vbwg raas modulation: raas modulation: novel strategies for reducing cardiovascular risk

VBWG

RAAS Modulation:RAAS Modulation:

Novel Strategies Novel Strategies for Reducing for Reducing

Cardiovascular RiskCardiovascular Risk

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• The diabetes crisis• CVD and the aging patient

Epidemiology/Guideline Update:

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CHD risk rises sharply in middle age

0.01.4

3.0

11.6 11.5

16.8

0.3 0.21.6

3.6

6.3

10.3

0

5

10

15

20

Men Women

AHA. Heart Disease and Stroke Statistics—2005 Update.

NHANES 1999–2002

% Population

20–34 35–44 45–54 55–64 65–74 ≥75

Age

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CV disease: Leading cause of death in Americans

0

100

200

300

400

500

A Total CVD*B Cancer D Chronic lower respiratory diseases

C Accidents

433,825

288,768

69,257 60,71334,301

493,623

268,503

64,10338,94841,877

Deaths(1000s)

*CHD, stroke, HF, hypertension, arterial diseasesData compiled for 2002

Men

Women

F Alzheimer’s Disease E Diabetes

CDC/NCHS and NHLBI.

A B C D E A B C F E

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Obesity (BMI ≥30 kg/m2)

Population(%)

30

25

2000 2001 2002 2003

*Jan–June

20

15

02004*

8

6

4

2

02000 2001 2002 2003 2004*

Diagnosed diabetes

CDC. 2004 NHIS; www.cdc.gov/nchs/nhis.htm.

21.823.0

23.9 23.724.3 5.9

6.4 6.5 6.6 6.6

Obesity and diabetes among US adults:Growing prevalence

+11.9%

+11.5%

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ACC/AHA 2002 Guideline Update for Management of Patients with Chronic Stable Angina: Asymptomatic patients

Class I recommendations for pharmacotherapy to prevent MI and death

1. Aspirin in the absence of contraindication in patients with prior MI (Level of evidence: A)

2. -Blockers as initial therapy in absence of contraindications in patients with prior MI (Level of evidence: B)

3. Lipid-lowering therapy in patients with documented CAD and LDL-C >130 mg/dL, with target LDL <100 mg/dL (Level of evidence: A)

4. ACEI in patients with CAD who have diabetes and/or systolic dysfunction (Level of evidence: A)

Gibbons RJ et al. J Am Coll Cardiol. 2003;41:159-68.

Based on HOPE

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Based on HOPE and EUROPA

ACP recommendations for ACEI in chronic stable angina or asymptomatic CAD

• To prevent MI or death and reduce symptoms in patients with chronic stable angina (Level of evidence: A)

• To prevent MI and death in asymptomatic patients with:– Evidence of CAD and with systolic dysfunction

(Level of evidence: A)– Diabetes with (Level of evidence: A) or without evidence

of CAD (Level of evidence: B)

Snow V et al. Ann Intern Med. 2004;141:562-7.

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RAAS: Central Role in the Pathogenesis of

Cardiovascular Disease

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RAAS: Sites of intervention with ACEIs, ARBs

Angiotensinogen

Angiotensin I

Renin

ACEinhibitors

Angiotensin-convertingenzyme (ACE)

Angiotensin II

AT1 receptor

Angiotensin receptorblockers

AT2 receptor

Atherosclerosis, hypertension Vascular protection?

Adapted from Nickenig G. Circulation. 2004;110:1013-20.

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RAAS: Other potential sites of intervention

Struthers AD, MacDonald TM. Cardiovasc Res. 2004;61:663-70.Jacoby DS, Rader DJ. Arch Intern Med. 2003;163:1155-64.

Zisman LS. Eur Heart J. 2005;26:322-4.

Effects

Aldosterone endothelial function, thrombosisvascular compliance,baroreceptor function,fibrosis

Cathepsin G Angiotensinogen Ang IIChymostatin-sensitive system

Chymase Ang I Ang II

ACE2 Ang I Ang (1–9), Ang (1–7)

VBWG

Impaired

NO synthase

Ang II and mechanisms of atherosclerosis

Jacoby DS, Rader DJ. Arch Intern Med. 2003;163:1155-64.

IL-6

MCP-1

PDGF LOX-1

PAI-1

TF

TGF-

VCAM

ICAM

Angiotensin II

Lipid oxidation

Thrombosis

Inflammation

Proliferation fibrosis

Adhesion

Endothelial

dysfunction

Endothelial

dysfunction

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PERTINENT: ACE inhibition NO via eNOS activity

Ferrari R et al. www.europa-trial.org

0

1

2

3

4

2.5

3.5

2.4

2.93.3

Controlsn = 45

Placebon = 44

Placebon = 44

Perindopriln = 43

Perindopriln = 43

P < 0.01*P < 0.05†

Baseline 1 Year

eNOSactivity in HUVECs

(pmol/min/mg protein)

Controls CAD patients

* vs baseline† perindopril vs placeboPERindopril – Thrombosis, InflammatioN, Endothelial dysfunction and Neurohormonal activation Trial (substudy of EUROPA)HUVEC = human umbilical vein endothelial cell

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AT1 receptor blockade improves flow-mediated vasodilation122 Hypertensive patients treated for 2 months

*P < 0.05 vs baseline and vs placebo Koh KK et al. Am J Cardiol. 2004;93:1432-5.

