0current Therapeutic research
Volume 69, Number i, February 2008
Effectiveness of Hydrochlorothiazide in Combination with Telmisartan and Olmesartan in Adults with Moderate Hypertension Not Controlled with Monotherapy: A Prospective, Randomized, Open-Label, Blinded End Point (PROBE), Parallel-Arm Study
Roberto Fogari, MD; Annalisa Zoppi, MD; Amedeo Mugellini, MD; Paola Preti, MD; Maurizio Destro, MD; Andrea Rinaldi, MD; and Giuseppe Derosa, MD
Department of Internal Medicine and Therapeutics, Centro per l'lpertensione e la Fisiopatologia Cardiovascolare, University of Pavia, Pavia, Italy
ABSTRACT
Background: The potential combinations of antihypertensive agents are many, and making rational choices depends on the characteristics of each drug and on their complementary mechanisms of action.
Objective: The aim of this study was to evaluate the effectiveness of adding hydrochlorothiazide (HCTZ) 12.5 mg to olmesartan 20 mg or telmisartan 80 mg on blood pressure (BP) in patients with moderate hypertension.
methods: Consecutive outpatients at the Centro per l'lpertensione e la Fisiopatologia Cardiovascolare, University of Pavia, Pavia, Italy, of both sexes aged 39 to 75 years were considered eligible for enrollment if they had a sitting diastolic BP (DBP) >99 mm Hg and <110 mm Hg at the end of an initial 2-week washout period. Patients were randomized to olmesartan 20 mg QD or telmisartan 80 mg QD according to a prospective, open-label, blinded end point, parallel-arm design. After 8 weeks of monotherapy, patients whose BP was not controlled (DBP >90 mm Hg) received HCTZ 12.5 mg QD for 8 additional weeks. Clinical and ambulatory BPs were measured at the end of the washout period and at the end of both treatment periods. Adverse events (AEs) were recorded from spontaneous reports and direct inquiry from investigators.
results: One hundred forty-five patients, all of whom were white, were recruited for the study. After the initial washout period, 13 patients did not meet the inclusion criteria and 6 refused to continue. A total of 126 white patients (69 men, 57 women; mean [SD] age, 60.2 [11.6] years) were randomized to receive monotherapy. Of these, 35 patients (56%) in the olmesartan group and 33 (52%) in the telmisartan group had previously received antihypertensive therapy. At the end of monotherapy, the 52 patients in the olmesartan group and the 49 patients in the telmisartan treatment group who were still in the study and had their BP inadequately controlled by treatment had HCTZ 12.5 mg QD added to their treatment regimen. Both combinations induced a
Accepted for publication November 26, 2007. doi:10.1016/j.curtheres.2008.02.003
© 2008 Excerpta Medica Inc. All rights reserved. 0011-393X/$32.00
greater ambulatory mean (SD) systolic BP (SBP) and DBP reduction than monotherapy (SBP: 145.3 [6.1] in the olmesartan group and 140.1 [6.4] in the telmisartan group, P < 0.05; DBP: 88.1 [5.1] in the olmesartan group and 84.9 [4.9] in the telmisartan group, P < 0.05). The mean (SD) reduction from baseline in the telmisartan/HCTZ-treated patients (21.5 [10.1]/14.6 [5.2] mm Hg for 24 hours, 21.8 [10.2]/14.9 [5.2] mm Hg for daytime, and 20.4 [10.3]/13.7 [5.9] mm Hg for nighttime; all, P < 0.001 vs baseline) was significantly greater than that observed in the olmesartan/HCTZ-treated patients (18.8 [9.8]/12.3 [4.9] mm Hg for 24 hours, 19.3 [9.8]/12.8 [4.9] mm Hg for daytime, and 17.4 [10.2]/10.6 [5.5] mm Hg for nighttime; all, P < 0.001 vs baseline), with a significant difference between the 2 treatment groups (P < 0.01). Compared with monotherapy, the add-on effect of HCTZ 12.5 mg QD administration was significantly greater in the telmisartan group than in the olmesartan group (P < 0.05); the difference being more evident for nighttime BP values (SBP, P = 0.031; DBP, P = 0.025). Reported AEs were similar in the olmesartan/HCTZ and the telmisartan/HCTZ groups (4 patients [7%] vs 3 patients [6%]).
