Long-Term Safety and Antihypertensive Efficacy of Irbesartan: Pooled Results of Five Open-Label Studies

CLIN. AND EXPER. HYPERTENSION, 21(8), 1273-1295 (1999)

LONG-TERM SAFETY A N D ANTIHYPERTENSIVE EFFICACY OF IRBESARTAN: POOLED RESULTS OF FIVE OPEN-LABEL STUDIES

Thomas Littlejohn 111, MD,' Ravi Saini, PhD: Kenneth Kassler-Taub, MD? SG Chrysant, MD3 and T Marbury, MD4

'Piedmont Medical Research Associates, Winston-Salem, NC. 'Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ.

30klahoma Cardiovascular and Hypertension Center, Oklahoma City, OK. 40rland0 Clinic Research Center, Orlando, FL.

Key Words: irbesartan, angiotensin I1 receptor antagonist, hypertension, hydrochlorothiazide, long-term trial

ABSTRACT

An analysis of 5 multicenter, open-label studies was conducted to evaluate the long-term safety and efficacy of irbesartan in 1,006 patients with seated diastolic blood pressure (SeDBP) 95-1 10 mm Hg. Irbesartan monotherapy was started at 75 mg and titrated to 300 mg at 2- to 4-week intervals to achieve normalized blood pressure (SeDBP < 90 mm Hg). If normalized BP was not attained with irbesartan 300 mg alone, adjunctive medications could be added. At 12 months of therapy, the mean reduction in seated systolic blood pressure/SeDBP was 21.0/15.8 mm Hg, and 83% (684/821) of patients were normalized. Of those normalized, 64% were receiving irbesartan monotherapy and 86% were receiving irbesartan or irbesartan/hydrochlorothiazide only. No evidence of tachyphylaxis to the antihypertensive effect of irbesartan was noted. Thus, long-term irbesartan therapy, with or without other antihypertensives, achieved and maintained normalized BP in the majority of patients and was well tolerated.

1273

Copyright Q 1999 by Marcel Dekker, Inc. www .dekker . corn

Clin

Exp

Hyp

erte

ns D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y M

cMas

ter

Uni

vers

ity o

n 11

/18/

14Fo

r pe

rson

al u

se o

nly.

1274 LI'ITLEJOHN ET AL.

INTRODUCTION

The need for improved blood pressure (BP) control becomes apparent

when the consequences of hypertension are investigated. The pathophysiologic

effects of untreated hypertension include long-term effects on cardiovascular,

renal, and ocular systems (1). Hypertension is associated with increased risk of

coronary heart disease, cerebrovascular diseases, and renal impairment which in

turn leads to increased morbidity and mortality (1).

In actual clinical practice, adequate BP control is achieved in a minority of

patients who are receiving antihypertensive therapy (1 -3). According to the Joint

National Committee on Prevention, Detection, Evaluation, and Treatment of High

Blood Pressure (JNC VI), only 27% of patients with hypertension have their BP

under control (1). It has been shown that less than one-third of patients who are

receiving angiotensin-converting enzyme (ACE) inhibitors, calcium channel

blockers, beta-blockers, or diuretics continue therapy for more than 1 year (4,5).

Furthermore, the likelihood of discontinuation of a treatment regimen has been

shown to be significantly related to the initial class of antihypertensive prescribed.

An analysis of over 3 million prescriptions for antihypertensive drugs found that

only 26% of patients started on ACE inhibitors remained compliant by the start of

the fifth year, with calcium channel blockers (20%), diuretics (19%), and beta-

blockers (16%) showing even lower continuation rates (6). Though reasons for

discontinuation or switching of therapy were not available, the relative likelihood

of discontinuation tends to follow the reported tolerability for these drug classes.

Clin

Exp

Hyp

erte

ns D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y M

cMas

ter

Uni

vers

ity o

n 11

/18/

14Fo

r pe

rson

al u

se o

nly.

LONG-TERM EFFICACY/SAFETY OF IRBESARTAN 1275

Consequently, an effective antihypertensive agent with a superior safety and

tolerability profile, and thus a possibility of improved compliance, has the

potential to offer better long-term control of BP than currently available agents.

One of the more promising approaches to treating hypertension in recent

years has been blockade of the renin-angiotensin system (RAS) with the use of

ACE inhibitors. The RAS is an important regulator of sodium and water balance

and is crucial to BP control. A component of the RAS, angiotensin 11, is a potent

vasoconstrictor peptide hormone formed by the enzymatic cleavage of angiotensin

I by ACE. Angiotensin I1 is thus the proximate mediator of the BP regulating

system by binding to specific high affinity cell surface receptors in target tissues.

