Role of RAAS Modulation: Recent Clinical Trials

Role of RAAS Modulation:Recent Clinical Trials

• CAD• Diabetes • ACEIs and ARBs

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Benefit of ACE inhibition in CADBenefit of ACE inhibition in CAD

EUROPA

HOPE

All CAD patientsAll CAD patients

Post-MI, HF, LVEF <40%

SOLVDSAVEAIRETRACE

SOLVD(prev)

High risk

Bertrand ME. Curr Med Res Opin. 2004;20:1559-69.

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EUROPA: EUropean trial on Reduction Of cardiac events with Perindopril in stable coronary Artery disease

EUROPA Investigators. Lancet. 2003;362:782-8.

Objective: Assess effects of the ACEI perindopril on CV risk in a broad-spectrum population with stable CAD and without HF

Design: N = 12,218, age ≥18 years, with CAD/without HF at randomization

Treatment: Perindopril 8 mg or placebo

Follow-up: 4.2 years

Primary outcome: CV death, nonfatal MI, cardiac arrest

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EUROPA: Baseline characteristics


Female

History of CAD

– MI

– PCI

– CABG

Documented CAD

– Angiographic evidence (stenosis >70% )

14.5

100

64.9

29.0

29.3

60.4

14.7

100

64.7

29.5

29.4

60.5

– Positive stress test

(in men w/chest pain)

History of stroke/TIA

PVD

Hypertension

Diabetes

Hypercholesterolemia

22.6

3.4

7.1

27.0

11.8

63.3

23.3

3.3

7.4

27.2

12.8

63.3

Placebo (%)(n = 6108)

Perindopril (%)

(n = 6110)

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EUROPA: Concomitant medications

Platelet inhibitors

Beta-blockers

Lipid-lowering agents

Nitrates

Calcium channel blockers

Diuretics

92

62

58

43

32

9

91

63

69

NA

NA

NA


Baseline (%) 3 Years (%)*

*Concomitant medications recorded in 11,547 patients

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EUROPA Investigators. Lancet. 2003;362:782-8.Fox KM. Br J Cardiol. 2004;11:195-204.

EUROPA: Primary outcome

12

4

10

0

1 3 4

14

0

Placebo

Perindopril 8 mg8

6

2

52

Primary outcome

(%)

Time (years)

10%

11%

14%

20%

CV death, MI, cardiac arrest

RRR 20% (95% CI: 9%–29%)AR 8.0% vs 9.9%

P = 0.0003

P < 0.05

P = 0.35

AR = absolute risk (perindopril vs placebo)

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RRR 24%AR 5.2% vs 6.8%

P < 0.001

EUROPA Investigators. Lancet. 2003;362:782–8.

Fatal and nonfatal MI

RRR 39%AR 1.0% vs 1.7%

P = 0.002

2

4

Events(%)

0

10

6

8

0 1 2 3 4 5

Years

Placebo

Perindopril8 mg

0.5

1.0

0.0

2.0

1.5

0 1 2 3 4 5

Years

Placebo

Perindopril8 mg

HF hospitalization

EUROPA: Effect of ACEI on fatal/nonfatal MI and HF hospitalizations

AR = absolute risk (perindopril vs placebo)

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8.0

14.8

7.9

6.1

3.5

5.2

CV mortality, MI, cardiac arrest

Total mortality, MI, UA, cardiac arrest

CV mortality, MI

Total mortality

CV mortality

Fatal/nonfatal MI

Favorsperindopril

Favorsplacebo

Perindopril (%)(n = 6110)

Placebo (%)(n = 6108)

9.9

17.1

9.8

6.9

4.1

6.8

0.5 1.0 2.0

EUROPA: Benefit of ACEI on primary and secondary outcomesN = 12,218

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5.6

0.1

1.6

9.4

1.0

Unstable angina

Cardiac arrest

Stroke

Revascularization

HF w/hospital admission

Favorsperindopril

Favorsplacebo

Perindopril (%)(n = 6110)

Placebo (%)(n = 6108)

6.0

0.2

1.7

9.8

1.7

0.5 1.0 2.0

EUROPA: Benefit of ACEI on selected secondary outcomesN = 12,218

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EUROPA: Consistent benefits in predefined subgroups