Conclusion: The addition of HCTZ 12.5 mg to telmisartan 80 mg monotherapy was associated with greater BP reduction than the addition of the same dose of HCTZ to olmesartan 20 mg monotherapy in these patients previously uncontrolled on monotherapy. (Curr Ther Res Clin Exp. 2008;69:1-15) © 2008 Excerpta Medica Inc.
key words: hydrochlorothiazide, telmisartan, olmesartan, hypertension.
INTRODUCTION
Guidelines1,2 for the treatment of hypertension indicate a blood pressure (BP) goal of <140/90 mm Hg in the general population with uncomplicated hypertension. Lower goals (130/80 mm Hg) are recommended for high-risk patients, such as those with concomitant renal disease, diabetes mellitus, or evidence of other target organ damage. These recommendations are supported by evidence accumulated from long-term trials suggesting that lower BP values are associated with better outcomes in a broad range of patients.3'4 Several studies5-8 have also found that >50% of patients with hypertension need >2 antihypertensive drugs to achieve their BP goals, regardless of the medication chosen as initial therapy. The advantages of combination therapy include greater BP reduction and response rates when compared with monotherapy. These are probably related to the simultaneous effect on several regulatory systems involved in abnormally elevated BP and to fewer adverse events (AEs), with consequent better tolerability and improved treatment compliance.9'10
Due to the large number of antihypertensive agents, the number of potential combinations is large. However, a rational choice has to be based on the characteristics of each agent and their complementary mechanisms of action.9'10 A logical combination might consist of a thiazide diuretic such as hydrochlorothiazide (HCTZ) and an angiotensin-receptor blocker (ARB).11-13 The salt depletion induced by the diuretic stimulates the release of renin from juxtaglomerular cells. This reactive hyperreninemia makes BP maintenance dependent on angiotensin II, thereby blunting the antihypertensive efficacy of the diuretic. The addition of an ARB makes it possible to counteract the
renin-angiotensin system activation elicited by the diuretic and, in this way, to enhance the BP-lowering effect of salt depletion.11-13 Even very low doses of HCTZ (12.5 mg/d) have been found to boost the BP-lowering effect of an ARB.14,15 Furthermore, such a combination provides advantages in terms of better tolerability, because ARBs are associated with preventing or attenuating some of the metabolic AEs of HCTZ, such as hypokalemia and hyperglycemia.12'13'15
Given the importance of these pharmacodynamic considerations in the clinical setting, the efficacy of the HCTZ/ARB combination needs to be assessed specifically for the individual ARB, especially when low doses of diuretic are used, as is often the case. In fact, the different pharmacokinetic properties of the various ARBs might produce different interactions with HCTZ, with possible consequences for clinical efficacy.16
The aim of this study was to evaluate the antihypertensive effect measured using ambulatory BP monitoring (ABPM) of the addition of HCTZ 12.5 mg* to monotherapy with telmisartan 80 mgt compared with the addition of the same dose of diuretic to monotherapy with olmesartan 20 mgi in adults with moderate hypertension not adequately controlled by monotherapy.
PATIENTS AND METHODS
This prospective, randomized, open-label, blinded end point evaluation (PROBE),17 parallel-arm study was conducted from January 2006 to January 2007 at the Centro per l'lpertensione e la Fisiopatologia Cardiovascolare, University of Pavia, Pavia, Italy. Consecutive outpatients of both sexes aged 39 to 75 years were considered eligible for enrollment if they had a sitting diastolic BP (DBP) >99 mm Hg and <110 mm Hg at the end of an initial 2-week washout period. The patients with a sitting DBP >110 mm Hg or sitting systolic BP (SBP) >200 mm Hg at the end of the washout period were excluded from the study, as were those with secondary or malignant hypertension, type 1 or type 2 diabetes mellitus, myocardial infarction or cerebrovascular accident within the preceding 6 months, heart failure, clinically significant valvular heart disease or arrhythmias, renal or hepatic insufficiency, pregnancy, or known hypersensitivity to the drugs used in the study.
The study protocol was approved by the ethics committee of the University of Pavia and written informed consent was obtained from all patients prior to inclusion in the study.
