relevance of at 1 blockade. adapted from mcconnaughey et al. j clin phamacol 1999;39: 547–59....

Relevance of AT1 blockade

Relevance of AT1 blockade

Adapted from McConnaughey et al. J Clin Phamacol 1999;39: 547–59.Adapted from McConnaughey et al. J Clin Phamacol 1999;39: 547–59.

AngiotensinII

ATAT11 Receptor Receptor ATAT22 Receptor Receptor

-sartan-sartan

Angiotensin II effects at the AT1 and AT2 receptorsAngiotensin II effects at the AT1 and AT2 receptors

VasoconstrictionActivate sympathetic activity

Increase sodium retentionIncrease vasopressin release

Promote myocyte hypertrophy and proliferationStimulate vascular and cardiac fibrosis

Stimulate plasminogen activator inhibitor 1Stimulate superoxide formation

VasoconstrictionActivate sympathetic activity

Increase sodium retentionIncrease vasopressin release

Promote myocyte hypertrophy and proliferationStimulate vascular and cardiac fibrosis

Stimulate plasminogen activator inhibitor 1Stimulate superoxide formation

AntiproliferationApotosis

Endothelial cell growth

Vasodilation (NO mediated?)Stimulate renal bradykinin and NO

AntiproliferationApotosis

Endothelial cell growth

Vasodilation (NO mediated?)Stimulate renal bradykinin and NO

ACE PATHWAY(< 30%)

NON-ACE PATHWAY(> 70%)

Angiotensin

AngiotensinogenAngiotensinogen

ChymaseToninCathepsinKallikrein

ChymaseToninCathepsinKallikreinAngiotensin IAngiotensin I

ReninRenin

ACEACE

McConnaughey et al. J Clin Phamacol 1999;39: 547–59.McConnaughey et al. J Clin Phamacol 1999;39: 547–59.

The Renin-Angiotensin Systemshowing ACE and non-ACE pathways

The Renin-Angiotensin Systemshowing ACE and non-ACE pathways

Angiotensin II, endothelial dysfunction and atherosclerosisAngiotensin II, endothelial dysfunction and atherosclerosis

NADH/NADPH oxidases

Free radicals

Endothelial dysfunction

Leucocyte adhesionSMC proliferation

Atherosclerosis

Angiotensin II

NO

Angiotensin II induces endothelial dysfunction and superoxide production

Angiotensin II induces endothelial dysfunction and superoxide production

Relaxation (%)Relaxation (%)

Concentration of Ach (log M)Concentration of Ach (log M)

Endothelial dysfunctionEndothelial dysfunction

Rajagopalan and Harrison. JCI 1996;97:1916–23.Rajagopalan and Harrison. JCI 1996;97:1916–23.

-9-9 -8-8 -7-7 -6-6

100100

8080

6060

4040

2020

00

Control

AII

AII+SOD

NADHNADH NADPHNADPH00

1010

2020

3030

4040

5050

(nmol/min)(nmol/min)

Griendling et al. Circ Res 1994;74:11–48.Griendling et al. Circ Res 1994;74:11–48.

Superoxide productionfrom NADH/NADPH oxidases

Superoxide productionfrom NADH/NADPH oxidases

ControlAII

AT1 blockadewith irbesartanAT1 blockade

with irbesartan

Responses to Ang I and [ProResponses to Ang I and [Pro1111DD-Ala-Ala1212] Ang I] Ang IResponses to Ang I and [ProResponses to Ang I and [Pro1111DD-Ala-Ala1212] Ang I] Ang I

McDonald et al. Circulation 2001;104:1805–8.McDonald et al. Circulation 2001;104:1805–8.

Angiotensin IAngiotensin I

Veno-Constriction

(%)

Veno-Constriction

(%)

8080

7070

6060

5050

4040

3030

2020

1010

00

[Pro-11D-Ala12] Angiotensin I[Pro-11D-Ala12] Angiotensin I

PrePre PostPost PrePre PostPost

PlaceboPlacebo CaptoprilCaptopril

PrePre PostPost PrePre PostPost

PlaceboPlacebo CaptoprilCaptopril

p = 0.002 p = 0.0007

IrbesartanIrbesartan

SBP response to exogenous Ang II (%)SBP response to exogenous Ang II (%)

Mazzolai L et al. Hypertension 1999;33:850–5.Mazzolai L et al. Hypertension 1999;33:850–5.

100100

8080

6060

4040

2020

00

00 55 1010 1515 2020 2525 3030 3535

Time (hours)Time (hours)

*

*

* ‡

*

*

* ‡

†

*

Superior inhibition of SBP to exogenous Ang II with irbesartan

Superior inhibition of SBP to exogenous Ang II with irbesartan

* p < 0.01 vs. placebo† p < 0.05 vs. placebo‡ p < 0.05 vs. other antagonists

* p < 0.01 vs. placebo† p < 0.05 vs. placebo‡ p < 0.05 vs. other antagonists

Values are mean ± SEM

Placebo

Losartan 50 mg

Valsartan 80 mg

Irbesartan 150 mg

Placebo

Losartan 50 mg

Valsartan 80 mg

Irbesartan 150 mg

Relative potency of AT1 blockersRelative potency of AT1 blockers

Day 1 Day 8

00

Plasma renin activity

(ng/ml•h)

Plasma renin activity

(ng/ml•h)

0 h0 h 4 h4 h 24 h24 h

55

1010

1515

2020

2525

0 h0 h 4 h4 h 24 h24 h

Maillard MP et al. Clin Pharmacol Ther 2002;71:68–76.Maillard MP et al. Clin Pharmacol Ther 2002;71:68–76.

Valsartan 80 mgValsartan 160 mgValsartan 80 mgValsartan 160 mg

Irbesartan 150 mgCandesartan 8 mgIrbesartan 150 mgCandesartan 8 mg

Valsartan 320 mgLosartan 50 mgValsartan 320 mgLosartan 50 mg

Increases in PRA reflect AT1 receptor blockadeIncreases in PRA reflect AT1 receptor blockade

Blood pressure lowering

Blood pressure lowering

N shown is at Week 8N shown is at Week 8

SeDBP from baseline (mmHg) SeDBP from baseline (mmHg)

†

Irbesartan300 mg(n = 134)




Losartan100 mg(n = 131)


Placebo(n = 138)Placebo(n = 138)

Time (weeks)Time (weeks)00 11 44 88

-12-12

-10-10

-8-8

-6-6

-4-4

-2-2

00

*

*

Irbesartan vs. losartanFixed dose mean change from baseline in trough SeDBP

Irbesartan vs. losartanFixed dose mean change from baseline in trough SeDBP

Kassler-Taub K et al. Am J Hypertens 1998;11:445–53.Kassler-Taub K et al. Am J Hypertens 1998;11:445–53.

