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© Continuing Medical Implementation ® …...bridging the care gap Vascular Protection ACE inhibitor Trials

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Page 1: © Continuing Medical Implementation ® …...bridging the care gap Vascular Protection ACE inhibitor Trials

© Continuing Medical Implementation ® …...bridging the care gap

Vascular Protection ACE inhibitor TrialsVascular Protection ACE inhibitor Trials

Page 2: © Continuing Medical Implementation ® …...bridging the care gap Vascular Protection ACE inhibitor Trials

Heart Outcomes Prevention Evaluation Study

A large, simple, randomized trial of Ramipril and vitamin E in

patients at high risk for cardiovascular events

Page 3: © Continuing Medical Implementation ® …...bridging the care gap Vascular Protection ACE inhibitor Trials

Final

Key Inclusion/Exclusion Criteria

Inclusion CriteriaPatients (age 55) at high risk for cardiovascular

events because of:• any evidence of vascular disease (CHD, stroke,

PVD)• diabetes + one other coronary risk factor

Exclusion CriteriaHeart failure or low EF

On ACE-I or Vitamin E

Page 4: © Continuing Medical Implementation ® …...bridging the care gap Vascular Protection ACE inhibitor Trials

Final

Randomized

Active Placebo SECURElow dose

Ramipril 4645 4652 244

Vitamin E 4761 4780

Total No for Ramipril N=9297

Total No for Vitamin E N=9451

Page 5: © Continuing Medical Implementation ® …...bridging the care gap Vascular Protection ACE inhibitor Trials

Final

Primary Adjudicated Events - Ramipril vs Placebo 1/2

Ramipril(%)

Plac(%)

RR 95% CI pNo. Rand. 4645 46521Outcome

MI,Stroke,CVDth 14.1 17.7 0.78 0.70-0.86 0.000002 CV Death* 6.1 8.1 0.75 0.64-0.87 0.0002 MI* 9.9 12.2 0.80 0.71-0.91 0.0005 Stroke* 3.4 4.9 0.69 0.56-0.84 0.0003 Non-CV Death 4.3 4.1 1.03 0.84-1.25 0.78 Mortality 10.4 12.2 0.84 0.75-0.95 0.0058

*not mutually exclusive

Page 6: © Continuing Medical Implementation ® …...bridging the care gap Vascular Protection ACE inhibitor Trials

Final

Ramipril(%)

Placebo(%)

Ramipril vs Placebo

RR 95% CI pNo. Rand 4645 46522 Outcomes

Unstable Angina 12.2 12.4 0.98 0.87-1.10 0.68 with ECG changes

3.9 4.0 0.96 0.79-1.18 0.72

HF Hosp 3.3 3.8 0.87 0.70-1.08 0.19 Revascularization 16.0 18.6 0.84 0.76-0.930.0005

Secondary Adjudicated Events - Ramipril vs Placebo 2/2

Page 7: © Continuing Medical Implementation ® …...bridging the care gap Vascular Protection ACE inhibitor Trials

Final

0

0.05

0.1

0.15

0.2

0 500 1000 1500

Days of Follow-up

Kaplan-Meier Rates

Ramipril Placebo

Primary Outcome - Ramipril vs Placebo

RR=0.78 (0.70-0.86)

P=0.000002

Page 8: © Continuing Medical Implementation ® …...bridging the care gap Vascular Protection ACE inhibitor Trials

Final

Prespecified Subgroups - Ramipril vs Placebo

0.6 0.8 1.0 1.2RR (95% CI)

CVD+

CVD-

Diabetes

+

Diabetes

-

No. Of

Pts.

8160

1137

3578

5719

Placebo Rate

18.7

10.1

19.8

16.5

Page 9: © Continuing Medical Implementation ® …...bridging the care gap Vascular Protection ACE inhibitor Trials

Final

Other Subgroups of Prior Stated Interest: Ramipril vs Placebo (1/2)

0.6 0.8 1.0 1.2

RR (95% CI)

Age<65Age 65+

MaleFemale

Hypertension+Hypertension-

CAD+CAD-

No. Of Pts.41695128

68172480

43554942

74751822

PlaceboRate14.120.7

18.714.8

19.416.3

18.514.2

Page 10: © Continuing Medical Implementation ® …...bridging the care gap Vascular Protection ACE inhibitor Trials

Final

Other Subgroups of Prior Stated Interest: Ramipril vs Placebo (2/2)

0.6 0.8 1.0 1.2

RR (95% CI)

CerebroVD+

CerebroVD-

PVD+

PVD-

MA+

MA-

No. Of Pts.

