Skip to main content
NCBI home page
The Journal of Clinical Hypertension logoLink to The Journal of Clinical Hypertension
. 2017 Jul 18;19(10):965–972. doi: 10.1111/jch.13053

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 1,2,✉, Laure Caillard 1,2, Edouard Chaussade 1,2, Intza Hernandorena 1,2, Clemence Boully 1,2
PMCID: PMC8030879  PMID: 28721700

Abstract

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 indapamide 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 significantly 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 lowering systolic BP in patients with hypertension aged 65 years and older.

Keywords: elderly, hypertension, indapamide SR/amlodipine combination, systolic blood pressure

1. INTRODUCTION

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 hypertension.5 In the Framingham cohort, hypertension increased the 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 hypertension, 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 efficient antihypertensive treatment in this population,10 and antihypertensive agents targeting alternative pathways, such as diuretics or calcium channel blockers (CCBs), may represent a more effective strategy.

Indeed, the main randomized control trials performed in elderly 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 included 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 detail 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 microalbuminuria that included 197 (35%) elderly patients.15 Mild to moderate hypertension was defined as an SBP of 140 to <180 mm Hg and DBP <110 mm Hg. The main exclusion criteria were a body mass index >40 kg/m2, ventricular rhythm disorders, plasma creatinine >150 μmol/L, potassium <3.5 or >5.5 mmol/L, uric acid >536 μmol/L, and hematuria or leukocyturia. After a 4‐week placebo run‐in period, patients were randomized to double‐blind treatment with indapamide SR 1.5 mg or enalapril 10 mg. Patients not at target BP (<140/85 mm Hg) after 6 weeks of monotherapy were uptitrated with the addition of amlodipine 5 mg, which could be followed 6 weeks later by a further uptitration to amlodipine 10 mg. Adjustment of antidiabetes medication was permitted from week 6 of the study. This post hoc analysis of the NESTOR trial included all patients with uncontrolled BP on initial monotherapy who received add‐on amlodipine and who were 65 years and older. A subanalysis was also performed in the subset of patients whose therapy combination was uptitrated to amlodipine 10 mg. The study was performed in accordance with Good Clinical Practice and approved by the ethics committees in each country (Argentina, Belgium, Brazil, Denmark, Finland, France, Hungary, Israel, Mexico, Poland, Portugal, Romania, Russian Federation, Spain, The Netherlands, United Kingdom, and Venezuela). Each patient gave written informed consent before enrollment.

All statistical analyses were performed in the intent‐to‐treat population (patients who received at least one dose of the combination with amlodipine) using SAS/PC Software version 9.2 (SAS Institute). For BP data, between‐group comparisons for changes (mean±SD) from baseline were performed using a linear model for analysis of covariance with treatment as a factor and baseline as a covariate. BP control was defined as a supine SBP <140 mm Hg and a supine DBP <90 mm Hg. Response to treatment was defined as BP control, a reduction from 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 amlodipine 10 mg (23 in the indapamide SR group and 26 in the enalapril group). Patient demographics and baseline characteristics were generally similar between groups, with a slightly longer duration of hypertension in the indapamide SR/amlodipine group (Table  1).

Table 1.

Baseline characteristics of patients 65 years and older receiving amlodipine 5 or 10 mg as add‐on therapy in the NESTOR trial

Indapamide SR amlodipine (n=53) Enalapril/amlodipine (n=54)
Age, y 70.8±4.2 70.1±3.8
Men, % 68 63
Body mass index, kg/m2 28.3±3.6 29.3±4.1
Duration of diabetes mellitus, month 124 (51–202) 121 (40–177)
Hypertension characteristics
Duration, month 119 (67–230) 81 (26–181)a
Previous antihypertensive treatment, % 81 78
SBP, mm Hg 168.0±8.5 166.3±7.9
DBP, mm Hg 93.1±7.5 92.1±6.4
Grade of hypertension, %
Grade 1 11 17
Grade 2 83 81
Grade 3 6 2
Isolated systolic hypertension 25 26
Open in a new tab

Values are mean±SD, median (quartile 1–quartile 3), or percentage of patients.

