A randomized, double-blind, active-controlled, parallel-group comparison of valsartan and amlodipine in the treatment of isolated systolic hypertension in elderly patients: The Val-Syst study

CLINICAL THERAPEUTICS® / VOL. 25, NO. 11, 2003

A Randomized, Double-Blind, Active-Controlled, Parallel-Group Comparison of Valsartan and Amlodipine in the Treatment of Isolated Systolic Hypertension in Elderly Patients: The Val-Syst Study Ettore Malacco, MD,1 Natale Varì, MD,2 Vincenzo Capuano, MD,3 Vitaliano Spagnuolo, MD,4 Carlo Borgnino, MD,5 and Paolo Palatini, MD,6 for the Val-Syst Investigators* 1Division

of Internal Medicine, Ospedale L. Sacco, University of Milan, Milan, Italy, of Cardiovascular Diseases, Vibo Valentia Hospital, Vibo Valentia, 3Cardiology Surgical Unit, G. Fucito Hospital, Mercato San Severino, 4Internal Medicine Surgical Unit, Annunziata Hospital, Cosenza, 5Department of Medicine, Novartis Farma S.p.A., Origgio, and 6Department of Clinical and Experimental Medicine, University of Padua, Padua, Italy 2Department

ABSTRACT

Background: Some antihypertensive therapies are limited by dose-dependent adverse effects (AEs). The angiotensin II receptor blocker valsartan has been shown to reduce blood pressure (BP) in a dose-related manner with minimal dose-limiting AEs. Amlodipine besylate is a potent dihydropyridine calcium channel blocker also with dose-related antihypertensive efficacy, but with possible dose-limiting AEs, particularly peripheral edema. Objectives: This study compared the risk/benefit profiles of valsartan and amlodipine in elderly patients who have isolated systolic hypertension (ISH). Methods: This 24-week, randomized, double-blind, active-controlled, titrationto-effect, parallel-group study was conducted at 35 outpatient centers in Italy. Elderly (aged 60–80 years) patients with ISH received oral treatment with valsartan 80-mg capsules or amlodipine 5-mg capsules once daily. After 8 weeks of treatment, the dose of the patients with poorly controlled systolic BP (SBP) was titrated to 160 mg (valsartan) or 10 mg (amlodipine) once daily. At week 16, if trough SBP was still not adequately controlled, a low-dose diuretic (hydrochlorothiazide [HCTZ] 12.5 mg) was added to the treatment regimen for an additional 8 weeks. Tolerability was assessed at all study visits using physical examination and patient interview. *The

Val-Syst Investigators are listed in the Acknowledgments.

Accepted for publication September 9, 2003. Printed in the USA. Reproduction in whole or part is not permitted. Copyright © 2003 Excerpta Medica, Inc.

0149-2918/03/$19.00

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Results: Of 421 randomized patients (231 women, 190 men; mean [SD] age, 69 [6] years), 208 were included in the valsartan group, and 213 in the amlodipine group. The efficacy of valsartan-based treatment in reducing SBP was similar to that of amlodipine-based treatment. With doubled doses, efficacy (change in SBP) increased significantly from baseline (both P < 0.01). The frequency of AEs doubled with amlodipine 10 mg but was not clinically relevant with valsartan 160 mg. Overall, AEs were observed in 31.9% of those receiving amlodipine versus 20.2% of the patients receiving valsartan (P < 0.003), with peripheral edema rates of 26.8% and 4.8%, respectively (P < 0.001). Conclusions: In this study population of elderly patients with ISH, valsartan— given alone or in combination with HCTZ 12.5 mg—showed similar efficacy but better tolerability than amlodipine-based treatment. (Clin Ther. 2003;25:2765– 2780) Copyright © 2003 Excerpta Medica, Inc. Key words: valsartan, amlodipine, hypertension, edema, side effects.

INTRODUCTION

Systolic blood pressure (SBP) is a strong predictor of cardiovascular morbidity and mortality.1,2 Encouraging long-term data from clinical trials strongly support the usefulness of aggressive antihypertensive treatment in elderly patients with high SBP (≥140 mm Hg).3 A meta-analysis3 of 8 studies of elderly patients with stage 2 (SBP 160–179 mm Hg) or higher isolated systolic hypertension (ISH) showed that treatment led to a 30% reduction in fatal and nonfatal cerebrovascular accident, a 26% reduction in fatal and nonfatal cardiovascular events, and a 13% reduction in total mortality. The latest World Health Organization–International Society of Hypertension Guidelines4 recommend monotherapy with diuretics or calcium channel blockers (CCBs) for the treatment of elderly patients with ISH. The established therapeutic goal in hypertensive patients is to reduce blood pressure (BP) to normotensive levels without affecting quality of life. In addition to lifestyle modifications (eg, reduced sodium, calorie, and alcohol intake; smoking cessation; and exercise), the optimal approach should include the use of drug(s) with minimal or no adverse effects (AEs). This is particularly important in elderly patients, in whom altered metabolism and an exaggerated drug sensitivity may modify the risk/benefit profile of the treatment. Given the lifelong nature of antihypertensive treatment, a drug that has better tolerability than another drug of similar efficacy can help increase treatment compliance and thus lead to the satisfactory control of BP in the long term. Regardless of drug choice, antihypertensive therapy in medical practice generally is started at a low dose, increased if BP response is inadequate, and then combined with a second drug if the increased dose fails to achieve the target BP. 2766