1013

8284

4046

5251

1956

7341

Placebo Rate

25.9

16.7

22.0

14.3

26.4

15.3

Page 11: © Continuing Medical Implementation ® …...bridging the care gap Vascular Protection ACE inhibitor Trials

Final

Ramipril vs Placebo Patients with Documented normal EF

[N= 4759; mean 0.59 (SD 0.11)]

Ramipril(%)

Placebo(%)

RR 95% CI P

N 2387 2372PrimaryOutcome

14.0 18.9 0.73 (0.63-0.84)0.00001

CV death 5.2 7.5 0.68 (0.54-0.86)0.0009

MI 10.7 14.1 0.75 (0.64-0.88)0.0005

Stroke 2.9 4.3 0.67 (0.50-0.91)0.0104

All HF 8.3 10.5 0.78 (0.65-0.94)0.0082

Revasc. 19.9 24.0 0.80 (0.71-0.91)0.0004

Page 12: © Continuing Medical Implementation ® …...bridging the care gap Vascular Protection ACE inhibitor Trials

Final

Conclusions: Ramipril vs Placebo

There is overwhelming evidence that Ramipril prevents:– CV death, strokes and MI– Heart Failure, Revascularization– Development of diabetes– Diabetic microvascular complications and

NephropathyThese benefits are consistently observed in a very

broad range of high risk patients and in addition to other effective therapies

The only adverse event is a 5% excess of cough

Page 13: © Continuing Medical Implementation ® …...bridging the care gap Vascular Protection ACE inhibitor Trials

Study endpointsStudy endpoints

CV mortality + non fatal MI + cardiac arrestCV mortality + non fatal MI + cardiac arrest

Primary endpointPrimary endpoint

Secondary endpointsSecondary endpoints

Total mortality + non fatal MI + unstable angina +Total mortality + non fatal MI + unstable angina +

cardiac arrestcardiac arrest

Heart failureHeart failure

Revascularisation (PCI/CABG)Revascularisation (PCI/CABG)

StrokeStroke

Page 14: © Continuing Medical Implementation ® …...bridging the care gap Vascular Protection ACE inhibitor Trials

DesignDesign

PlaceboPlacebo

00 1212 2424-1/2-1/2-1-1

Run-in periodRun-in period

RandomisationRandomisation

Follow-upFollow-up

MonthsMonths3636 4848

4 mg4 mg 8 mg8 mg

PerindoprilPerindopril

Perindopril 8 mg once dailyPerindopril 8 mg once daily

6060

Page 15: © Continuing Medical Implementation ® …...bridging the care gap Vascular Protection ACE inhibitor Trials

Selection criteriaSelection criteria

Male or female > 18 years of ageMale or female > 18 years of age

Documented coronary diseaseDocumented coronary disease

Not scheduled for revascularisationNot scheduled for revascularisation

No clinical signs of heart failureNo clinical signs of heart failure

Page 16: © Continuing Medical Implementation ® …...bridging the care gap Vascular Protection ACE inhibitor Trials

Selection criteriaSelection criteria

Male or female > 18 years of ageMale or female > 18 years of age

Documented coronary diseaseDocumented coronary disease

Not scheduled for revascularisationNot scheduled for revascularisation

No clinical signs of heart failureNo clinical signs of heart failure

Page 17: © Continuing Medical Implementation ® …...bridging the care gap Vascular Protection ACE inhibitor Trials

DocumentedDocumentedcoronary diseasecoronary disease

Previous MI > 3 monthsPrevious MI > 3 months

PCI / CABG > 6 monthsPCI / CABG > 6 months

Angiographic evidence (Angiographic evidence ( 70% stenosis) 70% stenosis)

In males with chest pain: positive exercise orIn males with chest pain: positive exercise or

stress teststress test

Page 18: © Continuing Medical Implementation ® …...bridging the care gap Vascular Protection ACE inhibitor Trials

Baseline characteristicsBaseline characteristics

Page 19: © Continuing Medical Implementation ® …...bridging the care gap Vascular Protection ACE inhibitor Trials

Patient flowPatient flow

CompletedCompleted6 1076 107

CompletedCompleted6 1086 108

PerindoprilPerindopril6 1106 110

PlaceboPlacebo6 1086 108

RandomisedRandomised12 21812 218

Not randomisedNot randomised1 4371 437

RegisteredRegistered13 65513 655

Page 20: © Continuing Medical Implementation ® …...bridging the care gap Vascular Protection ACE inhibitor Trials

