Relevance
of AT1 blockade
Angiotensin II effects at the AT1 and AT2 receptors
Angiotensin
II
-sartan
AT1 Receptor
AT2 Receptor
Vasoconstriction
Activate sympathetic activity
Antiproliferation
Apotosis
Endothelial cell growth
Increase sodium retention
Increase vasopressin release
Promote myocyte hypertrophy and proliferation
Stimulate vascular and cardiac fibrosis
Vasodilation (NO mediated?)
Stimulate renal bradykinin and NO
Stimulate plasminogen activator inhibitor 1
Stimulate superoxide formation
Adapted from McConnaughey et al. J Clin Phamacol 1999;39: 547–59.
The Renin-Angiotensin System
showing ACE and non-ACE pathways
ACE PATHWAY
(< 30%)
NON-ACE PATHWAY
(> 70%)
Angiotensinogen
Chymase
Tonin
Cathepsin
Kallikrein
Renin
Angiotensin I
ACE
Angiotensin
McConnaughey et al. J Clin Phamacol 1999;39: 547–59.
Angiotensin II, endothelial dysfunction and atherosclerosis
Angiotensin II
 NADH/NADPH oxidases
 Free radicals
 NO
Endothelial dysfunction
Leucocyte adhesion
SMC proliferation
Atherosclerosis
Angiotensin II induces endothelial dysfunction
and superoxide production
Superoxide production
from NADH/NADPH oxidases
Endothelial dysfunction
Relaxation (%)
(nmol/min)
50
0
20
40
40
30
60
Control
Control
AII
20
AII
80
AII+SOD
100
10
0
-9
-8
-7
-6
Concentration of Ach (log M)
Rajagopalan and Harrison. JCI 1996;97:1916–23.
NADH
NADPH
Griendling et al. Circ Res 1994;74:11–48.
AT1 blockade
with irbesartan
Responses to Ang I and [Pro11D-Ala12] Ang I
Angiotensin I
[Pro-11D-Ala12] Angiotensin I
80
70
p = 0.002
p = 0.0007
60
50
Veno40
Constriction
30
(%)
20
10
0
Pre Post
Pre Post
Pre Post
Placebo
Captopril
Placebo
Pre Post Irbesartan
Captopril
McDonald et al. Circulation 2001;104:1805–8.
Superior inhibition of SBP
to exogenous Ang II with irbesartan
SBP response to exogenous Ang II (%)
100
Placebo
80
*
Losartan 50 mg
†
*
Valsartan 80 mg
*
60
Irbesartan 150 mg
*
*
*‡
40
* p < 0.01 vs. placebo
† p < 0.05 vs. placebo
‡ p < 0.05 vs. other antagonists
20
*‡
Values are mean ± SEM
0
0
5
10
15
20
Time (hours)
25
30
35
Mazzolai L et al. Hypertension 1999;33:850–5.
Relative potency of AT1 blockers
25
Day 1
Day 8
20
Plasma renin 15
activity
(ng/ml•h)
10
5
0
0h
4h
24 h
Valsartan 80 mg
Valsartan 160 mg
Increases in PRA reflect AT1 receptor blockade
0h
Valsartan 320 mg
Losartan 50 mg
4h
24 h
Irbesartan 150 mg
Candesartan 8 mg
Maillard MP et al. Clin Pharmacol Ther 2002;71:68–76.
Blood pressure
lowering
Irbesartan vs. losartan
Fixed dose mean change from baseline in trough SeDBP
 SeDBP from baseline (mmHg)
0
-2
Placebo
(n = 138)
-4
Losartan
100 mg
(n = 131)
-6
* p < 0.01 vs. losartan
†p
< 0.02 vs. losartan
-8
-10
Irbesartan
300 mg
(n = 134)
*
†
-12
*
0
1
4
Time (weeks)
Irbesartan
150 mg
(n = 129)
8
N shown is at Week 8
Kassler-Taub K et al. Am J Hypertens 1998;11:445–53.
Irbesartan vs. losartan
Fixed dose mean change from baseline in trough SeSBP
 SeSBP from baseline (mmHg)
0
-2
Placebo
(n = 138)
-4
Losartan
100 mg
(n = 131)
-6
* p < 0.01 vs. losartan
-8
Irbesartan
150 mg
(n = 129)
-10
-12
-14
Irbesartan
300 mg
(n = 134)
-16
*
-18
N shown is at Week 8
0
1
4
Time (weeks)
8
Kassler-Taub K et al. Am J Hypertens 1998;11:445–53.
Irbesartan vs. valsartan
Superior reduction in trough 24-h Ambulatory BP
ADBP
ASBP
0
-2
 Trough ABP
from
baseline
(mmHg)
-4
(p = 0.035)
-6
-8
-10
(p < 0.01)
N = 426
-12
Irbesartan 150 mg
Valsartan 80 mg
Mancia G. Blood Pressure Monitoring 2002;7(2):135–42.
Irbesartan vs. valsartan
Superior reduction in mean 24-h Ambulatory BP
ADBP
ASBP
0
-2
 Mean ABP
from
baseline
(mmHg)
-4
-6
(p = 0.023)
-8
(p <
0.01)
-10
-12
Irbesartan 150 mg
Valsartan 80 mg
Mancia G. Blood Pressure Monitoring 2002;7(2):135–42.
