Dose-Related Antihypertensive Effects of Irbesartan in Patients With Mild-to-Moderate Hypertension

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1998;11:462– 470

Dose-Related Antihypertensive Effects of Irbesartan in Patients With Mild-to-Moderate Hypertension James L. Pool, Robert M. Guthrie, Thomas W. Littlejohn III, Philip Raskin, Alexander M.M. Shephard, Michael A. Weber, Matthew R. Weir, Thomas W. Wilson, James Wright, Kenneth B. Kassler-Taub, and Richard A. Reeves Two multicenter, double-blind, placebo-controlled, parallel group studies were conducted to evaluate the efficacy, safety, pharmacokinetics, and pharmacodynamics of the angiotensin II receptor (AT1 subtype) antagonist irbesartan. The effect of irbesartan withdrawal and the effect of adding hydrochlorothiazide (HCTZ) to irbesartan were also assessed. After a placebo lead-in phase, all patients were randomized to 8 weeks of double-blind therapy with either placebo (n 5 158) or irbesartan at doses of 1, 5, 10, 25, 50, 100, 200, or 300 mg (n 5 731 total) orally once daily. Irbesartan reduced blood pressure in a dose-related manner. Reductions from baseline in trough seated diastolic blood pressure ranged from 7.5 mm Hg for 50 mg irbesartan to 11.6 mm Hg for 300 mg irbesartan. At week 8, statistically significant reductions over placebo were observed in trough seated blood pressure with all irbesartan doses > 50 mg. These reductions reached statistical significance versus placebo within 2 weeks with 100, 200, and 300 mg irbesartan. Plasma irbesartan

concentrations correlated with dose. Angiotensin II and aldosterone levels generally showed dose-related changes, consistent with AT1 receptor blockade. In patients not controlled at 8 weeks, the addition of 12.5 mg HCTZ resulted in further dose-related reductions in blood pressure. Irbesartan demonstrated a placebo-like safety profile and no dose-related toxicity. Irbesartan, administered alone or in combination with HCTZ, was well tolerated. Withdrawal of irbesartan did not result in rebound hypertension or adverse events. Thus, once-daily irbesartan is both an effective and safe antihypertensive agent for the treatment of mild-tomoderate hypertension. Am J Hypertens 1998; 11:462–470 © 1998 American Journal of Hypertension, Ltd.

KEY WORDS:

Irbesartan, angiotensin II receptor antagonist, hypertension, plasma renin activity, drug withdrawal.

rbesartan (SR 47436, BMS-186295) is a potent, long-acting angiotensin II receptor antagonist with high selectivity for the AT1 receptor subtype.1–5 In healthy volunteers, irbesartan doses $ 25 mg increased renin and angiotensin II for 24 h

I

after drug administration, suggesting a long duration of action.4 A double-blind, placebo-controlled pilot study in patients with mild-to-moderate essential hypertension demonstrated that 1 week of oral irbesartan once daily (1, 25, and 100 mg) was well tolerated,

Received June 10, 1997. Accepted November 3, 1997. From the Departments of Medicine and Pharmacology, Baylor College of Medicine, Houston, Texas (JLP); Ohio State University College of Medicine, Columbus, Ohio (RMG); Piedmont Research Associates, Inc., Winston-Salem, North Carolina (TWL); University of Texas Southwestern Medical Center, Dallas, Texas (PR); University of Texas Health Science Center, San Antonio, Texas (AMMS); Research Medical Clinic, Long Beach, California (MAW); University of Maryland Hospital, Baltimore, Maryland (MRW); Royal Univer-

sity Hospital, Saskatoon, Saskatchewan, Canada (TWW); University Hospital, University of British Columbia Site, Vancouver, British Columbia, Canada (JW); and Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey (KBK-T, RAR). Address correspondence and reprint requests to James L. Pool, MD, Professor of Medicine and Pharmacology, Baylor College of Medicine, 6535 Fannin, Mail Station F-504, Houston, TX 77030; e-mail: [email protected]

© 1998 by the American Journal of Hypertension, Ltd. Published by Elsevier Science, Inc.