* p < 0.01 vs. losartan † p < 0.02 vs. losartan

* p < 0.01 vs. losartan † p < 0.02 vs. losartan

Irbesartan vs. losartanFixed dose mean change from baseline in trough SeSBP

Irbesartan vs. losartanFixed dose mean change from baseline in trough SeSBP

* p < 0.01 vs. losartan* p < 0.01 vs. losartan

*-18-18

-16-16

-14-14

-12-12

-10-10

-8-8

-6-6

-4-4

-2-2

00

00 11 44 88N shown is at Week 8N shown is at Week 8







Placebo(n = 138)Placebo(n = 138)

Kassler-Taub K et al. Am J Hypertens 1998;11:445–53.Kassler-Taub K et al. Am J Hypertens 1998;11:445–53.

SeSBP from baseline (mmHg) SeSBP from baseline (mmHg)

Time (weeks)Time (weeks)

Trough ABP from

baseline(mmHg)

Trough ABP from

baseline(mmHg)

ADBPADBP

Irbesartan vs. valsartanIrbesartan vs. valsartanSuperior reduction in trough 24-h Ambulatory BPSuperior reduction in trough 24-h Ambulatory BP

Irbesartan vs. valsartanIrbesartan vs. valsartanSuperior reduction in trough 24-h Ambulatory BPSuperior reduction in trough 24-h Ambulatory BP

Mancia G. Blood Pressure Monitoring 2002;7(2):135–42.Mancia G. Blood Pressure Monitoring 2002;7(2):135–42.

00

-2-2

-4-4

-6-6

-8-8

-10-10

-12-12

ASBPASBP

(p = 0.035)(p = 0.035)

(p < 0.01)(p < 0.01)

Irbesartan 150 mgIrbesartan 150 mg Valsartan 80 mgValsartan 80 mg

N = 426

ADBPADBP

Irbesartan vs. valsartanIrbesartan vs. valsartanSuperior reduction in mean 24-h Ambulatory BPSuperior reduction in mean 24-h Ambulatory BP

Irbesartan vs. valsartanIrbesartan vs. valsartanSuperior reduction in mean 24-h Ambulatory BPSuperior reduction in mean 24-h Ambulatory BP

00

-2-2

-4-4

-6-6

-8-8

-10-10

-12-12

ASBPASBP

(p = 0.023)(p = 0.023)

(p < 0.01)(p < 0.01)

Mean ABP from

baseline (mmHg)

Mean ABP from

baseline (mmHg)

Irbesartan 150 mgIrbesartan 150 mg Valsartan 80 mgValsartan 80 mg

Mancia G. Blood Pressure Monitoring 2002;7(2):135–42.Mancia G. Blood Pressure Monitoring 2002;7(2):135–42.

Irbesartan vs. losartan and valsartanOverall Summary

Irbesartan vs. losartan and valsartanOverall 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

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.

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

Irbesartan and enalapril equally lower mean ambulatory BP over 24-h

-16-16

-14-14

-12-12

-10-10

-8-8

-6-6

-4-4

-2-2

00

Mean reduction

in BP (mmHg)

Mean reduction

in BP (mmHg)

SBPSBP

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)

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)

DBPDBP

-14.7

-9.4

-12.6

-8.8

IrbesartanEnalapril

Coca A et al. Clinical Therapeutics 2002;1:12–38.Coca A et al. Clinical Therapeutics 2002;1:12–38.

00 22 44 66 88 1010 121200 22 44 66 88 1010 1212

Change in trough SeDBPChange in trough SeDBP

-45-45

-35-35

-25-25

-15-15

-5-5

-40-40

-30-30

-20-20

-10-10

00

Larochelle P et al. Am J Cardiol 1997;80:1613–15.Larochelle P et al. Am J Cardiol 1997;80:1613–15.

* 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

* 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

Change in trough SeSBPChange in trough SeSBP

Irbesartan 75–300 mg* (n = 95)Enalapril 10–40 mg* (n = 97)Irbesartan 75–300 mg* (n = 95)Enalapril 10–40 mg* (n = 97)

Change from

baseline (mmHg)

Change from

baseline (mmHg)

Irbesartan vs. enalapril in severe hypertensionIrbesartan vs. enalapril in severe hypertension

-45-45

-35-35

-25-25

-15-15

-5-5

-40-40

-30-30

-20-20

-10-10

00

Change from

baseline (mmHg)

Change from

baseline (mmHg)

Time (weeks)Time (weeks) Time (weeks)Time (weeks)

Dose response Dose response with irbesartan/HCTZ combination therapy with irbesartan/HCTZ combination therapy

and componentsand components

Dose response Dose response with irbesartan/HCTZ combination therapy with irbesartan/HCTZ combination therapy

and componentsand components

-16-16

-14-14

-12-12

-10-10

-8-8

-6-6

-4-4

-2-2

00

SeDBP(mmHg) SeDBP(mmHg)

Kochar M et al. Am J Hypertens 1999;12:797–805.Kochar M et al. Am J Hypertens 1999;12:797–805.

n = 40 patients per groupn = 40 patients per group

PlaceboPlaceboHCTZ 12.5 mgHCTZ 12.5 mg

Irbesartan 300 mg

Irbesartan 300 mg

Irbesartan 300 mgHCTZ 12.5 mg

Irbesartan 300 mgHCTZ 12.5 mg

-3.5-3.5

-6.2-6.2

-10.2-10.2

-15.0-15.0

Long-term efficacy withLong-term efficacy withirbesartan/HCTZ-based regimensirbesartan/HCTZ-based regimens

Long-term efficacy withLong-term efficacy withirbesartan/HCTZ-based regimensirbesartan/HCTZ-based regimens

-25-25

-20-20

-15-15

-10-10

-5-5

00

-14.2-15.7 -15.6

-19.1-20.7 -20.6

MonthMonth

22 66 1212

Raskin P et al. J Hum Hypertens 1999;13:68–7.Raskin P et al. J Hum Hypertens 1999;13:68–7.

BP (mmHg) BP

(mmHg)

SeDBPSeDBP SeSBPSeSBP

N = 1,098N = 1,098

Littlejohn T III et al. Clin Exp Hypertens 1999;21:1273–95.Littlejohn T III et al. Clin Exp Hypertens 1999;21:1273–95.

Long-term therapeutic response with irbesartanLong-term therapeutic response with irbesartanand irbesartan/HCTZ-based regimensand irbesartan/HCTZ-based regimens

Long-term therapeutic response with irbesartanLong-term therapeutic response with irbesartanand irbesartan/HCTZ-based regimensand irbesartan/HCTZ-based regimens

Normalized*Responder†Normalized*Responder†

*Trough SeDBP < 90 mmHg† Normalized or reduction from baseline of 10 mmHg*Trough SeDBP < 90 mmHg† Normalized or reduction from baseline of 10 mmHg

00

2020

4040

6060

8080

100100

8080 8383 81818787 9090 8787

Patients (%)

Patients (%)

66 1212 2424

N = 1,006N = 1,006

Time (months)Time (months)

Renoprotectiveeffects

Renoprotectiveeffects

Diabetes Care 2003;26 (Supp 1):594–598.Diabetes Care 2003;26 (Supp 1):594–598.

