a review of irbesartan in antihypertensive therapy: comparison with other antihypertensive agents

VOL. 62, No. 7, JULY 2001

A Review of lrbesartan in Antihypertensive Therapy: Comparison with Other Antihypertensive Agents Bernard Waeber, MD

Division of Clinical Pathophysiology and Medical Teaching, University Hospital, Lausanne, Switzerland

ABSTRACT Buckground: lrbesartan, an angiotensin 11 (Ail) receptor antagonist indi-

cated for the treatment of hypertension, has been found to be well tolerated and effective in reducing blood pressure in a dose-dependent manner.

OwecVve: The purpose of this article was to evaluate the literature on the efficacy and tolerability of irbesartan versus other agents commonly used in the treatment of hypertension.

M&/to&: A thorough search of databases such as MEDLlNE@/PubMed@ and Dialog was performed, and library resources were used to identify all clinical trials evaluating irbesartan versus other antihypertensive agents.

Rew/t.s: In the studies reviewed, irbesartan was found to be as effective in lowering blood pressure as comparator antihypertensive drugs belonging to different classes, including atenolol (beta-blocker), amlodipine (dihydropyridine calcium channel antagonist), hydrochlorothiazide (thiazide diuretic), and enalapril (angiotensin-converting enzyme inhibitor). In some studies, irbesartan was associated with a lower incidence of side effects than the comparator agent. In head-to-head clinical trials, irbesartan also demonstrated superior antihypertensive efficacy versus the All receptor antagonists losartan and valsartan.

Conc/usions: A review of the literature suggests that irbesartan provides antihypertensive efficacy that is comparable to or exceeds that of other antihypertensive agents while maintaining the good tolerability profile associated with the selective AI1 receptor antagonists.

Key words: irbesartan, hypertension, antihypertensive agents. (Curr Ther Res Clin Exp. 2001;62:505-523)

INTRODUCTION Hypertension is one of the leading causes of morbidity and mortality world- wide.’ Despite major efforts to diagnose and treat patients with high blood

Accepted for publication April 18, 200 1. Printed in the USA. Reproduction in whole or part is not permitted. 0011-393x/01/$1 9.00

505

CURRENT THERAPEUTIC RESEARCH@

pressure, only -1 of every 4 hypertensive patients in the United States achieves adequate blood pressure control (ie, <140/90 mm Hg) with currently available medications.‘*3 Although the low level of blood pressure control is attributable to several factors, a major contributor is the less-than-optimal tolerability profiles of most currently available antihypertensive agents.- For example, in a large survey on hypertension management, the percentage of patients with side effects was greater among those with poorly controlled blood pressure than in those with well-controlled blood pressure. The compliance rate was also lower among patients whose blood pressure was inadequately controlled.4 Uncon- trolled hypertension can have serious consequences; the risk of coronary heart disease, cerebrovascular disease, and renal impairment increases with elevated systemic blood pressure. Therefore, it appears worthwhile to expand the avail- ability of effective and well-tolerated antihypertensive agents with new mechanisms of action to enhance patient compliance.7

Angiotensin 11 (Ah) receptor antagonists, a newer class of antihypertensive agents, selectively block the AT, subtype of Al1 receptors, thus reducing the number of AI1 receptors available to bind to AIL8 Pharmacologic differences exist between drugs within this class that could result in different clinical profiles. This is especially true for duration of action. A sustained and smooth blood pressure-lowering effect is important to provide optimal protection against cardiovascular complications.

Irbesartan, an Al1 receptor antagonist, is indicated for the treatment of essential hypertension, alone or in combination with other antihypertensive agents.“” Clinical trials conducted in hypertensive patients have demonstrated that irbesartan is well tolerated” and effective in reducing blood pressure in a dose-dependent manner. ‘*,13 This review evaluates the results of controlled trials of irbesartan versus other agents commonly used in the treatment of hypertension.