According to the study design, after a 2-week washout period during which any previous antihypertensive treatment was discontinued, eligible patients were randomized to olmesartan 20-mg tablets QD or telmisartan 80-mg tablets QD. In Italy, these are the doses recommended for initiating antihypertensive treatment. Randomization was performed using a computer-generated random number sequence obtained from an investigator who was not involved in the patient recruitment. After 8 weeks of monotherapy, patients whose BP was not adequately controlled (DBP >90 mm Hg) were treated with the combination of olmesartan 20 mg and HCTZ 12.5 mg or telmisartan
*Trademark: Esidrex® (Novartis Pharmaceuticals, Basel, Switzerland). ^Trademark: Micardis® (Boehringer Ingelheim GmbH, Ingelheim, Germany). ^Trademark: Olpress® (Malesci, Firenze, Italy).
80 mg and HCTZ 12.5 mg, both administered QD in the morning for an additional 8 weeks. At the end of each period (washout [baseline], monotherapy, combination therapy), BP was measured in the clinic and by noninvasive ABPM. Clinic BP was obtained in the sitting position by the same investigator using a standard mercury sphygmomanometer 24 hours after drug administration. Three measurements taken at 2-minute intervals after the patient had been seated for 10 minutes were averaged and used as the clinic BP reference value. Heart rate (HR) was measured by palpating the radial artery after each BP measurement.
ABPM was performed during each 24-hour period using a clinically validated18 device (Spacelabs 90207, Spacelabs Healthcare, Issaquah, Washington) programmed to measure BP every 15 minutes. Each recording started in the morning immediately after clinic BP assessment and drug administration. Patients were instructed to remain motionless each time a reading was taken. The analysis of 24-hour BP recordings was preceded by removal of artifacts according to previously described editing criteria.19 Recordings were considered valid when no more than 2 nonconsecutive hours were missing over the 24-hour period. For each patient, the recordings were analyzed to obtain the following data relating to SBP, DBP, and HR: 24-hour mean values, daytime values (7 am—11 pm), nighttime values (11 pm—7 am), and hourly mean values.
The trough/peak (T/P) ratio, computed after selection of peak and trough changes, was also determined for each patient.20 Peak changes were calculated by selecting the hour with the maximal reduction in BP between hours 2 and 8 after drug administration and by averaging this change with the immediately adjacent hour in which the reduction was most evident. Trough BP changes were calculated by averaging the last 2 hours of the recordings.20 Based on the assumption that patients with hypertension are likely to receive the greatest benefit from treatment when the antihypertensive effects do not vary greatly during the day, the US Food and Drug Administration (FDA) guidelines indicate that the effect of an antihypertensive drug at the end of the dose interval (trough) should be no less than half to two thirds of the peak effect. Therefore, a T/P ratio of 50% to 66% is required for the efficacy of an antihypertensive agent to be considered satisfactory for its proposed dosage interval.21
The smoothness index (SI) was also computed by dividing the average of the 24-hour BP changes after treatment by the corresponding SD.22,23 The SI has been shown to more appropriately reflect whether treatment smoothly reduced BP throughout the 24-hour period than the T/P ratio.
At each visit, AEs that were spontaneously reported or elicited by indirect questioning by investigators blinded to patients' treatment were recorded. Serious AEs were defined as those requiring hospitalization or requiring drug withdrawal. Treatment compliance was assessed by counting the tablets remaining at each visit.
According to the PROBE design,17 the study outcomes were evaluated by physicians who were unaware of the type of treatment administered to the patients.
Statistical Analysis
It was determined that a sample size of 40 patients in each group would have 80% power to detect a difference of >2.5 mm Hg in the primary end point of the study, the
24-honr DBP at the end of the treatment, assuming that the common SD was 4 mm Hg using a 2-group t test with a 0.05 two-sided significance level. Assuming a 10% dropout rate, a total of 88 patients was deemed necessary for inclusion in the study.
All statistical analyses were conducted using SAS version 6.12 (SAS Institute, Inc., Cary, North Carolina). Analysis of variance was used for BP results. Differences in T/P ratios between treatments were evaluated by nonparametric tests (Wilcoxon signed-rank test, univariate), whereas the paired Student t test was used to assess the differences in SI. P < 0.05 was considered statistically significant. Data are shown as mean (SD).
RESULTS
One hundred forty-five patients, all of whom were white, were recruited for the study. After the initial washout period, 13 patients did not meet the inclusion criteria and 6 refused to continue. Consequently, 126 patients (69 men, 57 women; mean [SD] age, 60.2 [11.6] years) were randomized to receive olmesartan 20 mg (n = 63) or telmisartan 80 mg (n = 63) (Table I). A total of 101 patients completed the study: 17 patients (10 in the telmisartan group and 7 in the olmesartan group) were excluded because their clinic BP was normalized (< 140/90 mm Hg) by monotherapy; 5 patients (3 in the olmesartan group and 2 in the telmisartan group) because > 10% of all ABPM readings or > 1 reading per hour were missing or incorrect; 2 patients (1 in the olmesartan group and 1 in the telmisartan group) because of poor BP control; and 1 patient (olmesartan group) because of lack of cooperation.