0.15

1.14

1.66

1.32

0.0

0.5

1.0

1.5

2.0

Placebo(n = 30)

Irbesartan300 mg(n = 30)

Losartan100 mg(n = 31)

Candesartan16 mg

(n = 31)

FMD

inbrachialartery(%)

2.5

*

*

*

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Inflammation

IL-6

MCP-1

PDGF

Inflammation



Impaired

NO synthase

LOX-1

PAI-1

TF

TGF-

VCAM

ICAM

Lipid oxidation

Thrombosis


Endothelial

dysfunction

Adhesion

Angiotensin II

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ACE inhibition reduces oxidative stress and inflammation20 Patients with type 2 diabetes

Marketou ME et al. J Am Coll Cardiol. 2005;45 (suppl A):396A.

Baseline Perindopril 4 mg x 6 mos

* P < 0.05 vs baseline

TNF- IL-6Lipid peroxides

3.3

2.0

0

1

2

3

4

2.9

1.8

370

264

0

100

200

300

400

mol/L pg/mL

** *

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LOX-1

VCAM

ICAM



IL-6

MCP-1

PDGFImpaired

NO synthase

PAI-1

TF

TGF-

Thrombosis

Inflammation


Endothelial

dysfunction

Angiotensin II

Lipid oxidationLipid oxidation

AdhesionAdhesion

VBWGAT1, LOX-1 receptor cross-talk promotes adhesion molecule expression: Interaction between RAAS and dyslipidemia

Mehta JL, Li D. J Am Coll Cardiol. 2002;39:1429-35.

OxLDL

Endothelial cell

LOX-1

Endothelin

Shearstress

TNF-

Ang IIAT1 Scavenger

receptors??

ROS

MCP-1

eNOSBadFas

Monocyteattachment andactivation

AtherosclerosisDysfunctionApoptosisInjury

PKs

MAPKsNF-B

Adhesion moleculeexpression

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Ang II upregulates LOX-1 expression via lipoxygenase pathway

* P < 0.0001 vs control† P < 0.0001 vs Ang II‡ P < 0.05 vs Ang IIBai = baicalein (12-lipoxygenase inhibitor)

Human vascular smooth muscle cells

Limor R et al. Am J Hypertens. 2005;18:299-307.

Ang II10-7 mol/L+

losartan 10-5 mol/L

0

100

200

300

Control Ang II10-7 mol/L

Ang II10-7 mol/L+

Bai 10-5 mol/L

LOX-1mRNA

*

†‡

400

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TGF-



IL-6

MCP-1

PDGFImpaired

NO synthase

LOX-1

PAI-1

TF

VCAM

ICAM

Angiotensin II

Lipid oxidation

Thrombosis

Inflammation

Endothelial

dysfunction

Adhesion

ProliferationProliferation fibrosis

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HOPE: Dose-dependent effects of ramipril on LV mass and function

5.31

2.9

–1.9–3

0

2

4

68.21 7.86

–3.53–4

0

5

10

LV end-systolic volumeLV mass

Lonn E et al. J Am Coll Cardiol. 2004;43:2200-6.Mean baseline LVEF 58%, all groups

(mL)

(g)

PTrend = 0.001PTrend = 0.03

N = 446 follow-up, 4 years

Placebo Ramipril 2.5 mg

Ramipril 10 mg

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LIFE: Greater reduction in LV mass with angiotensin receptor blockade vs beta-blockade

Devereux RB et al. Circulation. 2004;110:1456-62.

Patients with hypertension and LVH

Change inLV mass

(g)

–50

–20

Year

–10

0

Losartan 50–100 mg (n = 457)

Atenolol 50–100 mg (n = 459)

–30

–40

1 2 3 4 5Lastvisit

P = 0.009 for all time points

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PAI-1

TF



IL-6

MCP-1

PDGFImpaired

NO synthase

LOX-1

TGF-

VCAM

ICAM

Angiotensin II

Lipid oxidation

Inflammation


Endothelial

dysfunction

AdhesionThrombosisThrombosis

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PAI-1 release: Differing effects of ACEinhibition vs AT1 receptor blockade

Ramipril 10 mg

Losartan 100 mg

–20

–15

–10

–5

0

5

10

15

1 3 4 6Weeks

in

PAI-1antigen(ng/mL)

Brown NJ et al. Hypertension 2002;40:859-65.P = 0.043, drug x time interaction

20 insulin-resistant, hypertensive patients treated for 6 weeks

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Change in PAI-1 antigen levels: Differing effects of ARBs

Koh KK et al. Atherosclerosis. 2004;177:155-60.

%Change

–40

20

40

60

Placebo

80

–20

0

Irbesartan 300 mg

Losartan 100 mg

Candesartan 16 mg

P < 0.01

P = 0.012P = 0.163

126 Patients with hypertension

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tPA release: Differing effects of ACEinhibition vs AT1 receptor blockade

Matsumoto T et al. J Am Coll Cardiol. 2003;41:1373-9.*P < 0.05 vs baseline

20

10

15

5

0.2

0

0 0.6 2.0

tPA antigenin coronary

sinus (ng/mL)

Bradykinin (g/min)

Perindopril 4 mg(n = 16)

Losartan 50 mg(n = 15)

Control(n = 14)

P < 0.05

*

**

**

* *

25

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Antiatherosclerotic effect of RAAS modulation: Clinical and experimental evidence

• Studies in several animal models of atherosclerosis demonstrated reduced lesion progression with ACE inhibitor or AT1 receptor blocker1

• Regression of human carotid plaque demonstrated with ramipril (SECURE2), losartan (LAARS3), and fosinopril (PHYLLIS4)

1Jacoby DS, Rader DJ. Arch Intern Med. 2003;163:1155-64.2Lonn E et al. Circulation. 2001:103;919-25.