Irbesartan vs. losartan and valsartan
Overall Summary
 Irbesartan provides more complete and sustained blockade
of Ang II effects than losartan or valsartan
 Irbesartan 300 mg provides superior efficacy compared
with the highest dose of losartan (100 mg)
 Elective titration of irbesartan provides superior antihypertensive
effect compared with elective titration of losartan
 The starting and usual maintenance dose of irbesartan
results in statistically superior reductions in blood pressure
vs. the starting dose of valsartan
Kassler-Taub K et al. Am J Hypertens 1998;11:445–53.
Oparil S et al. Clin Ther 1998;20: 398–409.
Mancia G. Blood Pressure Monitoring 2002;7(2):135–42.
Irbesartan and enalapril
equally lower mean ambulatory BP over 24-h
0
SBP
DBP
-2
-4
Mean
reduction
in BP
(mmHg)
-6
-8
-9.4
-8.8
-10
-12.6
-12
-14
-14.7
Irbesartan
Enalapril
-16
Multicentre, randomized, double-blind, 12-week, comparative trial.
Patients received either 150–300 mg/day of irbesartan (n = 111) or 10–20 mg/day of enalapril (n = 116)
Coca A et al. Clinical Therapeutics 2002;1:12–38.
Irbesartan vs. enalapril in severe hypertension
Change in trough SeSBP
Change
from
baseline
(mmHg)
Change in trough SeDBP
0
-5
-10
-15
-20
-25
-30
-35
-40
-45
Change
from
baseline
(mmHg)
0
2
4
6
8
10
12
0
-5
-10
-15
-20
-25
-30
-35
-40
-45
0
Time (weeks)
2
4
6
8
10
12
Time (weeks)
Irbesartan 75–300 mg* (n = 95)
Enalapril 10–40 mg* (n = 97)
* Titrated at week 1 for SeDBP  106 mmHg or at week 2 or thereafter for SeDBP  90 mmHg;
additional antihypertensive therapies added after week 4 for SeDBP  90 mmHg
Larochelle P et al. Am J Cardiol 1997;80:1613–15.
Dose response
with irbesartan/HCTZ combination therapy
and components
Placebo
HCTZ
12.5 mg
Irbesartan
300 mg
Irbesartan 300 mg
HCTZ 12.5 mg
0
-2
-4
-3.5
-6
 SeDBP
(mmHg)
-6.2
-8
-10
-10.2
-12
-14
-16
n = 40 patients per group
-15.0
Kochar M et al. Am J Hypertens 1999;12:797–805.
Long-term efficacy with
irbesartan/HCTZ-based regimens
Month
6
2
12
0
-5
 BP
(mmHg)
-10
-15
-14.2
-15.6
-15.7
-20
-19.1
-20.6
-20.7
N = 1,098
-25
SeDBP
SeSBP
Raskin P et al. J Hum Hypertens 1999;13:68–7.
Long-term therapeutic response with irbesartan
and irbesartan/HCTZ-based regimens
100
87
80
Patients
(%)
80
90
83
87
81
60
40
20
0
N = 1,006
6
Normalized*
Responder†
12
Time (months)
24
*Trough SeDBP < 90 mmHg
† Normalized or reduction from baseline of  10 mmHg
Littlejohn T III et al. Clin Exp Hypertens 1999;21:1273–95.
Renoprotective
effects
Definitions of abnormalities
in albumin excretion
Normal
Microalbuminuria
Clinical albuminuria
Spot collection
(µg/mg creatinine)
24h collection
(mg/24h)
Time collection
(µg/min)
< 30
< 30
< 20
30 -299
30 -299
20 -199
300
 300
 200
Diabetes Care 2003;26 (Supp 1):594–598.
Irbesartan reduces microalbuminuria in
type 2 diabetic patients
A randomized double-blind placebo-controlled crossover study
Normotensive diabetic subjects
Hypertensive diabetic subjects
AER 5 (µg/min)
AER 5 (µg/min)
180
160
140
120
100
80
60
40
20
0
180
160
140
120
100
80
60
40
20
0
*
*
Subgroup 1
Subgroup 2
*p < 0.01
Time 0
Placebo
*
*
Subgroup 1
Subgroup 2
Irbesartan
Sasso FC et al. Diabetes Care 2002;25:NR II.
Relative prognostic value of microalbuminuria
in type 2 Diabetes
10
10.02
8
6.52
Mortality 6
from CHD
(odds ratio) 4
3.20
2.32
2
0
Microalbuminuria
Smoking
Diastolic BP
Cholesterol
Eastman RC, Keen H. Lancet 1997;350(Suppl 1):29–32.
Microalbuminuria predicts future coronary events
in patients with type 2 diabetes
Remaining event free (%)
100
90
80
70
60
No microalbuminuria
Microalbuminuria
50
40
0
1
2
3
Follow-up (years)
4
5
86 pts with type 2 diabetes
No history of coronary artery disease
- 43 with microalbuminuria (AER > 200 g/min)
- 43 with normoalbuminuria
Remaining event free (%)
100
90
80
70
60
Neither SMI nor microalbuminuria
50
SMI, but no microalbuminuria
40
Microalbuminuria, but no SMI
30
Both SMI and microalbuminuria
20
0
1
2
3
4
Follow-up (years)
5
SMI = Silent myocardial ischemia
(> 1 mm ST depression on treadmill exercise)
Follow-up: 2.8 years; 23 coronary events
Rutter MK et al. J Am Coll Cardiol 2002;40:56–61.