PerindoprilPerindopril(mean (mean SD) SD)

Placebo Placebo (mean (mean SD) SD)

Age Age (yrs)(yrs) 60 60 9 9 60 60 9 9

Male Male (%)(%) 86 86 8585

Weight Weight (kg)(kg) 81 81 12 12 80 80 12 12

HR HR (bpm)(bpm) 68 68 10 10 68 68 10 10

SBP SBP (mmHg)(mmHg) 137 137 16 16 137 137 15 15

DBP DBP (mmHg)(mmHg) 82 82 8 8 82 82 8 8

Baseline characteristicsBaseline characteristics

Page 21: © Continuing Medical Implementation ® …...bridging the care gap Vascular Protection ACE inhibitor Trials

PerindoprilPerindopril(%)(%)

PlaceboPlacebo (%)(%)

Myocardial infarctionMyocardial infarction 64.964.9 64.764.7

RevascularisationRevascularisation 54.754.7 55.255.2

Stroke / TIAStroke / TIA 3.43.4 3.33.3

Heart failureHeart failure 1.31.3 1.21.2

Peripheral vascular Peripheral vascular diseasedisease 7.17.1 7.47.4

Medical historyMedical history

Page 22: © Continuing Medical Implementation ® …...bridging the care gap Vascular Protection ACE inhibitor Trials

PerindoprilPerindopril(%)(%)

PlaceboPlacebo

(%)(%)

HypertensionHypertension 27.027.0 27.227.2

Diabetes mellitusDiabetes mellitus 11.811.8 12.812.8

HypercholesterolaemiaHypercholesterolaemia 63.363.3 63.363.3

Current smokerCurrent smoker 15.415.4 15.115.1

Risk factorsRisk factors

Page 23: © Continuing Medical Implementation ® …...bridging the care gap Vascular Protection ACE inhibitor Trials

Perindopril Perindopril (%)(%)

PlaceboPlacebo(%)(%)

Platelet inhibitorsPlatelet inhibitors 91.991.9 92.792.7

-blockers-blockers 62.062.0 61.361.3

Lipid lowering drugsLipid lowering drugs 57.857.8 57.357.3

NitratesNitrates 42.842.8 43.043.0

Ca-blockersCa-blockers 31.731.7 31.031.0

DiureticsDiuretics 9.19.1 9.49.4

Oral anticoagulantsOral anticoagulants 4.44.4 4.24.2

Baseline medicationBaseline medication

Page 24: © Continuing Medical Implementation ® …...bridging the care gap Vascular Protection ACE inhibitor Trials

How does Europa compare with Hope?How does Europa compare with Hope?

A closer look at the Patients….A closer look at the Patients….

Page 25: © Continuing Medical Implementation ® …...bridging the care gap Vascular Protection ACE inhibitor Trials

PATIENT CHARACTERISTICSPATIENT CHARACTERISTICS

Total patients randomized

Mean age (range)

Previous MI (%)

Previous revascularization (%)

Peripheral vascular disease (%)

HOPE

437

65

44 55

60 (24-90)

53

9297

66 (>55)

12 236

Page 26: © Continuing Medical Implementation ® …...bridging the care gap Vascular Protection ACE inhibitor Trials

Evidence of coronary artery disease (%)

Hypertension (%)

Stroke (%)

Diabetes mellitus (%)

Aspirin or other antiplatelet agents (%)

Lipid-lowering agent (%)

-blockers (%)

HOPE

69

3963

7691

29

3

3912

27

11

81

47

100

PATIENT CHARACTERISTICSPATIENT CHARACTERISTICS

Page 27: © Continuing Medical Implementation ® …...bridging the care gap Vascular Protection ACE inhibitor Trials

ConclusionsConclusions

The risk level of patients in Europa was lower than The risk level of patients in Europa was lower than in Hope. This is supported by the patient profile but in Hope. This is supported by the patient profile but also the annual placebo mortality event rates which also the annual placebo mortality event rates which were 40% to 80% higher that those in Europa.were 40% to 80% higher that those in Europa.

The Europa patients were more aggressively treated The Europa patients were more aggressively treated as evident by the higher use of anti-platelet agents, as evident by the higher use of anti-platelet agents, lipid lowering agents and B-blockers.lipid lowering agents and B-blockers.