Inhibition of' ACE with the ACE inhibitor class of antihypertensive drugs

significantly lowers BP. Unfortunately, unwanted side effects, including dry

cough and, rarely, angioedema may limit the use of ACE inhibitors in many

patients (7-9).

Recently, a new class of antihypertensive agents, the angiotensin I1

receptor antagonists (AIIRAs), has been introduced for the treatment of

hypertension (1 0, 1 1). This class of drugs inhibit the pressor effect of angiotensin

I1 by blocking the type 1 subtype of the angiotensin I1 receptor (AT,). This

receptor subtype mediates most, if not all, of the hypertensive effects attributed to

angiotensin 11 (1 2). Irbesartan is a potent AIIRA that is highly selective for the

AT, receptor subtype (13). In clinical trials of up to 12 weeks in duration,

irbesartan, at once-daily doses up to 300 mg, demonstrated dose-related lowering

Clin

Exp

Hyp

erte

ns D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y M

cMas

ter

Uni

vers

ity o

n 11

/18/

14Fo

r pe

rson

al u

se o

nly.

1276 LITTLEJOHN ET AL.

of BP in hypertensive patients and placebo-like tolerability at all doses.( 14- 16)

This analysis of 5 multicenter, open-label studies was conducted to evaluate the

safety, tolerability, and antihypertensive efficacy of long-term, once-daily

administration of irbesartan (up to 300 mg), alone or in combination with other

adjunctive antihypertensive agents, in patients with mild-to-moderate

hypertension.

METHODS

Patients

Patients completing any of five 8- to 26-week double-blind, placebo- or

active-controlled, multicenter studies were eligible for a 1 -year or 2-year open-

label extension. Males and surgically sterile or postmenopausal females 2 18

years of age with seated diastolic BP (SeDBP) 95-1 10 mm Hg were eligible for

enrollment in the double-blind phase of the trials. Exclusion criteria included

secondary causes of hypertension, or significant cardiovascular, neurologic,

endocrinologic, gastrointestinal, or malignant disease. Patients must have

continued to meet exclusion criteria for participation in the open-label extensions.

Written informed consent was required of all patients before beginning open-label

therapy.

Protocols

The study designs of the 5 open-label extensions conducted at 152 sites in

North and South America and Europe, are graphically represented in figure 1. In

Clin

Exp

Hyp

erte

ns D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y M

cMas

ter

Uni

vers

ity o

n 11

/18/

14Fo

r pe

rson

al u

se o

nly.


U

U

irbesartan + HCTZ

I I irbesartan + atenolol or nifedipine'

irbesartan + HCTZ + atenolol or arnlodipine or nifedipine

9 irbesartan + atenolol or nifedipine + HCTZ'

substitution or addition of alternative antihypertensive agents

patient discontinued from study if BP > 140b 90 rnm Hg

' Study B in Table 1.

FIG. 1. Study design of open-label extensions.

each trial, the double-blind treatment period followed a 4- to 5-week single-blind

placebo lead-in period. Subjects completing the double-blind period had the

option of enrolling in open-label treatment with irbesartan and, if needed,

adjunctive treatment. There was no placebo lead-in prior to beginning open-label

therapy. During the open-label extensions, irbesartan monotherapy was initiated

at 75 mg once daily (one study began at 150 mg once daily) [TABLE 11.

Clin

Exp

Hyp

erte

ns D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y M

cMas

ter

Uni

vers

ity o

n 11

/18/

14Fo

r pe

rson

al u

se o

nly.


TABLE 1. Dosing Regimens During Open-label Extensions Study

A B C D E

Irbesartan starting dose (mg) 75 75 75 75 150

Irbesartan maximum dose (mg) 300 300 300 300 3 00

First adjunctive medication HCTZ ATEN HCTZ HCTZ HCTZ

or NIF (if necessary)

Second adjunctive medication NIF HCTZ ATEN AML ATEN

orNIF or ATEN orNIF HCTZ = hydrochlorothiazide; ATEN = atenolol; NIF = nifedipine; AML = amlodipine.

(if necessary)

Irbesartan was titrated at 2- to 4-week intervals to achieve target BP (< 140 mm

Hg seated systolic BP [SeSBP] and < 90 mm Hg SeDBP) to a maximum dosage

of 300 mg once daily. If target BP was not achieved, irbesartan was then

combined with one of several adjunctive antihypertensive agents, usually

hydrochlorothiazide (HCTZ) (12.5 mg titrated to 50 mg once daily). If BP

remained above 140/90 mm Hg, a third antihypertensive agent was added.

Finally, if target BP was still above 140/90 mm Hg, substitution or addition of

another antihypertensive agent was permitted. Other adjunctive antihypertensive

agents that were allowed included atenolol(25-100 mg once daily), amlodipine

(5-10 mg once daily), and sustained-release nifedipine (20-60 mg once daily).