0895-7061/98/$19.00 PII S0895-7061(97)00501-3

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and that 100 mg significantly reduced blood pressure for 24 h.1 In this article, we present the results of two doseranging studies of similar design. These studies were designed to further assess the antihypertensive efficacy, safety, pharmacokinetics, and pharmacodynamics of oral irbesartan. The effect of irbesartan withdrawal and the effect of adding hydrochlorothiazide (HCTZ) to irbesartan therapy were also assessed. METHODS Patient Selection The men and women in this study were 18 years of age or older and had a well-established history of mild-to-moderate essential hypertension (or, if newly diagnosed, a diastolic blood pressure [DBP] $ 95 mm Hg). The women were surgically sterile or postmenopausal. The exclusion criteria pertained to specific concomitant diseases that would present safety hazards, or to concomitant medications that might interfere with the assessment of the safety or efficacy of irbesartan. Study Design The two studies were conducted at 79 clinical centers in the US and Canada. Both studies began with a 4- to 5-week, single-blind lead-in phase in which patients ingested four placebo capsules every morning. (All antihypertensive medications were withdrawn after written informed consent and prior to the lead-in phase.) During this phase, seated DBP (SeDBP) measurements taken on days 22 and 29 (6 3 days) (optionally on days 29 and 36) had to be between 95 and 110 mm Hg inclusive, and the two measurements could not differ by . 8 mm Hg. An 8-week, double-blind, parallel group phase followed in which patients were randomized to one of the following treatment groups: 1, 5, 10, 25, 50, or 100 mg irbesartan or placebo (four capsules once daily) in Study 1, and 100, 200, or 300 mg irbesartan or placebo (three capsules once daily) in Study 2. Patients were monitored at 2-week intervals. After 8 weeks of double-blind therapy in Study 1, all patients ingested four single-blind placebo capsules once daily during a 1-week withdrawal period. Patients were seen on day 2 or 3 and day 6 or 7. After 8 weeks of double-blind therapy in Study 2, all patients continued double-blind therapy for an additional 2 weeks; however, patients whose blood pressure was not normalized at week 8 (trough SeDBP $ 90 mm Hg) also received open-label 12.5 mg HCTZ once daily. Observation Methods Efficacy At all clinic visits, trough (24 6 3 h after ingestion of study medication) seated and standing blood pressures were measured. Peak (defined as 3 6 1 h after the last dose of study medication) seated and

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standing blood pressures were measured on day 1 and at week 8. Blood pressure was measured using a mercury sphygmomanometer after 10 min of rest in the seated position. Three replicate measurements were taken 2 min apart. If the three SeDBP readings were not within 8 mm Hg of each other, an additional two readings were obtained and incorporated into the calculated mean. After 2 min of standing, three (or five) blood pressure measurements were similarly obtained. Pharmacokinetics and Pharmacodynamics In Study 1, venous blood samples were obtained at baseline (pharmacodynamic assessment only), after the first dose of double-blind study medication (peak only) and at week 8 (peak and trough) for plasma irbesartan concentration, plasma renin activity (PRA), and angiotensin II and aldosterone concentrations. PRA and angiotensin II samples were collected only at study sites with the requisite equipment and expertise, and were assayed only for the placebo, 50 mg irbesartan, and 100 mg irbesartan groups. Aldosterone assays were done for all patients at all sites. Irbesartan was analyzed by a validated high-performance liquid chromatographic procedure with fluorescence detection. Renin-angiotensin system (RAS) components were measured using commercially available radioimmunoassay kits that had demonstrated low crossreactivity with irbesartan. Safety Adverse events were recorded at all visits. At the end of the placebo lead-in phase, at weeks 4 and 8 of double-blind therapy, and after the HCTZ period in Study 2, blood and urine samples were obtained for standard laboratory tests. STATISTICAL METHODS Demographic and Baseline Characteristics Quantitative data were analyzed using a one-way analysis of variance (ANOVA) with treatment group as the factor. Qualitative data were assessed using a x2 test. Efficacy and Pharmacodynamic Measurements Based on the results of earlier clinical studies, the doses studied herein were expected to range from the noeffect region (;1 mg) to the clinically useful dose range (100 to 300 mg). A plot of mean trough blood pressure responses for the current studies suggested that this was the case, plus its shape resembled the lower half of a sigmoidal log(dose)-response curve, ie, the predicted shape for a receptor-antagonist drug.6 A quadratic function has been found to reasonably approximate the shape of the no-effect ‘‘knee’’ and early linear portions.7 Accordingly, after subtraction of the particular study’s mean placebo group change from baseline to 8 weeks, each available patient’s diastolic and systolic blood pressure reduction was plotted ver-

