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VBWG. Role of RAAS Modulation: Recent Clinical Trials. CAD Diabetes ACEIs and ARBs. VBWG. Benefit of ACE inhibition in CAD. SOLVD SAVE AIRE TRACE. Post-MI, HF, LVEF <40%. HOPE. SOLVD (prev). High risk. EUROPA. All CAD patients. Bertrand ME . Curr Med Res Opin. 2004;20:1559-69.

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Role of RAAS Modulation: Recent Clinical Trials

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Role of raas modulation recent clinical trials l.jpg

VBWG

Role of RAAS Modulation:Recent Clinical Trials

  • CAD

  • Diabetes

  • ACEIs and ARBs


Benefit of ace inhibition in cad l.jpg

VBWG

Benefit of ACE inhibition in CAD

SOLVDSAVEAIRETRACE

Post-MI, HF, LVEF <40%

HOPE

SOLVD

(prev)

High risk

EUROPA

All CAD patients

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


Slide3 l.jpg

VBWG

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

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

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


Europa baseline characteristics l.jpg

VBWG

EUROPA: Baseline characteristics

Perindopril (%)

(n = 6110)

Placebo (%)

(n = 6108)

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


Europa concomitant medications l.jpg

VBWG

EUROPA: Concomitant medications

Baseline (%)

3 Years (%)*

*Concomitant medications recorded in 11,547 patients

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


Europa primary outcome l.jpg

VBWG

EUROPA: Primary outcome

CV death, MI, cardiac arrest

14

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

P = 0.0003

12

Placebo

10

Perindopril 8 mg

8

Primary outcome

(%)

6

20%

14%

4

P < 0.05

11%

2

10%

0

P = 0.35

0

1

2

3

4

5

Time (years)

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

Fox KM. Br J Cardiol. 2004;11:195-204.

AR = absolute risk (perindopril vs placebo)


Europa effect of acei on fatal nonfatal mi and hf hospitalizations l.jpg

VBWG

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

Fatal and nonfatal MI

HF hospitalization

10

RRR 39%AR 1.0% vs 1.7%

P = 0.002

RRR 24%

AR 5.2% vs 6.8%P < 0.001

Placebo

2.0

Placebo

8

1.5

Perindopril8 mg

Perindopril8 mg

6

Events

(%)

1.0

4

0.5

2

0

0.0

0

1

2

3

4

5

0

1

2

3

4

5

Years

Years

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

AR = absolute risk (perindopril vs placebo)


Europa benefit of acei on primary and secondary outcomes l.jpg

EUROPA: Benefit of ACEI on primary and secondary outcomes

2.0

0.5

1.0

VBWG

N = 12,218

Perindopril (%)

(n = 6110)

Placebo (%)

(n = 6108)

Favors

perindopril

Favors

placebo

9.9

17.1

9.8

6.9

4.1

6.8

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

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


Europa benefit of acei on selected secondary outcomes l.jpg

EUROPA: Benefit of ACEI on selected secondary outcomes

2.0

0.5

1.0

VBWG

N = 12,218

Perindopril (%)

(n = 6110)

Placebo (%)

(n = 6108)

Favors

perindopril

Favors

placebo

6.0

0.2

1.7

9.8

1.7

5.6

0.1

1.6

9.4

1.0

Unstable angina

Cardiac arrest

Stroke

Revascularization

HF w/hospital admission

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


Europa consistent benefits in predefined subgroups l.jpg

0.5

1.0

2.0

VBWG

EUROPA: Consistent benefits in predefined subgroups

N = 12,218

Primary events (%)

Perindopril(n = 6110)

Placebo(n = 6108)

Favors

perindopril

Favors

placebo

n

10,4391779 3948 4439 3831

8.2 6.9 6.5 6.9 10.7

10.18.8 8.9 8.1 12.9

MaleFemale≤5556–65≥66

Age (years)

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


Europa consistent benefits in predefined subgroups continued l.jpg

0.5

1.0

2.0

VBWG

EUROPA: Consistent benefits in predefined subgroups (continued)

Primary events (%)

Previous MINo previous MI

Previous revascularizationNo previous revascularization

HypertensionNo hypertension

Diabetes mellitusNo diabetes mellitus

7910 4299

6709 5509

3312 8906

1502 10,716

Perindopril(n = 6110)

Placebo(n = 6108)