Male

Female

≤55

56–65

≥66

Perindopril(n = 6110)

Placebo(n = 6108)

0.5 1.0 2.0

n

10,439

1779

3948

4439

3831

8.2

6.9

6.5

6.9

10.7

10.1

8.8

8.9

8.1

12.9

Primary events (%)

Favorsperindopril

Favorsplacebo

Age (years)

N = 12,218

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EUROPA: Consistent benefits in predefined subgroups (continued)


Previous MI

No previous MI

Previous revascularization

No previous revascularization

Hypertension

No hypertension

Diabetes mellitus

No diabetes mellitus

Perindopril(n = 6110)

Placebo(n = 6108)

0.5 1.0 2.0

n

7910

4299

6709

5509

3312

8906

1502

10,716

8.9

6.4

6.6

9.6

9.8

7.3

12.6

7.4

11.3

7.3

8.0

12.2

12.0

9.1

15.5

9.0

Primary events (%)

Favorsperindopril

Favorsplacebo

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EUROPA: Benefit of perindopril was on top of recommended medications


7.0

9.3

7.6

8.7

9.9

7.1

0.5 1.0 2.0

8.3

11.9

10.2

9.4

11.7

9.0

Lipid-lowering drug

No lipid-lowering drug

-blockers

No -blockers

Calcium channel blockers

No calcium channel blockers

Favorsperindopril

Favorsplacebo Perindopril

(n = 6110) Placebo

(n = 6108)

Primary events (%)

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EUROPA: Risk reduction with perindopril EUROPA: Risk reduction with perindopril stratified by baseline systolic BP levelstratified by baseline systolic BP level

<120 120 to <140 140

Primaryendpoint

relative riskreduction withperindopril (%)

Remme WJ. Circulation. 2004;110(suppl):III-628.

Baseline SBP (mm Hg)

39

17 18

40

35

30

25

20

15

10

5

0

N = 12,218

No interaction between treatment and SBP:

P = 0.464

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EUROPA: Systolic BP reduction during run-in did not affect risk reduction during trial

RRR 20%RRR 20% RRR 18%RRR 18%

SBP decreaseduring run-in

No SBP decreaseduring run-in

0

2

4

6

8

10

12

n = 4263n = 4263

n = 4303n = 4303

n = 1841n = 1841

n = 1804n = 1804

Primaryevent(%)

PerindoprilPlacebo

Run in = 4 weeks when all patients receivedperindopril 8 mg

N = 12,218

Remme WJ. Circulation. 2004;110(suppl):III-628.

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EUROPA vs HOPE: Inclusion criteria

HOPE • Age ≥55 years • Females: 27%• No HF or LV dysfunction • High-risk of CV events

with history of – CAD, stroke, or peripheral

vascular disease– Diabetes + ≥1 CV risk factor

(hypertension, dyslipidemia, smoking, microalbuminuria)

EUROPA • Age ≥18 years• Females: 15% • No clinical HF• Documented CAD including

– Previous MI, PCI/CABG– Angiographic evidence of

CAD with/without previous coronary event

– Positive stress test (men)

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

HOPE patients were at higher risk than EUROPAHOPE patients were at higher risk than EUROPA

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EUROPA HOPE

Age, mean (yrs) 60 66

BP (mm Hg) 137/82 139/79

Known CAD (%) MI (%)

PVD (%)

Stroke/TIA (%)

Revascularization (%)

Diabetes (%)

Hypertension (%)

Hypercholesterolemia (%)

10065

7

3

58

12

27

63

8053

43

11

44

39

47

66


EUROPA vs HOPE: Study populationsVBWG

EUROPA vs HOPE: Event rates in placebo groups reflect differences in baseline risk

80% higher annual rate of CV and total mortality in HOPE80% higher annual rate of CV and total mortality in HOPE


CV mortality Total mortality

Annualizedevent ratein placebo

groups(%)

HOPEEUROPA

1.8

2.7

1.0

1.5

0.0

0.5

1.0

1.5

2.0

2.5

3.0

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EUROPA vs HOPE: Treatment more intensive in EUROPA than in HOPE