3Ludwig M et al. Clin Ther. 2002;24:1175-93.4Zanchetti A et al. Stroke. 2004;35:2807-12.

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ARB blunts MMP expression in human carotid plaques: Potential role in plaque stabilization

25.828.2

25.1

22.4

5.8 6.2 7.25.6

0

10

20

30

MMP-2 MMP-9 COX-2 mPGES-1P < 0.0001 all comparisonsARB = AT1

receptor blockadeMMP = matrix metalloproteinase

% Positive staining

Chlorthalidone Irbesartan

Cipollone F et al. Circulation. 2004;109:1482-8.

Carotid endarterectomy specimens

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Role of RAAS Modulation in CAD Patients

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ACE inhibition in CAD: Short-term trials in acute MI

Odds ratio (95% CI)

220/3044 (7.23%)

570/9682 (5.89%)

2035/29,028 (7.01%)

676/7460 (9.06%)

CONSENSUS-II*

Test for Heterogeneity: 2 5.8 (2p = 0.1) df = 3

Deaths (n)/Randomized (n)

GISSI-3

ISIS-4

CCS-1

Total

Control O-E Variance

1.0 1.25 1.50.750.5

727/7489 (9.71%)

650/9712(6.69%)

192/3046(6.30%)

2171/29,022(7.48%)

3501/49,214(7.11%)

3740/49,269(7.59%)

14.07

–39.06

–68.22

–24.14

–117.35

96.05

285.83

975.33

317.85

1675.06

ACEI

ACEI better Control better

Odds reduction (± SD)7 ± 2

Treat Eff: 2 (2p = 0.004)

ACE Inhibitor MI Collaborative Group. Circulation. 1998;97:2202-12.*IV infusion followed by oral therapy

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ACE inhibition in CAD: Long-term trials in post-MI LV dysfunction and HF

AIRE Study Investigators. Lancet. 1993;342:821-8.Køber L et al. N Engl J Med. 1995;333:1670-6.

SOLVD Investigators. N Engl J Med. 1991;325:293-302.SOLVD Investigators. N Engl J Med. 1992;327:685-91.

Pfeffer MA et al. N Engl J Med. 1992;327:669-77.

AIRE

TRACE

SOLVD

(Treatment)

SAVE

0.002

0.001

0.0036

0.019

0 5 10 15 20 25

Risk reduction in total mortality (%)

P

30

SOLVD

(Prevention)

0.30

27%

22%

8%

16%

19%

VBWGAldosterone blockade and AT1 receptor blockade: Trials in post-MI/LV dysfunction or HF

Pitt B et al. N Eng J Med. 1999;341:709-17.Pitt B et al. N Eng J Med. 2003;348:1309-21.

Pitt B et al. N Eng J Med. 2003;349:1893-906.

VALIANT

Months

CaptoprilValsartan

0.4

0.1

0.2

6 12 24 30 36

0.3

0.0

Probability of event

0% RR V vs CHR 1.00 (0.90–1.11)

P = 0.98

RALES

0.75

0.60

1.00

0

Placebo

Spironolactone

Months

Probability of survival

24 366

30% Risk reductionRR 0.70 (0.60–0.82)

P < 0.001

300.00

12 18

0.90

0.45

180

Valsartan/captopril

22

10

2

6 24 300

Eplerenone

Months

18

14

6

3612

EPHESUS15% Risk reductionRR 0.85 (0.75–0.96)

P = 0.008

Cumulativeincidence

(%)

Placebo

018

2% RR V/C vs CHR 0.98 (0.89–1.09)

P = 0.73)

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HOPE, QUIET, EUROPA, PEACE: Primary outcomes

HOPE Study Investigators. N Engl J Med. 2000;342:145-53.EUROPA Investigators. Lancet. 2003;362:782-8.

PEACE Trial Investigators. N Engl J Med. 2004;351:2058-68.Pitt B et al. Am J Cardiol. 2001;87:1058-63.

PEACE

HOPE

15

5

10

0

20

0

Placebo

Ramipril 10 mg

Time (years)

%Patients

2 41


P = 0.001

3

40

20

30

0

50

0

12

4

10

0

1 3 4

14

0

Placebo

Perindopril 8 mg

Time (years)

86

2

52

EUROPA20% Risk reductionRR 0.80 (0.71–0.91)

P = 0.0003

Placebo

Quinapril 20 mg

Time (years)1

4% Risk increaseRR 1.04 (0.89–1.22)

P = 0.6

10

2 3

QUIET

Time (years)

Trandolapril4 mgPlacebo

30

20

10

15

5

1 2 3 4 5

25

06

%Patients

4% Risk reductionHR 0.96 (0.88–1.06)

P = 0.43

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HOPE, EUROPA: Consistency of treatment benefit

Event rate (%)

ACEI Placebo 14.0 17.8

8.0 9.9

6.1 8.1

3.5 4.1

9.9 12.3

4.8 6.2

3.4 4.9 1.6 1.7

0.8 1.3

0.1 0.2

Composite outcome

CV mortality

Myocardial infarction

Stroke

Cardiac arrest

FavorsACE inhibitor

FavorsPlacebo

HOPE(ramipril 10 mg)

EUROPA(perindopril 8 mg)

HOPE Study Investigators. N Engl J Med. 2000;342:145-53.EUROPA Investigators. Lancet. 2003;362:782-8.