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sus log10(dose). After setting the placebo dose to 0.5 mg [to avoid the problem of log(0 mg)], the diastolic and systolic blood pressure data were fitted by separate second-order polynomial models. Because irbesartan is devoid of agonist properties,2 the curves have not been plotted below the point where the predicted blood pressure reduction equals 0. Analysis of covariance (ANCOVA) was used to compare the treatment groups with regard to changes from baseline in trough blood pressure. The ANCOVA model included terms for treatment, site, and baseline blood pressure. Individual treatment groups were compared with each other using t tests generated from the ANCOVA. Peak blood pressure, and blood pressure during the withdrawal period in Study 1, were analyzed similarly, except the model only included terms for treatment and baseline. Trough:peak ratios were calculated for SeDBP at week 8. A placebo-adjusted peak was computed for each of the irbesartan groups by first subtracting the placebo group’s change from baseline from the irbesartan group’s change from baseline. The placeboadjusted trough values were calculated similarly. Treatment comparisons were carried out on the proportion of patients normalized (trough SeDBP , 90 mm Hg) at week 8 using the Cochran-Mantel Haenszel test, stratified by site. In Study 1, Pearson product moment correlation coefficients between the RAS components, plasma irbesartan concentrations, and change from baseline to week 8 in trough SeDBP were calculated. All statistical tests were two-sided and carried out at a significance level of a 5 0.05. RESULTS

TABLE 1. DEMOGRAPHIC AND BASELINE CHARACTERISTICS Characteristic Gender Male Female Race White Black Other Age Mean, years (SD) , 65 years $ 65 years Baseline SeDBP Mean, mm Hg (SD) , 104 mm Hg $ 104 mm Hg Baseline SeSBP Mean, mm Hg (SD)

Study 1 (n 5 570)

Study 2 (n 5 319)

67% 33%

69% 31%

81% 16% 3%

83% 13% 4%

54.2 (10.3) 84% 16%

52.8 (10.2) 88% 12%

101.0 (4.3) 71% 29%

100.7 (4.2) 76% 24%

152.9 (14.4)

149.8 (13.6)

SeDBP, seated diastolic blood pressure; SeSBP, seated systolic blood pressure; SD, standard deviation.

significantly different from placebo. At week 8, statistically significant reductions over placebo were observed in trough SeDBP with all irbesartan doses $ 50 mg (Table 2). Irbesartan also significantly reduced trough SeSBP over placebo with all doses $ 100 mg. Irbesartan also reduced standing blood pressure to a similar extent as that observed for seated blood pressure (data omitted for brevity). Reductions in Peak Seated Blood Pressure At week 8, statistically significant, dose-related reductions over placebo were observed in peak SeDBP and SeSBP with all irbesartan doses $ 50 mg (Table 2).

Demographic and Baseline Characteristics A total of 889 patients were randomized (570 in Study 1 and 319 in Study 2). Within each study, no statistically significant differences were observed among the treatment groups. Baseline blood pressure and demographics were very similar in the two studies (Table 1).

Trough:Peak Ratios Trough:peak ratios for SeDBP at week 8, corrected for the parallel placebo group pattern, were . 55% for all irbesartan doses $ 50 mg (Table 2).