METHODS A thorough search of databases such as MEDLINE@/PubMed@ and Dialog was conducted and library resources were used to identify all double-blind, controlled clinical trials conducted to date evaluating irbesartan versus other antihypertensive agents. Key words included but were not limited to the following: irbesatian, antihypertensive agents, and hypertension. The Table summarizes the studies reviewed in this paper.lP2’

IRBESARTAN VERSUS A BETA-BLOCKER Irbesartan and the beta-blocker atenolol were evaluated in a randomized, double-blind study to compare the antihypertensive efficacy and tolerability of the 2 agents. l4 A total of 231 patients with mild to moderate hypertension (seated diastolic blood pressure [SeDBP] between 95 mm Hg and 110 mm Hg)

B. Waeber

were randomized to receive irbesartan 75 mg once daily (n = 110) or atenolol 50 mg once daily (n = 121) for 24 weeks. If SeDBP was 290 mm Hg at week 6, doses were doubled. If SeDBP was 290 mm Hg at week 12, or any time there after, doses were doubled and open-label hydrochlorothiazide (HCTZ) or sustained-release nifedipine was added. By week 12,50% and 52% of the irbesartan- treated and atenolol-treated patients, respectively, were receiving the starting dose. At week 12,67% of irbesartan-treated patients and 61% of atenolol-treated patients were receiving monotherapy. Both treatments significantly lowered blood pressure through week 24 (Figure 1). There were no statistically significant differences between treatment groups. At week 12 (ie, before the addition of an adjunctive antihypertensive agent), the percentage of patients achieving normalized DBP (trough SeDBP 590 mm Hg) was slightly higher in the irbe sartan group (61%) than in the atenolol group (55%). The percentage of total responders (normalized DBP or a decrease in SeDBP of z~ 10 mm Hg) at week 12 was 72% in the irbesartan group compared with 63% in the atenolol group. The incidence of serious adverse events and discontinuations due to adverse events were higher in the atenolol-treated group compared with the irbesartan-treated group (3.3% vs 1.8%, and 9.1% vs 4.5%, respectively). Although there was no difference between groups in the overall incidence of adverse events, more patients receiving atenolol experienced fatigue, dizziness, and bradycardia compared with patients receiving irbesartan (7.4% vs 2.7%, 5.8% vs 2.7%, and 2.5% vs O%, respectively). Thus, irbesartan was at least as effective as atenolol in lowering blood pressure and was associated with a lower incidence of certain side effects than atenolol in this study population.

A second double-blind, randomized, 48week study15 compared the effects of irbesartan versus atenolol on the regression of left ventricular hypertrophy (LVH) in 115 male and female hypertensive patients with a left ventricular mass index (LVMI) of >131 g/m* and >lOO g/m*, respectively. Patients were randomized to receive irbesartan 150 mg once daily or atenolol 50 mg once daily. If at week 6 SeDBP was 290 mm Hg, doses were doubled; HCTZ or felodipine was added at &week intervals thereafter if SeDBP remained 290 mm Hg. By week 48, 34% of irbesartan-treated patients and 45% of atenolol-treated patients were receiving monotherapy. Both regimens produced similar reductions in blood pressure throughout the 48 weeks of treatment; however, LVH regressed earlier and to a greater degree with irbesartan therapy compared with atenolol therapy. At week 12, mean change from baseline in LVMI was -5.76 g/m* in the irbesartan group compared with -0.45 g/m* in the atenolol group. By week 48, mean change from baseline was -19.66 g/m* for irbesartan-treated patients and -11.97 g/m* for atenolol-treated patients. Drug-related adverse events were nearly 2-fold greater with atenolol treatment compared with irbesartan treatment (67% vs 34%). Thus, irbesartan reduced left ventricular mass more effectively than did atenolol and was better tolerated in this sample of patients with LVH and hypertension.

507

Tab

le.

Su

mm

ary

of

com

par

ativ

e an

tih

yper

ten

sive

tr

ials

in

volv

ing

irb

esar

tan

.

Stu

dy

Stu

dy

Po

pu

lati

on

S

tud

y D

esig

n

Reg

imen

s

Stu

mp

e et

alI4

23

1 p

atie

nts

wit

h

mild

to

mo

der

ate

hyp

erte

nsi

on

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an e

t al

” 11

5 h

yper

ten

sive

mal

e an

d f

emal

e p

atie

nts

wit

h

LV

MI

of

>131

g

/m2

and

>lO

O

g/m

’, re

spec

tive

ly

Neu

tel

et a

ll6

181

pat

ien

ts w

ith

m

ild t

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od

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sio

n

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hl

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ll7

47

hyp

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nsi

ve p

atie

nts

wit

h

typ

e 2

dia

bet

es m

ellit

us

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ran

et

all8

20

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t ven

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= h

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(6.2

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8.