Abbreviations: NESTOR, Natrilix SR vs Enalapril in Hypertensive Type 2 Diabetics With Microalbuminuria; SR, sustained‐release.

a

Statistical difference between groups (P=.087). Grade of hypertension was defined according to the highest level of blood pressure value, whether systolic blood pressure (SBP) or diastolic blood pressure (DBP): for grade 1, SBP=140 to 159 mm Hg and/or DBP=90 to 99 mm Hg; for grade 2, SBP=160 to 179 mm Hg and/or DBP=100 to 109 mm Hg; and for grade 3, SBP ≥180 mm Hg and/or DBP ≥110 mm Hg.

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 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 uptitrated 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/amlodipine as compared with enalapril/amlodipine (intergroup comparison: −6.2 mm Hg; 95% CI, −11.4 to −0.9 [P=.022] (Figure 1).

Figure 1.

Figure 1

Open in a new tab

Reduction in systolic blood pressure from baseline to the end of treatment in patients 65 years and older receiving amlodipine 5 or 10 mg as add‐on therapy in the indapamide SR group (n=53) vs the enalapril group (n=54). Changes from baseline within group are presented as means±SD, and differences between groups as an estimate of the changes adjusted for baseline, 95% CI

DBP reduction was not statistically different in both groups (intergroup comparisons: −2.1 mm Hg; 95% CI, −5.0 to 0.9 [P=.173]). Pulse pressure (PP) reduction, although even more pronounced in the indapamide SR/amlodipine group, was not statistically different in both groups (intergroup comparisons: −4.0; 95% CI, −8.3 to 0.2 [P=.064]).

At the end of treatment, mean SBP/DBP fell below the BP target level of 140/85 mm Hg in the indapamide SR/amlodipine group (138.4±10.1/79.2±7.5 mm Hg) but not in the enalapril/amlodipine group (143.9±16.4/81.0±8.2 mm Hg). BP control was achieved by 59% of patients in the indapamide SR/amlodipine group and by 48% 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 parameters) decreased from baseline in both treatment groups (by −29.5±12.8/−12.6±8.8/−16.9±12.1 mm Hg in the indapamide SR/amlodipine 10‐mg group and by −24.2±13.1/−11.8±7.0/−12.4±11.3 mm 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 reduction 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, respectively), 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 decreased by −12.6±8.8 in the indapamide SR/amlodipine 10‐mg group (P<.001) and by −11.85±7.0 in the enalapril/amlodipine 10‐mg group (P<.001). DBP reduction from baseline to end of treatment was similar in both groups (intergroup comparison: 0.3 mm Hg; 95% CI, −3.5 to −4.0 [NS]).

Figure 2.

Figure 2

Open in a new tab

Reduction in systolic blood pressure from baseline to the end of treatment in patients 65 years and older uptitrated to amlodipine 10 mg as add‐on therapy in the indapamide SR group (n=22) vs the enalapril group (n=24). Changes from baseline within group are presented as means±SD, and difference between groups as an estimate of the changes adjusted for baseline, 95% CI

BP control was achieved in 64% of patients in the indapamide SR/amlodipine 10‐mg group and by 50% of patients in the enalapril/amlodipine 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 within the normal range. A decrease in creatinine clearance was also noted with both treatments over 1 year, which was more pronounced 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 metabolically neutral with no observed effects on lipid or glucose metabolism. No relevant changes were observed for other parameters in any group.

Table 2.

Laboratory parameters in patients 65 years and older receiving amlodipine 5 or 10 mg as add‐on therapy

Indapamide SR/amlodipine (n=53) Enalapril/amlodipine (n=54) P value (intergroup 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
Change from baseline 26±73a 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
Change from baseline −5.3±6.8a −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
Change from baseline −1.5±2.8a −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
Open in a new tab

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.

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 common 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/amlodipine 10 mg (22% vs 24% with enalapril/amlodipine 10 mg).