Definitions of abnormalities in albumin excretion

Definitions of abnormalities in albumin excretion

Normal

Microalbuminuria

Clinical albuminuria

Normal

Microalbuminuria

Clinical albuminuria

< 30

30 -299

300

< 30

30 -299

300

Spot collection(µg/mg creatinine)

Spot collection(µg/mg creatinine)

< 30

30 -299

300

< 30

30 -299

300

24h collection(mg/24h)

24h collection(mg/24h)

< 20

20 -199

200

< 20

20 -199

200

Time collection(µg/min)

Time collection(µg/min)

*p < 0.01*p < 0.01

Sasso FC et al. Diabetes Care 2002;25:NR II.Sasso FC et al. Diabetes Care 2002;25:NR II.

Irbesartan reduces microalbuminuria in type 2 diabetic patients

Irbesartan reduces microalbuminuria in type 2 diabetic patients

A randomized double-blind placebo-controlled crossover studyA randomized double-blind placebo-controlled crossover study

180180

160160140140

120120

1001008080

606040402020

00

AER 5 (µg/min)AER 5 (µg/min)

180180

160160140140

120120

1001008080

606040402020

00

AER 5 (µg/min)AER 5 (µg/min)

Normotensive diabetic subjectsNormotensive diabetic subjects Hypertensive diabetic subjectsHypertensive diabetic subjects

Subgroup 1Subgroup 1 Subgroup 2Subgroup 2 Subgroup 1Subgroup 1 Subgroup 2Subgroup 2

** **** **

Time 0Time 0 PlaceboPlacebo IrbesartanIrbesartan

Relative prognostic value of microalbuminuriain type 2 Diabetes

Relative prognostic value of microalbuminuriain type 2 Diabetes

Eastman RC, Keen H. Lancet 1997;350(Suppl 1):29–32.Eastman RC, Keen H. Lancet 1997;350(Suppl 1):29–32.

MicroalbuminuriaMicroalbuminuria SmokingSmoking Diastolic BPDiastolic BP

Mortality from CHD (odds ratio)

Mortality from CHD (odds ratio)

CholesterolCholesterol

10.0210.02

6.526.52

2.322.323.203.20

1010

88

66

44

22

00

Microalbuminuria predicts future coronary events in patients with type 2 diabetes

Microalbuminuria predicts future coronary events in patients with type 2 diabetes

Remaining event free (%)Remaining event free (%)100100

9090

8080

7070

6060

5050

4040

No microalbuminuriaMicroalbuminuria

00 11 22 33 44 55

Follow-up (years)Follow-up (years)

86 pts with type 2 diabetesNo history of coronary artery disease

- 43 with microalbuminuria (AER > 200 g/min)- 43 with normoalbuminuria

86 pts with type 2 diabetesNo history of coronary artery disease

- 43 with microalbuminuria (AER > 200 g/min)- 43 with normoalbuminuria

Rutter MK et al. J Am Coll Cardiol 2002;40:56–61.Rutter MK et al. J Am Coll Cardiol 2002;40:56–61.

100100

9090

8080

7070

6060

5050

2020

00 11 22 33 44 55

Follow-up (years)Follow-up (years)

40403030

Neither SMI nor microalbuminuriaSMI, but no microalbuminuriaMicroalbuminuria, but no SMIBoth SMI and microalbuminuria

Neither SMI nor microalbuminuriaSMI, but no microalbuminuriaMicroalbuminuria, but no SMIBoth SMI and microalbuminuria

SMI = Silent myocardial ischemia(> 1 mm ST depression on treadmill exercise)

Follow-up: 2.8 years; 23 coronary events

SMI = Silent myocardial ischemia(> 1 mm ST depression on treadmill exercise)

Follow-up: 2.8 years; 23 coronary events

Remaining event free (%)Remaining event free (%)

Prognostic value of microalbuminuria in initially untreated hypertensive (n = 99) and normotensive (n = 21)

non-diabetic subjects followed for 10 years

Prognostic value of microalbuminuria in initially untreated hypertensive (n = 99) and normotensive (n = 21)

non-diabetic subjects followed for 10 years

Ljungman S et al. Am J Hypertens 1996;9:770–8.Ljungman S et al. Am J Hypertens 1996;9:770–8.

1010

1212

1414

1616

1818

2020

00

Baseline urinary albuminexcretion

(median, mg/24-h)

Baseline urinary albuminexcretion

(median, mg/24-h)

p = 0.015p = 0.015

No CV events(n = 101)

No CV events(n = 101)

Developed CVD(n = 19)

Developed CVD(n = 19)

Microalbuminuria predicts coronary events in subjects with essential hypertension

Microalbuminuria predicts coronary events in subjects with essential hypertension

Jensen JS et al. Hypertension 2000;35:898–903.Jensen JS et al. Hypertension 2000;35:898–903.

00 22 33 44 55 66 77 88 99 101011

Proportion without ischemic

heart disease (%)

Proportion without ischemic

heart disease (%)

100100

9595

9090

8585

8080

7575

7070

NormoalbuminuriaMicroalbuminuria(UA/Cr ratio > 1.07 mg/mmol)

204 hypertensive subjects drawn from 2,085 general population subjectsNo previous CV events, no diabetes, no renal or urinary diseaseFollow-up from 1983–84 till 199318 coronary events

204 hypertensive subjects drawn from 2,085 general population subjectsNo previous CV events, no diabetes, no renal or urinary diseaseFollow-up from 1983–84 till 199318 coronary events

Time (years)Time (years)

PRIMEPRIME

IRMA 2IRMA 2 IDNTIDNTPreventionPrevention ProtectionProtection

ESRD ESRD

Early StageEarly Stage Late StageLate Stage End StageEnd Stage

Microalbuminuria Microalbuminuria ProteinuriaProteinuria

PRIME: PRogram for Irbesartan Mortality and Morbidity EvaluationsIRMA 2: IRbesartan in Patients with Type 2 Diabetes and Microalbuminuria IDNT: Irbesartan Diabetic Nephropathy TrialESRD: End-stage renal disease

PRIME: PRogram for Irbesartan Mortality and Morbidity EvaluationsIRMA 2: IRbesartan in Patients with Type 2 Diabetes and Microalbuminuria IDNT: Irbesartan Diabetic Nephropathy TrialESRD: End-stage renal disease

Cardiovascular morbidity and mortalityCardiovascular morbidity and mortalityCardiovascular morbidity and mortalityCardiovascular morbidity and mortality

PRIMETime course of type 2 diabetic renal disease

PRIMETime course of type 2 diabetic renal disease

Double-blind treatmentDouble-blind treatmentScreening/EnrollmentScreening/Enrollment

IRMA 2Study design

IRMA 2Study design

590 patients with type 2 diabetes, microalbuminuria (albumin excretion rate 20 – 200 g/min), normal renal function, and hypertension

590 patients with type 2 diabetes, microalbuminuria (albumin excretion rate 20 – 200 g/min), normal renal function, and hypertension

Up to 5 weeksUp to 5 weeks

Irbesartan 150 mg

Follow-up: 2 years Follow-up: 2 years

Placebo

Irbesartan 300 mg

Parving H-H et al. N Engl J Med 2001;345:870–8.Parving H-H et al. N Engl J Med 2001;345:870–8.

