Download Irbesartan 150 mg

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