Hazard ratio 0.5 1.0 1.5

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HOPE, EUROPA: Concomitant CV therapy

2.01.0

Added benefit No added benefit

0.6 0.8

Lipid-lowering drugNo lipid-lowering drug

-BlockersNo -blockers

HOPE

EUROPA

EUROPA Investigators. Lancet. 2003;362:782-8. Dagenais GR et al. Circulation. 2001;104:522-6.

EUROPA: perindopril 8 mg

HOPE: ramipril 10 mg

Lipid-lowering drugNo lipid-lowering drug

HOPE

EUROPA

-BlockersNo -blockers

Hazard ratio

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PEACE: Prevention of Events with Angiotensin Converting Enzyme inhibition

PEACE Trial Investigators. N Engl J Med. 2004;351:2058-68.

Objective: Assess effect of ACEI in patients with stable CAD and normal/slightly reduced LV function

Design: 8290 patients randomized to trandolapril 4 mg or placebo

Follow-up: 4.8 years

Primaryoutcome: CV death, nonfatal MI, CABG, PCI

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PEACE Trial Investigators. N Engl J Med. 2004;351:2058-68.

PEACE: Primary outcome

Trandolapril4 mg

Placebo30

20

10

15

5

1 2 3 4 5

25

0

6

%Patients

Time (years)

CV death, MI, CABG/PCI; N = 8290

4% Risk reductionHR 0.96 (0.88–1.06)

P = 0.43

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ACE inhibitor Key inclusion criteria Primary outcome

EUROPA

N = 12,218 (4.2 years)

Perindopril 8 mg CAD

No heart failure

Age ≥18 years

CV death, MI, cardiac arrest

PEACE

N = 8290

(4.8 years)

Trandolapril 4 mg CAD

LVEF ≥40%

Age ≥50 years

CV death, MI, coronary revascularization

QUIET

N = 1750 (2.25 years)

Quinapril 20 mg PTCA, atherectomy

Normal LVEF

CV death, MI, coronary revasc, cardiac arrest, hosp for angina

EUROPA Investigators. Lancet. 2003;362:782-8.HOPE Study Investigators. N Engl J Med. 2000;342:145-53.


ACEI outcome trials in CAD patients without HF

HOPE

N = 9297

(4.5 years)

Ramipril 10 mg Vascular disease (80% had CAD)

LVEF ≥40%, or

No heart failure

Age ≥55 years

CV death, MI, stroke

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N 9,297 12,218 8,290 1,750

Follow-up (yrs) 4.5 4.2 4.8 2.3

ACEI/dose (mg) R-10 P-8 T-4 Q-20

Age (yrs) 66 60 64 58

Men (%) 73 85 82 82

CAD/Cor rev (%) 80/44 100/55 100/72 100/100

Diabetes (%) 39 12 17 16

HTN (%) 47 27 46 47

Prior MI (%) 53 65 55 49

EF NA NA 58 59

PVD (%) 43 7 NA NA

ACEI outcome trials in CAD patientswithout HF: Key baseline characteristics



HOPE EUROPA PEACE QUIET

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HOPE EUROPA PEACE QUIET

Antiplatelet agents (%) 76 92 91 73

-Blockers (%) 40 62 60 26

Lipid-lowering agents (%) 29/49* 58/68† 70 0/14*

Calcium antagonists (%) 47 32 36 0/7*

Diuretics (%) 15 10 13 NA



*at study end†at 3 yrs

ACEI outcome trials in CAD patients without HF: CV therapies at entry/during study

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BP (mm Hg) HOPE EUROPA PEACE QUIET

At entry 139/79 137/82 133/78 123/74

Average ∆ BP during follow-up (active vs placebo)

3.3/1.2 5/2 3/1.2 NA



Sleight P et al. Lancet 2001;358:2130-1.

ACEI outcome trials in CAD patients without HF: BP at entry/during study

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HOPE Study Investigators. N Engl J Med. 2000;342:145-53. EUROPA Investigators. Lancet. 2003;362:782-8.


ACEI outcome trials in CAD patients without HF: Differences in baseline CV risk

HOPE EUROPA PEACE

Annualizedevent rate in placebo group

(%/yr)

CV death Nonfatal MIQUIET

1.8

1.00.8 0.7

2.7

1.5

1.1

2.0

0.0

1.0

2.0

3.0

VBWG



Anderson RN, Smith BL. Natl Vital Stat Rep. 2005;53:1-90.

ACEI outcome trials in CAD patients without HF: Annualized all-cause mortality— placebo vs general population

*Mean age in years

HOPE(66*)

EUROPA(60*)

PEACE(64*)

All-causemortality

rate(%/yr)

QUIET(58*)

2.42.7

1.0

1.7 1.61.4

0.0

1.0

2.0

3.0

Age group

55–64 years65–74 years

Generalpopulation

Generalpopulation

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ACEI outcome trials in CAD patients without HF: Annualized CV mortality— placebo vs general population

*Mean age in years



Anderson RN, Smith BL. Natl Vital Stat Rep. 2005;53:1-90.

CV mortality

rate(%/yr)

0.0

0.5

1.0

1.5

2.0

HOPE(66*)

EUROPA(60*)

PEACE(64*)

QUIET(58*)

Age group55–64 years65–74 years

0.7

1.8

0.3

0.81.0

0.7

Generalpopulation

Generalpopulation

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ACEI outcome trials in CAD patients without HF: Cumulative evidence

Yusuf S, Pogue J. N Engl J Med. 2005;352:937-9.