Once target BP was achieved, patients were maintained on that regimen with

follow-up visits at least every 12 weeks. If, despite titration to the maximum

permitted doses of study drugs, target BP was still not achieved, the patient was

discontinued from the study.

Clin

Exp

Hyp

erte

ns D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y M

cMas

ter

Uni

vers

ity o

n 11

/18/

14Fo

r pe

rson

al u

se o

nly.


At each visit, SeSBP, SeDBP, standing systolic BP (StSBP), and standing

diastolic BP (StDBP) were measured with a standard, calibrated mercury

sphygmomanometer. The mean of 3 to 5 measurements taken at 1 minute

intervals was used. Seated and standing heart rates were determined by pulse

count.

Safety was assessed by monitoring the incidence of newly occurring

adverse events (AEs), clinical laboratory parameters, and physical examinations.

AEs included those that began or worsened during the open-label periods (ie,

treatment-emergent AEs). AEs were further categorized as serious AEs (SAEs),

adverse drug experiences (ADEs; AEs that were related, possibly related, or of

unknown relationship to study drugs), and discontinuations as a result of AEs.

Blood and urine samples were obtained for standard hematology, serum

chemistry, and urinalysis tests prior to the start of open-label therapy, every 8

weeks during the titration phase, and generally every 3 to 4 months thereafter. A

complete physical examination was performed prior to the start of open-label

therapy and annually thereafter. In addition, a brief physical examination was

performed during each follow-up visit.

Statistical methods

No statistical tests were performed. Available data from all patients who

received at least 1 dose of study medication during the open-label extensions were

included in the analysis of efficacy and safety. Efficacy was primarily evaluated

Clin

Exp

Hyp

erte

ns D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y M

cMas

ter

Uni

vers

ity o

n 11

/18/

14Fo

r pe

rson

al u

se o

nly.


by determining the change from baseline (ie, measurements made prior to

randomization to double-blind treatment) in trough (24 f 3 hours after previous

dose) SeDBP and trough SeSBP, and the therapeutic response. Therapeutic

response was defined as the proportion of patients whose BP was normalized

(trough SeDBP < 90 mm Hg); the proportion of total responders (normalized

patients or those whose trough SeDBP decreased by at least 10 mm Hg but was

still above 90 mm Hg); and the proportion of patients who achieved target BP

(< 140k 90 mm Hg). For the safety analyses, baseline was defined as the end of

the double-blind period (ie, prior to the start of open-label therapy).

RESULTS

Patient demomat4ics

Patient demographics and baseline efficacy variables are presented in

TABLE 2. Demographic and baseline characteristics were similar across studies

with the following exceptions. Study D was designed to evaluate elderly patients

(2 65 years of age); the mean age in Study D was 71 years compared with 57

years overall. Studies B and D had 47% and 52% females, respectively,

compared with 40% overall. Mean values for seated and standing BP and heart

rate were similar in all studies.

Patients discontinued therapy over the course of the study for a variety of

reasons. Only 9.1% of patients discontinued because of an AE. Other reasons for

discontinuation included patient request and concomitant medication use. A

Clin

Exp

Hyp

erte

ns D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y M

cMas

ter

Uni

vers

ity o

n 11

/18/

14Fo

r pe

rson

al u

se o

nly.


TABLE 2. Demographic and Baseline Characteristics

Characteristic N = 1,006 Age, years Mean (SD) Range 2 65 years, YO Gender, % Male Female Race, YO White Black Other SeSBP, nun Hg Mean (SD) SeDBP, mm Hg

56.6 (1 1.5)

28 22-8 8

60 40

92 5 3

155.2 (16.0)

Mean (SD) 100.5 (4.2) SD = standard deviation; SeSBP = seated systolic

blood pressure; SeDBP = seated diastolic blood pressure.

progressive decrease in the number of patients included in the efficacy analysis

was observed over time. This occurred primarily because many patients did not

return for efficacy evaluations or failed to return within the day range windows (5

3 days) and were therefore excluded from analysis at that timepoint.

Treatment regimens

A summary of treatment regimens is shown in TABLE 3. Nearly 85% of

patients received either irbesartan monotherapy or irbesartan/HCTZ at 12 months.

Few patients required the use of concomitant atenolol, amlodipine, or nifedipine

for BP control.

Clin

Exp

Hyp

erte

ns D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y M

cMas

ter

Uni

vers

ity o

n 11

/18/

14Fo

r pe

rson

al u

se o

nly.

TABL

E 3.