A 0 Atenolol 50 or 100 mg/d 0 lrbesartan 75 or 150 mg/d

-241 I I I I I I I I I I I I 0 2 4 6 8 10 12 14 16 18 20 22 24

Week

-6-

-9 -

-12-

-15-

-18-

-21 -

-241 I I I I I I I I I I I I 0 2 4 6 8 10 12 14 16 18 20 22 24

Week

Figure 1. Mean change from baseline in (A) trough seated systolic blood pressure (SeSBP) and (B) trough seated diastolic blood pressure (SeDBP) in patients with mild to moderate hypertension treated with atenolol50 or 100 mg/d (n = 121) or irbesartan 75 or 150 mg/d (n = 110). Reprinted with permission from Stumpe et al.14

510

B. Waeber

IRBESARTAN VERSUS A CALCIUM CHANNEL ANTAGONIST The antihypertensive efficacy and tolerability of irbesartan were compared with those of amlodipine, a calcium channel antagonist, in patients with mild to moderate hypertension in a randomized, double-blind, parallel-group study.16 A total of 181 patients with mild to moderate hypertension were randomized to receive irbesartan 150 mg once daily (n = 89) or amlodipine 5 mg once daily (n = 92) for 4 weeks. After 4 weeks of treatment, there was no statistically significant difference in the degree of SeDBP reduction between the 2 regimens. The mean reduction from baseline in SeDBP was -9.4 mm Hg in the irbesartan group and -9.6 mm Hg in the amlodipine group. At week 4, the percentage of patients with normalized DBP was similar in the 2 treatment groups (54% in the irbesartan group and 56% in the amlodipine group). Sixty-two percent and 63% of patients treated with irbesartan and amlodipine, respectively, responded to therapy at 4 weeks. Adverse-event rates were similar in the 2 groups. Over the 4-week period, the starting doses of irbesartan and amlodipine were similarly effective and well tolerated.

Another 12-week, randomized, double-blind, active-controlled pilot s tudy was conducted to compare the effects of irbesartan (n = 24) with those of amlodipine (n = 23) in patients with hypertension (seated systolic blood pressure [SeSBP] 140-185 mm Hg, SeDBP 90-110 mm Hg, or receiving pharmacologic treatment for hypertension) and nephropathy secondary to type 2 diabetes. 17 The respective starting dosages of irbesartan and amlodipine were 75 mg once daily and 2.5 mg once daily. Irbesartan and amlodipine doses were doubled at weeks 4 and 8 for all patients. Patients receiving irbesartan had decreased urine protein excretion compared with baseline (mean change of -8.5%), whereas patients receiving amlodipine had increased urine protein excretion (mean change of +19.7%). Amlodipine also decreased creatinine clearance significantly more than did irbesartan (P < 0.01). Thus, while amlodipine decreased renal function (increased urine excretion and decreased creatinine clearance), irbesartan exhibited beneficial effects on renal function (decreased protein excretion). Both treatments similarly reduced trough SeDBP at all time points. Incidence of adverse events was higher in the amlodipine group than in the irbesartan group (61% vs 46%). Similarly, the incidence of serious adverse events was higher in patients treated with amlodipine compared with patients receiving irbesartan (22% vs 4%).

IRBESARTAN VERSUS AN ANGIOTENSIN-CONVERTING ENZYME INHIBITOR

Irbesartan Versus Enalapril in Patients with Mild to Moderate Hypertension Mimran et a118 conducted a randomized, double-blind, parallel-group s tudy to compare the efficacy and tolerability of irbesartan and enalapril, an angiotensin-

511


converting enzyme (ACE) inhibitor. A total of 200 patients with mild to moderate hypertension were randomized to receive irbesartan 75 mg once daily (n = 98) or enalapril 10 mg once daily (n = 102) for 12 weeks. Doses were doubled after 4 and/or 8 weeks of therapy if SeDBP was 290 mm Hg. Blood pressure was lowered significantly from baseline in both treatment groups (Figure 2) with no statistically significant differences between groups. At week 12, 66% and 63% of patients treated with irbesartan and enalapril, respectively, achieved normal DBP.