00

7070

130130

160160

00 33 66 99 1212 1515 1818 2121 2424 2727


Mean SeSBP

and SeDBP

(mmHg)

Mean SeSBP

and SeDBP

(mmHg)

8080

9090

100100

110110

120120

140140

150150

ControlIrbesartan 150 mgIrbesartan 300 mg



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 groupConcomitant 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

IRMA 2Blood pressure response

IRMA 2Blood pressure response

SeSBP

SeDBP

00 33 66 1212 1818 2222 242400

55

1010

1515

2020

Follow-up (months)Follow-up (months)

Subjects (%)

Subjects (%)


70% RRRp < 0.001

70% RRRp < 0.001

IRMA 2 Primary endpoint: Time to overt proteinuria

IRMA 2 Primary endpoint: Time to overt proteinuria


3535

4545

4040

3030

2525

2020

1515

1010

55

00

Subjects (%)

Subjects (%)

Control(n = 201)Control(n = 201)

150 mg(n = 195)150 mg

(n = 195)300 mg

(n = 194)300 mg

(n = 194)


24%24%

34%34%

21%21%

IRMA 2Normalization of urinary albumin excretion rate

IRMA 2Normalization of urinary albumin excretion rate


p = 0.006

IRMA 2 Adverse outcomes

IRMA 2 Adverse outcomes


Cardiovascular events

Serious adverse events

Discontinuations due to adverse events


Serious adverse events

Discontinuations due to adverse events

18

47

19

18

47

19

(8.7)

(22.8)

(9.2)

(8.7)

(22.8)

(9.2)

ControlControl

14

32

18

14

32

18

(6.9)

(15.8)

(8.9)

(6.9)

(15.8)

(8.9)

Irbesartan(150 mg)

Irbesartan(150 mg)

9

30

11

9

30

11

(4.5)

(15.0)

(5.5)

(4.5)

(15.0)

(5.5)

Irbesartan(300 mg)

Irbesartan(300 mg)

No. of adverse outcomes (%)No. of adverse outcomes (%)

Proteinuria levels predict stroke Proteinuria levels predict stroke and CHD events in type 2 diabetesand CHD events in type 2 diabetesProteinuria levels predict stroke Proteinuria levels predict stroke and CHD events in type 2 diabetesand CHD events in type 2 diabetes

U-Prot = Urinary protein concentrationU-Prot = Urinary protein concentration

1.01.0

0.90.9

0.80.8

0.70.7

0.60.6

0.50.5

0000 1010 2020 3030 4040 5050 6060 7070 8080 9090 StrokeStroke CHD eventsCHD events

p < 0.001

Incidence (%)Incidence (%)Survival curves(CV mortality)Survival curves(CV mortality)


Overall: p < 0.001

00

1010

2020

3030

4040

U-Prot < 150 mg/LU-Prot < 150 mg/L U-Prot 150-300 mg/LU-Prot 150-300 mg/L U-Prot > 300 mg/LU-Prot > 300 mg/L

Miettinen H et al. Stroke 1996;27:2033–9.Miettinen H et al. Stroke 1996;27:2033–9.

> 300

< 150

150-300

140140

160160

100100

120120

6060

8080

2020

4040

00

44

11

33

22GFR

(ml/min)GFR

(ml/min)

Protein excretion(g/day)

Protein excretion(g/day)

Pre-clinical Diabetic Renal Disease

Pre-clinical Diabetic Renal Disease Overt ProteinuriaOvert Proteinuria

Micro-albuminuria

Micro-albuminuria

Proteinuria

PersistentMicroalbuminuria

Adapted from Mogensen CE. Kidney Int 1982;21:673. and Friedman EA. Kidney Int 1982;21:780.Adapted from Mogensen CE. Kidney Int 1982;21:673. and Friedman EA. Kidney Int 1982;21:780.

Time (yrs 10)Time (yrs 10)00 2020

Course of diabetic renal diseaseCourse of diabetic renal disease

Screening for microalbuminuria: ADA guidelinesScreening for microalbuminuria: ADA guidelines

Test for microalbuminuria

+ for albumin

Condition that may invalidateurine albumin excretion?

Treat and/or wait until resolved.Repeat test. + for protein?

Repeat microalbuminuria testtwice within 3–6 month period

Microalbuminuria, begin treatment

2 of 3 test positive?Rescreen in one year

YesYes

YesYes NoNo

YesYes

YesYes

NoNo

Diabetes Care 2003;26 (Supp 1):594–598.Diabetes Care 2003;26 (Supp 1):594–598.

IDNTIDNTStudy designStudy design

IDNTIDNTStudy designStudy design

Double-blind treatmentDouble-blind treatmentScreening/EnrollmentScreening/Enrollment

1,715 patients with type 2 diabetes, proteinuria 900 mg/d, and hypertension1,715 patients with type 2 diabetes, proteinuria 900 mg/d, and hypertension

Up to 5 weeksUp to 5 weeks

Placebo*

Irbesartan*

Amlodipine*

Minimum follow-up: approximately 2 years

(average 3 years)

Minimum follow-up: approximately 2 years

(average 3 years)

Collaborative Study Group. Rodby RA et al. Nephrol Dial Transplant 2000;15:487–97.Collaborative Study Group. Rodby RA et al. Nephrol Dial Transplant 2000;15:487–97.

* Adjunctive antihypertensive therapies (excluding ACE inhibitors, angiotensin II receptor antagonists, and calcium channel blockers) added to each arm to achieve equal blood pressure reduction

* Adjunctive antihypertensive therapies (excluding ACE inhibitors, angiotensin II receptor antagonists, and calcium channel blockers) added to each arm to achieve equal blood pressure reduction

BP (mmHg)

BP (mmHg)

IrbesartanAmlodipineControl

IrbesartanAmlodipineControl

00 66 1212 1818 2424 3030 3636 4242 4848 5454

Follow-up visit (months)Follow-up visit (months)

8080

100100

120120

140140

160160

SBP

Mean

DBP

IDNTSystolic, mean, and diastolic BP response

IDNTSystolic, mean, and diastolic BP response

Lewis EJ et al. N Engl J Med 2001;345(12):851–60.Lewis EJ et al. N Engl J Med 2001;345(12):851–60.