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BP is reduced to a similar extent by almost all first-line drugs when they are prescribed at pharmacologically comparable doses, but for some of these drugs, dose increases may be limited by the onset of dose-dependent AEs. The recently introduced class of angiotensin II receptor blockers (ARBs) has proved to be better tolerated than other leading classes of antihypertensive agents.5,6 Valsartan is a potent, highly selective angiotensin I–subtype ARB that has been shown to reduce BP in a dose-related manner at up to 320 mg with minimal dose-limiting AEs.6,7 We conducted a review of the English-language literature through a MEDLINE/PubMed search (key terms: diuretic, valsartan; years: 1997–2003). This review revealed that in 8 studies,8–14 patients who received the combination of valsartan 80 to 160 mg plus a diuretic (hydrochlorothiazide [HCTZ] 12.5 or 25 mg) had significantly greater reductions in SBP/diastolic BP (DBP) than patients who received monotherapy with either agent,8,9,15 with a tolerability profile that was similar to that of placebo.15 Amlodipine besylate is a potent dihydropyridine CCB that has long been established as a first-line treatment for hypertension. It has dose-related antihypertensive efficacy at doses up to 10 mg, but also possible dose-limiting AEs, particularly peripheral edema.16,17 The purpose of this study was to compare the risk/benefit profiles of valsartan and amlodipine in elderly patients with ISH. Similar antihypertensive efficacy was to be achieved with both drugs by means of a stepwise approach aimed at reaching a given BP goal (SBP <140 mm Hg), thus reflecting clinical practice. Given the particular population selected for the study, low-dose HCTZ 12.5 mg was considered a rational choice for the addition of a second drug in nonresponders. PATIENTS AND METHODS Patients

This 24-week, randomized, double-blind, active-controlled, titration-to-effect, parallel-group study was conducted at 35 outpatient centers in Italy. Patients aged 60 to 80 years with ISH (SBP 160–220 mm Hg and DBP <90 mm Hg after a 2week placebo washout period) were eligible to participate. The main exclusion criteria were evidence of orthostatic hypotension (a decrease in sitting SBP of ≥20 mm Hg and/or a decrease in sitting DBP of ≥10 mm Hg on standing) or malignant hypertension; a history of transient ischemic attack or cerebrovascular accident within the preceding 6 months; evidence of a secondary type of hypertension; overt heart failure or a history of heart failure; a history of myocardial infarction within the preceding 6 months; angina pectoris; clinically relevant arrhythmia; clinically significant valvular heart disease; evidence of hepatic disease; abnormal serum potassium level; evidence of renal impairment (serum creatinine level >1.5 times the upper limit of normal); type 1 2767

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diabetes mellitus; type 2 diabetes mellitus with poor glucose control (persistent fasting blood glucose >200 mg/dL) or peripheral neuropathy or autonomic neuropathy; and hypersensitivity to ARBs, angiotensin-converting enzyme inhibitors, thiazide diuretics, or dihydropyridine-type CCBs. The study was conducted in accordance with Good Clinical Practice guidelines and the Declaration of Helsinki, and the protocol was approved by the ethics committee at each institution. All patients provided written informed consent before entering the study. Methods

After the washout period, patients were randomized to receive oral treatment with either valsartan 80-mg capsules or amlodipine 5-mg capsules once daily. Randomization was centralized, and the treatments were stratified within each center. The allocation sequence was generated using a computerized list of random set numbers, and the drug containers were numbered to implement the random allocation sequence. Blinding of investigators and patients was maintained using identical capsules for all medications administered, which were supplied in identical bottles by the study sponsor. Trial drug codes were not available to the investigators or personnel involved in the monitoring of the trial until its completion and final data review. Efficacy Assessment

Study visits were scheduled at weeks 0, 4, 8, 12, 16, 20, and 24 of treatment. At each visit, participants underwent a complete physical examination. Just before dosing (8:00 AM–10:00 AM), sitting BP was measured 3 times using a standard sphygmomanometer. The mean of the 3 measurements was calculated. The patient’s arm in which the highest sitting SBP was found at baseline (week 0) was the arm used for all subsequent readings throughout the study. The same investigator obtained BP readings in individual patients at each visit at the same time of day and using the same equipment. Korotkoff’s phase 5 was used to define DBP, and the pulse pressure (SBP – DBP) was calculated. Heart rate (HR) was measured by the same investigator over 1 minute. BP and HR also were measured after the patients had been standing for 2 minutes. If adequate BP control (trough SBP <140 mm Hg) was not achieved after 8 weeks of treatment, the dose was doubled (to 160 mg valsartan or 10 mg amlodipine once daily). If trough SBP was still ≥140 mm Hg after an additional 8 weeks (ie, nonresponders), low-dose HCTZ (12.5 mg) was added for a final 8-week period (Figure 1). Patients were asked to take the trial medication(s) once a day at ~8:00 AM irrespective of meals, except on the days of the scheduled visits, when the trial medication(s) were administered in the investigator’s office after BP was measured. 2768

E. Malacco et al. V 160 mg + HCTZ 12.5 mg V 160 mg V 80 mg A 5 mg A 10 mg A 10 mg + HCTZ 12.5 mg Week

–2

0

4

8

12

16

20

24

N=

422

421

410

398

383

370

364

355

Figure 1. Study design. V = valsartan; A = amlodipine; HCTZ = hydrochlorothiazide.

