Extension studies show sustained benefits with ACEI

Treatment Ramipril Enalapril Enalapril Ramipril

Follow-up 15 mos 10 yrs 12 yrs 7.2 yrs

Characteristic Clinical HF, NYHA class IV HF, LV High CV risk,post-MI HF dysfunction no LV dysfunction

no HF

Results RRR 36% Overall survival Extended Reduced major in mortality prolonged survival CV events and

by 50% by 9.4 mo new diabetes by 34%

Summary Continue ACEI Beneficial effect Sustained Sustainedindefinitely post-MI maintained improvement benefit with

several yrs in survival long-term use

AIREX CONSENSUS X-SOLVD HOPE-TOO

1997 1999 2003 2005

Hall AS et al. Lancet. 1997;349:1493-7.Swedberg K et al. Eur Heart J. 1999;20:136-9.

Jong P et al. Lancet. 2003;361:1843-8.HOPE/HOPE-TOO Study Investigators. Circulation. 2005;112:1339-46.

Dosageimportant

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HOPE-TOO: Study disposition

Ramipril(n = 3393)

Placebo (n = 3393)

Follow-up ACEI therapy:>90% ramipril

“Late” ACEI:Placebo patients

from HOPE

Open-labelACEI therapy

(n = 2211)

“Early” ACEI:Ramipril patients

from HOPE

Open-labelACEI therapy

(n = 2317)

Primary analysis

174 study centers(n = 6786)

HOPE-TOO participantsagreed to passive follow-up

(n = 4528)

Adapted from HOPE/HOPE-TOO Study Investigators. Circulation. 2005;112:1339-46.

Inclusion criteria:Age ≥55 years

Hx: CAD, stroke, PVD ordiabetes + ≥1 CV

risk factor

Exclusion criteria:CHF, known EF <0.4,

Uncontrolled HTN; MI or stroke ≤4 wks; current ACEI,

vit E use

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HOPE-TOO: Baseline characteristics in extended follow-up

CharacteristicRamipril (%)(n = 3393)

Placebo (%)(n = 3393)

CAD 79.5 81.2MI 52.3 53.5Stroke 11.1 11.3PAD 40.4 43.2Hypertension 47.1 45.0Diabetes 38.5 38.2Elevated total-C 64.8 66.2Current cigarette smoking 13.4 14.2Medications

-Blockers 39.8 40.1Aspirin or other antiplatelet agents 74.8 77.0Lipid-lowering drugs 28.5 29.3Diuretics 15.6 15.2Calcium channel blockers 46.1 47.3

LV hypertrophy on ECG 7.7 8.3Microalbuminuria 19.3 20.3

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HOPE/HOPE-TOO Study Investigators. Circulation. 2005;112:1339-46.

HOPE-TOO: Primary outcome (CV death, MI, stroke)

HOPE/HOPE-TOO Study Investigators. Circulation. 2005;112:1339-46.

30

RRR = 17%P = 0.0002

0 1 2 3 4 5 6 70

Placebo

Ramipril

Years

Primary outcome

(% HOPE-TOO patients)

25

20

15

10

5

46524645

44324456

42044256

39814079

36473789

27192819

19232075

15501731

PlaceboRamipril

n

HOPE-TOO begins

Main HOPE study ends

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HOPE-TOO: Additional risk reduction in major CV events and new-onset diabetes

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HOPE/HOPE-TOO Study Investigators. Circulation. 2005;112:1339-41.

19%

34%

16%

RevascularizationNew-onset

diabetesMI0

5

25

15

20

10

30

35

%Reduction

with ramipril

Benefit of treatment with ACEI

• Sustained, irreversible, favorable ventricular/vascular remodeling

• RAAS blockade provides sustainable, favorableeffect on glucose homeostasis

• Benefits are additive to ancillary therapy and extend to all patients, independent of baseline risk

• “Earlier” rather than later initiation provides longer-term protection

HOPE/HOPE-TOO Study Investigators. Circulation. 2005;112:1339-46.

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