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

0

20

40

60

80

100

Antiplateletdrugs*

Beta-blockers

Lipid-lowering

drugs

Baseline medication

%

75

92

39

62

28

57

HOPEEUROPA

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EUROPA: Clinical implications

• In optimally treated CAD patients, perindopril 8 mg significantly reduced

– CV mortality + nonfatal MI + cardiac arrest: 20%

– CV mortality + nonfatal MI: 19%

– Fatal + nonfatal MI: 24%

– Heart failure hospitalization: 39%

• Benefits exhibited on top of recommended therapy (aspirin, -blockers, lipid-lowering agents)

• Benefits consistent across all predefined subgroups

• Baseline BP and changes in BP had no significant impact on outcome

EUROPA Investigators. Lancet. 2003;362:782-8.Remme WJ. Circulation. 2004;110(suppl):III-628.

Treatment with perindopril should be considered in all Treatment with perindopril should be considered in all CAD patients, including patients at low riskCAD patients, including patients at low risk

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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: N = 8290 randomized

Treatment: 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

0

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EUROPA vs PEACE: Differences in compliance

EUROPA (perindopril 8 mg) PEACE (trandolapril 4 mg)

EUROPA Investigators. Lancet. 2003;362:782-8.PEACE Trial Investigators. N Engl J Med. 2004;351:2058-68.

0

20

40

60

80

100

On study ACEI

At targetACEI dose

Patients (%)

93

68.6

8174.5

3 Years

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ACEI trials in CAD without HF: Primary outcomes

HOPE Study Investigators. N Engl J Med. 2000;342:145-53.Pitt B et al. Am J Cardiol. 2001;87:1058-63.

PEACECV death/MI/CABG/PCI

HOPECV death/MI/stroke

15

5

10

0

20

0

Placebo

Ramipril 10 mg

Time (years)

%

2 41


P < 0.001

3Time (years)

12

4

10

0

1 3 4

14

0

Placebo

Perindopril 8 mg

86

2

52

EUROPACV death/MI/cardiac arrest


P = 0.0003

40

20

30

0

50

0

Placebo

Quinapril 20 mg

Time (years)1

4% Risk increaseHR 1.04 (0.89–1.22)

P = 0.6

10

2 3

QUIETAll CV events

Time (years)

Trandolapril4 mg

Placebo30

20

10

15

5

1 2 3 4 5

25

06


P = 0.43

EUROPA Investigators. Lancet. 2003;362:782-8.PEACE Trial Investigators. N Engl J Med. 2004;351:2058-68.

%

%

%

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N 12,218 9297 8290 1750

Follow-up (yrs) 4.2 4.5 4.8 2.3

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

Age (yrs) 60 66 64 58

Men (%) 85 73 82 82

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

Diabetes (%) 12 39 17 16

Hypertension (%) 27 47 46 47

Prior MI (%) 65 53 55 49

Ejection fraction (%) NA NA 58 59

PVD (%) 7 43 NA NA

ACEI trials in CAD patients without HF: Key baseline characteristics


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

EUROPA HOPE PEACE QUIET

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EUROPA, HOPE, PEACE, QUIET: 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).

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EUROPA HOPE PEACE QUIET

Antiplatelet agents (%) 92 76 91 73

-Blockers (%) 62 40 60 26

Lipid-lowering agents (%) 58/69* 29/49† 70 0/14†

Calcium antagonists (%) 31 47 36 0/7†

Diuretics (%) 9 15 13 NA



*at 3 yrs†at study end

EUROPA, HOPE, PEACE, QUIET: CV therapies at entry/during study

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

BP (mm Hg) EUROPA HOPE PEACE QUIET

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

BP in ACEI group 128/78* 136/76† 129/74‡ NA

Difference in mean BP during follow-up (ACEI vs placebo)

5/2 3.3/1.2 3/1.2 NA



*Run-in BP maintained during study†at study end‡at 3 years

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


HOPE, EUROPA, PEACE, QUIET: Differences in baseline CV risk

HOPE EUROPA PEACE

Annualized event rate in placebo group

(%/yr)

CV death Nonfatal MI

QUIET

1.8

1.00.8 0.7

2.7

1.5

1.1

2.0

0.0

1.0

2.0

3.0

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EUROPA, HOPE: Consistent benefit of ACEI on CV outcomes

Event rate (%)

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)


Hazard ratio 0.5 1.0 1.5

ACEI Placebo

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• Totality of clinical trial evidence supports ACEI for treatment of stable CAD patients with/without HF

• Benefits have been shown in patients at all levels of risk

• All ACEIs may not have comparable effects for all indications

• Consider evidence and guidelines in selection of an ACEI and dose.

