Ettore Ambrosioni Department of Internal Medicine 1, University of Bologna, Sant’Orsola Hospital, Bologna, Italy

Michele Bombelli · Giuseppe Mancia Department of Clinical Medicine and Prevention, University of Milano-Bicocca, St. Gerardo Hospital, Milan, Italy

Giovanni Cerasola · Giuseppe Mulè Università di Palermo, Dipartimento di Medicina Interna, Malattie Cardiovascolari e Nefrourologiche, Cattedra di Medicina Interna, European Society of Hypertension Centre of Excellence, Palermo, Italy

Francesco Cipollone Atherosclerosis, Hypertension and Dyslipidemia Unit, G.d’Annunzio University of Chieti-Pescara, Chieti-Pescara, Italy

Claudio Ferri Department of Internal Medicine and Public Health, University of L’Aquila, Coppito (AQ), Italy

Irene Grazioli* · Gabriella Melzi* () Medical Department, Solvay Pharma S.p.A *, Via della Libertà, 30–10095 Grugliasco (Turin), Italy. E-mail: gabriella.melzi@solvay.com

Cristiana Leprotti First Department of Internal Medicine, Venice City Hospital, Venice, Italy

Amedeo Mugellini Department of Internal Medicine and Therapeutics, Centro per l’Ipertensione e Fisiopatologia Cardiovascolare, University of Pavia, Pavia, Italy

Adv Ther (2010) 27(5): 16.DOI 10.1007/s12325-010-0032-7

ORIGINAL RESEARCH

Ambulatory Monitoring of Systolic Hypertension in the Elderly: Eprosartan/Hydrochlorothiazide Compared with Losartan/Hydrochlorothiazide (INSIST Trial)

Ettore Ambrosioni · Michele Bombelli · Giovanni Cerasola · Francesco Cipollone · Claudio Ferri · Irene Grazioli ·

Cristiana Leprotti · Giuseppe Mancia · Gabriella Melzi · Amedeo Mugellini · Giuseppe Mulè ·

Giuseppe Palasciano · Antonio Salvetti · Bruno Trimarco

Received: March 31, 2010 / Published online: © Springer Healthcare 2010

Giuseppe Palasciano Clinica Medica ‘A. Murri’, Department of Internal & Public Medicine, University Medical School of Bari, Bari, Italy

Antonio Salvetti Department of Internal Medicine, University of Pisa, Pisa, Italy

Bruno Trimarco Division of Internal Medicine, Department of Clinical Medicine & Cardiovascular Sciences, ‘Federico II’ University of Naples, Naples, Italy *Solvay Pharmaceuticals is now Abbott

ABSTRACT

Introduction: Systolic hypertension is very common in the elderly and is strongly associated with the risk of cardiovascular and cerebrovascular events. The control of systolic hypertension is difficult and most patients require combination antihypertensive therapy. Few data are available regarding the efficacy of angiotensin II receptor antagonists on systolic hypertension of the elderly. The aim of this double-blind, double-dummy, randomized, parallel-group, multicenter study was to assess the efficacy of eprosartan 600 mg in combination with hydrochlorothiazide (HCTZ)

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12.5 mg in comparison with losartan 50 mg in combination with HCTZ 12.5 mg, in reducing blood pressure in elderly patients with grade 2 systolic hypertension who did not optimally respond to eprosartan or losartan monotherapy. Methods: After a 3-week placebo wash-out, 155 patients with an Office trough sitting systolic blood pressure (Office sitSBP) ≥160 mmHg and <180 mmHg were randomized to eprosartan 600 mg (n=78) or losartan 50 mg (n=77) once daily for 6 weeks. In patients not optimally responding to monotherapy (Office sitSBP≥

130 mmHg) 12.5 mg HCTZ was added as fixed combination once daily for 6 weeks. A 24-hour ambulatory blood pressure monitoring (ABPM) was performed at the end of wash-out and at the end of the fixed-combination period. Results: No statistically significant difference was found between eprosartan/HCTZ and losartan/HCTZ on the primary endpoint (24-hour ABPM SBP) with an adjusted mean difference between treatments of 3.1 mmHg (95% CI: –0.32-6.59). However, the mean 24-hour ABPM SBP significantly decreased by 16.7 mmHg with eprosartan/HCTZ and 20.3 mmHg with losartan/HCTZ (P<0.001 vs. baseline). The mean Office sitSBP significantly decreased by 28.7 mmHg and 29.6 mmHg respectively, with eprosartan/HCTZ and losartan/HCTZ (P<0.001 vs.baseline and vs. monotherapy). Conclusion: In this study, eprosartan/HCTZ did not demonstrate to be superior to losartan/HCTZ in reducing ABPM systolic hypertension in the elderly.

