High Blood Press Cardiovasc Prev 2008; 15 (4): 275-282ORIGINAL RESEARCH ARTICLE 1120-9879/08/0004-0275/$48.00/0

© 2008 Adis Data Information BV. All rights reserved.

Efficacy and Acceptability of IndapamideSustained Release in Elderly High-RiskHypertensive Patientsthe ARGUS Study

Zhanna D. Kobalava, Yulia V. Kotovskaya and Valentin S. Moiseev, on behalf of the ARGUS Investigators

Russian People’s Friendship University, Moscow, Russia

Objective: To assess the efficacy and acceptability of indapamide sustained-release (SR) monotherapy inAbstractelderly high-risk patients with moderate to severe hypertension.Methods: 1277 hypertensive patients older than 55 years with moderate to severe hypertension, including 91%with systolic blood pressure (SBP) >160 mmHg and at least one cardiovascular risk factor (age >65 years, male,diabetes mellitus, coronary heart disease [CHD], cerebrovascular disease, dyslipidaemia, obesity, smoking) wereenrolled in this observational study. They received indapamide SR 1.5 mg, one tablet daily, for 3 months. Bloodpressure (BP) was assessed monthly by sphygmomanometer. Statistical analyses were performed using the χ2

test, analysis of variance, and the Newman-Keuls test.Results: After 3 months of treatment with indapamide SR, SBP had decreased by 34 ± 3 mmHg and diastolic BP(DBP) by 12 ± 6 mmHg (both p < 0.001). Ninety-two percent of patients responded to therapy (SBP/DBPreduction >20/10 mmHg) and 52% were normalized (SBP <140 mmHg and DBP <90 mmHg). BP targets werereached in 48% of patients older than 65 years, 31% of diabetic patients, and 33% of patients with CHD. Therewere no changes in serum creatinine, glucose or lipid parameters, and 3% of patients had hypokalaemia(<3.5 mmol/L). The patients self-assessment scores regarding general state of health improved and 34% ofpatients reported ‘excellent’ health after treatment.Conclusions: In the high-risk patients of the ARGUS study, monotherapy with indapamide SR showedantihypertensive efficacy with good acceptability and no changes in metabolic parameters over a 3-monthperiod. Indapamide SR monotherapy normalized BP in half of the patients treated and proved an appropriatefirst-line treatment in hypertensive patients older than 55 years with added cardiovascular risk factors.

Received for publication 22 September 2008; accepted for publication 4 November 2008.Key words: hypertension, risk factors, indapamide sustained release, daily practice, elderly.

High blood pressure (BP) correlates with increased cardio- older than 55 years with added risk factors remains an unmetmedical need.vascular (CV) morbidity and mortality. The probability of CV

Thiazide diuretics are recommended by international guidelinesoutcome is determined not only by BP itself, but also by theas being particularly useful for treating high-risk hypertensive

presence or absence of concomitant risk factors, such as hypercho-patients.[1-4] These recommendations are based on data from nu-

lesterolaemia, diabetes mellitus and history of stroke.[1-4] Despite merous multicentre, controlled, randomized trials,[5-9] which havethe armamentarium of antihypertensive drugs available, achieving convincingly demonstrated that the treatment of hypertensionadequate BP control in daily practice in hypertensive patients significantly reduces cardiovascular, cerebrovascular, and corona-

276 Kobalava et al.

ry morbidity and mortality. Moreover, these studies confirm that Materials and Methodsthiazide diuretics and calcium antagonists are useful for the first-

line treatment of hypertension in the elderly.[10] Indapamide, a Study Design

thiazide-like diuretic, has been available for many years in aThis observational, multicentre, open-label, non-comparative

2.5-mg immediate-release formulation. In order to allow the samestudy of efficacy and acceptability of indapamide SR was carried

antihypertensive efficacy with a smoother pharmacokinetic pro-out with the participation of 140 outpatient physicians from 14

file, a sustained-release (SR) formulation was developed.[11,12] The regional centres in Russia. The study protocol was approved by annew formulation avoids unnecessary plasma peak concentrations Ethics Committee.and is associated with less hypokalaemia than the old formula- After giving their written informed consent, patients visited

their physicians monthly for 3 months. At each visit, the patientstion.[13,14] Indapamide SR is an effective antihypertensive drug,were provided with printed information to educate them aboutwhich has been proven to protect two of the main target organs ofhypertension and current strategies of hypertensive treatment,high BP: the heart, through the regression of left ventricularincluding nonpharmacological interventions, such as a low-salthypertrophy;[15] and the kidney, by decreasing microalbumin-diet.