The risk level of patients in Europa was lower than The risk level of patients in Europa was lower than in Hope. This is supported by the patient profile but in Hope. This is supported by the patient profile but also the annual placebo mortality event rates which also the annual placebo mortality event rates which were 40% to 80% higher that those in Europa.were 40% to 80% higher that those in Europa.

The Europa patients were more aggressively treated The Europa patients were more aggressively treated as evident by the higher use of anti-platelet agents, as evident by the higher use of anti-platelet agents, lipid lowering agents and B-blockers.lipid lowering agents and B-blockers.

Page 28: © Continuing Medical Implementation ® …...bridging the care gap Vascular Protection ACE inhibitor Trials

ResultsResults

Page 29: © Continuing Medical Implementation ® …...bridging the care gap Vascular Protection ACE inhibitor Trials

Primary endpointPrimary endpoint

% CV death, MI or cardiac arrest% CV death, MI or cardiac arrest

Placebo annual event rate: 2.4%Placebo annual event rate: 2.4%

Perindopril Perindopril

PlaceboPlacebop = 0.0003p = 0.0003RRR: RRR: 20%20%

YearsYears00

22

44

66

88

1010

1212

1414

00 11 22 33 44 55

Page 30: © Continuing Medical Implementation ® …...bridging the care gap Vascular Protection ACE inhibitor Trials

Primary endpointPrimary endpoint

RRR: 20% [95% CI : 9 - 29]RRR: 20% [95% CI : 9 - 29]CV death, MI or cardiac arrestCV death, MI or cardiac arrest

00

100100

200200

300300

400400

500500

600600

700700

No eventsNo events

PerindoprilPerindopril(6 110)(6 110)

8.0%8.0%

488488

PlaceboPlacebo(6 108)(6 108)

9.9%9.9%

603603

Page 31: © Continuing Medical Implementation ® …...bridging the care gap Vascular Protection ACE inhibitor Trials

Sub-groups analysisSub-groups analysis

RRR RRR (%)(%)

0.50.5 1.01.0 2.02.0

Perindopril betterPerindopril better Placebo betterPlacebo better

Previous MIPrevious MI

No previous MINo previous MI

22.422.4

12.112.1

Age Age 56 yrs 56 yrs

Age 57 - 65Age 57 - 65

Age > 65 yrsAge > 65 yrs

27.327.3

14.314.3

18.218.2

MaleMale

FemaleFemale

19.319.3

22.022.0

Page 32: © Continuing Medical Implementation ® …...bridging the care gap Vascular Protection ACE inhibitor Trials

Sub-groups analysisSub-groups analysis

0.50.5 1.01.0 2.02.0

HypertensionHypertension

RRR RRR (%)(%)PerindoprilPerindoprilbetterbetter

PlaceboPlacebobetterbetter

No hypertensionNo hypertension

Diabetes mellitusDiabetes mellitus

No diabetes mellitusNo diabetes mellitus

Stroke/TIAStroke/TIA

No stroke/TIANo stroke/TIA

18.618.6

19.919.9

18.918.9

19.019.0

15.815.8

19.919.9

Page 33: © Continuing Medical Implementation ® …...bridging the care gap Vascular Protection ACE inhibitor Trials

92% patients on platelet inhibitors92% patients on platelet inhibitors

Sub-groups analysisSub-groups analysis

RRR RRR (%)(%)

Lipid lowering drugLipid lowering drug

PerindoprilPerindoprilbetterbetter

PlaceboPlacebobetterbetter

0.50.5 1.01.0 2.02.0

No lipid lowering drugNo lipid lowering drug

-blockers-blockers

No No -blockers-blockers

Calcium blockersCalcium blockers

No calcium blockersNo calcium blockers

16.316.3

22.322.3

26.426.4

7.07.0

15.815.8

22.222.2

Page 34: © Continuing Medical Implementation ® …...bridging the care gap Vascular Protection ACE inhibitor Trials

Secondary endpointsSecondary endpoints

Fatal & non fatal MI, unstable anginaFatal & non fatal MI, unstable angina

0.50.5 1.01.0 2.02.0

Perindopril betterPerindopril better Placebo betterPlacebo better

Total mortality, MI, UAP,CATotal mortality, MI, UAP,CA

CV mortality & MICV mortality & MI

CV mortality, MI & strokeCV mortality, MI & stroke

CV mortality, MI, revascularisationCV mortality, MI, revascularisation

CV mortality, MI, unstable anginaCV mortality, MI, unstable angina

Non fatal and fatal MINon fatal and fatal MI

Total mortalityTotal mortality

CV mortalityCV mortality

Unstable anginaUnstable angina

Cardiac arrest Cardiac arrest

StrokeStroke

RevascularisationRevascularisation

Heart failureHeart failure

RRR RRR (%)(%)