Keywords: ambulatory blood pressure monitoring; elderly; eprosartan; hydrochlorothiazide; hypertension; losartan

INTRODUCTION

Large epidemiological trials, such as the Framingham study and the Multiple Risk Factors

Intervention Trial (MRFIT), have shown that systolic blood pressure (SBP) is an independent, continuous, and modifiable risk factor for all cardiovascular events.1,2 The Brisighella Heart Study demonstrated a strong, graded, and independent association between SBP, pulse pressure (PPr), and cardiovascular events,3 with a 109% increased risk of combined coronary and cerebrovascular disease at SBP ≥160 mmHg (grade 2 hypertension or more). Trends of increasing risk with increasing levels of blood pressure were statistically significant for SBP and PPr, but not for diastolic blood pressure (DBP).4 A meta-analysis of 61 prospective observational studies showed that SBP is as strongly associated with the age-specific mortality rates from stroke as from coronary heart disease, at least until a SBP of 115 mmHg.5

Isolated systolic hypertension (ISH) occurs in about 15% of people aged 60 years or older and the control of SBP is becoming more and more important due to the increased prevalence of elderly people in the population.6 The Systolic Hypertension in Europe (SYST-Eur) trial has shown that the antihypertensive treatment of ISH in patients 60 years of age or older reduces the incidence of stroke by 42%, of all cardiac endpoints by 26%, and of all cardiovascular endpoints combined by 31%.6 Normalization of SBP (SBP <140 mmHg)7 is therefore at least as an important objective as the control of DBP, which was long considered to be the primary target of antihypertensive treatment.8 However, the Pressioni Arteriose Monitorate E Loro Associazioni (PAMELA) study showed that Office SBP control was less frequent than DBP control. The same trend was observed for home and 24-hour blood pressure measurements.9 Furthermore, in a recent Italian survey of an overall sample of 52,715 hypertensive patients, despite the high percentage of patients on stable antihypertensive treatment, mean

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SBP levels were consistently higher than the normality threshold.10

In fact, most patients require combination therapy with two or more antihypertensive agents to adequately control blood pressure to targets recommended by European and US Joint National Committee guidelines.7,11 In the Hypertension Optimal Treatment (HOT) trial, about 70% of patients required two or more drugs to reach the blood pressure target.12 Also, in large outcome trials, the percentage of patients treated with monotherapy was low (11% with losartan and 12% with atenolol in the Losartan Intervention For Endpoint [LIFE] trial; 34% with eprosartan and 33% with nitrendipine in the Morbidity and Mortality after Stroke Eprosartan Compared with Nitrendipine for Secondary Prevention [MOSES] trial).13,14 The proportion of hypertensive patients reaching blood pressure targets on combination therapy has been placed at 40% to 75%.15

Angiotensin receptor antagonists (ARB) are frequently combined with low-dose diuretics to increase the antihypertensive effect. The incremental blood pressure reduction between the starting doses of ARB and the combinations of ARB with hydrochlorothiazide (HCTZ) is substantial, indicating that combination therapy is a more effective strategy than monotherapy dose titration.16

Eprosartan is a highly selective, nonpeptide, nonbiphenyl ARB which has shown to effectively reduce blood pressure in large, double-blind, randomized, placebo- and active-controlled clinical trials.17-23 In hypertensive elderly patients, eprosartan is at least as efficacious as enalapril and may be better tolerated.24,25 It has been suggested that the efficacy achieved for SBP in patients on eprosartan could be due to the inhibition of sympathetic activation mediated by the antagonism of the prejunctional AT1 receptors, as shown in animal models and in

humans.26,27 The combination of eprosartan 600 mg with HCTZ 12.5 mg has been shown to lower blood pressure in patients not adequately controlled by eprosartan monotherapy.28

Losartan was the first marketed ARB and is considered the gold standard in comparative clinical trials with ARB.29 Losartan and eprosartan have shown their efficacy in reducing cardiovascular risk in large outcome trials.13,14 In the LIFE study, which involved more than 9000 patients with hypertension and left ventricular hypertrophy, the losartan-based regimen significantly reduced the risk of the combined endpoint of cardiovascular death, stroke, and myocardial infarction by 13% compared with atenolol.13 The MOSES trial, performed on 1400 patients with previous transient ischemic attack or stroke, showed that eprosartan was significantly more effective than nitrendipine in reducing the primary combined endpoint of total mortality, cardiovascular, and cerebrovascular events by 21%.14 In both studies, the better efficacy of the ARB in reducing cardiovascular risk has been obtained with the same blood pressure reduction as the comparator.