Tolerability Assessment

Tolerability was assessed on the basis of the incidence of the most frequent AEs as listed in the product information18 of valsartan and amlodipine: headache, dizziness/vertigo, fatigue, cough, viral infection, upper respiratory tract infection, diarrhea, abdominal pain, nausea, peripheral edema, somnolence, flushing, and arrhythmia. The occurrence of any of these events was assessed at each visit by physical examination and by patient interview. Any new AE not present at the baseline visit was recorded, whereas medical conditions present at baseline that remained unchanged at subsequent visits were not considered AEs. The severity of an AE was defined using a qualitative assessment of its intensity as determined by the investigator or reported by the patient. The degree of peripheral edema (pedal, ankle, or pretibial) during the course of treatment was assessed at each visit by applying gentle pressure on the pretibial area to elicit skin indentation. The edema was considered mild if it was present on examination but the patient was not aware of it (asymptomatic); moderate if it was present on examination and the patient was aware of it (symptomatic) but it did not interfere with activities of daily living; or severe if it was present on examination, the patient was aware of it (symptomatic), and it interfered with activities of daily living. Routine laboratory tests and 12-lead electrocardiography (ECG) also were performed by an investigator for tolerability assessment at baseline and study end. Laboratory assessment was centralized (Centro Diagnostico Exacta, Verona, Italy) and included complete blood count, hemoglobin level, hematocrit, fasting serum glucose level, serum creatinine level, blood urea nitrogen, electrolytes, uric acid level, alanine and aspartate aminotransferase activities, total bilirubin level, and total and high-density lipoprotein cholesterol levels. The laboratory was certified ISO 9001:2000 by the Swiss Association for Quality and Management System, Zollinkofen, Switzerland. 2769

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Statistical Analysis

Two primary end points (one for efficacy and the other for tolerability) were considered jointly to assess (1) whether the therapeutic efficacy (sitting SBP) of the 2 regimens was similar and (2) whether the valsartan-based treatment was more tolerable than the amlodipine-based treatment. Because both end points had to be achieved, no correction of the overall significance level was required. The analysis of therapeutic similarity was run in the per-protocol (PP) data set and confirmed in the intent-to-treat (ITT) data set (all randomized patients who had a postbaseline SBP assessment). All ITT patients who completed the 24-week study without major protocol violations were included in the PP data set. The efficacy of the 2 treatments was considered similar if the 95% CI of the amlodipine/ valsartan difference excluded differences ≤5 mm Hg. Least-squares estimates of the changes from baseline and their variances were obtained with an analysis of covariance model, using the baseline values as covariates. Subsequently, the better tolerability of the valsartan-based treatment had to be demonstrated by comparing the rate of patients with AEs using the Mantel-Haenszel test and stratifying by center. All randomized patients were included in the tolerability analysis. All tests on secondary efficacy variables (sitting DBP and pulse pressure, HR, BP on standing) were run 2-sided at the 0.05 level of significance. The proportions of patients achieving a sitting SBP <140 mm Hg were calculated for both treatment groups. SAS version 8.0 (SAS Institute Inc., Cary, North Carolina) was used for statistical analysis. Sample Size Considerations

We hypothesized a common SD of the decrease in sitting SBP of 15 mm Hg and that the observed difference between amlodipine and valsartan would not exceed 2 mm Hg. The maximum nonclinically relevant between-treatment difference was set at 5 mm Hg. Assuming an estimated 5% of early withdrawals, ≥200 patients per group were needed for the 2-tailed 95% CI to extend 3 mm Hg from the observed between-treatment difference. This method is equivalent to testing for noninferiority assuming the equivalence of the 2 treatments and a nonclinically relevant between-treatment difference of 5 mm Hg with 94% power. The expected incidences of AEs were 17% and 30%, respectively, in the valsartan-based and amlodipine-based treatment groups. With ≥200 patients per group, a significant difference between the above rates of AEs at the 0.05 level of significance could be demonstrated with 86% power. Because all of the treated patients were considered for this analysis, no allowance for dropouts was needed. The overall power of the joint tests was slightly more than 80%. 2770