The overall incidence of adverse events was similar between treatment groups. The incidence of cough was greater in the enalapril group (17%) compared with the irbesartan group (10%). One patient (1%) in the irbesartan group and 3 patients (2.9%) in the enalapril group discontinued therapy due to adverse events. Thus, the efficacy and tolerability of irbesartan and enalapril were comparable, except for a lower incidence of cough in the irbesartan group, in this sample of patients with mild to moderate hypertension.

lrbesartan Versus Enalapril In Patients with Severe Hypertension A second randomized, double-blind, parallel-group trial comparing the efficacy and tolerability of irbesartan versus enalapril was conducted in patients with severe hypertension (SeDBP between 115 mm Hg and 130 mm Hg).” A total of 182 patients with severe hypertension were randomized in a 2:l ratio to receive irbesartan 150 mg once daily (n = 121) or enalapril 20 mg once daily (n = 61) for 12 weeks. At week 1, if SeDBP was 2106 mm Hg, the dose of the study drug could be doubled at the discretion of the investigator. If at week 2 SeDBP was 290 mm Hg, the dose of the study medication had to be doubled. Doses could also be titrated at the discretion of the investigator. If SeDBP was 290 mm Hg at week 4, open-label HCTZ was added, followed by long-acting nifedipine and/ or atenolol. By week 4,55% of patients in both treatment groups were receiving adjunct HCTZ and by week 12, 9% and 7% of irbesartan-treated and enalapril- treated patients, respectively, were receiving monotherapy. At week 12, both treatment groups experienced comparable reductions in SeDBP and SeSBP. Mean changes from baseline were -29.6/-40.1 mm Hg and -30.5/-39.3 mm Hg for the irbesartan- and enalapril-treated groups, respectively. The percentage of patients with normalized DBP by week 12 was 59% for patients treated with irbesartan and 57% for patients treated with enalapril. The percentage of patients who demonstrated a response to treatment at week 12 was also comparable between treatment groups (100% of the irbesartan-treated patients and 98% of the enalapril-treated patients).

The incidence of adverse events was 55% in the irbesartan group and 64% in the enalapril group. Significantly more patients receiving enalapril experienced cough (13.1%) compared with patients receiving irbesartan (2.5%, P = 0.007). More patients in the enalapril group experienced dizziness (18%) compared

512

6. Waeber

0 Enalapril 10 or 20 mg/d 0 lrbesartan 75 or 150 mg/d

A

c ._

-20 I I I I I I 0 2 4 6 8 10 12

Week

B 0

I I I I 1 4 6 a 10 12

Week

Figure 2. Mean change from baseline in (A) trough seated systolic blood pressure (SeSBP) and (B) trough seated diastolic blood pressure (SeDBP) in patients with mild to moderate hypertension treated with enalapril 10 or 20 mg/d (n = 102) or irbesartan 75 or 150 mg/d (n = 98). Reprinted with permission from Mimran et al.”

with patients in the irbesartan group (9.1%). Discontinuation rates were similar between treatment groups. In this sample of patients with severe hypertension, irbesartan was as effective as enalapril in lowering blood pressure and demonstrated a good tolerability profile.