Pooled all-cause mortality results

482/4645 (10.4)

375/6110 (6.1)

299/4158 (7.2)

1156/14,913 (7.8)

HOPE

EUROPA

PEACE

Total

Control P

1.0 3.0 5.00.80.6

1323/14,892 (8.9)

420/6108(6.9)

569/4652(12.2)

334/4132(8.1)

0.005

0.098

0.126

< 0.001

ACEI

ACEI Control

Odds ratio

No. of deaths/no. of patients (%)

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ACEI outcome trials in CAD patients without HF: Totality of trial evidence

MI

Stroke

All-cause death

Event rate (%)

Favors ACEIACEI

Revascularization

Favors placeboPlacebo

7.5

6.4

2.1

15.5

8.9

7.7

2.7

16.3

0.86

0.86

0.77

0.93

0.0004

0.0004

0.0004

0.025

0.5 0.75 1.251Odds ratio

P

Pepine CJ, Probstfield JL. Vasc Bio Clin Pract. CME Monograph; UF College of Medicine. 2004;6(3).

HOPE, EUROPA, PEACE, QUIET

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CAMELOT: Trial of BP reduction with ACEI or CCB in CAD patients without HF

Study design: Randomized, double-blind, multicenter, 24-month trial in patients with angiographically documented CAD, LVEF ≥40%, and no HF (N = 1991)

Treatment: Amlodipine (10 mg), enalapril (20 mg), or placebo added to background therapy with -blockers and/or diuretics

Primaryoutcome: Incidence of CV events for amlodipine

vs placebo

IVUS substudy: Measurement of atherosclerosis progression using IVUS (n = 274)

Outcome: Change in percent atheroma volume Nissen SE et al. JAMA. 2004;292:2217-26.

VBWG

CAMELOT: Reduction in primary outcome with amlodipine and enalapril

No. at risk

Placebo 655 588 558 525 488

Enalapril 673 608 572 553 529

Amlodipine 663 623 599 574 535

Nissen et al. JAMA. 2004;292:2217-26.Primary outcome = incidence of CV events

Cumulative CV events(proportion)

0

0.25

0.20

0.10

0.05

6 12 18 24Months

0.15

0

Placebo

Amlodipine

Enalapril

HR (95% CI)A vs P: 0.69 (0.54–0.88)E vs P: 0.85 (0.67–1.07)A vs E: 0.81 (0.63–1.04)

P = 0.16

P = 0.1P = 0.003

VBWG

CAMELOT: Clinical implications

• Optimal BP levels in CAD patients may be ~120 mm Hg systolic

• Regression of CAD suggested with systolic BP reduction >10 mm Hg

• Hemodynamic effects may also modulate clinical outcome

• Increasing evidence to support the following strategies:– Combinations of drugs with differing modes of action– Lower BP targets in special populations

Pepine CJ. JAMA. 2004;292:2271-3.

VBWG

• Cumulative evidence supports ACE inhibitors for stable CAD patients with/without clinical signs of HF

• Not all ACE inhibitors can be assumed to have comparable effects for all indications – Dose and individual properties of ACEIs are important

• Benefit may depend on risk level – Benefit may be less in patients with well controlled risk factors

• Randomized clinical trial evidence and guidelines should guide selection of effective ACE inhibitor and dose for CAD patients without HF

Pitt B. N Engl J Med. 2004;351:2115-7.

ACEI outcome trials in CAD patients without HF: Clinical implications

VBWG

Factors that may lead to divergent results in ACEI trials

• Underdosing – Dose-related effects on vascular and myocardial tissue

– Dose for CAD patients can’t be predicted from studies in HF or hypertension

• Differences may exist among ACEIs

• Differences in baseline risk (age, diabetes, HTN, PAD)

• Inclusion of revascularization in primary outcome

• Lack of power

• Poor adherence to assigned treatmentPitt B et al. Am J Cardiol. 2004;87:1058-63.

Yusuf S, Pogue J. N Engl J Med. 2005;352:937-8.Pitt B. N Engl J Med. 2004;351:2115-7.

Pepine CJ, Probstfield JL. Vasc Bio Clin Pract. CME Monograph; UF College of Medicine. 2004;6(3).

VBWG

Are all ACEIs the same: Survival post-MI by ACEI at discharge

P < 0.001 log-rank

100

90

80

70121086420

Months

Captopril

Ramipril

Quinapril

Fosinopril

Lisinopril

Enalapril

Perindopril

Unadjusted cumulative

survival(%)

N = 7512

Pilote L et al. Ann Intern Med. 2004;141:102-12.

n = 421

n = 905

n = 276

n = 889

n = 2201

n = 2577

n = 243

VBWG

Ongoing major outcomes trials of RAAS modulation

Patients Treatment

Follow-up (years)

Primary outcome

ONTARGET* 55 years with CAD, stroke, PAD, or diabetes + end-organ damage

(N = 25,620)

Ramipril 10 mg

Telmisartan 80 mg

Ramipril 10 mg + telmisartan 80 mg

5.5 CV death, MI, stroke, hosp for heart failure

TRANSCEND† 55 years, ACEI intolerant, with CAD, stroke, PAD, or diabetes + end-organ damage

(N = 5776)

Telmisartan 80 mg

Placebo

5.5 CV death, MI, stroke, hosp for heart failure

ONTARGET/TRANSCEND Investigators. Am Heart J. 2004;148:52-61.

*Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial†Telmisartan Randomized Assessment Study in ACE Intolerant Subjects with Cardiovascular Disease

VBWG

RAAS Modulation in Patients With Diabetes

VBWG

HOPE Study Investigators. Lancet. 2000;355:253-9.Daly CA et al. Eur Heart J. 2005. epub;April 28.

MICRO-HOPE PERSUADE

Patients: Diabetes + CVD Diabetes + CAD

or ≥1 CV risk factor No heart failure

Normal LV functionN = 3577 N = 1502

ACE inhibitor: Ramipril 10 mg Perindopril 8 mg

Follow-up (years): 4.5 4.2

Primary CV death/MI/ CV death/MI/outcome: stroke cardiac arrest

MICRO-HOPE, PERSUADE: ACEI in high-risk patients with diabetes

PERindopril SUbstudy in coronary Artery disease and DiabEtes (substudy of EUROPA)

VBWG

HOPE Study Investigators. Lancet. 2000;355:253-9.Daly CA et al. Eur Heart J. 2005. In press.

PERSUADE(N = 1502)

CV death/MI/cardiac arrest

MICRO-HOPE(N = 3577)

CV death/MI/stroke

MICRO-HOPE, PERSUADE: Primary outcome

Placebo

Ramipril10 mg

25

20

15

10

5

0

%

Follow-up (years)

0 1 2 3 4 5


P = 0.000420

15

10

5

00 1 2 3 4 5

Follow-up (years)

Placebo

Perindopril8 mg

19% Risk reductionP = 0.131

25

VBWG

MICRO-HOPE, PERSUADE: Consistency of benefit

HOPE Study Investigators. Lancet. 2000;355:253-9.Daly CA et al. Eur Heart J. 2005. In press.

Primary outcome

Total mortality

CV mortality

All MI

Stroke

0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8

Favors ACEI Favors placebo

Relative risk (95% CI)

MICRO-HOPE(N = 3577)

PERSUADE(N = 1502)

VBWG

HOPE Study Investigators. Lancet. 2000;355:253-9.

3.0

2.5

2.0

1.5

1.0

0.5

0 1 2 3 4.5

Placebo

Ramipril 10 mg

Mean albumin-creatinine ratio

Years

P = 0.001

P = 0.02

0

10

20

30

40

Overtnephro-pathy

CV deathStrokeMI

Riskreduction

(%)P = 0.027

P = 0.0001

P = 0.007

P = 0.01

22

3337

24

N = 3577 (32% with microalbuminuria)

MICRO-HOPE: ACEI improves renal and CV outcomes in type 2 diabetes

VBWG

LIFE: Comparison of treatment effects in overall population vs with diabetesPatients with hypertension and LVH

Dahlöf B et al. Lancet. 2002;359:995-1003. Lindholm LH et al. Lancet. 2002;359:1004-10.

0.5 1.0 1.5

Overall (n = 9193)

Diabetes (n = 1195)0.206

0.028

0.001

0.204

0.491

0.373

Favors losartan50–100 mg

Favors atenolol50–100 mg

P

CV death

Stroke

MI

Hazard ratio

VBWG

Effects of ARBs in type 2 diabetes: Renal and CV outcomes

Lewis EJ et al. N Engl J Med. 2001;345:851-60.Brenner BM et al. N Engl J Med. 2001;345:861-9.Parving HH et al. N Engl J Med. 2001;345:870-8.

*Doubling of baseline serum creatinine, end-stage renal disease (IDNT, RENAAL): progression todiabetic nephropathy (IRMA-2)

Study(N) ARB

Primary outcome: Renal disease progression*

Secondaryoutcomes

(CV)

Average duration(years)

IDNT

(N = 1715)

Irbesartan 300 mg/d vs amlodipine 10 mg

20% vs placebo, (P = 0.02) and 23% vs amlodipine (P = 0.006)

Combined CV outcomes: NS

2.6

RENAAL

(N = 1514)

Losartan 100 mg/d vs placebo†

16% (P = 0.02) CV morbidity and mortality: NS HF hospitalization 32%

3.4

IRMA-2

(N = 590)

Irbesartan 150–300 mg vs placebo

39% with 150 mg (P = 0.08)70% with 300 mg (P < 0.001)

Nonfatal CV events: NS

2

VBWG

Impact of Lifestyle Changeand Pharmacologic Therapy

on Diabetes/CVPrevention Strategies

VBWG

INTERHEART: Positive impact of lifestyle factors on acute MI

Yusuf S et al. Lancet. 2004;364:937-52.

Risk factor

Current smoking

Diabetes

Hypertension

Abdominal obesity

Psychosocial factors

0.25 0.5 1.0 2 4 8 16

Odds ratio (99% CI)

Fruits/Vegetables

Exercise

Alcohol

ApoB/ApoA1 ratio

Women

Men

VBWG

Randomized controlled trials of Mediterranean-style diets in CAD patients: Fatal/nonfatal CV events

Parikh P et al. J Am Coll Cardiol. 2005;45:1379-87.

1989Diet and Reinfarction Trial(N = 2000) 29% all-cause mortality 27% MI

1999Lyon Diet Heart Study(N = 605) 68% cardiac death, MI

1999GISSI-Prevenzione(N = 11,324) 20% all-cause mortality 30% CV mortality

2002Indo-Mediterranean Diet Heart Study(N = 1000) 33% fatal MI

1997Indian Experiment of InfarctSurvival Trial(N = 360) 50% cardiac death 48% MI

VBWG

Prospective cohort studies of Mediterranean-style diets: Mortality

Parikh P et al. J Am Coll Cardiol. 2005;45:1379-87.Trichopoulou A et al. BMJ. 2005;330:991-7.Knoops KTB et al. JAMA. 2004;292:1433-9.

