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2008 59: 230 originally published online 2 April 2008ANGIOLOGYKorantzopoulos and Gregory Giannoulis

Stavros Antonopoulos, Stelios Kokkoris, Styliani Gerakari, Sotirios Mikros, Thomas Nitsotolis, Despina Vikeli, PanagiotisEssential Hypertension

Comparison of Monotherapy Versus Combination Antihypertensive Therapy in Elderly Patients With  

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230

Comparison of Monotherapy Versus Combination Antihypertensive Therapy in Elderly Patients With Essential Hypertension

Stavros Antonopoulos, MD, PhD, Stelios Kokkoris, MD, Styliani Gerakari, MD,Sotirios Mikros, MD, Thomas Nitsotolis, MD, Despina Vikeli, MD,Panagiotis Korantzopoulos, MD, PhD, and Gregory Giannoulis, MD, PhD

values less than 140/90 mm Hg.3,4 Current recommen-dations about pharmacological therapy are mainlybased on the comparative benefits obtained by the var-ious classes of antihypertensive agents, such as diuret-ics, β-blockers, calcium channel blockers (CCB),angiotensin-converting enzyme inhibitors (ACE-i),angiotensin receptor blockers (ARB), and α-blockers.5-7

Although the majority of antihypertensive drugsadministered as monotherapy have similar overallefficacy, there is considerable variation in individualresponse indicating an alternative strategy of com-bining different antihypertensive agents to reachdesirable blood pressure targets. Effective combina-tion therapy consists of drugs with different modesof action to achieve an additive antihypertensiveeffect, as well as to mitigate the compensatory mech-anisms that limit the decrease in blood pressure.8,9

The effectiveness of combination therapy in theelderly population as first-line treatment has not beenwell examined. Thus, the aim of the present studywas to compare the efficacy of monotherapy versus

Arterial hypertension represents a major healthhazard associated with coronary heart disease,stroke, peripheral vascular disease, chronic

renal failure, and atherothrombosis.1 Solid evidencesuggests that blood pressure-lowering drugs exert ben-eficial effects on cardiovascular morbidity and mortal-ity. Population surveys in different countries indicatethat both systolic blood pressure (SBP) and diastolicblood pressure (DBP) thresholds are valuable tools forguidance of treatment.2 The primary goal of manage-ment of the hypertensive patient without diabetes mel-litus or renal impairment is to achieve blood pressure

Authors sought to compare the efficacy of monotherapyversus combination antihypertensive therapy in elderlypatients. Patients in this study, aged 65 to 85 years, weredivided into 4 groups and entered an 8-week treatmentperiod. First group: 22 patients, amlodipine 5 mg/dincreasing to 10 mg; second: 20 patients, eprosartan 600mg/d increasing to 600 mg twice a day; third: 21 patients,amlodipine 5 mg/d and indapamide 2.5 mg/d, increasingamlodipine to 10 mg/d; fourth: 23 patients, imidapril 10mg/d and indapamide 2.5 mg/d, imidapril doubled to 20mg/d. A greater drop in systolic and in diastolic bloodpressure was obtained by combination of amlodipine and

indapamide compared with amlodipine or eprosartanmonotherapy. Imidapril and indapamide showed similarefficacy compared with eprosartan monotherapy but notwith amlodipine monotherapy. Amlodipine and inda-pamide appeared more effective than imidapril andindapamide in diastolic blood pressure. Combinationtreatment with amlodipine and indapamide or imidapriland indapamide effectively reduces blood pressure in eld-erly patients with essential hypertension.

Keywords: hypertension; antihypertensive drugs; eld-erly; amlodipine; eprosartan; indapamide; imidapril

From the 2nd Department of Internal Medicine, Tzanio GeneralHospital of Piraeus, Athens (SA, SK, SG, SM, TN, DV, GG),and Department of Cardiology, G.Hatzikosta General Hospitalof Ioannina, Ioannina (PK), Greece.