Dis

tribu

tion o

f Dos

es at

Mon

th 1

2 Pe

rcen

t of p

atie

nts r

ecei

ving

R

egim

en

All

patie

nts

Nor

mal

ized

Pa

tient

s in

who

m ta

rget

pa

tient

s*

BP w

as a

chie

vedt

N

= 82

1 N

= 68

4182

1 N

= 5

20/8

21

Irbe

sarta

n 75

to 1

00 m

g 27

.6

30.7

33

.3

Irbe

sarta

n 15

0 to

225

mg

21.0

21

.1

20.6

Ir

besa

rtan 3

00 m

g 13

.2

12.4

12

.3

Irbe

sarta

n 300

mg

+ HCT

Z 12

.5

12.0

12

.5

12.5

mg

25 m

g

50 m

g

antih

yper

tens

ive t

hera

py*

antih

yper

tens

ive t

hera

py

Irbe

sarta

n 300

mg

+ H

CTZ

7.8

7.0

7.3

Irbe

sarta

n 300

mg

+ H

CTZ

1.9

1.6

1.7

Irbe

sarta

n + H

CTZ

+ ot

her

9.4

8.6

7.9

Irbe

sarta

n + ot

her

4.5

4.7

2.7

Oth

er d

ose c

ombi

natio

n 2.

1 1.

9 1.

7 To

tal

100

100

100

N =

num

ber o

f pat

ient

s at M

onth

12

who

had

a S

eDB

P as

sess

men

t; H

CTZ

= hy

droc

hlor

othi

azid

e.

* Nor

mal

ized

= tr

ough

SeD

BP

< 90

mm

Hg.

Ta

rget

BP

= <

140

k 90

mm

Hg.

* A

teno

lol,

amlo

dipi

ne, o

r nife

dipi

ne.

r, 2

Clin

Exp

Hyp

erte

ns D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y M

cMas

ter

Uni

vers

ity o

n 11

/18/

14Fo

r pe

rson

al u

se o

nly.

LONG-TERM EFFICACY/SAFE'TY OF IRBESARTAN

-12 -

-16 -

-20 -

1283

-4 i + SeDBP +- SeSBP

-241 I I I I I I

0 2 4 6 8 1 0 1 2 18 24

Months of open-label therapy

FIG. 2. Irbesartan reduced mean trough seated diastolic blood pressure (SeDBP) and seated systolic blood pressure (SeSBP) from baseline at all timepoints.

Blood uressure changes

Treatment with irbesartan, alone or in combination with other

antihypertensive agents, resulted in substantial mean decreases from baseline in

trough SeSBP and trough SeDBP at all timepoints (figure 2). Mean trough seated

BP reductions from baseline reached a maximum between 6 and 8 months at

approximately 21/16 mm Hg and were maintained at that level through 12

months. At 18 and 24 months, when the sample size had decreased to 241 and

1 30 patients, respectively, mean trough seated BP reductions from baseline were

slightly less at 19/15 mm Hg and 174 5 rnm Hg, respectively. As mentioned

earlier, the decrease in sample size was primarily due to the fact that many

patients did not return for efficacy evaluations at these later timepoints or failed to

return within the day range windows.

Clin

Exp

Hyp

erte

ns D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y M

cMas

ter

Uni

vers

ity o

n 11

/18/

14Fo

r pe

rson

al u

se o

nly.


Decreases from baseline in trough standing BP were similar to those

observed for trough seated BP (data omitted for brevity). There were no clinically

significant changes from baseline in heart rate (data omitted for brevity).

TheraDeutic resDonse

Normalization (trough SeDBP < 90 mm Hg) and total responder rates

(normalized or 2 10 mm Hg reduction from baseline trough SeDBP) reached near

maximal levels at the 6-month timepoint with 80% of patients normalized and

87% of patients responding. At 12 months, these rates increased to 83% and 90%,

respectively, and remained in this range for the next 12 months (figure 3). At 6

months, the percentage of patients achieving target BP (< 140/< 90 mm Hg) was

near maximal at 66%. The percentage of patients achieving target BP was similar

to the 6-month timepoint at 12,18, and 24 months of treatment (figure 3).

From the total of patients in the 5 studies combined, 83% (684/821) were

normalized at the 12-month timepoint. Of those normalized, 64% were receiving

irbesartan monotherapy and 86% were receiving irbesartan or irbesartan plus

HCTZ only. Of those patients who achieved target BP (520/821) at 12 months,

66% were on irbesartan monotherapy and 88% were receiving irbesartan

monotherapy or i r b e s M C T Z .

Safety

Mean duration of exposure to study medication during the open-label

studies was 391.4 days for patients receiving any irbesartan therapy and 276.4

Clin

Exp

Hyp

erte

ns D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y M

cMas

ter

Uni

vers

ity o

n 11

/18/

14Fo

r pe

rson

al u

se o

nly.