2002Nurses’ Health Study(N = 84,688)45% fatal CHD

2004The Healthy Aging: A Longitudinal Study in Europe (N = 2339)23% all-cause mortality

2002Physician’s Health Study(N = 20,551)*

2005European Prospective Investigation into Cancer and Nutrition–elderly cohort (N = 74,607)†

2003Cardiovascular Health Study(N = 5,201)*

2003European Prospective Investigation into Cancer and Nutrition–Greek cohort (N = 22,043)†

*Blood levels of n-3 fatty acids inversely related to death†Greater adherence associated with lower mortality

VBWG

Decrease in mortality with Mediterranean diet: EPIC–elderly prospective cohort study

Trichopoulou A et al. BMJ. 2005;330:991-7.

Objective: Assess effect on mortality of modified Mediterranean diet in subjects free from CHD, stroke, or cancer

Design: N = 74,607, age ≥60 years, from 9 European countries Dietary adherence estimated on scale of 0 (low) to 9 (high)

Follow-up: Median 89 months

Result: Each 2-unit in adherence = 8% all-cause mortality (95% CI, 3%–12%)

VBWG

Mediterranean diet reduces the metabolic syndrome

Esposito K et al. JAMA. 2004;292:1440-6.

82

20

9

84

18

9

34

11

1

66

138

0

15

30

45

60

75

90

Mediterranean diet Control diet

Baseline 2 years

% Patients

Metabolic syndrome components (N)

53 4 53 4

P < 0.001 for effect of Mediterranean vs control diet

VBWG

Diabetes Prevention Program: Impact of lifestyle intervention or metformin

Diabetes Prevention Program Research Group. N Engl J Med. 2002;346:393-403.

0

0

10

20

30

40

0.5 1.0 1.5 2.0 2.5 3.2 3.5 4.0

Year

N = 3234, no diabetesAge 50 years207 lbsGlucose 107

• Lose 5–10 lbs

• Exercise 2.5 hrs/wk

Placebo

Metformin

LifestyleCumulativeincidence of

diabetes(%)

31%

58%

P

< 0.001

< 0.001

VBWG

Diabetes Prevention Program: Impact of PPAR agonist

Diabetes Prevention Program Research Group. Diabetes. 2005;54:1150-6.

10

15

5

0

1.5(237)

Cumulativeincidence

(%)

Years (n)

1.0(739)

0.5(1568)

0.0(2343)

75% vs placebo P <0.001

*Terminated early after 1.5 years

Placebo

Metformin

Lifestyle

Troglitazone*

VBWG

Diabetes Prevention Program: Impact of lifestyle intervention or metformin on development of metabolic syndrome

Orchard TJ et al. Ann Intern Med. 2005;142:611-9.

N = 3234 with impaired glucose tolerance (FG ≥95 mg/dL);47% without metabolic syndrome at baseline

0.75

0.45

0.15

0.30

0.00

1 2 3 4

0.60

Placebo group(n = 490)

Metformin group(n = 503)

Lifestyle group(n = 530)

Cumulativeincidence ofmetabolicsyndrome

0Time since randomization (year)

*vs placebo

17%

51%

P*

0.03

<0.001

VBWG

HOPE/HOPE-TOO: Prevention of diabetesNew diabetes, all patients

Bosch J. Circulation. 2005; in press.

0.12

0.06

0.02

0.04

0.00

1 2 3 4

0.08

0.10

Hazardratio

HOPE studytermination

RR 0.70 (CI, 0.57–0.86)

5 6 7

Placebo

Ramipril

Years

VBWG

100

30

20

10

0STOP-2

INSIG

HT

ALLHAT

% Reduction of new diabetes

INVEST

ALPINE

SCOPE

CHARM

ANBP2

LIFE

HOPE

ALLHAT

CAPPP

STOP-2

VALUE

PEACE

ASCOT

Pepine CJ, Cooper-Dehoff RM. J Am Coll Cardiol. 2004;44:509-12.

Sever PS et al. Lancet. 2003;361:1149-58.Randomized active treatment vs control (e.g. placebo, diuretic, or β-blocker diuretic)

CV pharmacotherapy: Impact on newly diagnosed diabetes

ACEI or ARBCA + ACEI or ARBCA

VBWG

Ongoing trials of diabetes prevention with RAAS modulation

Gerstein HC et al. Diabetologia. 2004;47:1519-27.Califf RM. Eur Heart J Suppl. 2003;5 (suppl C):C13-18.

Leiter LA, Lewanczuk RZ. Am J Hypertens. 2005;18:121-8.

Patients Treatment Follow-up

DREAM* Impaired glucose tolerance or impaired fasting glucose

(N = 5269)

Ramipril 15 mg

Rosiglitazone 8 mg

Placebo

3 yrs 2006

NAVIGATOR† Impaired glucose tolerance

(N = 9518)

Valsartan 160 mg

Nateglinide 60 mg

Valsartan 160 mg +nateglinide 60 mg

Placebo

Until accrual of 1000 CV events

2007

* Diabetes Reduction Approaches with Ramipril and Rosiglitazone Medications†Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research

Anticipated completion

VBWG

Peri-Interventional Careof CAD Patients:

Optimal Discharge Strategies

VBWG

ACC/AHA recommendations: Discharge medical therapy after STEMI

Antman EM et al. J Am Coll Cardiol. 2004;44:671-719.

