VBWG

HOPE-TOO: HOPE-TOO: Results of the Results of the

HOPE Study Extension HOPE Study Extension

VBWG

HOPE-TOO: Rationale

• HOPE-TOO was an extension of the HOPE trial, which examined the effects of ACE inhibition in reducing major CV events in high-risk patients with vascular disease or diabetes

• HOPE-TOO was designed to assess whether the CV and metabolic benefits of ramipril were sustained over time and occurred in subgroups based on varying risk and concomitant treatment

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

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HOPE-TOO: Study design

• 4528 HOPE patients at 174 centers who agreed to further follow-up

• Blinded treatment ended and patients were advised to use ACEI

• 2.6-year post-trial extension

• ACEI use during extension– HOPE ramipril arm (n = 2317): 72% – HOPE placebo arm (n = 2211): 68% – >90% of all HOPE-TOO patients used ramipril

Heart Outcomes Prevention Evaluation–The Ongoing Outcomes

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

VBWGMajor CV events and new diagnosis of diabetes for combined in-trial and post-trial periods

No. of patients (%)

New diagnosis of diabetes

Revascularization

Stroke

CV death

MI

MI, stroke, or CV death

Ramipril(n = 3393)

Placebo(n = 3393)

699 (20.6)

485 (14.3)

174 (5.1)

327 (9.6)

767 (22.6)

152 (7.3)

820 (24.2)

581 (17.1)

215 (6.3)

374 (11.0)

880 (25.9)

216 (10.3)

RR (95% CI) P*

0.83 (0.75–0.91)

0.81 (0.72–0.92)

0.79 (0.65–0.97)

0.86 (0.74–1.00)

0.84 (0.76–0.92)

0.69 (0.56–0.85)

0.0002

0.0007

0.023

0.045

0.0003

0.0006

*Calculated by log-rank test and data on all participants in the study extension, censored for period of observation

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

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

RRR = relative risk reduction 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

VBWGHOPE-TOO: Effect of ACEI on major CV events and new-onset diabetes

No. of HOPE patients (%)

New diagnosis of diabetes

Revascularization

Stroke

CV death

MI

MI, stroke,or CV death

1.31.21.11.00.90.80.70.60.50.40.3 1.4 1.5

Ramipril(n = 2317)

Placebo(n = 2211)

RR (95% CI)

220 (7.9)

146 (5.1)

59 (2.0)

133 (4.4)

235 (9.1)

48 (2.7)

225 (8.4)

169 (6.1)

56 (1.9)

126 (4.2)

259 (10.5)

70 (4.0)

*Event rates were calculated as proportions of events in those study participants who were event-free at the end of the in-trial period.

Event*

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

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HOPE-TOO: Additional reduction in MI

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

25

RRR = 19%P = 0.0007

00 1 2 3 4 5 6 7

Placebo

Ramipril

MI(% HOPE-TOO

patients)

20

15

10

5

Years46524645

44744484

42824309

40884159

37703875

28142900

19992137

16121791

PlaceboRamipril

n

HOPE-TOO begins

Main HOPE study ends

VBWGHOPE-TOO: Additional reduction in new-onset diabetes

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

12

6

2

4

0

1 2 3 4

8

10

5 6 7

Placebo

Ramipril

Years

RRR 31% P = 0.0006

HOPE-TOO begins

Main HOPE study ends

28832837

28032763

27042672

26002587

23922431

18131853

12691324

10211092

New-onsetdiabetes

(% HOPE-TOO patients)

PlaceboRamipril

n

VBWGHOPE-TOO: Sustained reduction in stroke

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

10

RRR = 21%P = 0.023

0

Placebo

Ramipril

8

6

4

2

Years46524645

45234539

43674391

41884263

38874000

29533011

21152225

17341876

0 1 2 3 4 5 6 7PlaceboRamipril

n

Stroke(% HOPE-TOO

patients)

HOPE-TOO begins

Main HOPE study ends

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HOPE-TOO: Sustained reduction in CV death

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

15

RRR = 14%P = 0.045

0

Placebo

Ramipril

10

5

Years46524645

45694567

44534448

43094346

40274097

30613100

22032295

18081946

0 1 2 3 4 5 6 7PlaceboRamipril

n

CV death(% HOPE-TOO

patients)

HOPE-TOO begins

Main HOPE study ends

VBWG

HOPE/HOPE-TOO: Benefits at all levelsof risk and with other life-saving drugs

Group No. ofpatients

Lipid meds –Lipid meds +

BB –BB +

ASA –

ASA +

High

Medium

Low

Overall 9297

3083

3100

3114

6813

2484

36735624

26586639

Placeborate

17.7

9.8

16.1

26.9

17.3

19.1

18.217.4

14.019.3

InteractionP-value

0.51

0.0019

0.89

0.68

0.6 0.8 1.0 1.2

Lipid meds –Lipid meds +

Group No. ofpatients

BB –BB +

ASA –

ASA +

High

Medium

Low

Overall 6786

2299

2247

2240

4974

1812

27124074

19604826

Placeborate

24.2

15.2

22.6

34.5

23.5

26.0

26.222.8

18.726.4

InteractionP-value

0.67

0.0043

0.20

0.78

0.6 0.8 1.0 1.2

HOPE HOPE-TOO

Primary outcome = CV death/MI/stroke

RR (95% CI) RR (95% CI)

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

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HOPE-TOO: Study conclusions

• The benefits of ramipril were maintained during post-trial follow-up for CV death, stroke, and hospitalization for heart failure

• Additional reductions in MI, revascularization and new-onset diabetes were also observed despite similar rates of ACEI use in the randomized groups

• The reduction in CV outcomes demonstrated in the HOPE trial is most likely an underestimate of the full effects of long-term ramipril therapy

• Subgroup analyses demonstrate the benefits observed are additive to those of other life-saving therapies, and extend to all patients with vascular disease, independent of their baseline risk

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