513


IRRESARTAN VERSUS A DWRETIC A double-blind, placebcxontrolled study by Kochar et a12’ evaluated the efficacy and tolerability of once-daily irbesartan and HCTZ, a thiazide diuretic, across their respective dose ranges. A total of 683 patients with mild to moderate hypertension were randomized to receive 1 of 16 treatment regimens consisting of monotherapy or different combinations of irbesartan (37.5, 100, or 300 mg once daily) and HCTZ (6.25, 12.5, or 25 mg once daily) for 8 weeks. The data were analyzed using response surface modeling. Both irbesartan and HCTZ monotherapy effectively reduced blood pressure. By weeks 2, 4, 6, and 8, dose-related reductions in trough seated blood pressure were observed with increasing doses of both irbesartan alone and HCTZ alone. The mean changes from baseline in trough blood pressure were -2.3/-3.5 mm Hg for patients receiving placebo, -7.5/-7.1 mm Hg (irbesartan 37.5 mg) to -14.9/-10.2 mm Hg (irbesartan 300 mg) for patients receiving irbesartan monotherapy, -4.6/-5.1 mm Hg (HCTZ 6.25 mg) to -11.5/-8.3 mm Hg (HCTZ 25 mg) for patients receiving HCTZ monotherapy, and -10.2/-&l mm Hg (irbesartan 37.5 mg + HCTZ 6.25 mg) to -23.11/-14.4 mm Hg (irbesartan 300 mg + HCTZ 25 mg) for the combination groups. The percentage of patients with normalized DBP increased with increasing doses of either irbesartan (up to 49% for irbesartan 300 mg) or HCTZ (up to 47% for HCTZ 25 mg). The percentage of total responders was 24% for the placebo group, 35% to 58% for the irbesartan monotherapy group, 36% to 53% for the HCTZ monotherapy group, and 44% to 80% in the irbesartan/HCTZ combination groups. Although no statistical analysis was performed, by week 8 the mean change from baseline in trough blood pressure was greater for patients treated with only irbesartan 300 mg (-14.9/-10.2 mm Hg) compared with patients treated with only HCTZ 25 mg (-11.5/-8.3 mm Hg). The combination produced greater blood pressure reduction than either drug alone (-23.1/-14.4 mm Hg for irbesartan 300 mg + HCTZ 25 mg).

All treatments were well tolerated. Serum potassium levels tended to decrease and serum uric acid levels tended to increase in a dose-dependent manner with HCTZ therapy. When irbesartan was given in conjunction with HCTZ, these biochemical abnormalities were blunted. Thus, the combination of irbesartan plus HCTZ is effective in reducing blood pressure, and it may at- tenuate the adverse metabolic effects of HCTZ.

IRBESARTAN VERSUS OTHER ANGIOTENSIN II RECEPTOR ANTAGONISTS

ldmrartan Versus Losartan An 8-week, randomized, doubleblind, placebo-controlled tria121 was performed to evaluate the antihypertensive efficacy and tolerability of irbesartan 150 mg and 300 mg once daily compared with the highest recommended dose of lo-

514

B. Waeber

sartan, 100 mg, administered once daily. A total of 567 patients with mild to moderate hypertension were randomized to receive irbesartan 150 mg (n = 142) irbesartan 300 mg (n = 140) losartan 100 mg (n = 138) or placebo (n = 147). Both doses of irbesartan and losartan reduced blood pressure significantly compared with placebo (P < 0.001) at all assessment points. At week 8, patients receiving irbesartan 300-mg experienced a significantly greater reduction in SeDBP and SeSBP compared with those receiving losartan 100 mg (P c 0.01, Figure 3). At weeks 1 and 4, SeDBP was significantly more reduced versus baseline in the irbesartan 300-mg group compared with the losartan 100 mg group (P < 0.01 at week 1; P = 0.017 at week 4). lrbe sartan 150 mg produced reductions in SeDBP and SeSBP comparable to those produced by losartan 100 mg. At week 8, 52% of patients receiving irbesartan 300 mg had achieved normalization of DBP, compared with 42% of patients receiving losartan 100 mg. The corresponding response rates at week 8 were 63% and 56%. All therapies were well tolerated, although the 300-mg dose of irbesartan was associated with the lowest incidence of adverse events and discontinuations.