Monitoring of 24-hour ambulatory blood pressure (ABPM), with multiple measurements recorded during usual daily activities, would be expected to provide a better assessment and an additional clinical value for the risk of cardiovascular disease related to blood pressure, because it correlates with hypertensive target organ damage more closely than Office blood pressure.30 31 Recently, the Ohasama Study showed that ISH, as determined by 24-hour ABPM measurements, was associated with a high risk of stroke, suggesting that the prognosis of hypertensive patients would be improved by focusing treatment on 24-hour systolic ABPM.32

ABPM is usually several mmHg lower than Office blood pressure: in fact, Office values of 140/90 mmHg approximately correspond to 24-hour average values of 125/80 mmHg.30 Due

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to these considerations, the actual approach to hypertension management should be the use of systolic ABPM as the main criterion and outcome measure.7 ABPM data of the fixed-combination therapy with eprosartan/HCTZ have not been published. The aim of this double-blind, double-dummy, randomized, parallel-group, multicenter study was to assess the efficacy of eprosartan 600 mg in combination with HCTZ 12.5 mg, in comparison with losartan 50 mg in combination with HCTZ 12.5 mg, in reducing ABPM SBP in elderly patients with grade 2 systolic hypertension who did not optimally respond to eprosartan or losartan monotherapy (INSIST trial).

MATERIALS AND METHODS

Patient Selection

In this multicenter study, male or female outpatients (60 years of age or older) who met the World Health Organization (WHO)/ISH criteria33 for grade 2 systolic hypertension were enrolled by 10 specialist hypertension centers throughout Italy. Patients were eligible for inclusion if they had a newly diagnosed grade 2 systolic hypertension (average Office sitting systolic blood pressure [sitSBP] ≥160 mmHg and <180 mmHg); or they were on antihypertensive treatment, but average Office sitSBP was ≥140 mmHg and <180 mmHg; or they were on antihypertensive treatment, but experienced undesirable side effects, and an Office sitting diastolic blood pressure (sitDBP) <110 mmHg was also required. Patients were excluded if they had a difference between left and right arm blood pressure measurements (>20 mmHg for Office sitSBP and/or >10 mmHg for Office sitDBP) or secondary hypertension. Moreover, patients were excluded if they had severe diseases (cerebrovascular or coronary heart or vascular disease in the last 12 months, New York

Heart Association [NYHA] class III-IV congestive heart failure, obesity, unstable diabetes mellitus, proteinuria, and/or elevation of serum creatinine ≥1.2 mg/dL, grade III-IV hypertensive retinopathy). Other exclusion criteria were major disturbances of cognitive function, gout or raised serum uric acid, clinically significant hepatic disease, or clinically relevant abnormal potassium or sodium plasma levels. Patients were also excluded if they were known to be nonresponders or if they had a history of hypersensitivity (including angioedema) to eprosartan, losartan, or HCTZ.

The protocol and informed consent form were approved by independent ethics committees at each center. A description of the study risks and benefits was provided to all participants who gave written informed consent prior to entry in the study. The study was conducted according to the International Conference on Harmonization Good Clinical Practices.