Primary Efficacy Measurements Figure 1 shows the mean reductions from baseline (less placebo values) in trough blood pressure for each dose group and the best-fit quadratic curves (n 5 813 patients). Both the systolic and diastolic blood pressure models were statistically significant (P , .0001). For trough SeDBP, both the linear and quadratic terms were significant (P , .002), indicative of a curvilinear dose-response relationship in this dose range. For trough seated systolic blood pressure (SeSBP), the linear term was significant (P , .0001) and the quadratic term was marginally significant (P 5 .078). Blood pressure responses to the lowest doses of irbesartan, 1 to 25 mg daily, were inconsistent and not

Therapeutic Response At week 8, the percentage of patients normalized (trough SeDBP , 90 mm Hg) was statistically significantly greater with 100 mg (Study 2 only), 200 mg, and 300 mg irbesartan than with placebo (Figure 2). Although no statistical analysis was performed, the percentage of patients who responded (defined as normalized or trough SeDBP reduction $ 10 mm Hg) at week 8 was greater in each irbesartan group than in the placebo group (Figure 2). A general dose-response relationship was apparent. Irbesartan at a dose of 300 mg normalized blood pressure in 60% (47 of 78) of patients (P , .01 v placebo) and was associated with the greatest percentage of responders, 67% (52 of 78).

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FIGURE 1. a. Mean trough SeDBP reductions at 8 weeks and best-fit quadratic model (n 5 813). b. Mean trough SeSBP reductions at 8 weeks and bestfit quadratic model (n 5 813).

Time Course of Blood Pressure Reduction Reductions over placebo in trough SeDBP reached statistical significance by week 2 with 100, 200, and 300 mg irbesartan, and by week 4 with 50 mg irbesartan (Fig-

ure 3). These blood pressure reductions remained statistically significant at all subsequent visits during double-blind therapy. Similar results were observed for trough SeSBP (data not shown).

TABLE 2. REDUCTIONS IN TROUGH AND PEAK SEATED BLOOD PRESSURES AND ESTIMATED TROUGH:PEAK RATIOS FOR SEATED DIASTOLIC BLOOD PRESSURE AT WEEK 8 Irbesartan Once-Daily Dose, mg 50 (Study 1) Trough BP N Adjusted mean change in SeDBP, mm Hg (SE) SeSBP, mm Hg (SE) Peak BP N Adjusted mean change in SeDBP, mm Hg (SE) SeSBP, mm Hg (SE) Estimated trough: peak ratio

77 27.5 (0.78)* 27.9 (1.36) 73 210.4 (0.94)† 210.1 (1.52)* 65%

100 (Study 1) 73 28.4 (0.81)† 210.1 (1.42)† 69 210.5 (0.96)† 212.6 (1.57)† 72%

100 (Study 2) 79 29.7 (0.85)† 210.5 (1.32)† 66 212.9 (1.11)† 214.6 (1.53)† 58%

200 (Study 2) 75 29.8 (0.85)† 210.1 (1.33)† 67 212.9 (1.10)† 215.2 (1.52)† 62%

300 (Study 2) 78 211.6 (0.85)† 213.0 (1.33)† 70 214.2 (1.07)† 216.7 (1.48)† 69%

SE, standard error; BP, blood pressure; SeDBP, seated diastolic blood pressure; SeSBP, seated systolic blood pressure. * P , .05 versus placebo. † P , .01 versus placebo.

Placebo (Study 1) 74 25.3 (0.80) 24.3 (1.40) 70 26.1 (0.96) 25.2 (1.55) —

Placebo (Study 2) 73 25.5 (0.87) 25.0 (1.37) 60 25.8 (1.16) 24.9 (1.61) —

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FIGURE 2. Percentage of patients normalized (trough seated diastolic blood pressure , 90 mm Hg) and percentage of responders (normalized or reduction in trough SeDBP $ 10 mm Hg from baseline).

Subgroup Analyses In both studies, the reductions from baseline in trough blood pressure were of similar magnitude for the subgroups of gender and age (, 65 and $ 65 years of age). Although the reductions appeared somewhat smaller in blacks, the number of elderly and black patients was too small to allow definite conclusions. Effect of Irbesartan Withdrawal Following withdrawal of double-blind therapy in Study 1, reductions in trough SeDBP for each treatment group became smaller (Figure 3). However, there was no indication of rebound hypertension and, at the last visit, the 50 and 100 mg irbesartan groups still showed a statistically significant advantage over placebo of 2.8 and 3.1 mm Hg, respectively. Similar results were observed for trough SeSBP (data not shown).