Address correspondence to: Panagiotis Korantzopoulos, MD, PhD,Department of Cardiology, G. Hatzikosta General Hospital ofIoannina, Ioannina 45001, Greece; e-mail: pan-kor@mailbox.gr.,p.korantzopoulos@yahoo.gr

AngiologyVolume 59 Number 2

April/May 2008 230-235© 2008 Sage Publications

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Antihypertensive Therapy in the Elderly / Antonopoulos et al 231

combination antihypertensive therapy in elderlypatients with essential hypertension. Second, wesought to examine potential differences in the safetyprofile of each regimen.

Patients and Methods

Study Population

This randomized, 4-parallel group study was conductedin our outpatient Hypertension Unit between October2003 and December 2004. Outpatients of both sexes,aged 65 to 85 years with uncomplicated mild to mod-erate essential hypertension, were eligible for inclusionin the study. Essential hypertension was defined as fol-lows: supine DBP greater than 95 mm Hg but less than114 mm Hg and/or supine SBP greater than 160 mmHg but less than 210 mm Hg.10,11

Patients were excluded if they had secondaryhypertension, including renovascular hypertension, orcomplicated hypertension associated with coronaryartery disease, congestive heart failure (New York HeartAssociation functional class II-IV), or grade IVretinopathy. Other exclusion criteria were history ofventricular arrhythmia, significant prolongation of QTinterval on the electrocardiogram, renal failure (creati-nine level > 16.9 mg/L), liver disease (aspartate amino-transferase or alanine aminotransferase > 3 × uppernormal limit), diabetes mellitus (type 1 or 2 requiringtreatment with insulin or hypoglycemic agents), obesity(body mass index (BMI) > 30 kg/m2, hypercholes-terolemia, or any severe disease likely to interfere withthe conduct of the study. Baseline plasma potassium,creatinine, uric acid, glucose, total cholesterol, andhepatic enzymes were within the normal range. Patientswho mentioned an adverse effect after previous admin-istration of the examined agent were also excluded. Noother antihypertensive drug or treatment was permittedduring the study period, and all previously taken med-ications were discontinued at enrollment before the 15-day washout period.

In addition, all patients entered the study wereinstructed to follow a healthy diet (DASH eating plan—Dietary Approaches to Stop Hypertension), as well as toadopt lifestyle modification measures, such as regularexercise, weight reduction, sodium restriction, andavoidance of heavy alcohol drinking.12 The protocol wasapproved by the local ethics committee, and all patientsprovided written informed consent before enrolment.

Study Protocol

Following a 15-day washout period, the patientsentered an 8-week active treatment period and wererandomly divided into 4 groups. The first group con-sisted of 22 patients (mean age = 73.7 years; meanBMI = 27.7 kg/m2) who received amlodipine 5 mgonce daily (od) that was increased to 10 mg after thefirst 4 weeks. The second group consisted of 20patients of mean age 72.2 years and mean BMI 27.5kg/m2 who received eprosartan 600 mg/d for the first 4weeks that was increased to 600 mg twice a day there-after. The third group consisted of 21 patients of meanage 72.7 years and mean BMI 27.6 kg/m2 whoreceived amlodipine 5 mg/d and indapamide 2.5 mg/dfor the first 4 weeks and amlodipine 10 mg/d in com-bination with a fixed dose of indapamide 2.5 mg/d forthe next 4 weeks. Finally, the fourth group consisted of23 patients of mean age 71.5 years and mean BMI of27.7 kg/m2 who received imidapril 10 mg/d in combi-nation with indapamide 2.5 mg/d; however, the dose ofthe former was doubled after the first 4 weeks.

The primary objective of the study was to evaluatethe relative antihypertensive efficacy of the aforemen-tioned antihypertensive regimens; 2 consisting of singleagents (amlodipine 5 mg or 10 mg, eprosartan 600 mgor 1200 mg), and 2 consisting of combinations of 2agents (amlodipine 5 mg/10 mg od and indapamide 2.5mg od or imidapril 10 mg/20 mg od and indapamide2.5 mg od); in elderly hypertensive patients. The sec-ondary aim of our study was to evaluate the safety pro-file of each regimen.