Study Design and Treatments

This study was designed as a double-blind, double-dummy, randomized, parallel-group, multicenter study. After a 3-week placebo wash-out period, during which any previous antihypertensive treatment was discontinued, patients with an average Office sitSBP ≥160 mmHg and <180 mmHg were randomized to eprosartan 600 mg or losartan 50 mg once daily for 6 weeks (monotherapy period). The randomization list was derived from a computer-generated code list. Patients whose average Office SBP was <130 mmHg after monotherapy were discharged from the study. Patients who did not optimally respond to eprosartan or losartan monotherapy (average Office sitSBP ≥130 mmHg after 6 weeks) entered the double-blind fixed-combination period, and 12.5 mg HCTZ once daily was added to eprosartan 600 mg or losartan 50 mg for 6 weeks. At the time of the study planning, losartan 50 mg/HCTZ 12.5 mg was the only

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dosage marketed in Italy. In the eprosartan group, each dose of study medication consisted of one tablet of eprosartan 600 mg (or one encapsulated tablet of eprosartan 600 mg/HCTZ 12.5mg during the fixed-combination period) and one placebo capsule matching the tablet of losartan; in the losartan group, each dose of study medication consisted of one encapsulated losartan 50 mg (or one encapsulated losartan 50 mg/HCTZ 12.5 mg during the fixed-combination period) and one placebo tablet matching the tablet of eprosartan. Patients were instructed to take the study drug each morning at approximately the same time. During the 15-week study period (placebo wash-out, monotherapy, fixed combination), the use of any other antihypertensive drug was not permitted.

Patients were scheduled to be seen in the morning at the end of the wash-out, at the end of monotherapy, and at the end of the fixed-combination period. At each visit, Office blood pressure and pulse rate were measured before taking the study drug. During the placebo wash-out period, Office blood pressure was measured during an interim visit to check the safety limits.

A 24-hour ABPM was performed at the end of the wash-out and at the end of the fixed-combination period, starting respectively after the intake of the last dose of placebo and of the last dose of the fixed combination.

A 12-lead electrocardiogram (ECG) and laboratory tests including blood chemistry and urine analysis were performed at screening and final visits. At the final visit, unused tablets and capsules, and empty boxes were returned and counted to assess compliance.

Blood Pressure MeasurementsABPM

A 24-hour ABPM was performed using the SpaceLabs 90207 device (SpaceLabs Inc., Redmond, WA). The device was attached on the morning

after the last intake of the study medication. Blood pressure was recorded at 20-minute intervals throughout the whole 24-hour recording period. Patients were advised to be awake and out of bed during the last 4 hours of the 24-hour recording to avoid a confounding reduction in blood pressure associated with sleep.

Hourly means were calculated for each patient and used to calculate mean blood pressure values over the following prespecified intervals: the whole 24-hour period, the last 4 hours of the dosing interval, daytime (6:00 am-10:00 pm), and nighttime (10:00 pm-6:00 am).

The criteria to consider the ABPM assessable were: at least 21 valid hours without consecutive missing hours, at least one valid measurement per hour during all valid hours, and the presence of at least 70% of the expected readings.

Office Blood PressureOffice blood pressure was measured using an

oscillometric automated pressure measuring device (Omron 705 CP, Omron, IL). At screening visit, blood pressure was measured at both arms and the arm with the highest average blood pressure recording was used for all the subsequent assessments. The arm was supported at heart level, using the same cuff size and the same equipment. Measurements were taken at each visit at the same time (±1 hour) in the morning. Patients had to remain seated for at least 5 minutes and then three measurements of blood pressure, spaced by 2 minutes, were taken.7 The average of the three measurements of sitSBP and sitDBP was recorded. After the measurement of SBP, the patient was asked to stand for 1 minute and then standing SBP (staSBP) and standing DBP (staDBP) were measured.

EndpointsThe mean change from the end of wash-out to

the end of the fixed-combination period of ABPM (mean 24 hours) SBP was the primary endpoint

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to compare eprosartan/HCTZ and losartan/HCTZ. Secondary efficacy parameters were also assessed (mean change from the end of wash-out to the end of the fixed-combination period): ABPM (mean 24 hours) PPr (SBP-DBP); ABPM SBP at daytime (6:00am-10:00 pm); ABPM SBP at nighttime (10:00 pm-6:00 am); ABPM SBP in the last 4 hours before taking the study medication; hourly systolic ABPM; ABPM response rate defined as percentage of patients with ABPM (mean 24 hours) SBP <125 mmHg.

Comparing the ABPM data at the end of the wash-out with those at the end of the fixed-combination period, the following parameters were also calculated: trough/peak ratio (T/P ratio): the through value was the mean change of SBP of the last 2 hours during ABPM; the peak value was the mean of maximal change of SBP and the change of the next adjacent hour estimated during the interval between the second and the eighth hour of ABPM; smoothness index (SI): ratio between the mean 24 hours of the hourly changes (ΔH) of SBP and the standard deviation of the mean (SDΔH); percentage of patients with SI >1. Moreover, other secondary efficacy parameters were: Office trough sitSBP; Office trough sitting PPr (SBP–DBP); Office trough staSBP.