A 12-week, randomized, double-blind, elective titration study was per- formedz2 to evaluate the efficacy and tolerability of these same 2 agents. A total of 432 patients with mild to moderate hypertension were randomly assigned to receive irbesartan 150 mg once daily (n = 213) or losartan 50 mg once daily (n = 219). If at week 4 SeDBP was 290 mm Hg, the dose of the study medication was doubled. If at week 8 SeDBP was 290 mm Hg, doses were doubled (if not doubled at week 4) or HCTZ was added if irbesartan or losartan were already at maximally titrated doses. In cases in which HCTZ was added to losartan therapy, the losartan dose was decreased to 50 mg to be consistent with the prescribing information. By week 8, 47% and 39% of irbesartan-treated and losartan-treated patients, respectively, were receiving the starting dose of the study drugs. By week 12, 60% of irbesartan-treated patients were receiving monotherapy and 40% were receiving adjunct HCTZ. Among losartan-treated patients, 52% were receiving monotherapy at week 12 and 48% were receiving adjunct HCTZ. At weeks 8 and 12, the mean change from baseline in trough SeDBP was significantly greater for patients receiving irbesartan (-10.2 and -13.8 mm Hg at weeks 8 and 12, respectively) than for those receiving losartan (-7.9 and -10.8 mm Hg at weeks 8 and 12, respectively) (P c 0.02 at week 8; P < 0.002 at week 12). The SeSBP was also significantly more reduced at week 12 in the irbesartan-treated patients compared with losartan-treated patients (-18.9 mm Hg vs -13.9 mm Hg; P < 0.02). In evaluable patients at week 12, the response rates (normalized DBP or a DBP decrease of 2 10 mm Hg) were greater with irbesartan treatment (78% [ 139/178]) compared with losartan treatment (64% [ 123/192]; PC 0.01). Both treatments were similarly well tolerated. In these 2 head-to-head studies of patients with mild to moderate hypertension, irbesartan was more effective than losartan in lowering blood pressure.

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A

0

G -3

a= FE -6

ZE -9

“Z ES -12

2x -15 c ._ -18

0 Placebo 0 Losartan 100 mg/d 0 lrbesartan 150 mg/d + lrbesartan 300 mg/d

-21 I I I I I I 1 I I 0 1 2 3 4 5 6 7 8

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-6

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Figure 3. Mean change from baseline in (A) trough seated systolic blood pressure (SeSBP) and (B) trough seated diastolic blood pressure (SeDBP) in patients with mild to moderate hypertension treated with losartan 100 mg/d, irbesartan 150 or 300 mg/d, or placebo. P < 0.001 versus placebo at all times for all active groups. *P < 0.01 versus losartan. +P = 0.017 versus losartan. Reprinted with permission from Kassler-Taub et al.”

lrbesartan Versus Valsartan In an C&week, double-blind, randomized study of the antihypertensive efficacy of irbesartan versus valsartan, 23 426 patients with mild to moderate hypertension were randomized to receive the recommended starting and maintenance doses

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of irbesartan (150 mg once daily) or valsartan (80 mg once daily). At week 8 (Figure 4) irbesartan reduced trough ambulatory SBP/DBP (-11.6/-6.7 mm Hg) significantly more than did valsartan (-7.5/-4.8 mm Hg) (P c 0.01 for SBP; P = 0.035 for DBP). Irbesartan also produced significantly greater reductions compared with valsartan in mean 24hour SBP (-10.2 vs -7.8 mm Hg; P < 0.01) and DBP (-6.4 vs -4.8 mm Hg; P = 0.02). Irbesartan was also significantly more effective than valsartan with respect to rates of DBP normalization (52.5% v$ 38.2%; P = 0.004) and DBP response rates (63.9% vs 44.3%; P c 0.0001) at week 8. Both irbesartan and valsartan were well tolerated. The results of this study indicated that irbesartan 150 mg was more effective than valsartan 80 mg in reducing blood pressure in this sample of patients with mild to moderate hypertension.

lrbesartan Versus Losartan, Valsartan, and Candesartan: Pharmacodynamics The results of the aforementioned studies comparing irbesartan, losartan, and valsartan are supported by pharmacodynamic studies in healthy subjects. A randomized, double-blind, placebo-controlled, 4-way crossover study was performed in 12 healthy subjects to evaluate the degree and time course of Al1 receptor blockade by irbesartan, losartan, and valsartan.24 Subjects were ran domized to receive a single dose of irbesartan 150 mg, valsartan 80 mg, losartan 50 mg, or placebo. Treatments were separated by a l-week washout period;.

q Valsartan 80 mg/d n lrbesartan 150 mg/d

ASBP ADBP

I I

P < 0.01

Figure 4. Mean change from baseline in trough ambulatory diastolic blood pressure (ADBP) and trough ambulatory systolic blood pressure (ASBP). Adapted with permission from Mancia et al.23

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Figure 5 shows the inhibition of SBP response to exogenous AI1 before and after administration of the 3 agents. Blockade was measured by a standard in vitro binding assay. All 3 agents significantly blocked SBP response to AI1 4 hours (P < 0.01) and 24 hours (P < 0.01) after dosing. Blockade produced by irbesartan 150 mg, however, was significantly greater than that produced by losartan or valsartan (P < 0.01 at 4 hours and P < 0.05 at 24 hours). At 30 hours, Al1 pressor effects were still blunted by all 3 drugs. However, AI1 receptor blockade was significantly greater with irbesartan (45%) than with losartan (21%; P < 0.05) or valsartan (26%; P < 0.05).