The criteria of response to treatment weredefined as follows. Supine SBP (sSBP) < 140 mmHg and supine DBP (sDBP) < 90 mm Hg and/or adecrease in sDBP > 10 mm Hg and/or a decrease insSBP > 20 mm Hg.

All blood pressure measurements were performedas follows. In brief, after 5-minute rest, 3 consecutivemeasurements were taken and the third was consid-ered for evaluation. The same process was used for thefollow-up monitoring. The systolic value correspondedto phase 1 and the diastolic value to phase 5 of theKorotkoff sounds. Measurements were performed bythe same investigator on the same arm.13 Blood pres-sure measurements were recorded at baseline, as wellas at the follow-up visits on weeks 4 and 8.

The patients were instructed to contact our outpa-tient clinic whenever they had symptoms sugges-tive of an adverse drug reaction. In addition, a

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232 Angiology / Vol. 59, No. 2, April/May 2008

detailed history regarding adverse effects was obtained,and complete blood and urine examinations were per-formed during the follow-up visits.

Statistical Analysis

The statistical analysis was performed using 1-wayanalysis of variance (ANOVA) after the fundamentalrequirements concerning the distributions withinthe groups were satisfied, namely, all groups fol-lowed the normal distribution, as revealed by MonteCarlo–enhanced Kolmogorov-Smirnof nonparamet-ric procedure. Levene’s test for equal variances wasperformed before every execution of ANOVA proce-dure. Post hoc analysis of multiple comparisons wasperformed using the Tuckey, Scheffe, Bonferroni,and least significant difference methods. A P valueless than .05 was considered statistically significant.

Results

The final study population consisted of 86 patients.The baseline clinical and demographic characteristicsof patients are shown in Table 1. At baseline condi-tions, the 4 groups did not differ in terms of age, sex,and BMI. No patient was lost during follow-up. Thepercentage of patients who reached the target bloodpressure in each group at week 4 and week 8 was:group 1, 22.7% and 40.9%; group 2, 47.6% and 80.9%;group 3, 25% and 40%; group 4, 39.1% and 69.5%,respectively.

Comparison of the effectiveness of each regimen atthe end of the fourth week revealed no statistically

significant decrease in either DBP or SBP among the4 groups (F test statistic = 1.733, P = .167 for SBP andF test statistic = 1.388, P = .252 for DBP), with theexception of amlodipine 5 mg and indapamide 2.5 mg combination, which decreased more effi-ciently the SBP compared with eprosartan 600 mgmonotherapy by a mean of 5.70 mm Hg (weaklysignificant, P = .025).

However, on week 8, there was a clear differencein the efficacy of each of the 4 treatments (Levene’stest for equal variances gave P = .550 for SBP and P =.333 for DBP) (Tables 2 and3). The F test statisticswere 5.979 (P = .001) for SBP and 7.313 (P < .001)for DBP. Post hoc analysis of multiple comparisonsdisclosed that on week 8, the combination of theamlodipine 10 mg and indapamide 2.5 mg achieved agreater drop in SBP, as well as in DBP, compared witheither amlodipine 10 mg or eprosartan 1200 mgmonotherapy (P < .027 and P < .001, respectively).Similarly, the combination of imidapril 20 mg andindapamide 2.5 mg showed greater efficacy comparedwith eprosartan 1200 mg monotherapy (P = .003, onlyfor SBP) but not compared with amlodipine 10 mgmonotherapy. The combination of amlodipine 10 mgand indapamide 2.5 mg appeared to be more effectivethan the combination of imidapril 20 mg and inda-pamide 2.5 mg only in DBP reduction (P = .002).

Furthermore, in terms of safety, the combinationregimens showed acceptable and comparable tolera-bility. No adverse events or allergic reactions werereported during the 8-week period of treatment inany of the study groups. In addition, there were noclinically significant changes in hematological orbiochemical parameters.