LONG-TERM EFFICACYBAFETY OF IRBESARTAN 1285

0 Responders Normalized

H TargetBP 100

2 4 6 12 24

Months of open-label therapy

FIG. 3. Therapeutic success with irbesartan during long-term therapy. Target blood pressure (< 140k 90 mm Hg), normalization rates (trough SeDBP < 90 mm Hg), and total responder rates (normalized or 2 10 mm Hg reduction from baseline trough SeDBP).

days for the patients who received irbesartan monotherapy alone.

ADEs (ie, AEs that were related, possibly related, or of unknown

relationship to study drugs), discontinuations due to AEs, and SAEs are

summarized in TABLE 4. Of the 1,006 patients included in the open-label

periods, only 6 patients (0.6%) discontinued because of treatment failure. Three

deaths occurred during the open-label extensions, all of which were judged by the

investigators to be unrelated to study medication (1 coronary occlusion, 1

myocardial infarction, 1 Goodpasture’s Syndrome). The most common AEs (ie,

all those reported without regard to causality) for patients treated with any

Clin

Exp

Hyp

erte

ns D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y M

cMas

ter

Uni

vers

ity o

n 11

/18/

14Fo

r pe

rson

al u

se o

nly.

TABL

E 4.

Saf

ety o

f Irb

esar

tan

Dur

ing

Long

-term

The

rapy

Pe

rcen

t of

patie

nts

Any

Ir

besa

rtan

Ir

besa

rtad

Ir

besa

rtad

HC

TZ

f ir

besa

rtan

m

onot

hera

py

HC

TZ

adju

nctiv

e med

icat

ion

N =

1.00

6 N

= 1.

006

N =

342

N =

362

Adv

erse

dru

g 28

20

20

24

Disc

ontin

uatio

ns du

e 9.

1 6.

3 5.

3 6.

6

Serio

us ad

vers

e eve

nts

8.6

5.7

6.1

7.5

expe

rienc

es

to a

dver

se ev

ents

N =

num

ber o

f pat

ient

s; H

CTZ

= hy

droc

hlor

othi

azid

e.

Clin

Exp

Hyp

erte

ns D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y M

cMas

ter

Uni

vers

ity o

n 11

/18/

14Fo

r pe

rson

al u

se o

nly.

TAB

LE 5

. M

ost C

omm

on A

dver

se E

vent

s Pe

rcen

t of p

atie

nts

Adv

erse

eve

nt

Any

Ir

besa

rtan

Ir

besa

rtan

l Ir

besa

rtad

ir

besa

rtan

m

onot

hera

py

HC

TZ

H

CT

Z k

ad

junc

tive

ther

apy

N =

362

N =

1,0

06

N =

1,0

06

N =

342

14.8

10

.0

10.5

12

.7

8.2

4.6

6.7

9.1

7.5

5.9

2.9

3.6

6.6

4.7

3.5

5.0

5.9

3.8

3.8

5.0

5.5

4.1

3.2

3.6

Mus

culo

skel

etal

pain

U

pper

resp

irato

ry in

fect

ion

Diz

zine

ss

Hea

dach

e C

ough

Fa

tigue

In

fluen

za

Phar

yngi

tis

Sinu

s abn

orm

ality

Tr

ache

obro

nchi

tis

Ras

h

14.8

11

.0

8.5

10.2

5.5

4.3

<2

2.

2 5.4

3.7

4.1

4.7

5.3

3.5

4.1

4.1

3.8

<2

3.

5 5.

0 N

= n

umbe

r of p

atie

nts;

HC

TZ =

hyd

roch

loro

thia

zide

.

0 9 Z ii! P z

Clin

Exp

Hyp

erte

ns D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y M

cMas

ter

Uni

vers

ity o

n 11

/18/

14Fo

r pe

rson

al u

se o

nly.


irbesartan regimen were musculoskeletal pain (1 4.8%), upper respiratory infection

(14.8%), dizziness (8.2%), and headache (7.5%) [TABLE 51.

The incidence of marked abnormalities in laboratory parameters was low

and was unaccompanied by symptoms. There were no clinically significant mean

changes fiom baseline in laboratory analytes or physical examination findings.

Mean changes from baseline laboratory values ranged from -0.05 to 0.04 mEqL

for serum potassium, -0.13 to 0.13 mg/dL for serum uric acid, -0.04 to 0.02

mg/dL for serum creatinine, and 2.5 to 8.9 mg/& for serum glucose.