uria.[16]

At the selection visit, all antihypertensive therapy was discon-While indapamide SR has been shown to be suitable for high- tinued, so all patients were free of any hypertensive treatment for

risk hypertensive patients,[16-19] there are, however, still some at least 1 week before starting indapamide SR. Patients receivedpoints requiring further investigation such as the acceptability monotherapy with indapamide SR, one tablet daily, in the morning

(from 8 am to 11 am) for 3 months.profile of indapamide SR in this specific population, the patient’s

perception of the treatment, and whether a monotherapy in dailyPatients

practice in an elderly high-risk hypertensive population allows

fulfilment of the BP goals. Men and women over 55 years of age with hypertensiondefined as systolic BP (SBP) 140–209 mmHg and diastolic BPThese issues were addressed in a Russian epidemiological(DBP) <115 mmHg (assessed by three consecutive measurementssurvey, which was designed to involve general practitioners andat least 1 minute apart) and at least one cardiovascular risk factor

thus promote the practical application of current treatment stan-or disease (age >65 years old, male gender, diabetes, dys-

dards in high-risk patients in daily practice. The survey revealedlipidaemia, obesity, cigarette smoking, CHD or cerebrovascular

that patients over 55 years of age were rarely treated with thiazide- disease) were selected. Exclusion criteria included serum creati-type diuretics. It evaluated physicians’ perceptions of hyperten- nine >150 μmol/L and albuminuria >1 g/dL.sion diagnosis and management in the elderly. Physicians’ habits

Assessment of Efficacyin the prescription of hypertensive drugs were also analysed. Only

56% of physicians questioned during the survey mentioned thia- The primary efficacy endpoint was the magnitude of SBP andzide-type diuretics as first-line treatment of hypertension in the DBP decrease over 3 months of indapamide SR monotherapyelderly and, in practice, only 41% of elderly hypertensive patients compared with baseline. The secondary efficacy endpoints wereactually received thiazide-type diuretics. The low prescription rate the percentage of patients who achieved target BP (normalization)

and who responded to therapy (responders).of thiazide-type diuretics has a negative impact on target BPNormalization of BP was defined as achieving a target SBPachievement.[20]

<140 mmHg and target DBP <90 mmHg (SBP <130/DBP <80The main aim of this ARGUS (Arterial hypeRtension in the

mmHg in diabetic patients). Subjects were classified as respondersGroUp of elder patientS) study was to assess the efficacy and

to the therapy if their SBP and DBP had decreased by ≥20/10acceptability of the thiazide-like indapamide SR, one tablet daily, mmHg from baseline, respectively, independently of whether thefor 3 months in high-risk hypertensive patients over 55 years of target BP was achieved. Patients with isolated systolic hyperten-age, the majority had one or more concomitant risk factors, such as sion (ISH) were considered as responders if their SBP had de-diabetes or CHD. creased by ≥20 mmHg.

© 2008 Adis Data Information BV. All rights reserved. High Blood Press Cardiovasc Prev 2008; 15 (4)

Indapamide Sustained Release in Elderly High-Risk Hypertensive Patients 277

BP was measured by sphygmomanometer three times at 1-min- baseline are presented in table I, which shows that 91% of patientsute intervals, after at least 5 minutes rest in the supine position. were classified as high risk.Heart rate was measured for 1 minute before every measurement

SBP in the range of 140–160 mmHg was found in 12% ofof BP.

patients, who were therefore excluded from the efficacy analysis

because of deviation from inclusion criteria, hence the efficacy ofAssessment of Acceptabilityindapamide SR was assessed in 1121 patients.