Subjects (%)

Subjects (%)

00 66 1212 1818 2424 3030 3636 4242 4848 5454


6060

00

1010

2020

3030

4040

5050

6060

7070

Irbesartan

Amlodipine

Control

IDNT primary endpointTime to doubling of serum creatinine, ESRD, or death

IDNT primary endpointTime to doubling of serum creatinine, ESRD, or death

RRR = 23%p = 0.006

p = NS

RRR = 20%p = 0.02


RRR: Relative Risk ReductionRRR: Relative Risk Reduction

IDNTTime to doubling of serum creatinine

IDNTTime to doubling of serum creatinine

00 66 1212 1818 2424 3030 3636 4242 4848 5454


6060

00

1010

2020

3030

4040

5050

6060

7070

Irbesartan

Amlodipine

Control

RRR = 37%p < 0.001

p = NS

RRR = 33%p = 0.003

Subjects (%)

Subjects (%)


Irbesartan

Control + amlodipine

00

1010

3030

4040

2020

IDNTTime to ESRD

IDNTTime to ESRD

RRR = 23%p = 0.004

00 66 1212 1818 2424 3030 3636 4242 4848 5454

Follow-up (months)Follow-up (months)6060

Subjects (%)

Subjects (%)

Lewis EJ et al. N Engl J Med 2001;345(12):851–60.Data on file, Sanofi-Synthelabo/Bristol-Myers Squibb.Lewis EJ et al. N Engl J Med 2001;345(12):851–60.Data on file, Sanofi-Synthelabo/Bristol-Myers Squibb.

00 66 1212 1818 2424 3030 3636 4242 4848 5454 6060 6666 7272 7878

0.00.0

0.10.1

0.20.2

0.30.3

0.40.4

0.50.5

0.60.6

The role of irbesartan in the treatment of diabetic kidney diseaseThe role of irbesartan in the treatment of diabetic kidney disease

(Doubling of serum creatinine or ESRD)(Doubling of serum creatinine or ESRD)

Patients reaching

Scr doubling or ESRD (fraction)

Patients reaching

Scr doubling or ESRD (fraction)

Follow-up time (months)Follow-up time (months)

Irbesartan

Amlodipine

Placebo

RRR = 34%p = 0.0002 RRR = 26%

p = 0.011RRR = -12%p = 0.32

Time to renal endpoint by treatment assignmentTime to renal endpoint by treatment assignment

Lewis EJ et al. N Engl J Med 2001;345(12):851–60.Data on file, Sanofi-Synthelabo/Bristol-Myers Squibb.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

Time to the development of ESRD after doubling serum creatinine


0.00.0 0.50.5 1.01.0 1.51.5

1.01.0

0.90.9

0.80.8

0.70.7

0.60.6

0.50.5

0.40.4

0.30.3

0.20.2

0.10.1

00

Time after creatinine doubling (years)Time after creatinine doubling (years)

6868 3737 1717 55n at risk:n at risk:

Proportion with event

Proportion with event

Type 1 diabetic nephropathy

Type 1 diabetic nephropathy

Lewis EJ et al. N Engl J Med 2001;345:851–60.Lewis EJ et al. N Engl J Med 2001;345:851–60.

IDNTAdverse outcomes

IDNTAdverse outcomes

Early serum creatinine rise

D/C due to hyperkalemia

Stopped study medicine

SAEs/1000 days on drug

Early serum creatinine rise

D/C due to hyperkalemia

Stopped study medicine

SAEs/1000 days on drug

0

11

134

2.0

0

11

134

2.0

(1.9)

(23)

(1.9)

(23)


0

3

133

2.5

0

3

133

2.5

(0.5)

(23)

(0.5)

(23)

AmlodipineAmlodipine

1

2

140

2.3

1

2

140

2.3

(0.4)

(25)

(0.4)

(25)

ControlControl

No. of adverse outcomes (%)No. of adverse outcomes (%)

End-Stage

Progression

Initiation

“At Risk”

Cardiovasculardisease

Cardiovasculardisease

CHFCHF

Arteriosclerotic cardiovascular disease eventsArteriosclerotic cardiovascular disease events

Coronary artery diseaseLeft ventricular hypertrophyCoronary artery diseaseLeft ventricular hypertrophy

Elderly,DM, BPElderly,DM, BP

Chronic Renaldisease

Chronic Renaldisease

ESRDESRD

Chronic renal insufficiency ( GFR)

Chronic renal insufficiency ( GFR)

Albuminuria Proteinuria

Albuminuria Proteinuria

Elderly,DM, BP

Elderly,DM, BP

Adapted from Sarnak and Levey, Am J Kidney Dis 2000;35:S117–31.Adapted from Sarnak and Levey, Am J Kidney Dis 2000;35:S117–31.

Cardiovascular and renal disease continuumCardiovascular and renal disease continuum

Markers ofcardiovascular risk

Markers ofcardiovascular risk

Irbesartan decreases inflammatory marker levels in CAD patients

Irbesartan decreases inflammatory marker levels in CAD patients

Navalkar S et al. J Am Coll Cardiol 2001;37(2):440–4.Navalkar S et al. J Am Coll Cardiol 2001;37(2):440–4.

Level decrease

(%)

Level decrease

(%)

-60-60

-50-50

-40-40

-30-30

-20-20

-10-10

00

VCAM-1VCAM-1

-36%

-54% -52%

Serum TNF-RIISerum TNF-RII SuperoxideSuperoxide

33 normotensive patients with stable CAD

treated with irbesartan (75 to 150 mg/day) for 24 weeks

33 normotensive patients with stable CAD

treated with irbesartan (75 to 150 mg/day) for 24 weeks

Khan BV et al. J Am Coll Cardiol 2001;38(6):1662–7.Khan BV et al. J Am Coll Cardiol 2001;38(6):1662–7.

00

2020

4040

6060

8080

100100

00 44 1212

Monocyte binding

to receptor CD11

(%)

Monocyte binding

to receptor CD11

(%)


* *

* p < 0.05 vs. placeboPlaceboIrbesartanPlaceboIrbesartan

47 patients with documented coronary artery disease, previous CABG or PTCA Randomized, placebo-controlled Irbesartan (150 mg/d) or placebo for 12-week

47 patients with documented coronary artery disease, previous CABG or PTCA Randomized, placebo-controlled Irbesartan (150 mg/d) or placebo for 12-week

Irbesartan improves endothelial function in vasculature of CAD patients

Irbesartan improves endothelial function in vasculature of CAD patients

00

22

44

66

88

1010

Thiobarbituric acid

reactive substances

(µmol/L)

Thiobarbituric acid

reactive substances

(µmol/L)

* *

Khan BV et al. J Am Coll Cardiol 2001;38(6):1662–7.Khan BV et al. J Am Coll Cardiol 2001;38(6):1662–7.

00 44 1212

* p < 0.05 vs. placebo

Irbesartan reduces oxidative stress in CAD patientsIrbesartan reduces oxidative stress in CAD patients

IrbesartanIrbesartanPlaceboPlacebo


Cardiovascularstructure

Cardiovascularstructure

Irbesartan improves endothelial structureIrbesartan improves endothelial structure

Schiffrin et al. J Hypertens 2002;20:71–8.Schiffrin et al. J Hypertens 2002;20:71–8.