DISCUSSION

Based on data from the National Health and Nutrition Examination

Surveys (1976-1980 and 1988-1991), the number of hypertensive patients who

were aware of their condition increased, and the number of patients on

antihypertensive therapy increased as well (1). However, since publication of the

JNC V report in 1993, these improvements have started to decline; therefore, it is

not surprising that adequate control of BP is achieved in only a minority of

patients with hypertension (1 -3). One reason for the lack of BP control in

hypertensive patients can be attributed to noncompliance, which may be the result

of adverse side effects or inconvenient dosing schedules (3). For example,

diuretics often upset electrolyte balance and cause sexual dysfunction; calcium

channel blockers can cause headaches, dizziness, or peripheral edema; P-blockers

can cause fatigue, insomnia, and may exacerbate the risk of congestive heart

Clin

Exp

Hyp

erte

ns D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y M

cMas

ter

Uni

vers

ity o

n 11

/18/

14Fo

r pe

rson

al u

se o

nly.


failure; the use of ACE inhibitors is associated with an increased incidence of

cough and, occasionally angioedema (1). Although all of these drug classes

control hypertension in clinical trials, the adverse side effects associated with their

use in actual clinical settings may contribute to poor patient compliance. This

hypothesis is substantiated by data from a study that showed that fewer than one-

third of hypertensive patients receiving conventional antihypertensive therapies

continue treatment for more than 1 year (4). Thus, there is a need for

antihypertensive agents suitable for long-term use that possess the following

characteristics: 1) effective BP lowering; 2) an excellent safety and tolerability

profile; 3) a simple regimen such as once-daily dosing; and 4) no tachyphylaxis to

antihypertensive effect. An antihypertensive agent with these characteristics may

result in better long-term control of BP and subsequently, result in significant

reductions in the incidence of stroke and major cardiovascular disease.

In actual clinical practice, conventional antihypertensive agents do not

adequately control BP in the majority of patients (1 -3). Although randomized

controlled trials are recognized as the best trial design for estimating the benefits

and risks of therapy (1), it is difficult to predict long-term efficacy and safety in

actual practice based on short-term, strictly controlled clinical trials. The 5

extension studies presented in this paper employed an open-label design. Despite

the limitations of an open-label design, including potential investigator and

patient bias, these open-label extensions did mimic, as far as possible, the options

a clinician is likely to have when initiating antihypertensive therapy, such as

Clin

Exp

Hyp

erte

ns D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y M

cMas

ter

Uni

vers

ity o

n 11

/18/

14Fo

r pe

rson

al u

se o

nly.


titration to higher doses and addition of adjunctive antihypertensive agents if

adequate or target BP control is not achieved.

In these studies, irbesartan once daily, alone or in combination with other

antihypertensive agents, achieved and maintained normalized BP during long-

term therapy in the majority of patients with mild-to-moderate hypertension.

Systolic/diastolic blood pressure was reduced from baseline by 17/15 mm Hg at

24 months with 81% of patients being normalized (SeDBP < 90 mm Hg). A

combined regimen of irbesartan, HCTZ, and other adjunctive antihypertensive

agents (ie, atenolol, amlodipine, and nifedipine) was employed in less than 25%

of the patients at any timepoint. These results confirm and extend previous

findings of short-term irbesartan studies (14).

The sustained antihypertensive effect of irbesartan compares favorably

with that of other antihypertensive agents. The AIIRAs losartan (1 7), valsartan

(1 8), and candesartan (19) have also demonstrated long-term antihypertensive

efficacy in open-label extension trials. Long-term treatment (up to 2 years) of

elderly mild-to-moderate hypertensive patients with moexipril, alone or in

combination with HCTZ, resulted in normalization rates (SeDBP < 90 mm Hg) of

53% (20). Treatment of mild-to-moderate hypertensive patients for 5 years with

doxazosin or atenolol lowered blood pressure from baseline by 14/14 mm Hg and

16/17 m Hg and reduced SeDBP to 90 mm Hg or below in 73% and 78% of

patients, respectively (2 1). In the Treatment of Mild Hypertension Study

(TOMHS), patients with DBP 90-99 mm Hg received long-term nutritional-

Clin

Exp

Hyp

erte

ns D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y M

cMas

ter

Uni

vers

ity o

n 11

/18/

14Fo

r pe

rson

al u

se o

nly.


hygienic intervention plus either double-blind placebo, chlorthalidone, acebutolol,

doxazosin, amlodipine, or enalapril(22). The active regimens reduced systolic

blood pressure fiom baseline by 1 1.3 to 14.6 mm Hg and diastolic blood pressure

by 9.7 to 12.2 mm Hg at 48 months (22).

