | Limitations
This study is subject to some potential limitations. Although the cur-
rent subgroup analysis examined the efficacy and safety in partici-
pating elderly patients, but not octogenarians, it is not clear whether
these are representative of elderly patients in clinical practice and this
might limit the generalizability of the results. Although there were no
observed effects of either treatment on glucose metabolism, it should
be noted that the impact of study treatment on fasting plasma glucose
could not be assessed rigorously as physicians were allowed to adjust
diabetes mellitus medications as needed. In post hoc subgroup analy-
ses, the protection of randomization from selection bias may not apply
to specific subgroup analyses even if precautions are taken, ie, here,
the homogeneity of the BP characteristics after 6 weeks of monother-
apy was verified in both groups.
HANON et al.
5 | CONCLUSIONS
Hypertension in elderly patients is characterized by distinct patho-
physiological features, including an increase in sodium sensitivity and
decrease in activity of the renin-­angiotensin system. The results of
this analysis showed that an indapamide SR/amlodipine combination
was superior in reducing SBP compared with enalapril/amlodipine and
may be a more effective treatment strategy in elderly patients with
hypertension.
AUT HOR CONTRI B UTI O N S
All named authors meet the International Committee of Medical
Journal Editors (ICMJE) criteria for authorship for this article, take re-
sponsibility for the integrity of the work as a whole, and have given
final approval to the version to be published.
D ISCLOSU RE S
OH has received consultant/advisory/lecture fees from Daiichi-­
Sankyo, Bayer, Boehringer-­Ingelheim, BMS/Pfizer, Novartis, Servier,
Astra-­Zeneca, and Sanofi. LC, EC, IH, and CB report no disclosures.
Editorial assistance was provided by Julie Salzmann, Jenny Grice, and
John Plant and funded by Servier.
6 | COMPLIANCE WITH ETHICS
GUIDELINES
All procedures followed were in accordance with the ethical standards
of the responsible committee on human experimentation (institutional
and national) and with the Declaration of Helsinki. Informed consent
was obtained from all patients before being included in the study.
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How to cite this article: Hanon O, Caillard L, Chaussade E,
Hernandorena I, Boully C. Blood pressure–lowering efficacy of
indapamide SR/amlodipine combination in older patients with
hypertension: A post hoc analysis of the NESTOR trial (Natrilix
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https://doi.org/10.1111/jch.13053