• Both ramipril and perindopril reduce risk of CV events in stable CAD patients without HF

– Ramipril 10 mg has proven efficacy in CAD patients ≥55 yrs

– Perindopril 8 mg has proven efficacy in CAD patients ≥18 yrs

Pitt B. N Engl J Med. 2004;351:2115-7.EUROPA Investigators. Lancet. 2003;362:782-8.

HOPE Study Investigators. N Engl J Med. 2000;342:145-53.PEACE Trial Investigators. N Engl J Med. 2004;351:2058-68.

Should all patients with stable CAD without HF receive an ACEI? Interpreting evidence

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Evidence-based medicine: Updated guide-lines for ACEI in CAD patients without HF

“ACE inhibitors should be used as routine secondary prevention for patients with known CAD, particularly in diabetics without severe renal disease.” . . . R.J. Gibbons et al.

“The HOPE trial…confirms that the ACE inhibitor ramipril reduced CV death, MI, and stroke in patients who were at high risk for, or had, vascular disease in the absence ofheart failure.” . . . R.J. Gibbons et al.

EUROPA “showed that an ACE inhibitor can have a vasculoprotective effect in patients at lower risk than those enrolled in the HOPE study.” . . . V. Snow et al.

Gibbons RJ et al. 2002 ACC/AHA Practice Guidelines. www.acc.org; July 2005.Snow V et al. Ann Intern Med. 2004;141:562-7.

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ACP guidelines for ACEI in chronic stable angina or asymptomatic CAD

• Symptomatic patients with chronic stable angina (Level of evidence: A)

• Asymptomatic patients

– CAD with systolic dysfunction (Level of evidence: A)

– Diabetes with CAD (Level of evidence: A)

– Diabetes without CAD (Level of evidence: B)

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

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PERSUADE: PERindorpil SUbstudy of coronary Artery disease and DiabEtes: The diabetic substudy of EUROPA

Objective: Investigate the effect of long-term treatment with perindopril added to standard therapy on CV

events in diabetic patients with CAD and without

heart failure

Population: N = 1502 with known diabetes at randomization

Treatment: Perindopril 8 mg (n = 721) or placebo (n = 781)

Follow-up: 4.2 years Daly CA et al. Eur Heart J. 2005;26:1369-78.

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PERSUADE: Primary outcome

Cumulative frequency

(%)

Perindopril8 mg

Placebo

2 3 4 510

Years from randomization

0

4

8

12

16

20

RRR: 19%95% CI: –7% to 38%

P = 0.13

CV death, MI, cardiac arrest

Daly CA et al. Eur Heart J. 2005;26:1369-78.

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PERSUADE and EUROPA: Comparable outcomes

EUROPAPERSUADE Favors

perindoprilFavorsplacebo

Perindopril n = 6110

n = 721

Placebo n = 6108

n = 781

RRR (%)

PERSUADEEUROPA

CV mortality, nonfatal MI,cardiac arrest

488 603 2091 121 19

Total mortality375 420 11

73 93 15

CV mortality 215 249 1447 60 16

Fatal and nonfatal MI320 418 24

56 78 23

Non–Q-wave infarction 212 273 2337 60 34

Stroke 98 102 418 23 15

Heart failure13 26 4663 103 39

0.5 1.0 2.0


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PERSUADE and MICRO-HOPE: Consistency of benefit

Daly CA et al. Eur Heart J. 2005;26:1369-78.HOPE Study Investigators. Lancet. 2000;355:253-9.