Results fiom these studies demonstrate that irbesartan has an excellent

tolerability profile that does not limit treatment or compliance. The results also

confirm that irbesartan can be used safely with other commonly used

antihypertensive agents. Consistent with previous short-term trials with irbesartan

monotherapy (16), there were no safety concerns during long-term therapy with

irbesartan, alone or in combination with other antihypertensive agents. The

tolerability profile of irbesartan was similar when administered alone versus when

administered concomitantly with HCTZ or other adjunctive antihypertensive

agents in these studies. There was a low incidence of drug-related AEs associated

with any irbesartan regimen (20% to 28%). In short-term clinical trials, similar

drug-related AE rates of 2 1 YO for irbesartan and 20% for placebo have been

reported (1 6).

The long-term AE rates observed with irbesartan compare favorably with

those of other antihypertensive regimens. In a 50-week, open-label comparative

trial of mild-to-moderate hypertensive patients, therapy-related AE rates between

12 weeks and study endpoint were 54% for those receiving amlodipine, 47% for

those receiving amlodipine plus atenolol, 32% for those receiving HCTZ, and

24% for those receiving HCTZ plus atenolol(23). AEs were considered related or

possibly related to study drug for 55% of doxazosin-treated patients and 68% of

Clin

Exp

Hyp

erte

ns D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y M

cMas

ter

Uni

vers

ity o

n 11

/18/

14Fo

r pe

rson

al u

se o

nly.


atenolol-treated patients in a 5-year trial of mild-to-moderate hypertensive

patients (21).

The types of AEs reported during the open-label extensions were similar

to those reported during the double-blind phases of the trials, as well as during 4-

to 12-week, placebo-controlled, double-blind trials of irbesartan monotherapy

(16). The incidences of discontinuations due to AEs and SAEs were higher in the

present analysis (9.1% and 8.6%, respectively) compared with those during the

double-blind phases of the trials (7.1% and 3.9%, respectively), but this is most

likely a result of the longer exposure to study drugs andor the use of adjunctive

antihypertensive agents.

CONCLUSIONS

Long-term administration of irbesartan, alone or in combination with other

antihypertensive agents, is safe and well tolerated. At 12 months of therapy, 83%

of patients were normalized (trough SeDBP < 90 mm Hg) and of these, 64% and

86% were receiving irbesartan only or irbesartan plus HCTZ only, respectively.

Irbesartan, alone or in combination with other antihypertensive agents, has the

potential to improve the management of hypertension in settings of actual clinical

practice.

1. Joint National Committee on Prevention Detection Evaluation and Treatment of High Blood Pressure. The sixth report of the Joint National

Clin

Exp

Hyp

erte

ns D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y M

cMas

ter

Uni

vers

ity o

n 11

/18/

14Fo

r pe

rson

al u

se o

nly.


2.

3.

4.

5.

6.

7.

8.

9.

10.

1 1 .

12.

Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Arch Intern Med 1997; 157: 2413-2446.

Stockwell, D.H., Madhavan, S., Cohen, H., Gibson, G., Alderman, M.H. The determinants of hypertension awareness, treatment, and control in an insured population. Am J Public Health 1994; 84: 1768-1 774.

Burt, V.L., Whelton, P., Roccella, E.J., Brown, C., Cutler, J.A., Higgins, M., Horan, M.J., Labarthe, D. Prevalence of hypertension in the US adult population. Results from the Third National Health and Nutrition Examination Survey, 1988-1 991. Hypertension 1995; 25: 305-3 13.

McCombs, J.S., Nichol, M.B., Newman, C.M., Sclar, D.A. The costs of interrupting antihypertensive drug therapy in a Medicaid population. Med Care 1994; 32: 214-226.

Kaplan, N.M. Treatment of Hypertension: Drug Therapy. In: Kaplan NM., ed. Clinical Hypertension, 6 ed., Williams & Wilkins, Baltimore, MD, 1994; 191 -280.

Caro, J.J., Jackson, J., Speckman, J., Salas, M., Raggio, G. Compliance as a function of initial choice of antihypertensive drug. Am J Hypertens 1997; 10(pt 2): 141A (Abstract).

Simon, S.R., Black, H.R., Moser, M., Berland, W.E. Cough and ACE inhibitors. Arch Intern Med 1992; 152: 1698- 1700.

Israili, Z.H., Hall, W.D. Cough and angioneurotic edema associated with angiotensin- converting enzyme inhibitor therapy. A review of the literature and pathophysiology. Ann Intern Med 1992; 1 17: 234-242.

Fletcher, A.E., Palmer, A.J., Bulpitt, C.J. Cough with angiotensin converting enzyme inhibitors: how much of a problem? J Hypertens 1994; 12(suppl2): s43-s47.