Table 1. Baseline Characteristics of the Participants

Mean SBP Mean DBP Before Before

Mean Mean BMI ± Treatment TreatmentGroups N age (Yr) SD (Kg/m2) (mm Hg) (mm Hg)

Amlodipine 5 mg → Amlodipine 10 mg 22 73.73 27.773 ± 1.31 162.86 93.68Eprosartan 600 mg od → Eprosartan 20 72.20 27.550 ± 2.11 164.00 93.85

600 mg twice a dayAmlodipine 5 mg + Indapamide 2.5 mg → 21 72.70 27.6 ± 1.82 162.67 93.71

Amlodipine 10mg + Indapamide 2.5 mgImidapril 10 mg + Indapamide 2.5 mg → 23 71.5 27.7 ± 2.0 164.04 94.217

Imidapril 20 mg + Indapamide 2.5 mg

NOTE: BMI = body mass index; SD = standard deviation; SBP = systolic blood pressure; DBP = diastolic blood pressure; od = oncedaily.

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Antihypertensive Therapy in the Elderly / Antonopoulos et al 233

Discussion

The present randomized study supports the efficacyof combination antihypertensive therapy in elderlyhypertensive patients. We sought to examine theefficacy and safety of an 8-week treatment of essen-tial hypertension using different classes of antihy-pertensive agents.

In terms of efficacy, the superiority of combinationtreatment was verified. Our results showed that com-bination treatment not only achieved greater decline

in SBP and DBP but also resulted in higher proportionof patients reaching the target blood pressure of140/90 mm Hg. It became evident that treatment witha CCB (amlodipine 10 mg) or an ACE-i (imidapril 20mg), each combined with a diuretic (indapamide 2.5mg), is clearly more effective than an ARB (eprosartan1200 mg) or a CCB (amlodipine 10 mg) monotherapy.Our study showed that the combination of dihydropy-ridine CCB (amlodipine) and diuretic (indapamide)was slightly more effective compared with the combi-nation of ACE-i (imidapril) and diuretic (indapamide).

Table 2. Mean Difference of SBP on Week 8 Among the 4 Groups

SBP drop (drug2-drug1): F = 5.979 (P = .001)

Mean Difference on Week

Week 8 (mm Hg) Scheffé Bonferroni Tuckey LSD

Amlodipine1 vs Eprosartan2 −3.57 −9.52, 2.37 (.406) −9.20, 2.06 (.540) −9.03, 1.89 (.322) −7.72, .57 (.090)Amlodipine1 vs Amlodipine + 4.82a −1.05, 10.69 (.148) −.74, 10.38 (.129) −.57, 10.22 (.096) .73, 8.91 (.021)

Indapamide2

Amlodipine1 vs Imidapril + 2.73 −3.01, 8.47 (.608) −2.71, 8.16 (1.000) −2.54, 8.00 (.530) −1.27, 6.73 (.179)Indapamide2

Eprosartan1 vs Amlodipine + 8.40 a 2.38, 14.41 (.002) 2.70, 14.09 (.001) 2.87, 13.92 (.001) 4.21, 12.59 (.000)Indapamide2

Eprosartan1 vs Imidapril + 6.30 a .42, 12.18 (.031) .73, 11.87 (.018) .89, 11.71 (.016) −2.20, 10.40 (.003)Indapamide2

Amlodipine + Indapamide1 vs –2.10 −7.90, 3.71 (0.787) −7.60, 3.41 (1.000) −7.43, 3.24 (.733) −6.14, 1.95 (.306)Imidapril + Indapamide2

NOTE: SBP = systolic blood pressure; CI = confidence interval; LSD = least significant difference.aStatistically significant difference.