Response rate (percentage of patients with average Office sitSBP <140 mmHg or decreased by ≥20 mmHg) and optimal response rate (percentage of patients with average Office sitSBP <130 mmHg) were calculated at the end of monotherapy and at the end of the fixed-combination period. ABPM and Office DBP values were also recorded. All adverse events were assessed by the investigators for intensity, seriousness, and relationship to study medication.

Blood laboratory parameters (ALT/SGPT, AST/SGOT, Gamma-GT, potassium, sodium, creatinine, total cholesterol, HDL-C, LDL-C, triglycerides, fasting glucose, fibrinogen, and uric acid) were measured by the laboratory of each

center. Moreover, blood, protein, uric acid, and glucose were measured in the urine.

Statistical Analysis

The required sample size was estimated to be 128 patients (64 patients per group), giving the study a power of at least 0.80 to detect a mean difference of 5 mmHg (with a standard deviation of 10 mmHg) in ABPM SBP between patients receiving eprosartan/HCTZ and those receiving losartan/HCTZ, assuming a two-tailed test with a 0.05 significance level. Therefore, it was designed as a superiority study. Assuming that 15% of patients did not complete the study and that 6% of patients were responders to monotherapy, it was estimated that approximately 160 patients (80 patients per group) would need to be randomized.

The efficacy analysis was based on an intention-to-treat (ITT) approach that included all randomized patients who received at least one dose of study medication and had assessable data for ABPM at the end of wash-out and at the end of the fixed-combination period. A per-protocol (PP) sample including all patients without major violations of inclusion/exclusion criteria, or which might impact the efficacy of study medication, was also analyzed.

Moreover, the responders to monotherapy sample consisting of all patients who had available data for Office blood pressure at the end of wash-out and the end of monotherapy period and were responders to monotherapy (Office SBP <130 mmHg) was defined.

The primary and secondary efficacy endpoints concerning ABPM and Office blood pressure measurements were analyzed using analysis of covariance (ANCOVA) with baseline values as covariate. The 95% confidence interval was given for treatment comparisons.

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The T/P ratio was analyzed using a Wilcoxon test. The SI was analyzed by analysis of variance (ANOVA) with treatment and center as factors. The response rates and the SI >1 were analyzed using the Cochran-Mantel-Haenszel test. Within each treatment group, changes of blood pressure were analyzed using a two-sided paired t-test. Missing values for Office blood pressure were replaced by carrying forward the preceding value. Differences resulting in a P value ≤0.05 were considered to be statistically significant. All randomized patients who received at least one dose of study medication were included in the safety sample.

The ABPM recordings were electronically saved and stored in a central database. Data of ABPM were analyzed by validated software, SETI version 1.1 by Docleader Srl. Quintiles S.p.A. (Milan, Italy) were responsible for the full statistical analysis. SAS version 8.2 for Windows and Proc-StatXact 5 was used for the statistical analysis. All data analysis was carried out according to a pre-established analysis plan. The evaluation of the quality and completeness of the data, identification of important protocol deviations, and handling of problem cases were performed regularly and finally decided before locking and unblinding the database. All study personnel and participants were blinded to treatment assignment for the duration of the study.

RESULTS

Study Population

In total, 173 patients were assessed for eligibility and 155 were randomized across 10 centers in Italy (Figure 1). The efficacy analyses were based on the ITT, PP, and responders to monotherapy samples. The results from the ITT and the PP analysis were similar and only the results based on the ITT sample will be shown.

The safety sample consisted of 155 patients; 78 treated with eprosartan and 77 treated with losartan. Sixty-three patients with missing (n=9; 6%) or not assessable ABPM (n=30; 19%), who were responders to monotherapy (n=22; 14%) or had not taken combination therapy (n=2; 1%) were not included in the ITT sample, which therefore consisted of 92 patients: 47 treated with eprosartan and 45 treated with losartan. Five patients in the ITT sample were not included in the PP sample because of major protocol violations. Therefore, the number of patients included in the PP sample was 87 (44 eprosartan and 43 losartan).