Effect of Adding HCTZ in Nonresponders In Study 2, as expected, before addition of HCTZ the blood pressure reduction among the nonresponders (Figure 4) was less than that in the total study population (Table 2). The addition of 12.5 mg HCTZ daily for 2 weeks resulted in further dose-related decreases in blood pressure (Figure 4). The additional SeDBP reductions ranged from 1.6 mm Hg in the placebo group to 7.7 mm Hg in the 300 mg irbesartan group. The corresponding additional SeSBP reductions ranged from 0.3 to 12.0 mm Hg. Pharmacokinetics and Pharmacodynamics Plasma irbesartan concentrations in Study 1 increased with increasing doses at both peak and trough time points, without evidence of accumulation at peak from day 1 to week 8 (Table 3). At the peak time point on day 1 and

FIGURE 3. Time course of blood pressure response to irbesartan and the effect of irbesartan withdrawal.

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FIGURE 4. Unadjusted mean changes from baseline in trough seated diastolic and systolic blood pressure in patients requiring the addition of 12.5 mg HCTZ for trough seated diastolic blood pressure $ 90 mm Hg at week 8 (Study 2).

week 8, PRA and angiotensin II concentrations were greater (;1- to 3-fold over baseline) in the 50 and 100 mg irbesartan groups than in the placebo group, whereas suppression of plasma aldosterone generally increased with increasing dose (Table 3). At the trough time point at week 8, there were persistent elevations in PRA and angiotensin II concentrations, suggesting a 24-h duration of angiotensin II receptor blockade (Table 3).

Reductions at week 8 in trough SeDBP were statistically significantly correlated with peak PRA on day 1 and week 8, peak plasma angiotensin II and aldosterone concentrations at week 8 (inverse), and peak plasma irbesartan concentrations on day 1 and week 8 (Table 4). However, the blood pressure response to 50 or 100 mg irbesartan at week 8 was not related to baseline PRA or angiotensin II.

TABLE 3. PLASMA IRBESARTAN CONCENTRATION AND EFFECT OF IRBESARTAN ON RAS COMPONENTS Variable Median plasma irbesartan concentration, ng/mL Placebo Irbesartan 1 mg Irbesartan 5 mg Irbesartan 10 mg Irbesartan 25 mg Irbesartan 50 mg Irbesartan 100 mg Mean plasma PRA, ng AI/mL/h Placebo Irbesartan 50 mg Irbesartan 100 mg Mean plasma angiotensin II, pg/mL Placebo Irbesartan 50 mg Irbesartan 100 mg Mean plasma aldosterone, pg/mL Placebo Irbesartan 1 mg Irbesartan 5 mg Irbesartan 10 mg Irbesartan 25 mg Irbesartan 50 mg Irbesartan 100 mg

Baseline 0 0 0 0 0 0 0

Day 1 Peak 0 15 81 151 445 647 1376

Week 8 Peak 0 19 78 158 374 625 1328

Week 8 Trough 0 0 0 0 20 43 96

2.1 1.7 1.6

2.9 3.0 3.7

2.9 3.5 4.8

1.5 3.4 3.4

20.9 17.2 15.2

23.0 24.9 27.2

23.2 25.0 39.8

18.7 23.5 25.9

13.9 14.0 13.7 13.9 15.5 14.6 13.7

13.0 11.7 9.9 9.2 8.9 9.5 9.6

14.6 12.7 10.3 10.7 9.7 9.4 10.0

14.2 15.4 12.8 12.9 14.5 15.5 14.0

RAS, renin-angiotensin system; PRA, plasma renin activity; AI, angiotensin I.