CI for Difference (P value)

Table 3. Mean Difference of DBP on Week 8 Among the 4 Groups

DBP drop (drug2-drug1): F = 7.313 (P < .001)

Mean Difference on Week 8

Week 8 (mmHg) Scheffé Bonferroni Tuckey LSD

Amlodipine1 vs Eprosartan2 −.34 −3.65, 2.97 (.994) −3.47, 2.80 (1.000) −3.38, 2.70 (.991) −2.64, 1.97 (.773)Amlodipine1 vs Amlodipine + 4.51a 1.24, 7.78 (.003) 1.41, 7.60 (.001) 1.50, 7.51 (.001) 2.23, 6.78 (.000)

Indapamide2

Amlodipine1 vs Imidapril 1 + .972 −2.22, 4.17 (.860) −2.05, 4.00 (1.000) −1.96, 3.91 (.821) −1.25, 3.20 (.388)Indapamide2

Eprosartan1 vs Amlodipine + 4.84 a 1.50, 8.19 (.001) 1.67, 8.01 (.001) 1.77, 7.92 (.000) 2.51, 7.18 (.000)Indapamide2

Eprosartan1 vs Imidapril + 1.31 −1.97, 4.58 (.730) −1.79, 4.41 (1.000) −1.70, 4.32 (.666) −.97, 3.59 (.257)Indapamide 22

Amlodipine + Indapamide1 vs –3.53 a −6.77, −.30 (0.026) −6.60, -.47 (.015) −6.51, −.56 (.013) −5.79, −1.28 (.003)Imidapril + Indapamide2

NOTE: CI = confidence interval; DBP = diastolic blood pressure; LSD = least significant difference.aStatistically significant difference.

CI for Difference (P value)

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However, both combinations seemed to be superior tomonotherapies.

In more than two thirds of individuals, hyperten-sion cannot be controlled with 1 drug and will require2 or more antihypertensive agents selected from differ-ent drug classes.14-18 The evidence for recommendingcombination therapy, especially with CCBs and diuret-ics, in older patients is derived mainly from the antihy-pertensive and lipid-lowering treatment to preventheart attack trial study, in which 60% of those whoseblood pressure was controlled to <140/90 mm Hgreceived 2 or more agents, and overall, only 30% ofpatients were controlled with only 1 drug.14 This obser-vation supports the JNC 7 (Joint National Committeeon Prevention, Detection, Evaluation and Treatment ofhigh blood pressure) option that combination antihy-pertensive treatment in elderly persons represents anew therapeutic approach that confers cardiovasculardisease benefits beyond their blood pressure loweringeffects.19 In hypertensive patients with even lowerblood pressure goals, such as those with diabetes mel-litus or with substantially elevated blood pressure, 2 ormore antihypertensive drugs may be required.19

Another major study in favor of a fixed dose combina-tion antihypertensive therapy is the inclusive study,which assessed the efficacy and safety of an ARB (irbe-sartan) and a thiazide-type diuretic (hydrochloro-thiazide) in adults with uncontrolled blood pressure onantihypertensive monotherapy.20 Moreover, the lowdose combination therapy with perindopril (ACE-i) andindapamide showed greater efficacy than irbesartan,21

atenolol,22 and losartan23 monotherapy. Although ourpatients were followed up for a shorter time period, ourresults suggest efficacy at least as great as that seenwith regimens used in the aforementioned trials.

Conclusion

Our study indicated that combination treatment ofamlodipine 10 mg/indapamide 2.5 mg or imidapril 20mg/indapamide 2.5 mg effectively reduces blood pres-sure in elderly patients with essential hypertension.These observations support the practice of combina-tion therapy over other first-line antihypertensive treat-ments, such as ARBs, ACE-i, and CCB monotherapy.Of note, the aforementioned combination regimenshave an acceptable safety profile. Furthermore, ourfindings reinforce the official recommendations of JNC7 for the use of fixed low-dose combinations as a first-line, as well as maintenance treatment in essentialhypertension.19

However, larger studies of longer duration arenecessary to investigate the most effective combina-tion drug treatment for older individuals to accom-plish favorable blood pressure control, as well as toreduce stroke and cardiac events and to have bene-ficial effects on overall mortality rates.

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