The demographic and baseline characteristics of the ITT sample were not different between the two treatment groups (Table 1). Overall, 59% of the patients were male and 41% were female. The mean age was 67 years. All the patients were Caucasian. The mean body mass index (BMI) was 25.6 kg/m2. Overall, 47% of patients were alcohol consumers and 17% were smokers.

At the end of the wash-out period, mean Office SBP was 169.7 mmHg for eprosartan and 168.1 mmHg for losartan (Table 2); mean Office DBP was 87.6 and 89.0 mmHg, respectively.

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Therefore, DBP data will only be shown in a descriptive way.

Efficacy ABPM

No statistically significant difference was found between eprosartan/HCTZ and losartan/HCTZ on the primary endpoint (24-hour ABPM SBP) with an adjusted mean difference between treatments of 3.1 mmHg (95% CI: –0.32-6.59) (Table 2). After 12 weeks of treatment the reduction of 24-hour ABPM SBP was of 16.7 mmHg for eprosartan and of 20.3 mmHg for losartan, with a statistically significant difference within each group (P<0.001) (Table 2).

The 24-hour ABPM PPr, SBP at daytime and at nighttime, and SBP in the last 4 hours were not statistically significant different between groups, but the reduction after 12 weeks of treatment

were statistically significant within each group (Table 2).

The mean hourly SBP reduction before and after 12 weeks of treatment is shown in Figure 2. The ABPM SBP was <125 mmHg in 45% of eprosartan/HCTZ patients and 40% of losartan/HCTZ patients (Table 3).

The mean 24-hour ABPM DBP was <85 mmHg at baseline and <75 mmHg at the end of the fixed-combination period in both groups.

T/P Ratio and SIThe median T/P ratio of SBP was 0.65 and

0.86, respectively, for eprosartan and losartan, with a statistically significant difference in favor of losartan/HCTZ (P=0.038) (Table 3). The SI of SBP was 1.74 and 2.09, respectively, for eprosartan and losartan, without a statistically significant difference between groups (Table 3).

Figure 1. Overall patient disposition during the treatment period and reasons for exclusion. ITT=intention to treat;PP=per-protocol sample; SP=safety sample.

Screened(n=173)

Excluded (n=18)

Eprosartan(n=78)

SP sampleEprosartan

(n=78)

Excluded (n=22)3 No ABPM

17 Not assessable ABPM2 No combination therapy

SP sampleLosartan(n=77)

Losartan(n=77)

Randomized(n=155)

PP sample(n=43)

ITT sample(n=45)

Responders monotherapy(n=10)

Excluded (n=2)

PP sample(n=44)

ITT sample(n=47)

Responders monotherapy(n=12)

Excluded (n=3)

Excluded (n=19)6 No ABPM

13 Not assessable ABPM

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The proportion of patients with a SI >1 for SBP was 64% for eprosartan and 73% for losartan, without a statistically significant difference between groups (Table 3).

Office Blood Pressure The mean Office sitSBP, staSBP, and

Office PPr were not statistically significantly different between eprosartan or losartan fixed-combination therapy with HCTZ (Table 2).The mean Office sitSBP significantly decreased by 16.4 mmHg and 15.6 mmHg, respectively, with eprosartan and losartan monotherapy (P<0.001 vs. baseline).

The mean Office sitSBP, with eprosartan/HCTZ and losartan/HCTZ (P<0.001 vs. baseline and vs. monotherapy), significantly decreased from baseline by 28.7 mmHg and 29.6 mmHg, respectively (Table 2). The mean Office DBP was <85 mmHg after monotherapy and <80 mmHg after fixed-combination therapy with HCTZ in both treatment groups.

In patients who were responders after 6 weeks of monotherapy with eprosartan or losartan, the mean Office sitSBP significantly decreased by 45.2 mmHg and 41.3 mmHg, respectively, without differences between

groups (Table 2); the mean Office DBP was lower than 80 mmHg in both the groups.

Office SBP Response Rate

The proportion of responders (SBP <140 mmHg or decrease in SBP ≥20 mmHg) was higher after eprosartan monotherapy (51%) than after losartan monotherapy (33%), but it did not reach the statistical significance (P=0.06). The proportion of responders to the fixed combination was very high in both groups (75% for eprosartan/HCTZ and 84% for losartan/HCTZ), without a statistically significant difference. The proportion of optimal responders (Office SBP <130 mmHg) to the fixed combination was similar between the two groups (21% for eprosartan/HCTZ and 24% for losartan/HCTZ).