Prognostic value of microalbuminuria in initially
untreated hypertensive (n = 99) and normotensive (n = 21)
non-diabetic subjects followed for 10 years
20
18
p = 0.015
Baseline
16
urinary
albumin
14
excretion
(median, mg/24-h)
12
10
0
No CV events
(n = 101)
Developed CVD
(n = 19)
Ljungman S et al. Am J Hypertens 1996;9:770–8.
Microalbuminuria predicts coronary events
in subjects with essential hypertension
100
95
90
Proportion
without
85
ischemic
heart disease (%)
80
Normoalbuminuria
Microalbuminuria
(UA/Cr ratio > 1.07 mg/mmol)
75
70
0
1
2
3
4
5
6
7
8
9
10
Time (years)
204 hypertensive subjects drawn from 2,085 general population subjects
No previous CV events, no diabetes, no renal or urinary disease
Follow-up from 1983–84 till 1993
Jensen JS et al. Hypertension 2000;35:898–903.
18 coronary events
PRIME
Time course of type 2 diabetic renal disease
PRIME
Prevention
Protection
IRMA 2
Microalbuminuria
IDNT
Proteinuria
ESRD
Cardiovascular morbidity and mortality
Early Stage
PRIME:
IRMA 2:
IDNT:
ESRD:
Late Stage
End Stage
PRogram for Irbesartan Mortality and Morbidity Evaluations
IRbesartan in Patients with Type 2 Diabetes and Microalbuminuria
Irbesartan Diabetic Nephropathy Trial
End-stage renal disease
IRMA 2
Study design
590 patients with type 2 diabetes,
microalbuminuria (albumin excretion rate 20 – 200 g/min),
normal renal function, and hypertension
Screening/Enrollment
Double-blind treatment
Placebo
Irbesartan 150 mg
Irbesartan 300 mg
Up to 5 weeks
Follow-up: 2 years
Parving H-H et al. N Engl J Med 2001;345:870–8.
IRMA 2
Blood pressure response
160
150
SeSBP
140
Mean
SeSBP
and
SeDBP
(mmHg)
130
120
Control
Irbesartan 150 mg
Irbesartan 300 mg
110
100
90
SeDBP
80
70
0
0
3
6
9
12
15
18
Time (months)
21
24
27
Concomitant antihypertensive agents received by 56% of patients in the control group,
45% in the irbesartan 150 mg group, and 43% in the irbesartan 300 mg group
Parving H-H et al. N Engl J Med 2001;345:870–8.
IRMA 2
Primary endpoint: Time to overt proteinuria
20
Control
Irbesartan 150 mg
Irbesartan 300 mg
15
70%
RRR
p < 0.001
Subjects 10
(%)
5
0
0
3
6
12
18
22
24
Follow-up (months)
Parving H-H et al. N Engl J Med 2001;345:870–8.
IRMA 2
Normalization of urinary albumin excretion rate
45
p = 0.006
40
35
34%
30
Subjects
(%)
25
21%
24%
20
15
10
5
0
Control
(n = 201)
150 mg
(n = 195)
300 mg
(n = 194)
Irbesartan
Parving H-H et al. N Engl J Med 2001;345:870–8.
IRMA 2
Adverse outcomes
No. of adverse outcomes (%)
Control
Irbesartan
(150 mg)
Irbesartan
(300 mg)
Cardiovascular events
18
(8.7)
14
(6.9)
9
(4.5)
Serious adverse events
47
(22.8)
32
(15.8)
30
(15.0)
Discontinuations
due to adverse events
19
(9.2)
18
(8.9)
11
(5.5)
Parving H-H et al. N Engl J Med 2001;345:870–78.
Proteinuria levels predict stroke
and CHD events in type 2 diabetes
Survival curves
(CV mortality)
Incidence (%)
40
1.0
p < 0.001
< 150
0.9
30
0.8
150-300
0.7
20
0.6
> 300
0.5
10
Overall: p < 0.001
0
0
0 10 20 30 40 50 60 70 80 90
Time (months)
U-Prot < 150 mg/L
U-Prot = Urinary protein concentration
U-Prot 150-300 mg/L
Stroke
CHD events
U-Prot > 300 mg/L
Miettinen H et al. Stroke 1996;27:2033–9.
Course of diabetic renal disease
MicroPre-clinical
Diabetic Renal Disease albuminuria
Overt Proteinuria
160
4
140
120
3
100
GFR
(ml/min)
80
2
60
Protein
excretion
(g/day)
Proteinuria
40
1
Persistent
Microalbuminuria
20
0
0
Time (yrs 10)
20
Adapted from Mogensen CE. Kidney Int 1982;21:673.
and Friedman EA. Kidney Int 1982;21:780.
Screening for microalbuminuria: ADA guidelines
Test for microalbuminuria
+ for albumin
Yes
Condition that may invalidate
urine albumin excretion?