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RESULTS

Of 421 randomized patients (231 women, 190 men; mean [SD] age, 69 [6] years), 208 were assigned to the valsartan arm and 213 to the amlodipine arm. No statistically significant differences were observed in the baseline demographic and clinical characteristics of the 2 treatment groups. One hundred twenty-eight patients (61.5%) in the valsartan group and 134 patients (62.9%) in the amlodipine group had been treated with antihypertensive drugs before the study. Because 11 patients (2.6%) were lost to follow-up and did not undergo postbaseline efficacy assessment, 410 patients (97.4%; 204 [98.1%] in the valsartan group and 206 [96.7%] in the amlodipine group) were available for the ITT analysis. The study was completed by 355 patients (84.3%; 177 [85.1%] in the valsartan arm and 178 [83.6%] in the amlodipine arm). Thirty-one valsartan-treated patients (14.9%) and 35 amlodipine-treated patients (16.4%) withdrew from the study, most frequently because of AEs (11 [5.3%] and 14 [6.6%], respectively); other reasons were withdrawal of consent (11 [5.3%] and 13 [6.1%], respectively), loss to follow-up (4 [1.9%] and 4 [1.9%], respectively), unsatisfactory therapeutic effect (3 [1.4%] and 2 [0.9%], respectively), death (2 [1.0%] and 1 [0.5%], respectively), and abnormal laboratory results (1 receiving amlodipine [0.5%]). None of the deaths occurred during the initial washout period. Forty patients (9.5%; 18 [8.7%] in the valsartan group and 22 [10.3%] in the amlodipine group) had major protocol violations (baseline SBP <160 mm Hg, baseline DBP ≥90 mm Hg, or concomitant use of other antihypertensive drugs), and so 329 patients (78.1%; 166 [79.8%] and 163 [76.5%] in the valsartan and amlodipine groups, respectively) were available for the PP analysis. Primary End Points Sitting Systolic Blood Pressure

The mean sitting SBP was effectively reduced with both treatments throughout the study. The mean sitting BP values at baseline and the end of follow-up in the PP and ITT data sets are shown in Table I. The similarity of the 2 treatments according to our statistical assumptions on SBP can be seen in both data sets because the 2-sided 95% CIs were –2.21 to 2.13 (PP) and –4.01 to 0.94 (ITT), respectively. The mean (SD) changes in SBP/DBP from baseline were –30.7 (13.9)/–5.6 (6.1) mm Hg in the valsartan group and –32.2 (11.3)/–6.6 (6.1) mm Hg in the amlodipine group at week 16 (both P < 0.001 vs baseline) and, respectively, –33.4 (11.2)/–6.0 (6.0) mm Hg and –33.5 (10.0)/–6.5 (6.0) mm Hg at week 24 (both P < 0.001 vs baseline) (Figure 2). Tolerability

Table II summarizes the frequency of the AEs reported during the double-blind treatments. Patients reported ≥1 AE more frequently in the amlodipine group (68 patients [31.9%]) than in the valsartan group (42 patients [20.2%]) (P < 0.003). 2771

2772 –

≤90

≤140

–

≤90

≤140

85.6 (10.6) 85.8 (9.4)

83.8 (5.0) 84.1 (4.3)

169.4 (9.5) 169.9 (9.0)

86.2 (10.3) 86.0 (9.3)

83.6 (5.0) 83.8 (4.2)

169.8 (9.3) 169.8 (8.7)

Baseline, Mean (SD), mm Hg

60.7 (13.1) 60.1 (12.3)

78.6 (7.6) 78.0 (6.9)

139.3 (15.1) 138.0 (12.8)

58.8 (11.3) 59.1 (11.2)

77.6 (6.9) 77.2 (6.7)

136.4 (11.9) 136.3 (10.9)

Study End, Mean (SD), mm Hg†

PP = per protocol; ITT = intent-to-treat. *No significant between-treatment differences were found. †Week 24 (PP data set); week 24 or premature discontinuation (ITT data set).

ITT data set (valsartan, n = 204; amlodipine, n = 206) SBP Valsartan Amlodipine DBP Valsartan Amlodipine Pulse pressure Valsartan Amlodipine

PP data set (valsartan, n = 166; amlodipine, n = 163) SBP Valsartan Amlodipine DBP Valsartan Amlodipine Pulse pressure Valsartan Amlodipine

Data Set/Variable/Drug

Normal Value, mm Hg

–24.9 (0.77) –25.7 (0.77)

–5.3 (0.45) –6.1 (0.45)

–30.2 (0.89) –31.7 (0.89)

–27.4 (0.74) –27.0 (0.75)

–6.0 (0.46) –6.5 (0.46)

–33.4 (0.77) –33.5 (0.78)

Change from Baseline (Adjusted Mean [SEM])

–0.77

–0.78

–1.53

–0.41

–0.47

–0.04

Estimated Difference, Valsartan Versus Amlodipine (Adjusted)

–2.91 to 1.37

–2.04 to 0.48

–4.01 to 0.94

–1.66 to 2.48

–1.74 to 0.81

–2.21 to 2.13

95% CI

Table I. Sitting systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse pressure at baseline and at the end of the study.* CLINICAL THERAPEUTICS®

E. Malacco et al. Valsartan-based treatment Amlodipine-based treatment

SBP*

DBP†

Mean (SD) BP Decrease (mm Hg)

0

–10

–20

–30

–40

–50

Figure 2. Mean (SD) blood pressure (BP) decrease after 24 weeks of treatment in perprotocol efficacy analysis (valsartan, n = 166; amlodipine, n = 163). SBP = systolic BP; DBP = diastolic BP. *95% CI = –2.21 to 2.13. †95% CI = –1.74 to 0.81.