RAAS modulation ACEI for all patients (Level of evidence: A) ARB for ACEI-intolerant patients with HF or LVEF <0.40 (Level of evidence: B)

Aldosterone blocker for patients on ACEI with LVEF <0.40 and HF or diabetes (Level of evidence: A)

Lipid lowering Statins in patients with LDL-C >100 mg/dL (Level of evidence: A) or with LDL-C <100 mg/dL (Level of evidence: B)

Beta-blockade Beta-blockers for all patients except those with normal/near-normal ventricular function, successful reperfusion, absence of ventricular arrhythmias (Level of evidence: A)

Antiplatelet therapy Aspirin 75-162 mg for all patients (Level of evidence: A)

Class 1

VBWG

ACC/AHA recommendations: Dischargetherapy after unstable angina/NSTEMI

Braunwald E et al. J Am Coll Cardiol. 2002;40:1366-74.Available at www.acc.org

RAAS modulation ACEI for patients with CHF, LV dysfunction (EF <0.40), hypertension, or diabetes (Level of evidence: A)

Lipid lowering Lipid-lowering agents + diet in patients with LDL >130 mg/dL, including after revascularization (Level of evidence: A)

Lipid-lowering agents if LDL-C after diet is >100 mg/dL (Level of evidence: C)

Beta-blockade All patients (Level of evidence: B)

Antiplatelet therapy Aspirin 75-325 mg/d (Level of evidence: A)

Clopidogrel 75 mg/d if aspirin is contraindicated (Level of evidence: B)

Class 1

VBWG

Opportunity for optimizing discharge care

AHA. Heart Disease and Stroke Statistics–2005 Update.

0

200

400

600

800

1600

79 80 85 90 00 01

Year

Proceduresin thousands

0295

1000

1200

1400

Catheterizations Open heart BypassPTCA Endarterectomy Pacemakers

VBWG

Cutlip DE et al. Circulation. 2004;110:1226-30.

46.3%

37.9%

20.3%

0

10

20

30

40

50

0 1 2 3 4 5

Composite

Nontarget lesionEvent rate

(%)

Years

Target lesion

Nontarget-lesion events drive adverse outcomes 5 years after PCI1228 patients in 2nd generation coronary stent trials*

*non-drug eluting stents

VBWG

Improving long-term outcomes in patients with coronary stents

• With 2nd-generation stents, the stented lesion is relatively stable after the first 12 months

• Greatest opportunity for improvement in long-term outcomes is prevention of disease progression at other sites through aggressive risk-factor intervention

Cutlip DE et al. Circulation. 2004;110:1226-30.

VBWG

0

20

40

60

80

100

ACEI ClopidogrelStatinAspirin -Blocker

Patientsreceiving

correcttreatment

(%)

82

94

72

89

50

68 65

81

42

59

Lagging centers(lowest quartile)

Leading centers(highest quartile)

Ohman EM et al. Am Heart J. 2004;148 (suppl 5):S34-9.

CRUSADE: Variations among hospitals in discharge care65,426 UA/NSTEMI patients from participating hospital registries

VBWG

CRUSADE: Discharge care in men and women21,323 men and 14,552 woman with UA/NSTEMI

90.482.7

55.563.4

53.2

87.580.5

55.3 55.948.0

0

20

40

60

80

100

Aspirin -Blocker ACEI Statin Clopidogrel

Men Women

Blomkalns AL et al. J Am Coll Cardiol. 2005;45:832-7.

%Patients

VBWG

Mukherjee D et al. Circulation. 2004;109:745-9.

N = 1358

* Number of evidence-based medications used (aspirin, ACE inhibitor, -blocker, statin) vs number indicated

0.5 1.0 1.5 3.0

Lower mortality Higher mortality

2.00.0

IV

III

II

I

0.10 (0.03–0.42)

0.17 (0.04–0.75)

0.18 (0.04–0.77)

0.36 (0.08–1.75)

Appropriateness level*

Odds ratio (95% CI)

630

314

302

91

Evidence-based medications in ACS patients: Effect on 6-month mortality

n

VBWG

Guideline adherence reduces in-hospital mortality

Peterson ED et al. Circulation. 2002;106(suppl):II-722.*Proportion correct care out oftotal opportunities

NRMI-4; quality of care defined by ACC/AHA class I indications

0

20

40

60

80

100

-Blocker<24 h

Aspirin<24 h

Acutereper-fusion

GP llb/IIIa<24 h

ACEinhibitor

Lipidtherapy

Smokingadvice

Performancequartiles*

(%)

Lowest quartile (n = 271)

Highest quartile (n = 271)

0

5

10

15

20

%

In-hospital mortality

Lowestquartile

Highestquartile

VBWG

Medication class RRR (%)5-Year

CV-event risk (%)

None 0 20.0

Aspirin 25 15.0

-Blocker 25 11.3

ACE inhibitor 25 8.4

Lipid lowering 30 5.9

• Cumulative risk reduction if all 4 medication classes are used: ~70%

• NNT to prevent 1 major CV event in 5 years: 7

Fonarow GC. Rev Cardiovasc Med. 2003;4(suppl 3):S37-46.

Potential impact of CV-protective medication class in post-MI patientsImproving quality of care, quality of life

vbwg raas modulation: raas modulation: novel strategies for reducing cardiovascular risk

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