Yes
No
Treat and/or wait until resolved.
Repeat test. + for protein?
Yes
Repeat microalbuminuria test
twice within 3–6 month period
No
Rescreen in one year
2 of 3 test positive?
Yes
Microalbuminuria, begin treatment
Diabetes Care 2003;26 (Supp 1):594–598.
IDNT
Study design
1,715 patients with type 2 diabetes, proteinuria  900 mg/d, and hypertension
Screening/Enrollment
Double-blind treatment
Irbesartan*
Placebo*
Amlodipine*
Up to 5 weeks
* Adjunctive antihypertensive therapies (excluding ACE inhibitors,
angiotensin II receptor antagonists, and calcium channel blockers)
added to each arm to achieve equal blood pressure reduction
Minimum follow-up:
approximately 2 years
(average 3 years)
Collaborative Study Group. Rodby RA et al. Nephrol Dial Transplant 2000;15:487–97.
IDNT
Systolic, mean, and diastolic BP response
160
SBP
140
Irbesartan
Amlodipine
Control
BP 120
(mmHg)
Mean
100
DBP
80
0
6
12
18
24
30
36
Follow-up visit (months)
42
48
54
Lewis EJ et al. N Engl J Med 2001;345(12):851–60.
IDNT primary endpoint
Time to doubling of serum creatinine, ESRD, or death
70
Irbesartan
RRR = 23%
p = 0.006
60
Amlodipine
50
RRR = 20%
p = 0.02
p = NS
Control
40
Subjects
(%) 30
20
10
RRR: Relative Risk Reduction
0
0
6
12
18
24
30
36
42
48
54
60
Follow-up (months)
Lewis EJ et al. N Engl J Med 2001;345(12):851–60.
IDNT
Time to doubling of serum creatinine
70
Irbesartan
RRR = 37%
p < 0.001
60
Amlodipine
50
RRR = 33%
p = 0.003
p = NS
Control
40
Subjects
(%) 30
20
10
0
0
6
12
18
24
30
36
42
48
54
60
Follow-up (months)
Lewis EJ et al. N Engl J Med 2001;345(12):851–60.
IDNT
Time to ESRD
40
Irbesartan
30
Control + amlodipine
RRR = 23%
p = 0.004
Subjects
20
(%)
10
0
0
6
12
18
24
30
36
Follow-up (months)
42
48
54
60
Lewis EJ et al. N Engl J Med 2001;345(12):851–60.
Data on file, Sanofi-Synthelabo/Bristol-Myers Squibb.
The role of irbesartan in the treatment of diabetic kidney disease
Time to renal endpoint by treatment assignment
(Doubling of serum creatinine or ESRD)
Irbesartan
RRR = 34%
p = 0.0002
0.6
Amlodipine
RRR = -12%
p = 0.32
0.5
Placebo
Patients
0.4
reaching
Scr doubling
0.3
or ESRD
(fraction)
RRR = 26%
p = 0.011
0.2
0.1
0.0
0
6
12
18
24
30
36
42
48
54
60
66
72
78
Follow-up time (months)
Lewis EJ et al. N Engl J Med 2001;345(12):851–60.
Data on file, Sanofi-Synthelabo/Bristol-Myers Squibb.
Time to the development of ESRD
after doubling serum creatinine
1.0
Type 1 diabetic
nephropathy
0.9
0.8
0.7
0.6
Proportion 0.5
with event
0.4
0.3
0.2
0.1
0
0.0
0.5
1.0
1.5
Time after creatinine doubling (years)
n at risk:
68
37
17
5
Lewis EJ et al. N Engl J Med 1993;329(20):1456–62.
IDNT
Adverse outcomes
No. of adverse outcomes (%)
Irbesartan
Early serum creatinine rise
D/C due to hyperkalemia
0
11 (1.9)
Stopped study medicine
134
SAEs/1000 days on drug
2.0
(23)
Amlodipine
Control
0
1
3 (0.5)
2 (0.4)
133
2.5
(23)
140
(25)
2.3
Lewis EJ et al. N Engl J Med 2001;345:851–60.
Cardiovascular and renal disease continuum
ESRD
Chronic renal insufficiency
( GFR)
Albuminuria
Proteinuria
Elderly,
DM,  BP
Chronic Renal
disease
EndStage
Progression
Initiation
“At Risk”
CHF
Arteriosclerotic cardiovascular
disease events
Coronary artery disease
Left ventricular hypertrophy
Elderly,
DM,  BP
Cardiovascular
disease
Adapted from Sarnak and Levey, Am J Kidney Dis 2000;35:S117–31.
Markers of
cardiovascular risk
Irbesartan decreases inflammatory
marker levels in CAD patients
0
-10
-20
Level
decrease -30
(%)
-40
-36%
-50
-52%
-54%
-60
VCAM-1
Serum TNF-RII
Superoxide
33 normotensive patients with stable CAD
treated with irbesartan (75 to 150 mg/day) for 24 weeks
Navalkar S et al. J Am Coll Cardiol 2001;37(2):440–4.