14.014.0

19.319.3

17.417.4

11.311.3

15.515.5

16.516.5

23.923.9

11.011.0

13.913.9

7.17.1

45.645.6

4.34.3

4.24.2

39.239.2

Page 35: © Continuing Medical Implementation ® …...bridging the care gap Vascular Protection ACE inhibitor Trials

Fatal and non fatal MIFatal and non fatal MI

PerindoprilPerindopril

PlaceboPlacebo

00

22

44

66

88

1010

00 11 22 33 44 55 YearsYears

(%)(%)

p < 0.001p < 0.001RRR: 24%RRR: 24%

Page 36: © Continuing Medical Implementation ® …...bridging the care gap Vascular Protection ACE inhibitor Trials

Heart FailureHeart Failure

Perindopril Perindopril

PlaceboPlacebo

5500 11 22 33 44 YearsYears

p = 0.002p = 0.002RRR: 39%RRR: 39%

0.00.0

0.50.5

1.01.0

1.51.5

2.02.0(%)(%)

Page 37: © Continuing Medical Implementation ® …...bridging the care gap Vascular Protection ACE inhibitor Trials

-1-1 -1/2-1/2 00 33 66 1212 1818 2424 3030 3636 4242 4848 5454 6060

MonthsMonths

7070

8080

9090

100100

110110

120120

130130

140140

mmHgmmHg

Blood pressureBlood pressure

SBP: 5 mmHgSBP: 5 mmHgDBP: 2 mmHgDBP: 2 mmHg

Perindopril Perindopril 8mg8mg PlaceboPlacebo

Page 38: © Continuing Medical Implementation ® …...bridging the care gap Vascular Protection ACE inhibitor Trials

Adherence to treatmentAdherence to treatment

0 6 12 18 24 30 36

MonthsMonths

0

20

40

60

80

100

120(%)

PlaceboPlacebo

Perindopril Perindopril 8mg8mg

Page 39: © Continuing Medical Implementation ® …...bridging the care gap Vascular Protection ACE inhibitor Trials

ConclusionConclusion

Page 40: © Continuing Medical Implementation ® …...bridging the care gap Vascular Protection ACE inhibitor Trials

Summary of resultsSummary of results

In EUROPA, the largest and longest trial of stable,In EUROPA, the largest and longest trial of stable,

low risk CAD patients, perindopril 8 mg/dlow risk CAD patients, perindopril 8 mg/d

significantly reduced:significantly reduced:

CV mortality + non fatal MI + cardiac arrest:CV mortality + non fatal MI + cardiac arrest: 20%20% CV mortality and non fatal MI:CV mortality and non fatal MI: 19%19% Fatal + non fatal MI:Fatal + non fatal MI: 24%24% Heart failure:Heart failure: 39%39%

Page 41: © Continuing Medical Implementation ® …...bridging the care gap Vascular Protection ACE inhibitor Trials

Summary of resultsSummary of results

Benefits occurred on top of recommendedBenefits occurred on top of recommended

therapy therapy (92% platelet inhibitors, 58% lipid(92% platelet inhibitors, 58% lipid

lowering drugs, 62% lowering drugs, 62% -blockers)-blockers) and are and are

consistent across predefined sub-groupsconsistent across predefined sub-groups

Perindopril should be considered for chronicPerindopril should be considered for chronic

therapy in all patients with coronary diseasetherapy in all patients with coronary disease

Page 42: © Continuing Medical Implementation ® …...bridging the care gap Vascular Protection ACE inhibitor Trials

The Prevention of Events with Angiotensin

Converting Enzyme Inhibition (PEACE) Trial A double-blind, placebo-controlled, randomized trial

Sponsored by the National Heart, Lung, and Blood Institute

Study medication and additional support provided by Abbott Laboratories/Knoll

Marc Pfeffer, MD, Ph.D— grants and honorarium: Novartis, AstraZeneca, Bristol-Myers Squibb— licensing agreement with BWH with Novartis, Abbott, and Merck unrelated to sales or PEACE patient population

Page 43: © Continuing Medical Implementation ® …...bridging the care gap Vascular Protection ACE inhibitor Trials

Hypothesis

To test whether ACE inhibitor therapy, when added to modern conventional therapy, reduces CV mortality, MI, or coronary revascularization in low-risk,

stable CAD patients with normal or mildly reduced LV function.