4. DISCUSSION

In elderly patients with concomitant hypertension and type 2 diabetes 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 tolerated in elderly patients, with a safety profile comparable to that of the enalapril/amlodipine combination. The greater efficacy of the indapamide 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 reduction in patients 65 years and older (30 mm Hg) than the SBP reduction 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 reflected by a lower level of plasma renin activity, and may in part explain their lesser response to agents targeting this pathway.10 Several studies 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, 18, 19

Sodium sensitivity has been shown to increase with age, which makes the class of diuretic an obvious strategy in elderly patients because of its well‐established natriuretic effect.20 Indapamide SR is a thiazide‐like diuretic with both a mild natriuretic and vasodilating effect.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 elderly 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 hydrochlorothiazide 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 combination 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 octogenarians.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 chlorthalidone have the highest levels of evidence for cardiovascular protection 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 consistently 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

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 antihypertensive 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 fracture risk with treatment regimens that included a thiazide diuretic.32, 33 It has been suggested that the lower rates of calcium excretion observed with the use of thiazide diuretics may help preserve bone mineral density and thereby decrease the risk of fracture.31

While it is now commonly accepted that antihypertensive treatment is beneficial in elderly patients for reducing outcomes, there is still a lack of consensus on the SBP target to achieve in these patients.34 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 patients 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 baseline.35 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 treatment 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 colleagues36 suggested that greater use of diuretic agents in combination with angiotensin‐converting enzyme inhibitors and angiotensin receptor blockers in the intensive group of SPRINT may have resulted in more pronounced alterations in intrarenal hemodynamics and a subsequent 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 hypertension. 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 treatment adherence, one of the major problems in the management of hypertension. This adherence issue is usually amplified in elderly patients 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/amlodipine 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 elderly patients with hypertension in terms of SBP lowering and optimal adherence.

In summary, the results of the current analysis confirmed the primary 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 microalbuminuria, 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 current subgroup analysis examined the efficacy and safety in participating 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 analyses, 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 monotherapy was verified in both groups.

5. CONCLUSIONS

Hypertension in elderly patients is characterized by distinct pathophysiological 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.

AUTHOR CONTRIBUTIONS

All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given final approval to the version to be published.

DISCLOSURES

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.

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 SR vs Enalapril in Hypertensive Type 2 Diabetics With Microalbuminuria). J Clin Hypertens. 2017;19:965–972. 10.1111/jch.13053

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.