Irbesartan improves endothelial function
in vasculature of CAD patients
100
* p < 0.05 vs. placebo
Placebo
Irbesartan
80
Monocyte
binding
to receptor
CD11
(%)
60
40
*
*
20
0
0
4
Time (weeks)
12
47 patients with documented coronary artery disease, previous CABG or PTCA
Randomized, placebo-controlled
Irbesartan (150 mg/d) or placebo for 12-week
Khan BV et al. J Am Coll Cardiol 2001;38(6):1662–7.
Irbesartan reduces oxidative stress in CAD patients
10
* p < 0.05 vs. placebo
8
Thiobarbituric
6
acid
reactive
substances 4
(µmol/L)
*
*
2
0
0
4
Time (weeks)
Placebo
12
Irbesartan
Khan BV et al. J Am Coll Cardiol 2001;38(6):1662–7.
Cardiovascular
structure
Irbesartan improves endothelial structure
After 1 year
of atenolol
After 1 year
of irbesartan
External diameter (µm)
283 ± 21.7
286 ± 16.3
Internal diameter (µm)
243 ± 19.9
246 ± 18.0
Media width (µm)
19.7 ± 1.11
15.4 ± 0.66**
M/L ratio (%)
8.44 ± 0.49*
6.46 ± 0.30**
MCSA (µm2)
17,046 ± 2316
13,007 ± 1401
Parameter
M/L, media-to-lumen ratio; MCSA, media cross-sectional area
* p < 0.05; ** p < 0.01
Schiffrin et al. J Hypertens 2002;20:71–8.
Irbesartan improves endothelial function
-20
0
20
40
Relaxation
(%)
60
Normotensive
Untreated
Atenolol
Irbesartan
80
100
-10
-9
-8
-7
-6
-5
-4
Acetylcholine (log conc. mol/l)
-3
-9
-8
-7
-6
-5
-4
-3
-2
Nitroprusside (log conc. mol/l)
Schiffrin et al. J Hypertens 2002;20:71–8.
Cardiovascular
clinical events
IDNT
Time to renal or cardiovascular outcome
80
Irbesartan
70
RRR 16%
p = 0.043
Amlodipine
60
p = NS
RRR 16%
p = 0.035
Control
50
Subjects
(%) 40
30
20
10
0
0
6
12
18
24
30
36
Follow-up (months)
42
48
54
60
Data on file, Sanofi-Synthelabo/Bristol-Myers Squibb.
IDNT
Time to CHF
30
Irbesartan
RRR 37%
p < 0.001
Amlodipine
20
RRR 23%
p = 0.15
Placebo
Subjects
(%)
10
0
0
6
12
18
24
30
36
Follow-up (months)
42
48
54
60
Data on file, Sanofi-Synthelabo/Bristol-Myers Squibb.
Prevalence of LVH in hypertension
Stage 3: SBP  180; DBP  110
Stage
of
hypertension
12%
3% 8%
30%
90%
Stage 2: SBP = 160–179; DBP = 100–110
Stage 1: SBP = 140–159; DBP = 90–99
10
20
30
80
90
100
Hypertensive patients (%)
Tedesco MA et al. Clin Cardiol 2001;24:603–7.
Schmieder RE et al. J Hum Hyperten 2000;14:597–604.
Kahan T. J Hypertens 1998;16(suppl 7):23–29.
Regression of LVH predicts prognosis
Probability
of event-free survival (%)
100
Rate of events
(per 100 patient-years)
7
Regressors
(n = 52)
90
6
5
80
p = 0.002
4
70
3
60
2
Non-regressors
(n = 60)
50
1
40
0
100
200
300
400
Time to event (weeks)
500
Regressors
NonRegressors
0
Verdecchia P et al. Circulation 1998;97:48–54.
Reversal of LV hypertrophy
by antihypertensive treatment
Diuretics
-blockers
Calciumchannel
blockers
ACE
inhibitors
0
-5
Change in
LV mass
index (%)
7%
6%
9%
-10
13%
-15
-20
p < 0.01
p < 0.10
-25
Mean values and 95% confidence intervals adjusted for
duration are given
Schmieder RE et al. JAMA 1996; 275:1507–13.
LIFE
LVH regression and primary endpoint
Change from baseline (%)
in LVH determined by electrocardiography
0
Proportion of patients
with first event (%)
16
-2
14
-4
-6
12
4.4%
10
-8
-14
-16
-18
Atenolol
8
9.0%
-10
-12
Composite of CV Death,
stroke and MI
6
10.2%
p < 0.0001
Atenolol
Losartan
Cornell
Voltage-Duration
Product
Losartan
4
15.3%
p < 0.0001
Sokolow-Lyon
Voltage
2
Adjusted Risk Reduction:
13.0%, p = 0.021
0
0 6 12 18 24 30 36 42 48 54 60 66
Time (months)
Dahlöf B et al. Lancet 2002;359:995–1003.