External diameter (µm)

Internal diameter (µm)

Media width (µm)

M/L ratio (%)

MCSA (µm2)

External diameter (µm)

Internal diameter (µm)

Media width (µm)

M/L ratio (%)

MCSA (µm2)

283 ± 21.7

243 ± 19.9

19.7 ± 1.11

8.44 ± 0.49*

17,046 ± 2316

283 ± 21.7

243 ± 19.9

19.7 ± 1.11

8.44 ± 0.49*

17,046 ± 2316

After 1 yearof atenolol

After 1 yearof atenolol

286 ± 16.3

246 ± 18.0

15.4 ± 0.66**

6.46 ± 0.30**

13,007 ± 1401

286 ± 16.3

246 ± 18.0

15.4 ± 0.66**

6.46 ± 0.30**

13,007 ± 1401

After 1 yearof irbesartanAfter 1 yearof irbesartanParameterParameter

M/L, media-to-lumen ratio; MCSA, media cross-sectional area* p < 0.05; ** p < 0.01M/L, media-to-lumen ratio; MCSA, media cross-sectional area* p < 0.05; ** p < 0.01

Irbesartan improves endothelial functionIrbesartan improves endothelial function

NormotensiveUntreatedAtenololIrbesartan

NormotensiveUntreatedAtenololIrbesartan

Schiffrin et al. J Hypertens 2002;20:71–8.Schiffrin et al. J Hypertens 2002;20:71–8.

-20-20

00

2020

4040

6060

8080

100100

-10-10 -9-9 -8-8 -7-7 -6-6 -5-5 -4-4 -3-3

Acetylcholine (log conc. mol/l)Acetylcholine (log conc. mol/l)

-9-9 -8-8 -7-7 -6-6 -5-5 -4-4 -3-3

Nitroprusside (log conc. mol/l)Nitroprusside (log conc. mol/l)

-2-2

Relaxation

(%)

Relaxation

(%)

Cardiovascularclinical events

Cardiovascularclinical events

IDNTTime to renal or cardiovascular outcome

IDNTTime to renal or cardiovascular outcome

Subjects (%)

Subjects (%)

00 66 1212 1818 2424 3030 3636 4242 4848 5454


Irbesartan

Amlodipine

Control

RRR 16%p = 0.043

p = NS

RRR 16%p = 0.035

8080

7070

6060

5050

4040

3030

2020

1010

00

Data on file, Sanofi-Synthelabo/Bristol-Myers Squibb.Data on file, Sanofi-Synthelabo/Bristol-Myers Squibb.

IDNTTime to CHF

IDNTTime to CHF

00 66 1212 1818 2424 3030 3636 4242 4848 5454


3030

00

1010

2020

Irbesartan

Amlodipine

Placebo

RRR 37%p < 0.001 RRR 23%

p = 0.15

Subjects (%)

Subjects (%)

Data on file, Sanofi-Synthelabo/Bristol-Myers Squibb.

12%Stage

of hypertension

Stage of

hypertension

Stage 1: SBP = 140–159; DBP = 90–99Stage 1: SBP = 140–159; DBP = 90–998%

Stage 3: SBP 180; DBP 110Stage 3: SBP 180; DBP 110

Stage 2: SBP = 160–179; DBP = 100–110Stage 2: SBP = 160–179; DBP = 100–110

1010 2020 3030 8080 9090 100100

3%

Hypertensive patients (%)Hypertensive patients (%)

90%

30%

Prevalence of LVH in hypertensionPrevalence of LVH in hypertension

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.

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.

Time to event (weeks)Time to event (weeks)Verdecchia P et al. Circulation 1998;97:48–54.Verdecchia P et al. Circulation 1998;97:48–54.

Probability of event-free survival (%)Probability of event-free survival (%)

RegressorsRegressors Non-Regressors

Non-Regressors

4040

5050

6060

7070

8080

9090

100100

00 100100 200200 300300 400400 500500

Non-regressors (n = 60)

Regressors (n = 52)

p = 0.002

11

22

33

44

55

66

77

00

Rate of events (per 100 patient-years)

Rate of events (per 100 patient-years)

Regression of LVH predicts prognosisRegression of LVH predicts prognosis

Change in

LV mass

index (%)

Change in

LV mass

index (%)

00

-5-5

-10-10

-15-15

-20-20

-25-25

DiureticsDiuretics -blockers-blockers

Calcium-channelblockers

Calcium-channelblockers

ACEinhibitors

ACEinhibitors

7%6%

9%

13%

Schmieder RE et al. JAMA 1996; 275:1507–13.Schmieder RE et al. JAMA 1996; 275:1507–13.

Reversal of LV hypertrophy Reversal of LV hypertrophy by antihypertensive treatmentby antihypertensive treatmentReversal of LV hypertrophy Reversal of LV hypertrophy

by antihypertensive treatmentby antihypertensive treatment

Mean values and 95% confidence intervals adjusted for duration are given

Mean values and 95% confidence intervals adjusted for duration are given

p < 0.01

p < 0.10

Proportion of patients with first event (%)Proportion of patients with first event (%)

00

22

44

66

88

1010

1212

1414

1616

00 66 1212 1818 2424 3030 3636 4242 4848 5454 6060 6666

Adjusted Risk Reduction: 13.0%, p = 0.021


Change from baseline (%) in LVH determined by electrocardiographyChange from baseline (%) in LVH determined by electrocardiography

-18-18

-16-16

-14-14

-12-12

-10-10

-8-8

-6-6

-4-4

-2-2

00

p < 0.0001 p < 0.0001

p < 0.0001p < 0.0001

4.4%4.4%

10.2%10.2%

15.3%15.3%

9.0%9.0%

AtenololLosartanAtenololLosartan

Dahlöf B et al. Lancet 2002;359:995–1003.Dahlöf B et al. Lancet 2002;359:995–1003.

LIFELVH regression and primary endpoint

LIFELVH regression and primary endpoint

AtenololAtenolol

LosartanLosartan

CornellVoltage-Duration

Product

CornellVoltage-Duration

Product

Sokolow-LyonVoltage

Sokolow-LyonVoltage

Composite of CV Death, stroke and MIComposite of CV Death, stroke and MI

Comparison of SCOPE and LIFE resultsComparison of SCOPE and LIFE results


Stroke

New diabetes


Stroke

New diabetes

-13%

-26%

-25%

-13%

-26%

-25%

-11%

-21%

-20%

-11%

-21%

-20%

LIFE1

Losartan vs. AtenololLIFE1

Losartan vs. AtenololSCOPE2

Candesartan vs. ControlSCOPE2

Candesartan vs. Control

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.

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 150-300 mg

Atenolol50-100 mg

Single-blindPlacebo

Addition of HCTZ

12.5-25 mgif SeDBP

90 mmHg

Addition of Felodipine

5-10 mgif SeDBP

90 mmHg

Double-blind

Double-blind

Irbesartan and atenolol in hypertension and LVH: SILVHIA study design

Irbesartan and atenolol in hypertension and LVH: SILVHIA study design

-4-4 00 1212 2424 4848Time (weeks)Time (weeks)

** ** ** **

Malmqvist K, Kahan T et al. Am J Cardiol 2002:90;1107–12.Malmqvist K, Kahan T et al. Am J Cardiol 2002:90;1107–12.