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TABLE 4. CORRELATION BETWEEN CHANGE FROM BASELINE IN TROUGH SEATED DIASTOLIC BLOOD PRESSURE AT WEEK 8 AND THE RAS COMPONENTS AND PLASMA IRBESARTAN CONCENTRATION Variable, Time Point Baseline PRA Baseline plasma angiotensin II Baseline aldosterone Peak PRA, day 1 Trough PRA, week 8 Peak PRA, week 8 Peak plasma angiotensin II, day 1 Trough plasma angiotensin II, week 8 Peak plasma angiotensin II, week 8 Peak plasma aldosterone, day 1 Trough plasma aldosterone, week 8 Peak plasma aldosterone, week 8 Peak irbesartan plasma concentration, day 1 Peak irbesartan plasma concentration, week 8

n 108 109 207 105 107 107 110

r

P

20.15 .13 0.08 .39 0.04 .55 20.18 .06 20.15 .12 20.33 , .001 20.01 .90

108 20.04 106 20.16 209 10.10

.71 .10 .14

208 10.05

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211 10.15 , .03 216 20.17 215 20.22

.01 , .002

PRA, plasma renin activity; RAS, renin-angiotensin system.

Safety All doses of irbesartan were well tolerated without evidence of dose-related adverse events (Table 5). Discontinuation rates also showed no evident relationship to irbesartan dose (Table 6). Overall, , 1% of patients in both groups reported a serious ad-

verse event. None were deemed related to the study medication by the investigators. There were no deaths. No new or worsening adverse events were reported following irbesartan withdrawal in Study 1. In Study 2, 15.6% (15 of 96 patients) treated with irbesartan plus HCTZ and 6.4% (3 of 47 patients) treated with placebo plus HCTZ reported at least one adverse event. After HCTZ was added, no patient discontinued the study medication. Analysis of laboratory parameters, including potassium, uric acid, blood urea nitrogen, and creatinine revealed no clinically important trends. DISCUSSION These two dose-ranging studies are the first large scale trials of the angiotensin II receptor antagonist irbesartan. Selective angiotensin II receptor antagonists represent a new class of antihypertensive agents that inhibit the RAS through blockade of the AT1 subtype of angiotensin II receptors.8 In preclinical models, irbesartan has demonstrated a dose-response effect, as expected for a receptor antagonist. In the present studies, daily doses of 50 through 300 mg irbesartan for up to 8 weeks significantly reduced blood pressure in a dose-related manner in patients with mild-to-moderate essential hypertension. Taken together, these two studies demonstrate the existence of a relationship between irbesartan dose and antihypertensive effect, at least up to 300 mg daily. The major portion of the antihypertensive effect of irbesartan was evident within 2 weeks of starting therapy, with the maximum effect seen between 2 and 6

TABLE 5. FREQUENCY (IN %) OF ALL ADVERSE EVENTS, REGARDLESS OF THE RELATIONSHIP TO STUDY DRUG, OCCURRING IN AT LEAST 3% OF PATIENTS TREATED WITH EITHER IRBESARTAN OR PLACEBO DURING DOUBLE-BLIND THERAPY Irbesartan Once-Daily Dose, mg Adverse Event Headache Upper respiratory infection Musculoskeletal pain Dizziness Fatigue Diarrhea Sinus abnormality Cough Nausea/vomiting Edema Abdominal pain Ear infection Total number of adverse events Total number (%) of patients with at least one adverse event

1–25 (n 5 328)

50 (n 5 82)

100 (n 5 163)

200 (n 5 79)

300 (n 5 79)

All Irbesartan (n 5 731)

Placebo (n 5 158)

14.6 8.8 5.2 3.7 2.4 1.2 2.7 2.1 1.5 0.9 1.2 0 313

14.6 14.6 7.3 4.9 3.7 4.9 3.7 3.7 3.7 0 1.2 0 88

9.8 11.7 6.1 6.7 4.3 3.7 3.7 3.7 1.8 1.2 1.8 0 190

7.6 0 12.7 2.5 6.3 7.6 2.5 3.8 1.3 2.5 0 1.3 89

13.9 7.6 6.3 3.8 6.3 5.1 1.3 0 0 5.1 1.3 0 71

12.7 9.0 6.6 4.4 3.8 3.3 2.9 2.6 1.6 1.5 1.2 0.1 751

15.8 5.1 6.3 5.1 3.8 3.8 3.8 3.2 3.2 3.8 3.8 3.2 175

382 (52.3)