Favors

perindopril

Favors

placebo

n

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

15.59.0

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


Europa benefit of perindopril was on top of recommended medications l.jpg

VBWG

EUROPA: Benefit of perindopril was on top of recommended medications

Favors

perindopril

Primary events (%)

Favors

placebo

Perindopril(n = 6110)

Placebo(n = 6108)

Lipid-lowering drugNo lipid-lowering drug

-blockersNo -blockers

Calcium channel blockersNo calcium channel blockers

7.09.3

7.68.7

9.97.1

8.311.9

10.29.4

11.79.0

0.5

1.0

2.0

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


Europa risk reduction with perindopril stratified by baseline systolic bp level l.jpg

VBWG

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

N = 12,218

Baseline SBP (mm Hg)

<120

120 to <140

140

0

5

10

Primaryendpoint relative riskreduction withperindopril(%)

15

17

20

18

25

No interaction between treatment and SBP: P = 0.464

30

35

40

39

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


Europa systolic bp reduction during run in did not affect risk reduction during trial l.jpg

VBWG

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

N = 12,218

RRR 20%

RRR 18%

12

n = 1841

n = 4263

10

n = 1804

n = 4303

8

Primaryevent(%)

6

4

2

0

SBP decrease

during run-in

No SBP decrease

during run-in

Placebo

Perindopril

Run in = 4 weeks when all patients receivedperindopril 8 mg

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


Europa vs hope inclusion criteria l.jpg

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)

VBWG

EUROPA vs HOPE: Inclusion criteria

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)

HOPE patients were at higher risk than EUROPA

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


Europa vs hope study populations l.jpg

VBWG

EUROPA vs HOPE: Study populations

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

HOPE Study Investigators. N Engl J Med. 2000;342:145-53.


Europa vs hope event rates in placebo groups reflect differences in baseline risk l.jpg

VBWG

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

3.0

2.7

2.5

2.0

1.8

Annualized

event rate

in placebo groups

(%)

1.5

1.5

1.0

1.0

0.5

0.0

CV mortality

Total mortality

EUROPA

HOPE

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

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


Europa vs hope treatment more intensive in europa than in hope l.jpg

VBWG

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

Baseline medication

100

92

75

80

62

57

60

%

39

40

28

20

0

Antiplateletdrugs*

Beta-blockers

Lipid-loweringdrugs

EUROPA

HOPE

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

*Mostly aspirin


Europa clinical implications l.jpg

VBWG

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

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

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


    Peace p revention of e vents with a ngiotensin c onverting e nzyme inhibition l.jpg

    VBWG

    PEACE: Prevention of Events with Angiotensin Converting Enzyme inhibition

    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

    Primary

    outcome:CV death, nonfatal MI, CABG, PCI

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


    Peace primary outcome l.jpg

    VBWG

    PEACE: Primary outcome

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

    30

    4% Risk reduction

    HR 0.96 (0.88–1.06)

    P = 0.43

    Placebo

    25

    Trandolapril

    4 mg

    20

    Patients(%)

    15

    10

    5

    0

    0

    1

    2

    3

    4

    5

    6

    Time (years)

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


    Europa vs peace differences in compliance l.jpg

    VBWG

    EUROPA vs PEACE: Differences in compliance

    3 Years

    93

    100

    81

    74.5

    80

    68.6

    60

    Patients

    (%)

    40

    20

    0

    On study ACEI

    At targetACEI dose

    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.


    Acei trials in cad without hf primary outcomes l.jpg

    VBWG

    ACEI trials in CAD without HF: Primary outcomes

    EUROPA

    CV death/MI/cardiac arrest

    HOPECV death/MI/stroke

    14

    20

    Placebo

    Placebo

    12

    15

    10

    22% Risk reduction

    HR 0.78 (0.70–0.86)

    P < 0.001

    20% Risk reduction

    HR 0.80 (0.71–0.91)

    P = 0.0003

    Ramipril 10 mg

    8

    %

    %

    10

    6

    Perindopril 8 mg

    4

    5

    2

    0

    0

    0

    1

    2

    3

    4

    5

    0

    1

    2

    3

    4

    Time (years)

    Time (years)

    PEACECV death/MI/CABG/PCI

    QUIETAll CV events

    Placebo

    50

    30

    Quinapril 20 mg

    40

    25

    4% Risk increase

    HR 1.04 (0.89–1.22)

    P = 0.6

    20

    4% Risk reduction

    HR 0.96 (0.88–1.06)

    P = 0.43

    30

    Trandolapril

    4 mg

    %

    %

    Placebo

    15

    20

    10

    10

    5

    0

    0

    1

    2

    3

    4

    5

    6

    0

    1

    2

    3

    Time (years)

    Time (years)

    HOPE Study Investigators. N Engl J Med. 2000;342:145-53.