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)

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PERSUADE: Clinical implications

• Perindopril 8 mg once daily reduced CV events in patients

with CAD and diabetes

• Relative risk reduction in primary and secondary outcomes

with perindopril was similar to EUROPA

• Results extend the benefit of ACEI shown in MICRO-HOPE

to a lower-risk population with diabetes and CAD


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

N = 7512, Canadian pharmacy database

Reference = ramipril

Are all ACEIs the same? Survival 1-year post-MI by ACEI at discharge

P < 0.001 log-rank

100

90

80

121086420 Months

Captopril

Ramipril

Quinapril

Fosinopril

Lisinopril

Enalapril

Perindopril

Unadjusted cumulative

survival(%)

n = 421

n = 905

n = 276

n = 889

n = 2201

n = 2577

n = 243

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Multiple mechanisms of ACEI in atherosclerotic CVD

Lonn E et al. Eur Heart J. 2003;5(suppl):A43-8.

Blood pressure lowering

Cardioprotective effects

• Preload and afterload

• LV mass

• Sympathetic stimulation

• Reperfusion injury

• Improved myocardial remodeling

Vasculoprotective effects

• Direct antiatherogenic

• Enhance endogenous fibrinolysis

• Inhibit platelet aggregation

• Antimigratory for mononuclear cells

• Matrix formation

• Improve endothelial function

• Antioxidant

• Anti-inflammatory

• Protection from plaque rupture

• Improved arterial compliance and tone

Metabolic syndrome

• Lipid neutral

• Improved glucose metabolism

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Clinical trials of ARBs: CV outcomes

Similar

Greater with amlodipine (2.0/1.6 mm Hg)

Losartan vs atenolol

Valsartan vs amlodipine

Essential HTN

N = 9193

(4.8 years)

Essential HTN, high CV risk

N = 15,245

(4.3 years)

LIFE (2002)

VALUE (2004)

BPTreatment

Patients

(Follow-up)Trial (year)

HTN = hypertension

13% in primary outcome (CV death, MI, stroke) with ARB (P = 0.021) driven by 25% in stroke (P = 0.001)

No difference in CV death/MI

CV outcomes

Primary outcome similar at study end

Trend favors amlodipine at 3 and 6 months

Difficult to interpret due to BP difference

Dahlöf B et al. Lancet. 2002;359:995-1003. Julius S et al. Lancet. 2004;363:2022-31.

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LIFE: Effects of ARB vs -blockade on primary outcome and components

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

N = 9193 with hypertension and ECG-LVH

LIFE = Losartan Intervention for Endpoint Reduction in Hypertension

16

Proportionof patientswith first

event (%)

12

8

4

0

60 18 30 5442 66

AtenololLosartan

Primary composite endpoint(CV death/MI/stroke)

Adjusted RR 13.0%P = 0.021

(losartan vs atenolol)

Time (months)

5

10Risk

increase(%)

0

5

10

15

20

25

Primary outcome components

(Losartan vs atenolol)

Riskreduction

(%)

P = 0.206

CV death

P = 0.491

Stroke

MI

P = 0.001

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VALUE: Similar treatment effectson primary outcome at study end

14

4

2

0

Proportionof patientswith first

event (%)

0 12 3018 24 54 60 66

Time (months)

6

8

10

12

6 36 42 48

HR = 1.03; 95% CI 0.94–1.14; P = 0.49

Valsartan-based regimen

Amlodipine-based regimen

Julius S et al. Lancet. 2004;363:2049-51

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Timeinterval(mos)

∆ SBP(mm Hg)

Odds ratio Odds ratio

Favorsvalsartan

Favorsamlodipine

Favorsvalsartan

Favorsamlodipine

Primary outcome Myocardial infarction

0.5 1.0 2.0 4.0 0.5 1.0 2.0 4.0

All study 2.20–3 3.83–6 2.36–12 2.012–24 1.824–36 1.6

Study end 1.736–48 1.4

Julius S et al. Lancet. 2004;363:2022-31.

VALUE: SBP and outcome differencesduring consecutive time periods

VALUE = Valsartan Antihypertensive Long-Term Use Evaluation

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High risk condition ACE

inhibitor ARB

Heart failure √ √

Post-MI √

High CAD risk √

Diabetes √ √

Chronic kidney disease √ √

Recurrent stroke prevention √

JNC 7. JAMA. 2003;289:2560-72.

Evidence of benefit: ACEI vs ARB

Evidence from clinical trials supports the use of ACEIsvs ARBs in a broader range of high-risk conditions

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Documents

Role of RAAS Modulation: Recent Clinical Trials