AEs were mainly mild or moderate. The most prevalent AE in both treatment arms combined, peripheral edema, occurred with greater frequency in the patients receiving amlodipine (57 patients [26.8%]) than in those receiving valsartan (10 patients [4.8%]) (P < 0.001). Only 5 patients (2.4%) receiving valsartan had moderate to severe symptomatic peripheral edema compared with 27 patients (12.7%) receiving amlodipine. Symptomatic treatment-emergent peripheral edema was experienced transiently in some patients and persistently (during all subsequent visits) in others. Three patients (1.4%) in the valsartan group had persistent treatment-emergent peripheral edema compared with 32 patients (15.0%) in the amlodipine group. None of the patients treated with valsartan withdrew due to peripheral edema, but 9 (4.2%) treated with amlodipine did. Twenty-four patients (11.5%) receiving valsartan and 37 patients (17.4%) receiving amlodipine reported >1 AE; this difference was not significant. A total of 25 patients (5.9%) withdrew from the study because of AEs (11 [5.3%] in the valsartan group and 14 [6.6%] in the amlodipine group). Gastrointestinal AEs (diarrhea, nausea, abdominal pain, esophageal pain, and vomiting) were the main reason for study withdrawal among the valsartan-treated pa2773

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Table II. No. (%) of patients experiencing ≥1 adverse effect (AE) and no. (%) of withdrawals due to AEs. Valsartan (n = 208)

AE Headache* Peripheral edema*† Viral infection* Diarrhea* Dizziness/vertigo* Nausea* Upper respiratory tract infection* Somnolence* Cough* Abdominal pain* Arrhythmia* Angina Asthenia Cerebral ischemia Dyspnea Esophageal pain Fatigue* Malaise Urinary tract neoplasm Vomiting Flushing* Erythema Total patients experiencing ≥1 AE Patients experiencing >1 AE Patients withdrawing due to AEs¶ Serious Treatment related *This

Patients with AE 11 10 7 6 5 5 3 3 2 2 2 1 1 1 1 1 1 1 1 1 0 0 42 24

(5.3) (4.8) (3.4) (2.9) (2.4) (2.4) (1.4) (1.4) (1.0) (1.0) (1.0) (0.5) (0.5) (0.5) (0.5) (0.5) (0.5) (0.5) (0.5) (0.5) (0.0) (0.0) (20.2) (11.5) – – –

Withdrawals Due to AE 3 0 1 2 2 1 0 0 1 0 2 1 1 1 1 1 0 1 1 1 0 0

(1.4) (0.0) (0.5) (1.0) (1.0) (0.5) (0.0) (0.0) (0.5) (0.0) (1.0) (0.5) (0.5) (0.5) (0.5) (0.5) (0.0) (0.5) (0.5) (0.5) (0.0) (0.0) – – 11 (5.3) 3 (1.4) 8 (3.8)

Amlodipine (n = 213) Patients with AE 4 57 10 1 4 0 5 2 3 2 0 2 2 0 0 0 0 0 0 0 5 1 68 37

(1.9) (26.8)‡ (4.7) (0.5) (1.9) (0.0)§ (2.3) (0.9) (1.4) (0.9) (0.0) (0.9) (0.9) (0.0) (0.0) (0.0) (0.0) (0.0) (0.0) (0.0) (2.3) (0.5) (31.9)㛳 (17.4) – – –

Withdrawals Due to AE 2 9 1 0 1 0 0 1 0 0 0 2 2 0 0 0 0 0 0 0 2 1

(0.9) (4.2) (0.5) (0.0) (0.5) (0.0) (0.0) (0.5) (0.0) (0.0) (0.0) (0.9) (0.9) (0.0) (0.0) (0.0) (0.0) (0.0) (0.0) (0.0) (0.9) (0.5) – – 14 (6.6) 2 (0.9) 10 (4.7)

AE was considered treatment related. AE was moderate to severe in 5 patients (2.4%) in the valsartan group and in 27 patients (12.7%) in the amlodipine group. It was persistent and treatment emergent in 3 patients (1.4%) in the valsartan group and 32 patients (15.0%) in the amlodipine group. ‡P < 0.001 versus valsartan group (chi-square test). §P = 0.029 versus valsartan group (Fisher exact test). 㛳P < 0.003 versus valsartan group (Mantel-Haenszel test). ¶Some patients withdrew due to >1 AE. †This

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tients (5 [2.4%]), whereas peripheral edema was the main reason among the amlodipine-treated patients (9 [4.2%]). No laboratory abnormalities were attributed to valsartan or amlodipine, and no significant ECG changes were found. Secondary End Points