    Pitt B et al. Am J Cardiol. 2001;87:1058-63.

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

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


    Acei trials in cad patients without hf key baseline characteristics l.jpg

    VBWG

    ACEI trials in CAD patients without HF: Key baseline characteristics

    EUROPA HOPE PEACE QUIET

    N12,218 9297 8290 1750

    Follow-up (yrs) 4.24.5 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

    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.

    Pitt B et al. Am J Cardiol. 2001;87:1058-63.


    Europa hope peace quiet totality of trial evidence l.jpg

    VBWG

    EUROPA, HOPE, PEACE, QUIET: Totality of trial evidence

    Event rate (%)

    P

    ACEI

    Placebo

    Favors ACEI

    Favors placebo

    0.0004

    All-cause death

    7.5

    8.9

    0.86

    6.4

    7.7

    0.0004

    MI

    0.86

    2.1

    2.7

    0.0004

    Stroke

    0.77

    Revascularization

    15.5

    16.3

    0.025

    0.93

    0.5

    0.75

    1

    1.25

    Odds ratio

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


    Europa hope peace quiet cv therapies at entry during study l.jpg

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

    VBWG

    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.

    Pitt B et al. Am J Cardiol. 2001;87:1058-63.

    *at 3 yrs

    †at study end


    Acei outcome trials in cad patients without hf bp at entry during study l.jpg

    VBWG

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

    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.

    Pitt B et al. Am J Cardiol. 2001;87:1058-63.

    *Run-in BP maintained during study†at study end

    ‡at 3 years


    Hope europa peace quiet differences in baseline cv risk l.jpg

    VBWG

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

    3.0

    2.7

    2.0

    2.0

    1.8

    Annualized event rate in placebo group

    (%/yr)

    1.5

    1.1

    1.0

    1.0

    0.8

    0.7

    0.0

    CV death Nonfatal MI

    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.

    HOPE

    PEACE

    QUIET

    EUROPA


    Europa hope consistent benefit of acei on cv outcomes l.jpg

    VBWG

    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

    Favors

    ACE inhibitor

    Favors

    Placebo

    ACEI

    Placebo

    Composite outcome

    CV mortality

    Myocardial infarction

    Stroke

    Cardiac arrest

    HOPE(ramipril 10 mg)

    EUROPA(perindopril 8 mg)

    0.5

    1.0

    1.5

    Hazard ratio

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

    HOPE Study Investigators. N Engl J Med. 2000;342:145-53.


    Should all patients with stable cad without hf receive an acei interpreting evidence l.jpg

    VBWG

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

    • 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.


    Evidence based medicine updated guide lines for acei in cad patients without hf l.jpg

    VBWG

    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.


    Acp guidelines for acei in chronic stable angina or asymptomatic cad l.jpg

    VBWG

    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.


    Slide33 l.jpg

    VBWG

    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.


    Persuade primary outcome l.jpg

    VBWG

    PERSUADE: Primary outcome

    CV death, MI, cardiac arrest

    20

    RRR: 19%

    95% CI: –7% to 38%

    P = 0.13

    Placebo

    16

    Perindopril8 mg

    12

    Cumulative frequency

    (%)

    8

    4

    0

    0

    1

    2

    3

    4

    5

    Years from randomization

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


    Persuade and europa comparable outcomes l.jpg

    VBWG

    PERSUADE and EUROPA: Comparable outcomes

    Perindopriln = 6110

    n = 721

    Placebon = 6108

    n = 781

    RRR (%)

    EUROPA

    PERSUADE

    Favors

    perindopril

    Favors

    placebo

    488

    603

    20

    CV mortality, nonfatal MI,cardiac arrest

    91

    121

    19

    375

    420

    11

    Total mortality

    73

    93

    15

    215

    249

    14

    CV mortality

    47

    60

    16

    320

    418

    24

    Fatal and nonfatal MI

    56

    78

    23

    212

    273

    23

    Non–Q-wave infarction

    37

    60

    34

    98

    102

    4

    Stroke

    18

    23

    15

    63

    103

    39

    Heart failure

    13

    26

    46

    0.5

    1.0

    2.0

    EUROPA

    PERSUADE

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


    Persuade and micro hope consistency of benefit l.jpg

    VBWG

    PERSUADE and MICRO-HOPE: Consistency of benefit

    Favors ACEI

    Favors placebo

    Primary outcome

    Total mortality

    MICRO-HOPE

    (N = 3577)