REFERENCES

  • 1. Benjamin EJ, Blaha MJ, Chiuve SE, et al. Heart disease and stroke statistics—2017 update: a report from the American Heart Association. Circulation. 2017;135:e146‐e603. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2. O'Rourke MF, Hashimoto J. Mechanical factors in arterial aging: a clinical perspective. J Am Coll Cardiol. 2007;50:1‐13. [DOI] [PubMed] [Google Scholar]
  • 3. Wallace SM, Yasmin, McEniery CM, et al. Isolated systolic hypertension is characterized by increased aortic stiffness and endothelial dysfunction. Hypertension. 2007;50:228‐233. [DOI] [PubMed] [Google Scholar]
  • 4. Falaschetti E, Mindell J, Knott C, Poulter N. Hypertension management in England: a serial cross‐sectional study from 1994 to 2011. Lancet. 2014;383:1912‐1919. [DOI] [PubMed] [Google Scholar]
  • 5. Aronow WS, Fleg JL, Pepine CJ, et al. ACCF/AHA 2011 expert consensus document on hypertension in the elderly: a report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus documents developed in collaboration with the American Academy of Neurology, American Geriatrics Society, American Society for Preventive Cardiology, American Society of Hypertension, American Society of Nephrology, Association of Black Cardiologists, and European Society of Hypertension. J Am Coll Cardiol. 2011;57:2037‐2114. [DOI] [PubMed] [Google Scholar]
  • 6. Aronow WS. Hypertension‐related stroke prevention in the elderly. Curr Hypertens Rep. 2013;15:582‐589. [DOI] [PubMed] [Google Scholar]
  • 7. Turin TC, Okamura T, Afzal AR, et al. Hypertension and lifetime risk of stroke. J Hypertens. 2016;34:116‐122. [DOI] [PubMed] [Google Scholar]
  • 8. Turnbull F, Neal B, Ninomiya T, et al. Effects of different regimens to lower blood pressure on major cardiovascular events in older and younger adults: meta‐analysis of randomised trials. BMJ. 2008;336:1121‐1123. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9. Beckett NS, Peters R, Fletcher AE, et al. Treatment of hypertension in patients 80 years of age or older. N Engl J Med. 2008;358:1887‐1898. [DOI] [PubMed] [Google Scholar]
  • 10. Messerli FH, Sundgaard‐Riise K, Ventura HO, et al. Essential hypertension in the elderly: haemodynamics, intravascular volume, plasma renin activity, and circulating catecholamine levels. Lancet. 1983;2:983‐986. [DOI] [PubMed] [Google Scholar]
  • 11. SHEP Cooperative Research Group . Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. Final results of the Systolic Hypertension in the Elderly Program (SHEP). JAMA. 1991;265:3255‐3264. [PubMed] [Google Scholar]
  • 12. Staessen JA, Fagard R, Thijs L, et al. Randomised double‐blind comparison of placebo and active treatment for older patients with isolated systolic hypertension. The Systolic Hypertension in Europe (Syst‐Eur) Trial Investigators. Lancet. 1997;350:757‐764. [DOI] [PubMed] [Google Scholar]
  • 13. Mancia G, Fagard R, Narkiewicz K, et al. 2013 ESH/ESC Guidelines for the management of arterial hypertension: the Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). Eur Heart J. 2013;34:2159‐2219. [DOI] [PubMed] [Google Scholar]
  • 14. Marre M, Puig JG, Kokot F, et al. Equivalence of indapamide SR and enalapril on microalbuminuria reduction in hypertensive patients with type 2 diabetes: the NESTOR* study. J Hypertens. 2004;22:1613‐1622. [DOI] [PubMed] [Google Scholar]
  • 15. Puig JG, Marre M, Kokot F, et al. Efficacy of indapamide SR compared with enalapril in elderly hypertensive patients with type 2 diabetes. Am J Hypertens. 2007;20:90‐97. [DOI] [PubMed] [Google Scholar]
  • 16. Hanon O, Boully C, Caillard L, et al. Treatment of hypertensive patients with diabetes and microalbuminuria with combination indapamide SR/amlodipine: retrospective analysis of NESTOR. Am J Hypertens. 2015;28:1064‐1071. [DOI] [PubMed] [Google Scholar]
  • 17. The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group . Major outcomes in high‐risk hypertensive patients randomized to angiotensin‐converting enzyme inhibitor or calcium channel blocker vs diuretic: the antihypertensive and lipid‐lowering treatment to prevent heart attack trial (ALLHAT). JAMA. 2002;288:2981‐2997. [DOI] [PubMed] [Google Scholar]
  • 18. Morgan TO, Anderson AI, MacInnis RJ. ACE inhibitors, beta‐blockers, calcium blockers, and diuretics for the control of systolic hypertension. Am J Hypertens. 2001;14:241‐247. [DOI] [PubMed] [Google Scholar]
  • 19. Kario K, Hoshide S. Age‐related difference in the sleep pressure‐lowering effect between an angiotensin II receptor blocker and a calcium channel blocker in Asian hypertensives: the ACS1 Study. Hypertension. 2015;65:729‐735. [DOI] [PubMed] [Google Scholar]