The mean (SD) final pulse pressure in the valsartan group (PP data set) was 58.8 (11.3) mm Hg versus 59.1 (11.2) mm Hg in the amlodipine group; this difference was not significant. The mean HR did not change significantly with either treatment throughout the study (data not shown). Standing BP was effectively reduced from baseline by both drugs throughout the treatment period (both P < 0.01 at all time points), with no significant differences between the 2 regimens (data not shown). Other Assessments

SBP control (<140 mm Hg) was achieved by the end of the study in 124 patients (74.7%) treated with valsartan and 119 patients (73.0%) treated with amlodipine in the PP data set and in, respectively, 138 (67.6%) and 141 (68.4%) patients in the ITT data set; these differences were not significant. The design of the study allowed for an assessment of the risk/benefit profiles of the 2 drugs: (1) after the first 8-week period of monotherapy at the starting doses (valsartan 80 mg or amlodipine 5 mg); (2) after the second 8-week period of monotherapy with the doubled doses (valsartan 160 mg or amlodipine 10 mg) in the patients whose SBP had not normalized; and (3) after the third 8-week period when HCTZ was added in the nonresponders. During the study, the doses in 106 patients (51.0%) treated with valsartan and 93 (43.7%) treated with amlodipine were titrated to the higher level; HCTZ was added to the treatment regimen in 47 (22.6%) and 35 cases (16.4%), respectively; this difference was not significant (data not shown). With the starting dose, the mean (SD) changes in SBP versus baseline were –22.1 (15.4) mm Hg with valsartan 80 mg and –25.7 (13.3) mm Hg with amlodipine 5 mg, with AEs being reported by, respectively, 20 (9.6%) and 31 (14.6%) patients. In the patients who required doubled doses (mean [SD] SBP changes after the first 8-week period, –12.9 [12.9] mm Hg with valsartan 80 mg; –15.8 [10.2] mm Hg with amlodipine 5 mg), a comparable further decrease in sitting SBP was observed (–12.6 [13.4] mm Hg with valsartan 160 mg [P < 0.01]; –12.5 [12.1] mm Hg with amlodipine 10 mg [P < 0.01]), but the frequency of AEs in the patients treated with amlodipine 10 mg was 29.0% (27/93) (twice that observed with the 5-mg dose [P = 0.003]). On the contrary, the increase in the frequency of AEs observed with the increase in the valsartan dose from 80 mg (9.6% [20/208]) to 160 mg (11.3% [12/106]) was not clinically relevant. The addition of HCTZ led to a further reduction in mean (SD) SBP: –8.3 (11.7) mm Hg in the 2775

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valsartan-treated patients and –6.3 (10.2) mm Hg in the amlodipine-treated patients. New or worsening AEs occurred in, respectively, 8.5% (4/47) and 8.6% (3/35) of the patients. DISCUSSION

The primary objective of this study was to compare the risk/benefit ratio of valsartan-based antihypertensive treatment with that of amlodipine-based treatment in elderly patients with ISH. The results showed that valsartan-based treatment led to a similar reduction in SBP compared with amlodipine-based treatment, with a lower proportion of patients experiencing AEs. The lower incidence of peripheral edema observed in the valsartan group compared with the amlodipine group was observed at all of the titration steps. Furthermore, our data showed that valsartan had a further dose-related effect on BP when it was titrated from 80 to 160 mg once daily, without any worsening in tolerability, whereas the increased efficacy obtained by doubling the dose of amlodipine from 5 to 10 mg was accompanied by a doubling of the rate of AEs. This finding has important clinical implications: the absence of a doserelated increase in the incidence of AEs renders valsartan 160 mg more suitable for the treatment of ISH owing to its good risk/benefit profile. In the valsartan group, the addition of HCTZ led to a further clinically relevant reduction in SBP, which was slightly (but not statistically significantly) greater than that observed in the amlodipine-treated patients. This finding confirmed that the combination of valsartan with a diuretic is an optimal therapeutic choice in patients whose BP is not fully controlled by valsartan monotherapy. In the present study, we assessed elderly patients with ISH. However, it should be acknowledged that ISH is found in ~65% of all hypertensive conditions in the elderly.1 Thus, although our multiple exclusion criteria may limit the scope for extrapolation of our findings to all elderly hypertensive patients, the results were relevant to a large number of these patients. Four longitudinal studies,19–22 including the Hypertension Optimal Treatment (HOT) study,20 have shown that most hypertensive patients require combination therapy to achieve satisfactory BP control. However, despite this evidence, combination treatments are still underused in general practice. One study23 showed that ~39% of patients with uncontrolled BP are on monotherapy and that those receiving a 2- or 3-drug antihypertensive regimen do not receive a diuretic in 50% and 25% of cases, respectively. To improve antihypertensive treatment compliance and BP control in the general population, more attention should be paid to the risk/benefit ratio of the antihypertensive drugs; this ratio should drive physicians’ treatment decisions. At similar antihypertensive efficacy, the variable tolerability of different drugs should play a major role in determining physicians’ treatment choices, as toler2776