    CV mortality

    PERSUADE

    (N = 1502)

    All MI

    Stroke

    0.2

    0.4

    0.6

    0.8

    1.0

    1.2

    1.4

    1.6

    1.8

    Relative risk (95% CI)

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

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


    Persuade clinical implications l.jpg

    VBWG

    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

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


    Are all aceis the same survival 1 year post mi by acei at discharge l.jpg

    VBWG

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

    N = 7512, Canadian pharmacy database

    100

    90

    Unadjusted

    cumulativesurvival(%)

    Ramipril

    n = 905

    Perindopril

    n = 243

    Lisinopril

    n = 2201

    80

    Enalapril

    n = 2577

    Quinapril

    n = 276

    Fosinopril

    n = 889

    Captopril

    n = 421

    P < 0.001 log-rank

    0

    2

    4

    6

    8

    10

    12

    Months

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

    Reference = ramipril


    Multiple mechanisms of acei in atherosclerotic cvd l.jpg

    VBWG

    Multiple mechanisms of ACEI in atherosclerotic CVD

    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

    Blood pressure lowering

    Cardioprotective effects

    •  Preload and afterload

    •  LV mass

    •  Sympathetic stimulation

    •  Reperfusion injury

    • Improved myocardial remodeling

    Metabolic syndrome

    • Lipid neutral

    • Improved glucose metabolism

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


    Clinical trials of arbs cv outcomes l.jpg

    VBWG

    Clinical trials of ARBs: CV outcomes

    Trial (year)

    Patients

    (Follow-up)

    Treatment

    BP

    CV outcomes

    LIFE (2002)

    VALUE (2004)

    Essential HTN

    N = 9193

    (4.8 years)

    Essential HTN, high CV risk

    N = 15,245

    (4.3 years)

    Losartan vs atenolol

    Valsartan vs amlodipine

    Similar 

    Greater  with amlodipine (2.0/1.6 mm Hg)

    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

    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.

    HTN = hypertension


    Life effects of arb vs blockade on primary outcome and components l.jpg

    MI

    VBWG

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

    N = 9193 with hypertension and ECG-LVH

    Primary composite endpoint(CV death/MI/stroke)

    Primary outcome components

    (Losartan vs atenolol)

    16

    10

    Adjusted RR 13.0%

    P = 0.021

    (losartan vs atenolol)

    Riskincrease(%)

    5

    12

    CV death

    Stroke

    0

    Proportionof patientswith firstevent (%)

    P = 0.491

    Atenolol

    8

    5

    Losartan

    10

    Riskreduction(%)

    P = 0.206

    4

    15

    20

    0

    25

    0

    6

    18

    30

    42

    54

    66

    P = 0.001

    Time (months)

    LIFE = Losartan Intervention for Endpoint Reduction in Hypertension

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


    Value similar treatment effects on primary outcome at study end l.jpg

    VBWG

    VALUE: Similar treatment effectson primary outcome at study end

    14

    Valsartan-based regimen

    12

    10

    Proportionof patientswith firstevent (%)

    8

    6

    Amlodipine-based regimen

    4

    2

    HR = 1.03; 95% CI 0.94–1.14; P = 0.49

    0

    0

    6

    12

    18

    24

    30

    36

    42

    48

    54

    60

    66

    Time (months)

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


    Value sbp and outcome differences during consecutive time periods l.jpg

    VALUE: SBP and outcome differencesduring consecutive time periods

    VBWG

    Primary outcome

    Myocardial infarction

    Timeinterval(mos)

    ∆ SBP(mm Hg)

    Favorsvalsartan

    Favorsamlodipine

    Favorsvalsartan

    Favorsamlodipine

    All study

    2.2

    0–3

    3.8

    3–6

    2.3

    6–12

    2.0

    12–24

    1.8

    24–36

    1.6

    36–48

    1.4

    Study end

    1.7

    0.5

    1.0

    2.0

    4.0

    0.5

    1.0

    2.0

    4.0

    Odds ratio

    Odds ratio

    VALUE = Valsartan Antihypertensive Long-Term Use Evaluation

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


    Evidence of benefit acei vs arb l.jpg

    VBWG

    Evidence of benefit: ACEI vs ARB

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

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


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