Table I. Demographic and clinical characteristics of adult patients with moderate hypertension randomized to receive olmesartan 20 mg QD or telmisartan 80 mg QD monotherapy for 8 weeks followed by the addition of hydrochlorothiazide (HCTZ) 12.5 mg for 8 weeks (N = 126).*
Olmesartan/ Telmisartan/
Variable HCTZ HCTZ
Patients randomized 63 63
Age, mean (SD), y 60.1 (10.9) 59.9 (11.5)
Sex, no. (%)
Male 34 (54.0) 35 (55.6)
Female 29 (46.0) 28 (44.4)
BMI, mean (SD), kg/m2 25.6 (0.5) 25.4 (0.4)
SBP, mean (SD), mm Hg 169.1 (12.1) 169.7 (11.9)
DBP, mean (SD), mm Hg 104.1 (6.2) 103.7 (6.4)
HR, mean (SD), beats/min 74.7 (6.4) 74.9 (6.9)
Duration of hypertension, mean (SD), y 11.5 (5.9) 12.1 (6.4)
Smoking habit, no. (%) 10 (15.9) 13 (20.6)
Previous antihypertensive therapy, no. (%) 35 (56.4) 33 (52.8)
BMI = body mass index; SBP = systolic blood pressure; DBP = diastolic blood pressure; HR = heart rate. *No significant between-group differences were found.
The ABPM evaluation performed at the end of the monotherapy period found that both monotherapy treatments significantly (both, P < 0.001) reduced ambulatory SBP and DBP values compared with baseline. However, the mean decreases in 24-hour SBP and DBP were significantly greater with telmisartan than with olmesartan (SBP/DBP: 15.9 [8.8J/10.3 [5.13 mm Hg vs 13.6 [8.63/8.7 [4.93 mm Hg, respectively; P < 0.05); decreases in nighttime SBP and DBP were also significantly greater with telmisartan (SBP/DBP: 15.6 [8.23/10.7 [5.33 mm Hg vs 12.2 [7.53/8.1 [4.93 mm Hg; P < 0.05).
At the end of monotherapy, 52 patients in the olmesartan group and 49 in the telmisartan group had their BP inadequately controlled by treatment and were administered additional HCTZ 12.5 mg QD. The results of the study refer to these 101 patients. Demographic and clinical characteristics of the initial cohort are reported in Table I. No statistically significant between-group differences were found in any of the baseline characteristics.
Mean 24-hour, daytime, and nighttime ambulatory SBP and DBP values are reported in Table II. There was a further decrease in ambulatory BP at the end of the 8 weeks of combination therapy compared with the 8 weeks of monotherapy. Both treatment combinations significantly reduced both SBP and DBP from baseline to study end (all, P < 0.001). However, in the telmisartan/HCTZ-treated patients, the mean (SD) reductions from baseline (SBP/DBP: 21.5 [10.13/14.6 [5.23 mm Hg for 24 hours, 21.8 [10.23/ 14.9 [5.23 mm Hg for daytime, and 20.4 [10.33/13.7 [5.93 mm Hg for nighttime) were all significantly greater than in the olmesartan/HCTZ-treated patients (18.8 [9.83/ 12.3 [4.93 mm Hg for 24 hours, 19.3 [9.83/12.8 [4.93 mm Hg for daytime, and 17.4 [10.23/ 10.6 [5.53 mm Hg for nighttime) (all, P < 0.05) (Figure 1).
When considering the difference in ABPM between the end of monotherapy and the end of combination therapy, the mean decreases in 24-hour, daytime, and nighttime SBP and DBP values obtained with the addition of HCTZ 12.5 mg to telmisartan monotherapy (5.0/3.4, 5.9/3.8, and 4.7/4.2 mm Hg, respectively) were significantly greater than those obtained with the addition of HCTZ 12.5 mg to olmesartan monotherapy (3.8/2.8 mm Hg, P < 0.02; 4.8/2.9 mm Hg, P < 0.03; and 3.7/1.8 mm Hg, P < 0.02, respectively) (Figure 2).