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ability can positively affect patients’ acceptance of treatment. Noncompliance is currently a major problem that hinders the successful management of hypertension,24–26 because most patients are unwilling to experience AEs for what they consider to be merely a preventive measure. Many classes of antihypertensive agents are associated with AEs that may interfere with a patient’s quality of life and therefore ultimately affect treatment adherence. Various additional factors seem to be associated with poor compliance, including sex, age, level of education, employment status, socioeconomic status,27 and drug cost,28 but the different antihypertensive drug classes have significant and varying effects on patient compliance. Two studies29,30 have shown that the proportion of patients continuing their initial antihypertensive treatment is higher when the treatment is ARB based. CONCLUSIONS

In this study population of elderly patients with ISH, valsartan—either alone or in combination with HCTZ 12.5 mg—showed similar efficacy but better tolerability than amlodipine-based treatment. Our study also showed that the 160-mg dose of valsartan was more effective than the 80-mg dose in this patient population, without increasing the rate of AEs. Finally, our data showed that the combination of valsartan 160 mg and HCTZ 12.5 mg was effective and generally well tolerated. ACKNOWLEDGMENTS

This study was sponsored by Novartis Farma S.p.A. (Origgio, Italy). C. Borgnino, MD, is an employee of Novartis Farma S.p.A. E. Malacco, MD, and P. Palatini, MD, held a paid consultancy with Novartis Farma S.p.A. at the time of the study. We are indebted to R. Ferrara, MSc, for the statistical analysis of the study data. The Val-Syst Investigators comprised the following: B. Stagni, Bologna; P. Belluardo, A. Circo, A. La Rosa, and L.S. Malatino, Catania; V. Spagnuolo and M. Sprovieri, Cosenza; A. Caiazza and G. Rastelli, Fidenza; R. De Cesaris, A. Di Taranto, I. Panettieri, and A.P. Tedesco, Foggia; C. Ferri and M. Stati, L’Aquila; C. Dell’Oro and F. Locatelli, Lecco; D. Panuccio and M.R. Trabatti, Loiano; G.P. Benetti and P. Granata, Melegnano; G. Aucello and V. Capuano, Mercato San Severino; N. Frisina and M. Pedullà, Messina; S. Landini and F. Scanferla, Mestre; M.R. Meroni and L. Scandiani, Milan; G. Cudemo and O. de Divitiis, Naples; M. Campanini and R. Paracchini, Novara; F. Dorigatti and P. Palatini, Padua; G. Cerasola, G. Mulè, I. Muratori, and S. Novo, Palermo; M. Carnovali and C. Vecchio, Passirana di Rho; R. Fogari and A. Mugellini, Pavia; V. Donadon and G. Zanette, Pordenone; E. Degli Esposti and A. Pasi, Ravenna; S. Di Somma and F. Ferranti, Rome; L. Mos and O. Vriz, S. Daniele del Friuli; L. Buonincontri and R. Nami, Siena; G. Gaudio and A. Schizzarotto, Somma Lombardo; R. Carretta, L. 2777

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Macaluso, C. Mazzone, and S. Scardi, Trieste; A.M. Grandi and A. Venco, Varese; G.B. Ambrosio and C. Leprotti, Venice; N. Varì, Vibo Valentia; R. Dell’Aquila and M.P. Rodighiero, Vicenza; and A. Mazzer and M. Santonastaso, Vittorio Veneto, Italy. REFERENCES 1. Kannel WB. Historic perspectives on the relative contributions of diastolic and systolic blood pressure elevation to cardiovascular risk profile. Am Heart J. 1999;138: 205–210. 2. Hozawa A, Ohkubo T, Nagai K, et al. Prognosis of isolated systolic and isolated diastolic hypertension as assessed by self-measurement of blood pressure at home: The Ohasama study. Arch Intern Med. 2000;160:3301–3306. 3. Staessen JA, Gasowski J, Wang JG, et al. Risks of untreated and treated isolated systolic hypertension in the elderly: Meta-analysis of outcome trials [published correction appears in Lancet. 2001;357:724]. Lancet. 2000;355:865–872. 4. Guidelines Subcommittee. 1999 World Health Organization–International Society of Hypertension Guidelines for the Management of Hypertension. J Hypertens. 1999;17:151– 183. 5. Black HR, Graff A, Shute D, et al. Valsartan, a new angiotensin II antagonist for the treatment of essential hypertension: Efficacy, tolerability and safety compared to an angiotensin-converting enzyme inhibitor, lisinopril. J Hum Hypertens. 1997;11:483– 489. 6. Oparil S, Dyke S, Harris F, et al. The efficacy and safety of valsartan compared with placebo in the treatment of patients with essential hypertension. Clin Ther. 1996;18:797– 810. 7. Maillard MP, Wurzner G, Nussberger J, et al. Comparative angiotensin II receptor blockade in healthy volunteers: The importance of dosing. Clin Pharmacol Ther. 2002; 71:68–76. 8. Palatini P, Malacco E, Di Somma S, et al. Trough:peak ratio and smoothness index in the evaluation of 24-h blood pressure control in hypertension: A comparative study between valsartan/hydrochlorothiazide combination and amlodipine. Eur J Clin Pharmacol. 2002;57:765–770. 9. Waeber B, Aschwanden R, Sadecky L, Ferber P. Combination of hydrochlorothiazide or benazepril with valsartan in hypertensive patients unresponsive to valsartan alone. J Hypertens. 2001;19:2097–2104. 10. Mallion JM, Carretta R, Trenkwalder P, et al. Valsartan/hydrochlorothiazide is effective in hypertensive patients inadequately controlled by valsartan monotherapy. Blood Press Suppl. 2003;(Suppl 1):36–43. 11. Weir MR, Smith DH, Neutel JM, Bedigian MP. Valsartan alone or with a diuretic or ACE inhibitor as treatment for African American hypertensives: Relation to salt intake. Am J Hypertens. 2001;14:665–671. 2778