Another randomized, double-blind, 3-treatment, crossover trialz5 was conducted in 18 healthy subjects to evaluate the AU-antagonistic properties of irbesartan, losartan, and valsartan. Subjects were randomly assigned to receive irbesartan 150 mg, valsartan 80 mg, or losartan 50 mg on day 1 of each of 3 periods (single-dose treatment). On day 3 of each period, subjects received the same dose once daily for an additional 6 days, until day 8 (multiple-dose treatment). The treatment periods were separated by a 7-day washout period. Dose-response curves following AI1 infusions were calculated on day 1 (after single-dose treatment) and on day 8 (after multiple-dose treatment) at specified time periods. All 3 treatments inhibited the pressor effects of exogenous Ah. Maximum effects were observed 4 hours after irbesartan and valsartan dosing

0 Placebo 0 Losartan 50 mg 0 Valsartan 80 mg + lrbesartan 150 mg

I I 1 I I

10 15 20 25 30

Time (h)

Figure 5. Inhibition of systolic blood pressure response to exogenous angiotensin II in healthy subjects. *P < 0.01 versus placebo. +P < 0.05 versus placebo. *P < 0.05 versus losartan and valsartan. Adapted with permission from Mazzolai et al.24

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and 10 hours after losartan dosing. After single-dose administration, irbesartan blocked All significantly more than did losartan at 4 hours, 24 hours, and 47 hours (P c 0.05). In addition, irbesartan blocked AII significantly more than valsartan at 24 hours (P c 0.05). After multipledose administration, irbesartan produced significantly more blockade of AI1 at 4,24,36, and 47 hours compared with losartan (P < 0.05) and at 36 hours compared with valsartan (P < 0.05). The results of these 2 trials suggest that irbesartan exhibits greater Ah-antagonistic activity than losartan and valsartan. This greater AI1 inhibition may explain the comparative efficacy of irbesartan versus losartan and valsartan in head-tohead clinical trials.21-23

A double-blind, randomized, crossover study in 18 healthy subjects was conducted to evaluate the Ah-antagonistic effects of irbesartan 150 mg once dally and candesartan 8 mg once daily. 26V27 Subjects were crossed over to the other treatment arm after 1 week of treatment. To evaluate AI1 antagonism in vivo, plasma renin activity at rest and the rightward shift of the dose-effeot curves (blood pressure response to exogenous AI1 after treatment) were assessed. The radioligand rat lung receptor assay was used to determine the degree of receptor occupation in plasma ex vlvo. Irbesartan and candesartan similarly shifted the Al1 dose-effect curves to the right and demonstrated long- lasting AI1 antagonism. However, the antagonistic activity in plasma, as measured by the radioligand rat lung receptor assay, was significantly higher with irbesartan than with candesartan (P c 0.01). In addition, plasma renin activitk was significantly higher (P = 0.02) during periods of high antagonistic activltb after irbesartan administration. Thus, irbesartan and candesartan appear to have similar Ah-antagonistic effects in man, indicating similar extent and duration of activity at the AI1 receptor site. Whether the greater reactive rise in plasma renin activity observed with irbesartan reflects greater Al1 inhibition locally in the kidneys, and whether this translates into a clinical advantage for irbesartan, requires further study.

