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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)
Irbesartan300 mg(n = 134)
Irbesartan150 mg(n = 129)
Irbesartan150 mg(n = 129)
Losartan100 mg(n = 131)
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
Irbesartan300 mg(n = 134)
Irbesartan300 mg(n = 134)
Irbesartan150 mg(n = 129)
Irbesartan150 mg(n = 129)
Losartan100 mg(n = 131)
Losartan100 mg(n = 131)
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
Time (months)Time (months)
Mean SeSBP
and SeDBP
(mmHg)
Mean SeSBP
and SeDBP
(mmHg)
8080
9090
100100
110110
120120
140140
150150
ControlIrbesartan 150 mgIrbesartan 300 mg
ControlIrbesartan 150 mgIrbesartan 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.
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 (%)
ControlIrbesartan 150 mgIrbesartan 300 mg
70% RRRp < 0.001
70% RRRp < 0.001
IRMA 2 Primary endpoint: Time to overt proteinuria
IRMA 2 Primary endpoint: Time to overt proteinuria
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.
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)
IrbesartanIrbesartan
24%24%
34%34%
21%21%
IRMA 2Normalization of urinary albumin excretion rate
IRMA 2Normalization of urinary albumin excretion rate
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.
p = 0.006
IRMA 2 Adverse outcomes
IRMA 2 Adverse outcomes
Parving H-H et al. N Engl J Med 2001;345:870–78.Parving H-H et al. N Engl J Med 2001;345:870–78.
Cardiovascular events
Serious adverse events
Discontinuations due to adverse events
Cardiovascular 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)
Time (months)Time (months)
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
Follow-up (months)Follow-up (months)
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
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.
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
Follow-up (months)Follow-up (months)
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 (%)
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.
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
Lewis EJ et al. N Engl J Med 1993;329(20):1456–62.Lewis EJ et al. N Engl J Med 1993;329(20):1456–62.
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)
IrbesartanIrbesartan
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
(%)
Time (weeks)Time (weeks)
* *
* 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
Time (weeks)Time (weeks)
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
Follow-up (months)Follow-up (months)6060
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
Follow-up (months)Follow-up (months)6060
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
Time (months)Time (months)
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
Cardiovascular events
Stroke
New diabetes
Cardiovascular events
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
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
Irb vs. Ate p = 0.024Irbesartan p < 0.001Atenolol p < 0.001
Irb vs. Ate p = 0.024Irbesartan p < 0.001Atenolol p < 0.001
-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
Irb: p < 0.001Ate: p = 0.246Irb vs Ate: p = 0.006
Irb: p < 0.001Ate: p = 0.820Irb vs Ate: p = 0.033
Irb: p < 0.001Ate: p = 0.820Irb vs Ate: p = 0.033
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
Data on file, Sanofi-Synthelabo/Bristol-Myers Squibb.Data on file, Sanofi-Synthelabo/Bristol-Myers Squibb.
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
Data on file, Sanofi-Synthelabo/Bristol-Myers Squibb.Data on file, Sanofi-Synthelabo/Bristol-Myers Squibb.
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
Data on file, Sanofi-Synthelabo/Bristol-Myers Squibb.Data on file, Sanofi-Synthelabo/Bristol-Myers Squibb.
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
Data on file, Sanofi-Synthelabo/Bristol-Myers Squibb.Data on file, Sanofi-Synthelabo/Bristol-Myers Squibb.
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
Hasford et al. J Human Hypertension 2002;16:569–75.Hasford et al. J Human Hypertension 2002;16:569–75.
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 (%)
Proportionof patients persistentwith initial
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,
CCBs, diuretics, AIIRAs (excluding irbesartan)
Proportionof patients persistentwith initial
monotherapy (%)
Proportionof patients persistentwith initial
monotherapy (%)
ICE: Persistence with irbesartan vs. all other antihypertensives
ICE: Persistence with irbesartan vs. all other antihypertensives
Hasford et al. J Human Hypertension 2002;16:569–75.Hasford et al. J Human Hypertension 2002;16:569–75.
Irbesartan
All other antihypertensives*
p = 0.0001
Univariate analysis* p = 0.001, † p = 0.016 vs. irbesartan‡ Includes: ACE inhibitors, beta-blockers,
CCBs, diuretics, AIIRAs (excluding irbesartan)
Univariate analysis* p = 0.001, † p = 0.016 vs. irbesartan‡ Includes: ACE inhibitors, beta-blockers,
CCBs, diuretics, AIIRAs (excluding irbesartan)
ICE: Need for adjunctive therapy at one yearICE: Need for adjunctive therapy at one year
Hasford et al. J Human Hypertension 2002;16:569–75.Hasford et al. J Human Hypertension 2002;16:569–75.
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,
CCBs, diuretics, AIIRAs (excluding irbesartan)
Univariate analysis* p = 0.013 vs. irbesartan‡ Includes: ACE inhibitors, beta-blockers,
CCBs, diuretics, AIIRAs (excluding irbesartan)
ICE: Need for therapy switch at one yearICE: Need for therapy switch at one year
00
33
66
99
1212
1515
IrbesartanIrbesartan All otherantihypertensives‡
All otherantihypertensives‡
LosartanLosartan
9.0
13.6
8.0
Proportionof patientsswitched
from initialmonotherapy
(%)
Proportionof patientsswitched
from initialmonotherapy
(%)
*
Hasford et al. J Human Hypertension 2002;16:569–75.Hasford et al. J Human Hypertension 2002;16:569–75.
Univariate analysis* p = 0.01 vs. irbesartan‡ Includes: ACE inhibitors, beta-blockers,
CCBs, diuretics, AIIRAs (excluding irbesartan)
Univariate analysis* p = 0.01 vs. irbesartan‡ Includes: ACE inhibitors, beta-blockers,
CCBs, diuretics, AIIRAs (excluding irbesartan)
ICE: Discontinuations at one yearICE: Discontinuations at one year
00
55
1010
1515
2020
2525
Hasford et al. J Human Hypertension 2002;16:569–75.Hasford et al. J Human Hypertension 2002;16:569–75.
IrbesartanIrbesartan All otherantihypertensives‡
All otherantihypertensives‡
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
Hasford et al. J Human Hypertension 2002;16:569–75.Hasford et al. J Human Hypertension 2002;16:569–75.
Proportionof patients persistentwith initial
agent asmonotherapy
or combinationtherapy*
(%)
Proportionof patients persistentwith initial
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
Hasford et al. J Human Hypertension 2002;16:569–75.Hasford et al. J Human Hypertension 2002;16:569–75.
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