The hourly profile also found that the BP reduction obtained with the addition of HCTZ to telmisartan monotherapy was greater than that obtained with the addition of HCTZ to olmesartan monotherapy, particularly during the nighttime (Figure 3).
The mean T/P ratio computed at the end of combination treatment was above the threshold of 0.5. No significant differences were found in the T/P ratios for SBP or DBP between the 2 groups (Table III). The mean Sis for SBP and DBP were also similar in the 2 combination treatment groups.
Clinic BP data (Table IV) found a significant reduction in SBP and DBP with both olmesartan and telmisartan monotherapy compared with baseline. Again, the changes in both SBP and DBP compared with monotherapy were significantly greater when HCTZ 12.5 mg was added to telmisartan than to olmesartan (both, P < 0.05).
Four patients in the olmesartan/HCTZ group complained of 3 AEs (nausea [23, headache [13, and fatigue [13), while 3 patients in the telmisartan/HCTZ group complained of 2 AEs (fatigue [23 and nausea [13). The rate of AEs (7% with olmesartan/ HCTZ and 6% with telmisartan/HCTZ) was not significantly different between the
Table II. Mean (SD) 24-hour, daytime, and nighttime systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart rate (HR) measured using ambulatory blood pressure monitoring at baseline and after olmesartan 20 mg QD or telmisartan 80 mg QD monotherapy (8 weeks) and olmesartan/hydrochlorothiazide (HCTZ) 12.5 mg or telmisartan/HCTZ 12.5 mg (16 weeks).
24-Hour Daytime Nighttime
Monotherapy + HCTZ Monotherapy + HCTZ Monotherapy + HCTZ
Variable Baseline (8 Weeks) (16 Weeks) Baseline (8 Weeks) (16 Weeks) Baseline (8 Weeks) (16 Weeks)
SBP, mm Hg
Olmesartan 153.1 139.2 135.4 157.4 143.5 138.7 140.3 127.3 123.6
(10.3) (7.8) (8.1) (10.4) (8.3) (7.7) (10.7) (7.9) (7.5)
Telmisartan 152.9 137.1 132.1 157.2 142.1 136.2 140.1 123.7 119.0
(9.9) (8.2) (7.9) (10.1) (8.1) (7.3) (11.1) (8.5) (7.8)
p* 0.048 0.014 0.071 0.021 0.031 0.011
Pî <0.001 <0.001 <0.001 <0.001 <0.001 <0.001
DBP, mm Hg
Olmesartan 90.9 82.4 79.6 93.9 85.1 82.2 80.9 73.7 70.9
(6.1) (6.3) (5.9) (6.7) (5.9) (5.8) (5.8) (6.0) (6.1)
Telmisartan 91.5 80.6 77.2 94.3 84.1 80.3 81.4 71.3 67.1
(6.4) (5.8) (6.1) (6.9) (6.2) (5.7) (6.2) (5.7) (5.9)
p* 0.041 0.016 0.087 0.023 0.025 0.004
Pî <0.001 <0.001 <0.001 <0.001 <0.001 <0.001
HR, beats/min
Olmesartan 71.3 70.9 71.0 73.8 73.1 72.9 63.1 63.4 62.7
(6.7) (6.2) (6.4) (6.7) (7.1) (6.9) (5.7) (5.6) (5.3)
Telmisartan 70.9 71.1 71.2 73.6 72.6 73.1 62.9 64.3 64.3
(7.2) (7.8) (5.9) (6.9) (7.2) (7.2) (5.9) (6.1) (5.8)
p* 0.603 0.559 0.319 0.388 0.524 0.411
^Analysis of variance (ANOVA) between groups. TANOVA versus baseline.
□ Olmesartan/HCTZ
□ Telmisartan/HCTZ
24 Hours
Daytime
Nighttime
24 Hours Daytime Nighttime
o-|—--—1———i-—1—--
Figure 1. Mean (SD) changes in ambulatory (A) systolic blood pressure (SBP) and (B) diastolic blood pressure (DBP) from baseline to study end in adults with moderate hypertension treated for 8 weeks with olmesartan 20 mg QD or telmisartan 80 mg QD followed by the addition of hydrochlorothiazide (HCTZ) 12.5 mg for 8 weeks (in both groups, all changes from baseline were statistically significant; P < 0.001). Olmesartan versus telmisartan: *P = 0.014; +P = 0.02; *P = 0.011; §P = 0.016; HP = 0.023; 'P = 0.004.