  • 20. Weinberger MH. Salt sensitivity of blood pressure in humans. Hypertension. 1996;27:481‐490. [DOI] [PubMed] [Google Scholar]
  • 21. Waeber B, Rotaru C, Feihl F. Position of indapamide, a diuretic with vasorelaxant activities, in antihypertensive therapy. Expert Opin Pharmacother. 2012;13:1515‐1526. [DOI] [PubMed] [Google Scholar]
  • 22. Carter AJ, Gardiner DG, Burges RA. Natriuretic activity of amlodipine, diltiazem, and nitrendipine in saline‐loaded anesthetized dogs. J Cardiovasc Pharmacol. 1988;12(suppl 7):S34‐S38. [DOI] [PubMed] [Google Scholar]
  • 23. Cappuccio FP, Markandu ND, Sagnella GA, et al. Effects of amlodipine on urinary sodium excretion, renin‐angiotensin‐aldosterone system, atrial natriuretic peptide and blood pressure in essential hypertension. J Hum Hypertens. 1991;5:115‐119. [PubMed] [Google Scholar]
  • 24. Emeriau JP, Knauf H, Pujadas JO, et al. A comparison of indapamide SR 1.5 mg with both amlodipine 5 mg and hydrochlorothiazide 25 mg in elderly hypertensive patients: a randomized double‐blind controlled study. J Hypertens. 2001;19:343‐350. [DOI] [PubMed] [Google Scholar]
  • 25. Leonetti G, Emeriau JP, Knauf H, et al. Evaluation of long‐term efficacy and acceptability of indapamide SR in elderly hypertensive patients. Curr Med Res Opin. 2005;21:37‐46. [DOI] [PubMed] [Google Scholar]
  • 26. Ninomiya T, Zoungas S, Neal B, et al. Efficacy and safety of routine blood pressure lowering in older patients with diabetes: results from the ADVANCE trial. J Hypertens. 2010;28:1141‐1149. [PubMed] [Google Scholar]
  • 27. Weidmann P. Metabolic profile of indapamide sustained‐release in patients with hypertension: data from three randomised double‐blind studies. Drug Saf. 2001;24:1155‐1165. [DOI] [PubMed] [Google Scholar]
  • 28. Hanon O, Seux ML, Lenoir H, et al. Diuretics for cardiovascular prevention in the elderly. J Hum Hypertens. 2004;18(suppl 2):S15‐S22. [DOI] [PubMed] [Google Scholar]
  • 29. Chen P, Chaugai S, Zhao F, Wang DW. Cardioprotective effect of thiazide‐like diuretics: a meta‐analysis. Am J Hypertens. 2015;28:1453‐1463. [DOI] [PubMed] [Google Scholar]
  • 30. Fleg JL, Evans GW, Margolis KL, et al. Orthostatic hypotension in the ACCORD (Action to Control Cardiovascular Risk in Diabetes) blood pressure trial: prevalence, incidence, and prognostic significance. Hypertension. 2016;68:888‐895. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31. Peters R, Beckett N, Burch L, et al. The effect of treatment based on a diuretic (indapamide) +/− ACE inhibitor (perindopril) on fractures in the Hypertension in the Very Elderly Trial (HYVET). Age Ageing. 2010;39:609‐616. [DOI] [PubMed] [Google Scholar]
  • 32. Jones G, Nguyen T, Sambrook PN, Eisman JA. Thiazide diuretics and fractures: can meta‐analysis help? J Bone Miner Res. 1995;10:106‐111. [DOI] [PubMed] [Google Scholar]
  • 33. Wiens M, Etminan M, Gill SS, Takkouche B. Effects of antihypertensive drug treatments on fracture outcomes: a meta‐analysis of observational studies. J Intern Med. 2006;260:350‐362. [DOI] [PubMed] [Google Scholar]
  • 34. Wright JT Jr, Fine LJ, Lackland DT, Ogedegbe G, Dennison Himmelfarb CR. Evidence supporting a systolic blood pressure goal of less than 150 mm Hg in patients aged 60 years or older: the minority view. Ann Intern Med. 2014;160:499‐503. [DOI] [PubMed] [Google Scholar]
  • 35. Williamson JD, Supiano MA, Applegate WB, et al. Intensive vs standard blood pressure control and cardiovascular disease outcomes in adults aged ≥75 years: a randomized clinical trial. JAMA. 2016;315:2673‐2682. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36. Bavishi C, Bangalore S, Messerli FH. Outcomes of intensive blood pressure lowering in older hypertensive patients. J Am Coll Cardiol. 2017;69:486‐493. [DOI] [PubMed] [Google Scholar]
  • 37. National Institute for Health and Clinical Excellence . Hypertension in adults: diagnosis and management. http://nice.org.uk/guidance/cg127. Published: August 24, 2011. Accessed May 9, 2017.
  • 38. Rimoldi SF, Messerli FH, Chavez P, Stefanini GG, Scherrer U. Efficacy and safety of calcium channel blocker/diuretics combination therapy in hypertensive patients: a meta‐analysis. J Clin Hypertens (Greenwich). 2015;17:193‐199. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 39. Jadhav U, Hiremath J, Namjoshi DJ, et al. Blood pressure control with a single‐pill combination of indapamide sustained‐release and amlodipine in patients with hypertension: the EFFICIENT study. PLoS ONE. 2014;9:e92955. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from The Journal of Clinical Hypertension are provided here courtesy of Wiley

RESOURCES