Comparison of SCOPE and LIFE results
LIFE1
SCOPE2
Losartan vs. Atenolol
Candesartan vs. Control
Cardiovascular events
-13%
-11%
Stroke
-26%
-21%
New diabetes
-25%
-20%
1. Dahlöf B et al. Lancet 2002;359: 995–1003.
2. Sever P et al. J Renin Angiotensin Aldosterone Syst 2002;3(2):61–2.
Irbesartan and atenolol in hypertension and LVH:
SILVHIA study design
Irbesartan
150-300 mg
Single-blind
Placebo
Addition of
HCTZ
12.5-25 mg
if SeDBP
 90 mmHg
Doubleblind
Addition of
Felodipine
5-10 mg
if SeDBP
 90 mmHg
Atenolol
50-100 mg
Time (weeks)
-4
0
12
24
48
*
*
*
*
Malmqvist K, Kahan T et al. Am J Cardiol 2002:90;1107–12.
Irbesartan vs. atenolol in hypertension and LVH:
DBP reduction
Week
24
12
48
12
Week
24
48
0
-5
DBP
reduction
(%)
-9%
-11%
-10
-12%
-13%
-15
-18%
-20
Irbesartan
Irb vs. Ate
Irbesartan
Atenolol
p = 0.194
p < 0.001
p < 0.001
-16%
Atenolol
Malmqvist K, Kahan T et al. J Hypertens 2001:19(6);1167–76.
Irbesartan vs. atenolol in hypertension and LVH:
LVMI reduction
Week
24
12
48
12
Week
24
48
0
-1%
-4%
-5%
-5
-8%
LVMI
(%)
-9%
-10
-15
-16%
Irbesartan
Irb vs. Ate
Irbesartan
Atenolol
p = 0.024
p < 0.001
p < 0.001
Atenolol
-20
Malmqvist K, Kahan T et al. J Hypertens 2001:19(6);1167–76.
Irbesartan and atenolol in hypertension and LVH:
Effects on QT dispersion
Irb: p < 0.001
Ate: p = 0.246
Irb vs Ate: p = 0.006
Irb: p < 0.001
Ate: p = 0.820
Irb vs Ate: p = 0.033
60
60
ms
ms
40
40
0 12 48
0 12 48
Time (weeks)
0 12 48
0 12 48
Time (weeks)
Irbesartan
Atenolol
Malmqvist K et al. Am J Cardiol 2002:90;1107–12.
Maintenance of sinus rhythm
after conversion from persistent AF
1.0
0.9
0.8
0.7
Patients
free of
recurrences
(%)
Amiodarone + Irbesartan
Amiodarone
0.6
0.5
0.4
0.3
0.2
0.1
0.0
2-month lower recurrence rate of atrial fibrillation
Longer time to first arrhythmia recurrence
Benefit at a trial level and positive reflection
on homogeneity of refractory period
0
30
60
p = 0.008
Log Rank = 0.007
90 120 150 180 210 240 270 300 330 360 390
Follow-up (days)
Madrid AH, Moro C et al. Circulation 2002;106:331–6.
Irbesartan significantly increased probability
of maintaining sinus rhythm
100
p = 0.008 vs. amiodarone
80
85%
60
Probability
of maintaining
sinus rhythm (%) 40
63%
20
0
Irbesartan
+ amiodarone
Amiodarone
159 patients with persistent atrial fibrillation were randomized
to either amiodarone or amiodarone + irbesartan
Results are taken at 2-month follow-up visit
Madrid A et al. Circulation 2002;106:331–6.
Atrial remodeling:
potential mechanisms of efficacy of irbesartan
 Hemodynamic effect:
 Decreased atrial stretch
 Lowering end-diastolic left ventricular pressure
 Prevention of electrical remodeling:
 Direct action on ionic currents at the atrial level
 Modifying the sympathetic tone
 Preventing structural remodeling
 Reduction of atrial fibrosis
 Reduction of atrial dilation and apoptosis
Madrid A et al. Circulation 2002;106:331–6.
I-PRESERVE
Irbesartan in Heart Failure with
Preserved Systolic Function
Importance of heart failure (HF)
with preserved ejection fraction (EF)
 Approximately 50% of HF cases are due primarily
to diastolic dysfunction 1,2
 Compared to systolic HF, patients are older, more often
women, more hypertensive, and have less overt CAD 1,2
 In the USA, it is responsible for approximately 20,000 deaths
and 500,000 hospital admissions annually
 In the absence of clinical trials, treatment remains empirical
Prevalence of heart failure
10
Proportion with decreased LV systolic function
Proportion with preserved LV systolic function
9
8
8.8
8.2
7
7.5
6.7
6
Prevalence 5
(%)
4
6.4
5.1
4.8
4.5
4.2
3
3.1
4.9
4.2
2.9
2
1.7
1
2.1
1.5
0
USA
Finland England Sweden
Den.
Spain Portugal Nether.
(CHS) (Helsinki) (Poole) (Vasteras) (Copen.) (Asturias) (EPICA) (Rotter.)
Age range
Mean age
66–103
78
75–86
-
70–84
76
75
75
 50
-
> 40
60
> 25
68
55–95
65
Mortality of incident heart failure in CHS
160
140
120
100
Deaths
per 1,000
80
person-years
60
40
20
0
Intact EF
No HF
Low EF
Intact EF
Low EF
CHF
Gottdiener JS et al. Ann Intern Med 2002;137:631–9.
6-month outcome following
heart failure hospitalization
60
Low LVEF
Preserved LVEF
50
50
44
40
Patients
(%)
52
41
30
20
24
23
23
17
10
0
Readmission Readmission
CHF
Any
Death
Death or
readmission
Philbin EF et al. Am J Med 2000;109:605–13.