At each monthly visit, patients were questioned on the occur-Concomitant diseases were revealed in 1003 (89.5%) patients,

rence of adverse events, which were recorded and laboratory testsand 76% of patients had at least one concomitant condition. The

were performed. To evaluate the changes in the lipoprotein profile,most common concomitant diseases were CHD in 394 (35%)the artherogenic index is calculated according to the formula:patients, cerebrovascular disease in 374 (33%), joint disease inartherogenic index = total cholesterol/high-density lipoprotein-

cholesterol. 181 (16%), urogenital diseases in 147 (13%), chronic cholecysti-

tis/cholelithiasis in 105 (9%), diabetes in 102 (9%), and hypercho-Self-Assessment of Health Status lesterolaemia in 703 (55%). During the study, 33.5% of patients

received treatment for concomitant diseases, which remained un-The 1094 patients who completed the study self-assessed theirchanged. Among the patients included in the efficacy analysis, 890health status using the following 5-point scale: ‘worst ever’ = 1,

‘bad’ = 2, ‘good, but could be better’ = 3, ‘good’ = 4, ‘excellent’ = (79%) had received antihypertensive treatment during the year5. prior to inclusion (see details in table II).

Quality of life was assessed in 699 patients at inclusion and atthe end of treatment using a ‘Sickness Impact Profile’ question-naire.[21] Patients were asked to assess the severity of symptomsusing a 3-point scale: ‘no problems’ = 0, ‘some problems’ = 1,‘very severe problems’ = 2.

Statistical Analysis

The population for safety and acceptability analysis includedall patients enrolled in the study who took the study drug at leastonce and had at least one subsequent evaluation visit (n = 1277patients). The population for the efficacy analysis included pa-tients (n = 1121) who had SBP >160 mmHg and at least onecardiovascular risk factor.

Statistical data analysis was carried out using the computerprogram SPSS 8.0. Analysis of variance and Newman-Keuls testswere used for the comparison of quantitative parameters. Qualita-tive data were compared using the χ2 test (α = 5%).

Results

Baseline Characteristics of the Study Population

A total of 1277 patients, aged between 55–89 years of whom76% were women, were enrolled in the study. ISH was found in402 (31.5%) patients and previously untreated hypertension in 264(21%). The clinical and demographic patient characteristics at

Table I. Clinical and demographic patient characteristics at baseline (n =1277)

Parameter Value

Men/women (n) 303/974

Mean age (y) 65.8 ± 6.0

Duration of hypertension (y) 13.1 ± 7.4

Family history of hypertension [n (%)] 692 (54.1)

Baseline SBP (mmHg) 166.7 ± 8.6

Baseline DBP (mmHg) 91.8 ± 5.0

Baseline PP (mmHg) 76.3 ± 8.1

Baseline heart rate (beats/min) 73.4 ± 7.8

BMI (kg/m2) 29.2 ± 11.4

ISH [n (%)] 402 (31.5)

Newly diagnosed hypertension [n (%)] 39 (3.05)

Previously untreated hypertension [n (%)] 264 (20.7)

Risk of cardiovascular events [n (%)]

low 14 (1.1)

moderate 104 (8.1)

high 590 (46.2)

very high 569 (44.6)

Stage of hypertension [n (%)]

SBP 140–160 and DBP <100 mmHg [n (%)] 154 (12.1)

SBP 161–179 and DBP <110 mmHg [n (%)] 860 (67.3)

SBP 180–209 and/or DBP 110–114 mmHg [n (%)] 263 (20.6)

BMI = body mass index; DBP = diastolic blood pressure; ISH = isolatedsystolic hypertension; PP = pulse pressure; SBP = systolic blood pressure.

© 2008 Adis Data Information BV. All rights reserved. High Blood Press Cardiovasc Prev 2008; 15 (4)

278 Kobalava et al.

baseline, from 172.9 ± 13.1 to 139.4 ± 11.2 mmHg and from 91.7± 9.0 to 81.1 ± 8.8 mmHg, respectively (p < 0.001). The respectivedecreases in SBP, DBP and pulse pressure were of similar magni-tude in the different age groups (figure 2).

In this high-risk population of elderly patients (>65 years), thenormalization rate was 48% and 93.5%, hence indapamide SRefficacy in patients aged >65 years was similar to that in theoverall study population.