□ Olmesartan/HCTZ
□ Telmisartan/HCTZ
24 Hours
Daytime
Nighttime
j____i
24 Hours
Qr CQ Q
Daytime
Nighttime
j____i
Figure 2. Mean (SD) changes in ambulatory (A) systolic blood pressure (SBP) and (B) diastolic blood pressure (DBP) induced by the addition of hydrochlorothiazide (HCTZ) 12.5 mg for 8 weeks to olmesartan or telmisartan monotherapy in adults with moderate hypertension not previously controlled on 8 weeks of monotherapy. Telmisartan versus olmesartan: *P = 0.002; tp = 0.009; +P < 0.001; §P < 0.007.
■ Olmesartan/HCTZ □ Telmisartan/HCTZ
Time (h)
8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 1 2 3 4 5 6 7
■00 _9 -X ^ '
£ -3-
<1 -4H
-5--6-
E -1.5-E
£ -2.0-Q
« -2.5--3.0--3.5-
Time (h)
8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 1 2 3 4 5 6 7
Figure 3. Mean changes in hourly (A) systolic blood pressure (SBP) and (B) diastolic blood pressure (DBP) induced by the addition of hydrochlorothiazide (HCTZ) 12.5 mg for 8 weeks to olmesartan 20 mg QD or telmisartan 80 mg QD monotherapy in adults with moderate hypertension. *P < 0.01 versus the olmesartan group; +P < 0.05 versus the olmesartan group.
Table III. Mean (SD) trough/peak (T/P) ratio and smoothness index (SI) after 8 weeks of treatment with olmesartan 20 mg/hydrochlorothiazide (HCTZ) 12.5 mg QD and telmisartan 80 mg/HCTZ 12.5 mg QD.
Variable T/P Ratio SI
Olmesartan/HCTZ 0.56 (0.34) 2.54 (1.62)
Telmisartan/HCTZ 0.59 (0.33) 2.96 (1.66) DBP
Olmesartan/HCTZ 0.54 (0.28) 2.01 (1.08)
Telmisartan/HCTZ 0.61 (0.31) 2.49 (1.01)
SBP = systolic blood pressure; DBP = diastolic blood pressure.
Table IV. Mean (SD) blood pressure (BP) and heart rate (HR) monitored in the clinic at baseline and after olmesartan 20 mg QD or telmisartan 80 mg QD monotherapy (8 weeks) and olmesartan/hydrochlorothiazide (HCTZ) 12.5 mg or telmisartan/HCTZ 12.5 mg (16 weeks).
Variable Baseline Monotherapy + HCTZ
SBP, mm Hg
Olmesartan 170.5 (12.6) 153.1 (6.4)* 145.3 (6.1)f
Telmisartan 170.1 (12.1) 150.7 (6.1)* 140.1 (6.4)"
DBP, mm Hg
Olmesartan 104.1 (7.5) 94.2 (5.2)* 88.1 (5.IF
Telmisartan 103.7 (7.1) 93.3 (4.7)* 84.9 (4.9)"
HR, beats/min
Olmesartan 75.5 (7.4) 74.9 (6.9) 75.1 (6.8)
Telmisartan 75.3 (7.2) 75.1 (6.7) 75.4 (6.6)
SBP = systolic BP; DBP = diastolic BP *P < 0.01 versus baseline. T P < 0.001 versus baseline, ■fp < 0.05 versus olmesartan.
2 combination therapies and was similar to the rate observed with the corresponding monotherapy (3 patients [596] complained of nausea and headache with olmesartan and 2 [396] complained of nausea and fatigue with telmisartan). No serious AEs were considered to be possibly or probably related to the trial medications. No patient withdrew from the study because of AEs and no serious AEs were reported.
Based on counting the remaining tablets at each visit, 93% of the prescribed tablets were taken during telmisartan/HCTZ therapy and 9296 during olmesartan/HCTZ therapy, indicating good overall treatment compliance.
DISCUSSION
The results of the present study indicated that in moderately hypertensive patients combination therapy with both olmesartan 20 mg/HCTZ 12.5 mg and telmisartan 80 mg/ HCTZ 12.5 mg provided a clinically meaningful antihypertensive effect that was greater than that obtained with monotherapy. This is consistent with previous studies that reported that the addition of HCTZ enhanced the efficacy of telmisartan24-27 and olmesartan.16,28,29 However, the BP decrease resulting from the addition of HCTZ to telmisartan monotherapy was significantly greater than that observed when HCTZ was added to olmesartan monotherapy. This was true for SBP and DBP 24-hour mean values, as well as for daytime and nighttime mean values.