Timmermans, P.B.M.W.M., Wong, C.M., Chiu, A.T., Herblin, W.F., Benfield, P., Carini, D.J., Lee, R.J., Wexler, R.R., Saye, J.A.M., Smith, R.D. Angiotensin I1 receptors and angiotensin I1 receptor antagonists. Pharmacol Rev 1993; 45: 205-251.

Bauer, J.H., Reams, G.P. The angiotensin I1 type 1 receptor antagonists: A new class of antihypertensive drugs. Arch Intern Med 1995; 155: 1361- 1368.

Campbell, D.J. Endogenous angiotensin I1 levels and the mechanism of action of aneiotensin-converting: enzvme inhibitors and anniotensin receDtor

Y Y . Y

Clin

Exp

Hyp

erte

ns D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y M

cMas

ter

Uni

vers

ity o

n 11

/18/

14Fo

r pe

rson

al u

se o

nly.


type 1 antagonists. Clin Exp Pharmacol Physiol 1996; (suppl3): S125- S131.

13. Cazaubon, C., Gougat, J., Bousquet, F., Guiraudou, P., Gayraud, R., Lacour, C., Roccon, A., Galindo, G., Barthelemy, G., Gautret, B., Bernhart, C., Perreaut, P., Breliere, J.-C., Le Fur, G., Nisato, D. Pharmacological characterization of SR 47436, a new nonpeptide AT, subtype angiotensin I1 receptor antagonist. J Pharmacol Exp Ther 1993; 265: 826-834.

14. Reeves, R.A., Lin, C.-S., Kassler-Taub, K., Pouleur, H. Dose-related efficacy of irbesartan for hypertension: an integrated analysis. Hypertension 1998; 31: 1311-1316.

15. Pool, J.L., Guthrie, R.M., Littlejohn, T.W., 111, R a s h , P., Shepherd, A., Weber, M.A., Weir, M.R., Wilson, T.W., Wright, J., Kassler-Taub, K.B., Reeves, R.A. Dose-related antihypertensive effects of irbesartan in patients with mild-to-moderate hypertension. Am J Hypertens 1998; 11: 462-470.

16. Simon, T.A., Gelarden, T., Freitag, S.A., Kassler-Taub, K.B., Davies, R. Safety of irbesartan in the treatment of mild to moderate systemic hypertension. Am J Cardiol 1998; 82: 179-182.

17. McIntyre, M., Caffe, S.E., Michalak, R.A., Reid, J.L. Losartan, an orally active angiotensin (AT1) receptor antagonist: a review of its efficacy and safety in essential hypertension. Pharmacol Ther 1997; 74: 18 1-1 94.

18. Bremner, A.D., Baur, M., Oddou-Stock, P., Bodin, F. Valsartan: long-term efficacy and tolerability compared to lisinopril in elderly patients with essential hypertension. Clin Exp Hypertens 1997; 19: 1263- 1285.

19. Sever, P., Holzgreve, H. Long-term efficacy and tolerability of candesartan cilexetil in patients with mild to moderate hypertension. J Hum Hypertens 1997; 11 (SUppl2): S69-S73.

20. White, W.B., Stimpel, M. Long-term safety and efficacy of moexipril alone and in combination with hydrochlorothiazide in elderly patients with hypertension. J Hum Hypertens 1995; 9: 879-884.

2 1. Daae, L.N., Westlie, L. A 5-year comparison of doxazosin and atenolol in patients with mild-to- moderate hypertension: effects on blood pressure, serum lipids, and coronary heart disease risk. Blood Press 1998; 7: 39-45.

22. Neaton, J.D., Grimm, R.H.J., Prineas, R.J., Stamler, J., Grandits, G.A., Elmer, P.J., Cutler, J.A., Flack, J.M., Schoenberger, J.A., McDonald, R., Lewis, C.E., Liebson, P.R. Treatment of mild hypertension study. Final results. JAMA 1993; 270: 713-124.

Clin

Exp

Hyp

erte

ns D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y M

cMas

ter

Uni

vers

ity o

n 11

/18/

14Fo

r pe

rson

al u

se o

nly.


23. Adolphe, A.B., Vlachakis, N.D., Rofman, B.A., Brescia, D., Zellner, S.R. Long-term open evaluation of amlodipine vs hydrochlorothiazide in patients with essential hypertension. Int J Clin Pharmacol Res 1993: 13 : 203-2 10.

Submitted: 10127198 Revised: 02/04/99 Accepted: 02/04/99

Clin

Exp

Hyp

erte

ns D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y M

cMas

ter

Uni

vers

ity o

n 11

/18/

14Fo

r pe

rson

al u

se o

nly.

Documents

Long-Term Safety and Antihypertensive Efficacy of Irbesartan: Pooled Results of Five Open-Label Studies