Efficacy of Indapamide SR in Patients with Type 2

Table II. Previous antihypertensive treatment (n = 850)

Class of drugs No. of patients Percentage

ACE inhibitors 436 49

β-Blockers 221 25

Calcium-channel blockers 189 21

Combined treatment 157 18

Fixed-dose drug combinations 112 13

Clonidine 59 7

Diuretics 32 4

Other 24 3

No data 8 1Diabetes Mellitus

Efficacy AnalysisThe study population included only 102 (9%) patients (mean

age 65.8 ± 5.4 years) with type 2 diabetes, which were treatedMean values of supine SBP, DBP and heart rate, and meanusing dietary measures and oral hypoglycaemic agents, and withchanges from baseline after 3 months of indapamide SR mono-no clinical and metabolic signs of diabetic nephropathy.therapy are shown in table III. A significant decrease in BP was

In this subgroup of patients with diabetes, the metabolic find-achieved after 1 month of treatment, and SBP and DBP hadings revealed that after 3 months of indapamide SR monotherapy,decreased by 17.9 ± 2.8 and 5.9 ± 2.4 mmHg from baseline,there were no significant changes in serum glucose levels or in therespectively. In all patients, the BP reduction increased fromother biochemical parameters shown in table IV. After 1 month ofmonth 1/month 2 to month 3, by which the respective decreases intreatment, a serum concentration of potassium <3.5 mmol/L wasSBP, DBP and pulse pressure were 34.2 ± 3.1, 12.0 ± 6.0 and 22.0recorded in 2.9% patients, and at the last visit in one patient± 12.4 (p < 0.001) [figure 1].(1.0%).Overall, there were no significant heart rate changes, nor in any

of the subgroups described in sections 2.3–2.5. After 3 months of therapy, SBP had decreased from 173.4 ± 8.5to 145.3 ± 15.6 mmHg (p < 0.001), and DBP from 93.2 ± 8.4 toNormalization of BP was observed in 59% of the patients who80.9 ± 14.7 mmHg (p < 0.001) [see figure 2].had an initial SBP 161–179 mmHg and DBP <110 mmHg, where-

as normalization of BP occurred in 23% of the patients who had aninitial SBP of 180–209 mmHg and/or DBP of 110–114 mmHg.

Overall, in this high-risk population after 3 months of therapywith indapamide SR, target levels of SBP and DBP were achievedin 51.8% of patients and a further 40.6% of patients responded tothe therapy. Thus, a positive effect over 3 months of indapamideSR monotherapy was achieved in the majority of patients (92%).

Efficacy of Indapamide Sustained Release (SR) in Patients

Aged Over 65 Years

The 556 (43.5%) patients aged over 65 years represent asubgroup at even higher risk of cardiovascular events, with 55% ofthis population classified in the very high-risk class versus 36%among the younger patients (p < 0.001). Also, the use of concomi-tant therapy was more prevalent (42% vs 25%, p < 0.0001) and thebaseline DBP (91.7 ± 9.0 vs 94.5 ± 8.2 mmHg, p < 0.0001) wassignificantly lower than in younger patients.

In this subgroup of patients older than 65 years, the SBP andDBP after 3 months of treatment were significantly lower than at

Table III. Changes in blood pressure and heart rate after 3 months oftreatment with indapamide sustained release

Parameter Baseline 3 mo of treatment(n = 1121) (n = 1094)

SBP (mmHg) 173.1 ± 10.2 138.7 ± 4.4a

Δ (mmHg) 34.2 ± 3.1

% 20.2 ± 2.0

DBP (mmHg) 93.1 ± 6.4 80.8 ± 3.2a

Δ (mmHg) 12.0 ± 6.0

% 13.2 ± 5.1

Pulse pressure (mmHg) 79.9 ± 6.6 57.9 ± 6.0a

Δ (mmHg) 22.0 ± 12.4

% 27.5 ± 14.2

Heart rate (bpm) 72.1 ± 8.0 68.7 ± 7.6

Δ (bmp) 2.2 ± 3.0

% 2.6 ± 3.0

a p < 0.001 vs baseline.

bpm = beats per minute; DBP = diastolic blood pressure; SBP = systolicblood pressure; Δ indicates change.

© 2008 Adis Data Information BV. All rights reserved. High Blood Press Cardiovasc Prev 2008; 15 (4)