DISCUSSION A number of agents that act via different mechanisms are now available for the treatment of hypertension.28 This broad choice is very helpful since essential hypertension is a heterogeneous disease, which explains why it is still difficult to find for the individual hypertensive patient a drug regimen that is at the same time efficacious and well tolerated.2g

The aim of the present review was to compare the blood pressurdowering effect of irbesartan, a long-acting AI1 receptor antagonist, with that of other agents commonly used in the management of hypertension. Only double-blind controlled trials were considered in this review. Irbesartan was found to be as effective in lowering blood pressure as other drugs acting by different mechanisms, including atenolol (beta-blocker), amlodipine (dihydropyridine calcium channel antagonist), HCTZ (thiazide diuretic), and enalapril (ACE inhibi-

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tor).‘4-20 This is not surprising since the currently available antihypertensive agents generally decrease blood pressure to a similar extent, regardless of their mechanism of action.30 However, the studies reviewed in this paper were performed according to a parallel-group design. Their results, therefore, do not indicate whether the various drugs would have a similar effect in a given patient. Thus, a patient who is a good responder to irbesartan may be either a good or poor responder to another drug from a different class of agents.

AI1 receptor antagonists currently used for the treatment of hypertension specifically block the AT, subtype of the All receptor, which is known to me- diate the principal actions of All on the cardiovascular system.31 These antagonists are similar with regard to their hemodynamic effects. Characteristically, they lower blood pressure in a dose-dependent manner, without inducing any reflex heart rate acceleration. AI1 receptor antagonists differ in their pharma- cokinetic properties, which might influence the magnitude as well as the duration of their blood pressur+lowering effect. Some differences in favor of irbesartan were indeed found when this compound was compared with AI1 receptor antagonists such as losartan and valsartan, 2 substances known to have a shorter plasma half-life than irbesartan.8 The superiority of irbesartan versus these 2 compounds was demonstrated by measuring clinic blood pressure at trough (ie, before administration of the next morning dose).21-23 It was also confirmed, in the case of valsartan, by noninvasive ambulatory blood pressure monitoring.23 The most likely explanation for the increased antihypertensive efficacy observed with irbesartan is a more complete and longer-lasting blockade of the renin-angiotensin system, which would be in agreement with the results obtained in healthy volunteers (ie, the inhibition of the pressor response to exogenous AI1 induced by losartan, valsartan, and irbesartan).24*25

In all the studies reviewed, irbesartan had a good tolerability profile, with a low incidence of side effects. As discussed earlier, a good tolerability profile may help patients comply with chronic treatment.32

All receptor antagonists, like ACE inhibitors, lower blood pressure mainly by blocking the renin-angiotensin system. However, some differences exist between the 2 types of agents with regard to their mechanism of action.33 ACE inhibitors decrease the degradation of bradykinin, a peptide that can induce vasodilation by releasing nitric oxide and prostacyclin from the endothelium. During ACE inhibition, however, some AI1 can still be formed through ACE- independent pathways, for example, through chymase, an enzyme present in the heart and at the surface of endothelial cells. The blockade of the renin- angiotensin system provided by AI1 receptor antagonists is more specific since these compounds act directly at the receptor site. Currently available AI1 receptor antagonists, including irbesartan, selectively block the AT, subtype of the All receptor. During blockade of this receptor, AI1 is still able to stimulate the AT2 subtype of the AI1 receptor, with potentially ‘beneficial effects on the heart (decrease in cardiac hypertrophy and fibrosis). Thus, while All receptor

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antagonists and ACE inhibitors both reduce blood pressure effectively, All receptor antagonists may be of additional benefit in preventing target organ damage. Morbidity and mortality studies are still needed to clarify the relative benefits of these compounds in the treatment of high blood pressure.

CONCLUSIONS Irbesartan, a specific All receptor antagonist, is well tolerated and provides antihypertensive efficacy that is comparable to or exceeds that of other antihypertensive agents from different classes, including atenolol (beta-blocker), enalapril (ACE inhibitor), HCTZ (thiazide diuretic), and amlodipine (calcium channel antagonist). Compared with other All receptor antagonists such as losartan and valsartan, irbesartan appears to be more effective in controlling blood pressure while maintaining the good tolerability profile of this class of agents.

ACKNOWLEDGMENTS Financial support for the publication of this paper was provided by Bristol- Myers Squibb, Princeton, New Jersey, and Sanofi-Synthelabo, Paris, France.

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Address correspondence to: Bernard Waeber, MD Professor of Medicine Centre Hospitalier Universitaire Vaudois Division of Pathophysiology BH-19 10 11 Lausanne Switzerland

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a review of irbesartan in antihypertensive therapy: comparison with other antihypertensive agents

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