Safety

Eprosartan and losartan (and their fixed-combination therapy with HCTZ) were regarded as well-tolerated antihypertensive treatments. A total of six out of 155 patients reported at least one treatment-emergent adverse event (TEAE): three patients during eprosartan monotherapy, one patient during

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losartan monotherapy, one patient during eprosartan/HCTZ, and one patient during losartan/HCTZ. Three patients reported at least one related TEAE: two patients during eprosartan (dyspepsia and headache), and one patient during losartan (dysuria).

Three patients (one for serum potassium reduction during eprosartan, one for multiple fractures during eprosartan/HCTZ, and one for dysuria during losartan) dropped out because of adverse events. No clinically significant changes of ECG were found in any treatment group. Also, there were no changes observed from screening to end of monotherapy or to end of fixed combination in any laboratory parameter, except for one subject who

experienced low serum potassium as an adverse event (unrelated).

DISCUSSION

The aim of this double-blind, double-dummy, randomized, para l le l -group, multicenter study was to assess the efficacy of eprosartan 600 mg in combination with HCTZ 12.5 mg in comparison with losartan 50 mg in combination with HCTZ 12.5 mg in reducing ABPM SBP in elderly patients with grade 2 systolic hypertension who did not optimally respond to eprosartan or losartan monotherapy. In this study, it was chosen to compare the lowest marketed doses of eprosartan and

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losartan fixed-combination therapy with HCTZ. Moreover, 600 mg of eprosartan and 50 mg of losartan are commonly recognized as the respective defined daily dose. A study duration of 12 weeks (6 weeks of monotherapy followed by 6 weeks of fixed-combination therapy) is commonly used to assess the efficacy of antihypertensive drugs.16

In this study, elderly patients (mean age 67 years) with grade 2 systolic hypertension according to the WHO/ISH criteria33 were enrolled (baseline Office SBP ≥160 mmHg and <180 mmHg, and Office DBP <110 mmHg in all patients). Despite the patients being included in the study based on the Office blood pressure values, the ABPM values also confirmed that the patients were hypertensive. In fact, at baseline, mean ABPM SBP was 145.9 mmHg for eprosartan and 146.7 mmHg for losartan, which is higher than the 125 mmHg considered as normal ABPM SBP values.7 A study limitation was the randomization before the monotherapy arm, rather than at the time of HCTZ addition, which may have been a source of possible bias in the ITT population.

The primary and secondary parameters of this study are those reported in the most recent studies on hypertension using ABPM.34-36 However, ABPM is a more difficult method of blood pressure measurement than the usual Office method. Possible known reasons for nonassessable ABPM data are atrial fibrillation, frequent ectopic beats or other arrhythmias, poor patient compliance, and heavy physical activity; these factors generally contribute to 25%-30% of exclusion from the assessable sample.37 In this study, only 19% of patients were excluded from the ITT sample because of nonassessable ABPM data. Nevertheless, this percentage was higher than expected, considering the sample size. Regarding the primary endpoint (24-hour ABPM SBP), there was no statistically significant difference between treatment groups; therefore, eprosartan/HCTZ did not demonstrate superiority to losartan/HCTZ. The reduction

of ABPM of eprosartan 600/HCTZ 12.5 mg (16.7 mmHg) is similar to that published for losartan 50/HCTZ 12.5 mg (from 14.6 mmHg to 17.1 mmHg).34,36,38

In this study, losartan/HCTZ induced a reduction in 24-hour ABPM SBP of 20.3 mmHg. Therefore the encapsulation of losartan/HCTZ seems not to have influenced the efficacy of the drug. It should be noted that losartan 100/HCTZ 25 mg was not available at the time of the study and could be more efficacious in this population.

These ABPM SBP reductions of eprosartan/HCTZ and losartan/HCTZ are higher than those reported in a recent review of ABPM studies with ARB,39 probably because in this study only patients with systolic grade 2 hypertension were included. The other secondary ABPM parameters (24-hour ABPM PPr, daytime and nighttime SBP, and last 4 hours SBP) showed reductions comparable to those published for losartan/HCTZ.36 Moreover, the reduction of SBP during the last 4 hours showed that the antihypertensive effect of eprosartan/HCTZ is maintained until the administration of the following dose.