Why a RAS blocking agent?
 Patients with CHF and preserved LV systolic function
commonly have hypertension, LVH, renal impairment,
diabetes and atherosclerotic disease
 ACE inhibitors (HOPE) and ARBs (LIFE) are of benefit
in these conditions
 Patients with CHF and preserved LV systolic function
also frequently have RAAS activation as a result
of diuretic treatment
Dauterman KW et al. Am Heart J 1998;135 (6 Pt 2 Su):S-310–9.
Processes underlying diastolic dysfunction
Hypertension
Aging
Atherosclerosis
Diabetes
Myocardium
Hypertrophy
Fibrosis
Cellular dysfunction
Ischemia
Increased stiffness
Impaired relaxation
Blood Vessels
Hypertrophy
Altered elastin & collagen
Calcification
Endothelial dysfunction
Loss of compliance
Diastolic Dysfunction
Heart Failure
Adapted from B. Massie
Evidence for Treatment
of HF-PSF
Irbesartan for HF-PSF
(I-Preserve) trial
Hypothesis:
Irbesartan will reduce vascular and heart failure mortality
and morbidity in patients with HF-PSF
Design:
Double-blind, placebo-controlled trial of irbesartan in 3,600 patients
(1,440 events) involving 360 centers in 29 countries
Entry criteria:
Symptomatic CHF with EF  45% with recent HF hospitalization
or other findings consistent with diastolic dysfunction, with or without
ACEI background (limited to one-third)
Primary endpoint:
All-cause mortality and specified CV hospitalizations
Data on file, Sanofi-Synthelabo/Bristol-Myers Squibb.
Inclusion criteria
 Male or female of age  60 years
 Current HF symptoms (at least one of the following):
 Dyspnea on exertion
 Orthopnea
 Paroxysmal nocturnal dyspnea
 Left ventricular ejection fraction  45%
 Willing to provide written informed consent
AND
 Hospitalization for heart failure
within the past 6 months
and current NYHA II-IV symptoms
OR
 Current NYHA III-IV symptoms
and
 Corroborative evidence




Chest X-ray
LVH on ECG
LBBB
Echo (LVH or LA  4.5 cm)
Data on file, Sanofi-Synthelabo/Bristol-Myers Squibb.
Study design
IRBESARTAN
75 mg* 150 mg 300 mg
Enrollment
Period A
R
Titration
Period B
Maintenance
Period C
Single-blind
2 weeks
W2
W4
W8
M6
M 10
M 24–28
Final visit
PLACEBO
*Forced titration
Data on file, Sanofi-Synthelabo/Bristol-Myers Squibb.
Primary endpoint
 Time to death (all causes) or specified cardiovascular hospitalization
 CV hospitalization for:
Worsening heart failure
 Unstable angina
 Myocardial infarction

Ventricular dysrhythmia
 Atrial dysrhythmia
 Stroke

OR
 Myocardial infarction or stroke occurring during any hospitalization
Data on file, Sanofi-Synthelabo/Bristol-Myers Squibb.
Persistence
ICE: Study endpoints
Primary
 Proportion of patients at 1 year who had remained
on their same initially-prescribed monotherapy
 Median times on initial monotherapy
Secondary
Proportion of patients at 1 year who had
 Added to their initially-prescribed monotherapy
 Switched to another antihypertensive therapy
 Discontinued all antihypertensive therapies
Dose titration was allowed
Hasford et al. J Human Hypertension 2002;16:569–75.
ICE: Patient samples
3,026
Newly-diagnosed patients
initiated with monotherapy
2,416
Diuretics
(n = 422)
Beta-blockers
(n = 441)
AIIRAs
(n = 754)
All other AIIRAs*
(n = 374)
*Includes candesartan, eprosartan, losartan, and valsartan
ACE inhibitors
(n = 333)
CCBs
(n = 466)
Irbesartan
(n = 380)
Hasford et al. J Human Hypertension 2002;16:569–75.
ICE: Persistence with initial antihypertensive
monotherapy after 12 months
70
60
*
Proportion
of patients
persistent
with initial
monotherapy
(%)
50
40
30
*
*
*
*
42.0
43.6
44.7
CCBs
Losartan
49.7
†
60.8
51.3
34.4
20
10
0
Diuretics ACEIs
Univariate analysis
* p < 0.05; † p = 0.009 vs. irbesartan
‡ Excluding irbesartan
Beta- AIIRAs‡ Irbesartan
blockers
Hasford et al. J Human Hypertension 2002;16:569–75.
ICE: Persistence with irbesartan
vs. all other antihypertensives
100
90
Proportion
of patients
persistent
with initial
monotherapy
(%)
80
Irbesartan
70
60
p = 0.0001
50
40
All other antihypertensives*
30
0
100
200
300
400
Days on monotherapy
Multivariate analysis
*Includes: ACE inhibitors, beta-blockers,
CCBs, diuretics, AIIRAs (excluding irbesartan)
Hasford et al. J Human Hypertension 2002;16:569–75.