87 (55.1)

172 (52.4) 48 (58.5)

86 (52.8)

41 (51.9) 35 (44.3)

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TABLE 6. NUMBER (%) OF PATIENTS DISCONTINUED DUE TO ADVERSE EVENTS Irbesartan Once-Daily Dose, mg Study

1–25

50

100

200

300

Placebo

1 2 Total

19 (5.8) — 19 (5.8)

2 (2.4) — 2 (2.4)

1 (1.2) 0 1 (0.6)

— 2 (2.5) 2 (2.5)

— 0 0

1 (1.3) 2 (2.5) 3 (1.9)

weeks. The magnitude of blood pressure reduction from 2 weeks onwards was both statistically and clinically significant. At daily doses of 100 through 300 mg, irbesartan produced placebo-adjusted reductions in trough SeDBP of 3.1 to 6.1 mm Hg, which is in the range that has been associated with an important reduction in the risk from hypertension of stroke, coronary heart disease, and death.9 For patients not controlled by irbesartan alone, the addition of HCTZ produced further dose-related reductions in blood pressure. The effect was additive and consistent with the effects seen with the addition of diuretics to angiotensin converting enzyme (ACE) inhibitors and other agents that interrupt the RAS system.10,11 The RAS changes observed on day 1 and week 8 at approximately 3 h after dosing are consistent with blockade by irbesartan of the angiotensin II AT1 receptor-mediated aldosterone release and tonic inhibition of renin release. RAS assessments at the week 8 trough suggest that irbesartan provides at least a 24-h duration of AT1 receptor blockade during long-term use. These results are consistent with the duration of RAS changes and antagonism of angiotensin II pressor effects seen after single 50 and 100 mg doses in healthy volunteers.5 Plasma renin activity has been suggested as a possible guide to the choice of initial antihypertensive therapy; however, there is considerable controversy about its use,12 because pretreatment PRA explains , 10% of the variability in antihypertensive response.13 In the present study, baseline PRA also showed only a weak ability to predict blood pressure response (r 5 20.15; P 5 .13). Irbesartan demonstrated an excellent tolerability profile with no evidence of dose-related toxicity. Cough, a class effect of ACE inhibitors,14 was reported by a slightly lower percentage of patients in the irbesartan group (2.6%) compared with the placebo group (3.2%). Edema, a frequently reported adverse event associated with calcium channel blocker therapy (14% to 15% incidence),15,16 was also reported by a lower percentage of patients in the irbesartan group (1.5%) compared with the placebo group (3.8%). Fatigue, an adverse event associated with thiazide diuretics and

b-blockers,17,18 was reported by 3.8% of patients in both the irbesartan and placebo groups. The combination of irbesartan plus HCTZ was also well tolerated. Irbesartan withdrawal did not lead to excessive increases in blood pressure or adverse events, suggesting that irbesartan can be discontinued without dose-tapering and that occasional missed doses should not lead to a loss of blood pressure control. In conclusion, once-daily irbesartan is both an effective and very well-tolerated antihypertensive agent for the treatment of hypertension and has the potential to be a significant addition to the antihypertensive armamentarium. REFERENCES 1.

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de Bruijn B, Cocco G, Tyler HM: Multicenter placebocontrolled comparison of amlodipine and atenolol in mild to moderate hypertension. J Cardiovasc Pharmacol 1988;12(suppl 7):S107–S109. 16. Chan JCN, Critchley JAJH, Lappe JT, et al: Randomised, double-blind, parallel study of the anti-hypertensive efficacy and safety of losartan potassium compared with felodipine ER in elderly patients with mild to moderate hypertension. J Hum Hypertens 1995;9: 765–771. 17. Goldberg AI, Dunlay MC, Sweet CS: Safety and tolerability of losartan potassium, an angiotensin II receptor antagonist, compared with hydrochlorothiazide, atenolol, felodipine ER, and angiotensin-converting enzyme inhibitors for the treatment of systemic hypertension. Am J Cardiol 1995;75:793–795. 18. The Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: The sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of high blood pressure (JNC VI). Arch Intern Med 1997; 157:2413–2446.