The response rate of ABPM (ABPM SBP <125 mmHg) was high both in the eprosartan/HCTZ and in the losartan/HCTZ group (45% and 40%, respectively).

It has been shown that the SI is superior to the T/P ratio for assessing the homogeneity of the 24-hour reduction of blood pressure induced by antihypertensive drugs,40 because the SI is more reproducible and measures the 24-hour blood pressure variability. Moreover, the SI showed a negative relationship with the left ventricular hypertrophy, a greater SI being associated with a greater reduction in the left ventricular mass index.40 An SI of SBP inferior to 0.57, but not the T/P, was associated with an increase of carotid artery wall thickness.41

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In this study, a high value of SI for SBP (1.74) was found for eprosartan/HCTZ. The SI for SBP in the losartan/HCTZ group was higher (SI=2.09) compared with that reported in the literature for losartan (SI for SBP=0.96).38 A T/P ratio superior to 0.5 is required by the Food and Drug Administration (FDA) to reach the antihypertensive effect over 24 hours.42 In this study the T/P ratio of SBP was 0.65 for eprosartan/HCTZ and 0.86 for losartan/HCTZ. These values were higher than those previously published for losartan (0.52).38

Concerning the Office SBP, the reductions in Office SBP of eprosartan monotherapy (16.4 mmHg) and of losartan monotherapy (15.6 mmHg) confirm the published data, ranging from 10 mmHg to 16 mmHg.16,23,24,38 The Office SBP reductions found in this study are higher than those published for other ARB.39

Concerning the additional improvement of SBP obtained when an ARB is combined with HCTZ compared with ARB monotherapy, the Office SBP reductions of eprosartan/HCTZ and losartan/HCTZ were significantly higher compared with those of monotherapies. These reductions were greater than those published for other ARB at standard dosage in combination with a low dose (12.5 mg) or the highest dose (25 mg) of HCTZ,43,44 probably because in this study only patients with systolic grade 2 hypertension were included. A greater proportion of patients in the eprosartan group were responders to monotherapy (SBP <140 mmHg or reduction >20 mmHg) compared with losartan (51% vs. 33%). The response rates were similar and high (more than 75% of patients) for the fixed-combination therapy with HCTZ.

According to the recent guidelines on hypertension, instead of an increased dose of monotherapy, the lowest doses

of a combination therapy help to reduce adverse events and increase the compliance.7 Administration of two antihypertensive drugs, particularly as a fixed low-dose preparation, allows normalization of blood pressure without impairing the patient’s quality of life.45 In this study, eprosartan and losartan, and their fixed-combination therapies with HCTZ, showed a similar safety profile with a low number of adverse events.

In conclusion, this double-blind, double-dummy, randomized , para l le l -g roup, multicenter study has shown that eprosartan or losartan, in combination with HCTZ, are effective in reducing ABPM systolic hypertension in the elderly. To our knowledge, this is the first study where the ABPM was used to assess the efficacy of eprosartan/HCTZ.

ACKNOWLEDGMENTS The authors wish to acknowledge other investigators from Italy who participated in this study for the collection of data: Anna Belfiore (Clinica Medica ‘A. Murri’ – Department of Internal & Public Medicine, University Medical School of Bari, Italy), Luigi Guerrera (Division of Internal Medicine, Department of Clinical Medicine & Cardiovascular Sciences, ‘Federico II’ University of Naples, Italy), Armando Magagna (Department of Internal Medicine, University of Pisa, Italy), Barbara Pini (Atherosclerosis, Hypertension and Dyslipidemia Unit, G.d’Annunzio University of Chieti-Pescara, Italy), Letizia Valeri (Department of Internal Medicine and Public Health, University of L’Aquila, Italy), Maddalena Veronesi (Department of Internal Medicine 1, University of Bologna, Sant’Orsola Hospital, Italy). Furthermore, the authors wish to acknowledge Stefano Omboni (Docleader, Milan) for the technical support in the ABPM data analysis.

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This study was supported and funded by Solvay Pharma S.p.A. (Solvay Pharmaceuticals is now Abbott), Grugliasco (TO), Italy. Irene Grazioli and Gabriella Melzi are employees of Solvay Pharma S.p.A (Solvay Pharmaceuticals is now Abbott).

No conflict of interest about the work reported in this paper has been declared by any of the authors. This study is registered in the Italian website of clinical trials (http://oss-sper-clin.sanita.it/).

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