Irb vs. Ate p = 0.194Irbesartan p < 0.001Atenolol p < 0.001


-20-20

-15-15

-10-10

-5-5

001212

WeekWeek2424 4848 1212

WeekWeek2424 4848

DBP reduction

(%)

DBP reduction

(%)

Irbesartan vs. atenolol in hypertension and LVH: DBP reduction

Irbesartan vs. atenolol in hypertension and LVH: DBP reduction

-9%

-12%

-18%

-11%

-13%

-16%

Irbesartan Atenolol

Malmqvist K, Kahan T et al. J Hypertens 2001:19(6);1167–76.Malmqvist K, Kahan T et al. J Hypertens 2001:19(6);1167–76.

Irbesartan vs. atenolol in hypertension and LVH: LVMI reduction

Irbesartan vs. atenolol in hypertension and LVH: LVMI reduction



-20-20

-15-15

-10-10

-5-5

001212

WeekWeek2424 4848

IrbesartanIrbesartan AtenololAtenolol

1212WeekWeek

2424 4848

LVMI (%)

LVMI (%)

-9%

-1%-4%

-5%

-8%

-16%

Malmqvist K, Kahan T et al. J Hypertens 2001:19(6);1167–76.Malmqvist K, Kahan T et al. J Hypertens 2001:19(6);1167–76.

Irbesartan and atenolol in hypertension and LVH: Effects on QT dispersion

Irbesartan and atenolol in hypertension and LVH: Effects on QT dispersion

QT dispersionQT dispersion QTc dispersionQTc dispersion

Irb: p < 0.001Ate: p = 0.246Irb vs Ate: p = 0.006




6060

4040

msms

6060

4040

msms

00 1212 4848

Time (weeks)Time (weeks)00 1212 4848

IrbesartanIrbesartan AtenololAtenolol

Malmqvist K et al. Am J Cardiol 2002:90;1107–12.Malmqvist K et al. Am J Cardiol 2002:90;1107–12.

00 1212 4848

Time (weeks)Time (weeks)00 1212 4848

Maintenance of sinus rhythm after conversion from persistent AF

Maintenance of sinus rhythm after conversion from persistent AF

Amiodarone + Irbesartan

Amiodarone

1.01.0

0.90.9

0.80.8

0.70.7

0.60.6

0.50.5

0.40.4

0.30.3

0.20.2

0.10.1

0.00.0

Patients free of

recurrences (%)

Patients free of

recurrences (%)

00 3030 6060 9090 120120 150150 180180 210210 240240 270270 300300 330330 360360 390390

Follow-up (days)Follow-up (days)

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

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

p = 0.008Log Rank = 0.007

Madrid AH, Moro C et al. Circulation 2002;106:331–6.Madrid AH, Moro C et al. Circulation 2002;106:331–6.

Irbesartan significantly increased probability of maintaining sinus rhythm

Irbesartan significantly increased probability of maintaining sinus rhythm

00

2020

4040

6060

8080

100100

Probability of maintaining

sinus rhythm (%)

Probability of maintaining

sinus rhythm (%)

Irbesartan + amiodarone

Irbesartan + amiodarone

Madrid A et al. Circulation 2002;106:331–6.Madrid A et al. Circulation 2002;106:331–6.

p = 0.008 vs. amiodarone

AmiodaroneAmiodarone

85%85%

63%63%

159 patients with persistent atrial fibrillation were randomized to either amiodarone or amiodarone + irbesartan Results are taken at 2-month follow-up visit

159 patients with persistent atrial fibrillation were randomized to either amiodarone or amiodarone + irbesartan Results are taken at 2-month follow-up visit

Atrial remodeling: potential mechanisms of efficacy of irbesartan

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

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.Madrid A et al. Circulation 2002;106:331–6.

I-PRESERVEI-PRESERVE

Irbesartan in Heart Failure with

Preserved Systolic Function

Irbesartan in Heart Failure with

Preserved Systolic Function

Importance of heart failure (HF)with preserved ejection fraction (EF)

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

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 failurePrevalence of heart failure

USA(CHS)USA

(CHS)Finland

(Helsinki)Finland

(Helsinki)England(Poole)

England(Poole)

Sweden(Vasteras)Sweden

(Vasteras)Den.

(Copen.)Den.

(Copen.)Spain

(Asturias)Spain

(Asturias)Portugal(EPICA)Portugal(EPICA)

Nether.(Rotter.)Nether.(Rotter.)

66–10378

66–10378

75–86-

75–86-

70–8476

70–8476

75757575

50-

50-

> 4060

> 4060

> 2568

> 2568

55–9565

55–9565

Age rangeMean ageAge rangeMean age

00

11

22

33

44

55

66

77

88

99

1010

Prevalence(%)

Prevalence(%)

8.88.2

7.5

6.7 6.4

4.94.2

2.1

4.84.2

5.1

3.1

4.5

2.9

1.7 1.5

Proportion with decreased LV systolic functionProportion with preserved LV systolic function

Mortality of incident heart failure in CHSMortality of incident heart failure in CHS

Deaths per 1,000

person-years

Deaths per 1,000

person-years

00

2020

4040

6060

8080

100100

120120

140140

160160

Intact EFIntact EF Low EFLow EF Intact EFIntact EF Low EFLow EF

No HFNo HF CHFCHF

Gottdiener JS et al. Ann Intern Med 2002;137:631–9.Gottdiener JS et al. Ann Intern Med 2002;137:631–9.

6-month outcome followingheart failure hospitalization6-month outcome followingheart failure hospitalization

00

1010

2020

3030

4040

5050

6060

Patients (%)

Patients (%)

ReadmissionCHF

ReadmissionCHF

ReadmissionAny

ReadmissionAny

DeathDeath Death orreadmission

Death orreadmission

Low LVEFPreserved LVEFLow LVEFPreserved LVEF

24 23

4144

23

17

5250

Philbin EF et al. Am J Med 2000;109:605–13.Philbin EF et al. Am J Med 2000;109:605–13.

Why a RAS blocking agent?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

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.Dauterman KW et al. Am Heart J 1998;135 (6 Pt 2 Su):S-310–9.

Processes underlying diastolic dysfunctionProcesses underlying diastolic dysfunction

HypertensionAging

AtherosclerosisDiabetes

Blood VesselsHypertrophy

Altered elastin & collagenCalcification

Endothelial dysfunctionLoss of compliance

MyocardiumHypertrophy

FibrosisCellular dysfunction

IschemiaIncreased stiffness

Impaired relaxation

Diastolic Dysfunction

Heart FailureAdapted from B. MassieAdapted from B. Massie

Evidence for Treatmentof HF-PSF

Evidence for Treatmentof HF-PSF

Irbesartan for HF-PSF (I-Preserve) trial

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

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


Inclusion criteriaInclusion 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

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

Hospitalization for heart failurewithin the past 6 monthsand current NYHA II-IV symptoms

Hospitalization for heart failurewithin the past 6 monthsand current NYHA II-IV symptoms

Current NYHA III-IV symptomsand

Corroborative evidence Chest X-ray LVH on ECG LBBB Echo (LVH or LA 4.5 cm)

Current NYHA III-IV symptomsand

Corroborative evidence Chest X-ray LVH on ECG LBBB Echo (LVH or LA 4.5 cm)