E. Malacco et al.

12. Benz JR, Black HR, Graff A, et al. Valsartan and hydrochlorothiazide in patients with essential hypertension. A multiple dose, double-blind, placebo controlled trial comparing combination therapy with monotherapy. J Hum Hypertens. 1998;12:861–866. 13. Schmidt A, Adam SA, Kolloch R, et al. Antihypertensive effects of valsartan/hydrochlorothiazide combination in essential hypertension. Blood Press. 2001;10:230–237. 14. Palatini P, Malacco E, Fogari R, et al, for the Italian Collaborative Study Group. A multicenter, randomized double-blind study of valsartan/hydrochlorothiazide combination versus amlodipine in patients with mild to moderate hypertension. J Hypertens. 2001;19:1691–1696. 15. Wellington K, Faulds DM. Valsartan/hydrochlorothiazide: A review of its pharmacology, therapeutic efficacy and place in the management of hypertension. Drugs. 2002; 62:1983–2005. 16. Zanchetti A, Omboni S, La Commare P, et al. Efficacy, tolerability, and impact on quality of life of long-term treatment with manidipine or amlodipine in patients with essential hypertension. J Cardiovasc Pharmacol. 2001;38:642–650. 17. Messerli FH, Oparil S, Feng Z. Comparison of efficacy and side effects of combination therapy of angiotensin-converting enzyme inhibitor (benazepril) with calcium antagonist (either nifedipine or amlodipine) versus high-dose calcium antagonist monotherapy for systemic hypertension. Am J Cardiol. 2000;86:1182–1187. 18. Physicians’ Desk Reference. Montvale, NJ: Medical Economics; 2000:2015–2017; 2358–2360. 19. UK Prospective Diabetes Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38 [published correction appears in BMJ. 1999;318:29]. BMJ. 1998;317:703–713. 20. Hansson L, Zanchetti A, Carruthers SG, et al, for the HOT Study Group. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: Principal results of the Hypertension Optimal Treatment (HOT) randomized trial. Lancet. 1998;351:1755–1762. 21. Berlowitz DR, Ash AS, Hickey EC, et al. Inadequate management of blood pressure in a hypertensive population. N Engl J Med. 1998;339:1957–1963. 22. Girerd X, Hanon O, Babici D, et al. Rational choice for second antihypertensive agent after failure of the first monotherapy: Therapeutic strategy [in French]. Arch Mal Coeur Vaiss. 2002;95:723–726. 23. Amar J, Vaur L, Perret M, et al, for the PRATIK study investigators. Hypertension in high-risk patients: Beware of the underuse of effective combination therapy (results of the PRATIK study). J Hypertens. 2002;20:779–784. 24. Monane M, Bohn RL, Gurwitz JH, et al. Compliance with antihypertensive therapy among elderly Medicaid enrollees: The roles of age, gender, and race. Am J Public Health. 1996;86:1805–1808. 25. Costa FV. Compliance with antihypertensive treatment. Clin Exp Hypertens. 1996;18: 463–472. 2779

CLINICAL THERAPEUTICS®

26. Burt VL, Whelton P, Roccella EJ, et al. Prevalence of hypertension in the US adult population. Results from the Third National Health and Nutrition Examination Survey, 1988–1991. Hypertension. 1995;25:305–313. 27. Wang PS, Bohn RL, Knight E, et al. Noncompliance with antihypertensive medications: The impact of depressive symptoms and psychosocial factors. J Gen Intern Med. 2002;17:504–511. 28. Dusing R, Weisser B, Mengden T, Vetter H. Changes in antihypertensive therapy—the role of adverse effects and compliance. Blood Press. 1998;7:313–315. 29. Marentette MA, Gerth WC, Billings DK, Zarnke KB. Antihypertensive persistence and drug class. Can J Cardiol. 2002;18:649–656. 30. Gregoire JP, Moisan J, Guibert R, et al. Tolerability of antihypertensive drugs in a community-based setting. Clin Ther. 2001;23:715–726.

Address correspondence to: Paolo Palatini, MD, Dipartimento di Medicina Clinica e Sperimentale, Università di Padua, Via Giustiniani 2, 35128 Padua, Italy. E-mail: [email protected] 2780