The clinic BP findings confirmed that the antihypertensive effect of telmisartan/ HCTZ combination therapy was superior to that of olmesartan/HCTZ at the end of the dosing interval after 8 weeks of combination treatment. These findings also confirmed that the add-on effect of HCTZ 12.5 mg administration as compared with monotherapy was significantly greater in the telmisartan group than that in the olmesartan group.
A limitation of this study was the lack of a control group that received either no therapy or HCTZ monotherapy, as we were not able to exclude the possibility that some of the BP reduction was temporal. However, our findings agree with those of a previous study30 that found that HCTZ added to the ARB valsartan was more effective than when added to olmesartan in reducing BP values in moderately hypertensive patients inadequately controlled by monotherapy. In that study, plasma concentrations of HCTZ, which were determined after 8 weeks of combination therapy, were significantly greater in patients treated with valsartan/HCTZ than in those treated with olmesartan/HCTZ at each determination time (2, 4, and 24 hours after drug intake: 8.8 ng/mL, P < 0.05; 11.3 ng/mL, P < 0.05; 11.5 ng/mL, P < 0.05, respectively). This suggested that concomitant administration of olmesartan and HCTZ might decrease the bioavailability of HCTZ, at least at a dose of 12.5 mg. Although we did not determine HCTZ plasma concentrations, we hypothesize that the different pharmacokinetic profiles of telmisartan and olmesartan31,32 might result in a different pharmacokinetic interaction with low-dose HCTZ. Further data, however, are needed to confirm this hypothesis.
Because a continuous and graded relationship exists between BP values and cardiovascular risk, lower BP values are associated with better outcomes in a broad range of patients.33,34 A number of studies have shown that even minor decreases in BP are associated with a reduction in hypertension-related morbidity and mortality, particularly in high-risk patients.35 In the Heart Outcomes Prevention Evaluation study,7 a 3—mm Hg SBP reduction was associated with a 22% decrease in cardiovascular events (P < 0.001). Similarly, in the Felodipine Event Reduction study,36 an SBP/DBP reduction of 3.5/1.5 mm Hg was associated with a 28% reduction in cardiovascular end points (P < 0.001), and in the Study on Cognition and Prognosis in the Elderly,37 an SBP/DBP reduction of 3.2/1.6 mm Hg was associated with a significant decrease in the incidence of nonfatal stroke (P = 0.04). Thus, the modestly greater decrease in SBP/DBP values we observed with telmisartan/ HCTZ combination therapy might be clinically relevant in terms of cardiovascular protection.
When assessing the duration of the hypotensive action over 24 hours, the T/P ratios for SBP and DBP obtained with both olmesartan/HCTZ and telmisartan/HCTZ given once daily fulfilled the FDA guidelines38 (T/P ratio >50%) with no significant difference in the ratio between the 2 regimens. The observed T/P ratios indicated that the antihypertensive effect of both combination therapies was sustained throughout the entire 24-hour period, making them suitable for once-daily administration. The SI, which provides information about the homogeneity of the antihypertensive effect,22'23 was similar in the 2 treatment groups. A greater T/P ratio and SI value reflects less variability in BP, which has been demonstrated to have an independent effect on organ damage and disease prognosis.39
Both combination therapies were well tolerated. The incidence of AEs was comparable in the olmesartan/HCTZ and the telmisartan/HCTZ groups (7% and 6%, respectively) and similar to the rates observed with monotherapy. The AEs were of mild or moderate intensity and transient in duration. This is in line with the tolerability profiles of ARBs when administered alone or in combination with HCTZ.12-15
CONCLUSION
With the limitations due to the open design and the relatively short duration of treatment, findings of the present study indicated that in these adults with moderate hypertension not adequately controlled with monotherapy, the addition of HCTZ 12.5 mg to telmisar-tan 80 mg monotherapy was associated with greater ambulatory and clinic BP reductions than the addition of the same dose of HCTZ to olmesartan 20 mg monotherapy.
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Address correspondence to: Roberto Fogari, MD, Department of Internal Medicine and Therapeutics, Centro per l'lpertensione e la Fisiopatologia Cardiovascolare, P. le Golgi, 19 27100 Pavia, Italy. E-mail: r.fogari@unipv.it