ANDAND

OROR


Study designStudy design

EnrollmentPeriod A

EnrollmentPeriod A

Single-blind2 weeks

Single-blind2 weeks

R

IRBESARTANIRBESARTAN

TitrationPeriod BTitrationPeriod B

MaintenancePeriod C

MaintenancePeriod C

75 mg*75 mg* 150 mg150 mg

W 2W 2 W 4W 4 W 8W 8 M 6M 6 M 10M 10

PLACEBOPLACEBO

M 24–28Final visitM 24–28

Final visit

*Forced titration*Forced titration

300 mg


Primary endpointPrimary endpoint

Time to death (all causes) or specified cardiovascular hospitalization

CV hospitalization for:

OR

Myocardial infarction or stroke occurring during any hospitalization

Time to death (all causes) or specified cardiovascular hospitalization

CV hospitalization for:

OR

Myocardial infarction or stroke occurring during any hospitalization

Worsening heart failure Unstable angina Myocardial infarction

Worsening heart failure Unstable angina Myocardial infarction

Ventricular dysrhythmia Atrial dysrhythmia Stroke

Ventricular dysrhythmia Atrial dysrhythmia Stroke


PersistencePersistence

Hasford et al. J Human Hypertension 2002;16:569–75.Hasford et al. J Human Hypertension 2002;16:569–75.

ICE: Study endpointsICE: Study endpoints

Primary Proportion of patients at 1 year who had remained

on their same initially-prescribed monotherapy Median times on initial monotherapy

SecondaryProportion 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

Primary Proportion of patients at 1 year who had remained

on their same initially-prescribed monotherapy Median times on initial monotherapy

SecondaryProportion 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

ICE: Patient samplesICE: Patient samples

*Includes candesartan, eprosartan, losartan, and valsartan*Includes candesartan, eprosartan, losartan, and valsartan

3,0263,026

2,4162,416

All other AIIRAs*All other AIIRAs*(n = 374)(n = 374)

All other AIIRAs*All other AIIRAs*(n = 374)(n = 374)

Irbesartan(n = 380)

Irbesartan(n = 380)

Newly-diagnosed patients initiated with monotherapyNewly-diagnosed patients initiated with monotherapy


Diuretics(n = 422)Diuretics(n = 422)

CCBs(n = 466)

CCBs(n = 466)

Beta-blockers(n = 441)

Beta-blockers(n = 441)

ACE inhibitors(n = 333)

ACE inhibitors(n = 333)

AIIRAs(n = 754)AIIRAs(n = 754)

ICE: Persistence with initial antihypertensive monotherapy after 12 months

ICE: Persistence with initial antihypertensive monotherapy after 12 months

00

1010

2020

3030

4040

5050

6060

7070

DiureticsDiuretics ACEIsACEIs CCBsCCBs LosartanLosartan Beta-blockers

Beta-blockers

AIIRAs‡AIIRAs‡ IrbesartanIrbesartan

34.4

42.0 43.6 44.7

49.7 51.3

60.8

*

* * *

* †

Univariate analysis* p < 0.05; † p = 0.009 vs. irbesartan‡ Excluding irbesartan

Univariate analysis* p < 0.05; † p = 0.009 vs. irbesartan‡ Excluding irbesartan Hasford et al. J Human Hypertension 2002;16:569–75.Hasford et al. J Human Hypertension 2002;16:569–75.

Proportionof patients persistentwith initial

monotherapy (%)


monotherapy (%)

00 100100 200200 300300 400400

3030

4040

5050

6060

7070

8080

9090

100100

Days on monotherapyDays on monotherapy

Multivariate analysis*Includes: ACE inhibitors, beta-blockers,

CCBs, diuretics, AIIRAs (excluding irbesartan)

Multivariate analysis*Includes: ACE inhibitors, beta-blockers,



monotherapy (%)


monotherapy (%)

ICE: Persistence with irbesartan vs. all other antihypertensives

ICE: Persistence with irbesartan vs. all other antihypertensives


Irbesartan

All other antihypertensives*

p = 0.0001

Univariate analysis* p = 0.001, † p = 0.016 vs. irbesartan‡ Includes: ACE inhibitors, beta-blockers,


Univariate analysis* p = 0.001, † p = 0.016 vs. irbesartan‡ Includes: ACE inhibitors, beta-blockers,


ICE: Need for adjunctive therapy at one yearICE: Need for adjunctive therapy at one year


00

55

1010

1515

2020

2525

3030

IrbesartanIrbesartan All otherantihypertensives‡

All otherantihypertensives‡

LosartanLosartan

16.1

25.3 24.5

* †

Proportionof patients requiringadjunctive

therapy(%)

Proportionof patients requiringadjunctive

therapy(%)

Univariate analysis* p = 0.013 vs. irbesartan‡ Includes: ACE inhibitors, beta-blockers,




ICE: Need for therapy switch at one yearICE: Need for therapy switch at one year

00

33

66

99

1212

1515



LosartanLosartan

9.0

13.6

8.0

Proportionof patientsswitched

from initialmonotherapy

(%)

Proportionof patientsswitched

from initialmonotherapy

(%)

*






ICE: Discontinuations at one yearICE: Discontinuations at one year

00

55

1010

1515

2020

2525




LosartanLosartan

14.2

Proportionof patients

discontinuingantihypertensive

therapy(%)

Proportionof patients

discontinuingantihypertensive

therapy(%)

*

16.6

22.9

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)

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)

ICE: Persistence with initial antihypertensive agent at one year*

ICE: Persistence with initial antihypertensive agent at one year*

00

2020

4040

6060

8080



agent asmonotherapy

or combinationtherapy*

(%)


agent asmonotherapy

or combinationtherapy*

(%)

IrbesartanIrbesartan All otherantihypertensives**

All otherantihypertensives**

LosartanLosartan

76.8

69.5 69.2

† ‡

ICE: ConclusionsICE: 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

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


ACTIVEAtrial 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

ACTIVEAtrial 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 RationaleACTIVE 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

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 ObjectivesACTIVE 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

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

Clopidogrel 75mg/day*n=3,750

Placebo*n=3,750

48 months fu

ACTIVE DesignACTIVE DesignA

Suitable for OACn-=6,500

Unsuitable for OACn-=6,500

A: AllocationR: RandomizationOAC: Oral AnticoagulantTotal n= 14,000 patients with AF and evidence for high-risk of vascular event

* On top of ASA 75-100mg once daily

Clopidogrel 75mg/day*n=3,250

OACn=3,250

R

1 3 6 9 12 Every 6

1 3 6 129 Every 6

ACTIVE WPROBE

non inferiority trial

ACTIVE ADouble-blind

superiority trial

Irbesartan 150-300mgn> or = 5,000

Placebo*n> or = 5,000

R

1 3 6 9 12 Every 6

1 6 12 Every 6 3 9

ACTIVE IPartial, factorial, double-blindsuperiority trial

Allocated to ACTIVE AOr to ACTIVE W and eligible for ACTIVE I

R months

months

relevance of at 1 blockade. adapted from mcconnaughey et al. j clin phamacol 1999;39: 547–59....

Documents

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