ICE: Need for adjunctive therapy at one year
30
25
Proportion
of patients
requiring
adjunctive
therapy
(%)
†
*
25.3
24.5
20
15
16.1
10
5
0
Irbesartan
All other
antihypertensives‡
Univariate analysis
* p = 0.001, † p = 0.016 vs. irbesartan
‡ Includes: ACE inhibitors, beta-blockers,
CCBs, diuretics, AIIRAs (excluding irbesartan)
Losartan
Hasford et al. J Human Hypertension 2002;16:569–75.
ICE: Need for therapy switch at one year
15
*
13.6
12
Proportion
of patients
switched
from initial
monotherapy
(%)
9
9.0
8.0
6
3
0
Irbesartan
All other
antihypertensives‡
Univariate analysis
* p = 0.013 vs. irbesartan
‡ Includes: ACE inhibitors, beta-blockers,
CCBs, diuretics, AIIRAs (excluding irbesartan)
Losartan
Hasford et al. J Human Hypertension 2002;16:569–75.
ICE: Discontinuations at one year
25
*
22.9
20
Proportion
of patients
15
discontinuing
antihypertensive
10
therapy
(%)
16.6
14.2
5
0
Irbesartan
All other
antihypertensives‡
Univariate analysis
* p = 0.01 vs. irbesartan
‡ Includes: ACE inhibitors, beta-blockers,
CCBs, diuretics, AIIRAs (excluding irbesartan)
Losartan
Hasford et al. J Human Hypertension 2002;16:569–75.
ICE: Persistence with initial antihypertensive agent
at one year*
80
†
‡
69.5
69.2
All other
antihypertensives**
Losartan
76.8
Proportion
of patients
persistent
with initial
agent as
monotherapy
or combination
therapy*
(%)
60
40
20
0
Irbesartan
Univariate analysis
† p = 0.004, ‡ p = 0.048 vs. irbesartan
* Includes monotherapy or combination therapy with initially prescribed antihypertensive agent
** Includes: ACE inhibitors, beta-blockers, CCBs, diuretics, AIIRAs (excluding irbesartan)
Hasford et al. J Human Hypertension 2002;16:569–75.
ICE: Conclusions
 The initial choice of antihypertensive agent has a major
impact on persistence
 Patients started on irbesartan had significantly better
persistence than all other antihypertensive classes,
including other AIIRAs
 Persistence previously has been shown to be a major
determinant of long-term blood pressure control
Hasford et al. J Human Hypertension 2002;16:569–75.
ACTIVE
Atrial Fibrillation Clopidogrel Trial with
Irbesartan for Prevention of Vascular
Events
A phase III, multicenter, multinational, parallel
randomized controlled evaluation of clopidogrel plus
aspirin, with factorial evaluation of irbesartan, for the
prevention of vascular events in patients with atrial
fibrillation
ACTIVE Rationale
 Antiplatelet therapies are effective in the prevention of vascular
events in atherothrombosis in AF1,2
 More direct comparisons of antiplatelet therapies with anticoagulant
therapies in AF are needed3
 Anticoagulant therapies are associated with a greater risk of major
bleeds,3,4 have many contraindications and are burdensome to
patients
 Clopidogrel and ASA are synergistic1 – the combination is likely to
be more effective than ASA alone and may be non-inferior to oral
anticoagulant
 Irbesartan may reduce vascular events in AF by lowering blood
pressure and by the prevention of atrial remodelling5
1. Antithrombotic Trialists’ Collaboration. BMJ 2002;324:71–86.
2. PEP Trial. Lancet 2000; 355:1295–1302.
3. Taylor et al. BMJ 2001; 322:321–326.
4. Hart et al. Ann Intern Med 1999;13:492–501.
5. Nakashima. Circulation 2000; 10:2612–2617.
ACTIVE Objectives
 Primary objectives
 To evaluate whether clopidogrel plus acetylsalicylic acid
(ASA) is superior to ASA alone and non-inferior to
standard oral anticoagulant therapy in preventing vascular
events in patients with atrial fibrillation
 To evaluate whether blood pressure lowering with
irbesartan is superior to placebo in preventing vascular
events in patients with atrial fibrillation
 Secondary objectives
 To evaluate the safety of clopidogrel plus ASA in patients
with atrial fibrillation
 To evaluate the safety of irbesartan in patients with atrial
fibrillation
ACTIVE Design
A
Unsuitable for OAC
n-=6,500
Suitable for OAC
n-=6,500
ACTIVE A
Double-blind
superiority trial
ACTIVE W
PROBE
non inferiority trial
Clopidogrel 75mg/day*
n=3,750
Clopidogrel 75mg/day*
n=3,250
1
R
3
6
9
12
months
R
48 months fu
Every 6
Placebo*
n=3,750
OAC
n=3,250
1
3
6
9
12
Every 6
Allocated to ACTIVE A
Or to ACTIVE W and eligible for
ACTIVE I
ACTIVE I
Partial, factorial,
double-blind
superiority trial
1 3
9 12
R
Every 6
months
Placebo*
n> or = 5,000
1
* On top of ASA 75-100mg once daily
6
Irbesartan 150-300mg
n> or = 5,000
3
6
9 12
Every 6
A: Allocation
R: Randomization
OAC: Oral Anticoagulant
Total n= 14,000 patients with AF and evidence for high-risk of vascular event