Page 44: © Continuing Medical Implementation ® …...bridging the care gap Vascular Protection ACE inhibitor Trials

Inclusion Criteria

Age 50 years

Coronary artery disease— MI, or— CABG or PCI, or— Coronary angiogram with obstruction of 50%

luminal diameter in at least one native vessel

LVEF > 40%

Tolerated 2 week run-in of 2 mg/day trandolapril

Page 45: © Continuing Medical Implementation ® …...bridging the care gap Vascular Protection ACE inhibitor Trials

Major Exclusions

Current use or contraindication to ACE-I or ARB

CV event in previous 3 months

Planned elective coronary revasc

Creatinine > 2.0 mg/dl(177mmol/l)

Potassium > 5.5 mEq/L

Limited 5-year survival

Psychosocial condition precluding long-term adherence

Page 46: © Continuing Medical Implementation ® …...bridging the care gap Vascular Protection ACE inhibitor Trials

Comparison of Patients in the

HOPE, EUROPA, and PEACE TrialsCharacteristic

% (unless otherwise specified)

HOPE

n=9297

EUROPA

n=12218

PEACE

n=8290

Mean age 66 60 64

Prior MI 53 65 55

Diabetes mellitus 38 12 17

Prior CABG or PCI 40 55 72

Mean LV EF NA NA 58

Mean SBP/DBP 139/79 137/82 133/78

Aspirin/antiplatelet 76 92 91

Lipid lowering 29 58 70

Beta blocker 40 62 60

Page 47: © Continuing Medical Implementation ® …...bridging the care gap Vascular Protection ACE inhibitor Trials

Statistical Considerations 1º outcome: CV death, MI, or coronary

revasc

Sample size and assumptions— n = 8,100— 90% power, = 0.05— 18% relative reduction in incidence of primary

outcome— 19% cumulative incidence in placebo — 15% discontinuation of study drug in active

treatment — 15% crossover to open-label ACE-I in placebo

group

Statistical analysis— Intention-to-treat— Time to event log-rank test— Proportional-hazards regression

Page 48: © Continuing Medical Implementation ® …...bridging the care gap Vascular Protection ACE inhibitor Trials

Baseline Demographics

Characteristic

% (unless otherwise specified)

Trandolapril

(n=4158)

Placebo

(n=4132)

Age (mean+SD) 64+8 64+8

Women 19 17

Caucasian 92 93

Region

US (incl. Puerto Rico) 58 58

Canada 30 30

Italy 12 12

Page 49: © Continuing Medical Implementation ® …...bridging the care gap Vascular Protection ACE inhibitor Trials

Baseline Medical History

Characteristic, % Trandolapril Placebo

Documented MI 54 56

CABG or PCI 72 72

Diabetes 18 16

Hypertension 46 45

Stroke or TIA 7 6

Current cigarette use 14 15

Page 50: © Continuing Medical Implementation ® …...bridging the care gap Vascular Protection ACE inhibitor Trials

Baseline Measurements

Characteristic

Mean +SD

Trandolapril

Placebo

LVEF (%) 58+10 58+9

Systolic BP (mm Hg) 134+17 133+17

Diastolic BP (mm Hg) 78+10 78+10

Creatinine (mg/dl) 1.0+0.2 1.0+0.2

Cholesterol (mg/dl) 192+39 (4.9)

192+40

Page 51: © Continuing Medical Implementation ® …...bridging the care gap Vascular Protection ACE inhibitor Trials

Baseline Medications

Characteristic,% Trandolapril Placebo

Aspirin or antiplatelets 90 91

Lipid lowering drug 70 70

Beta blocker 60 60

Diuretic 13 13

Anticoagulant 5 5

Insulin 4 4

Digitalis 4 4

Antiarrhythmic 2 2

Page 52: © Continuing Medical Implementation ® …...bridging the care gap Vascular Protection ACE inhibitor Trials

Compliance

81.978.5

74.5

1.54.6

8.3

0

10

20

30

40

50

60

70

80

90

100

Per

cen

t

1 2 3 1 2 3

Percent taking trandolapril or an open

label ACE inhibitor

Percent taking an open label ACE

inhibitor

Trandolapril Placebo

Years

Page 53: © Continuing Medical Implementation ® …...bridging the care gap Vascular Protection ACE inhibitor Trials

Side Effects*

% Trandolapril

Placebo

P-value

Dizziness 32.9 31.1 N.S.

Cough 39.1 27.5 0.01

Skin rash 11.7 11.9 N.S.

Headache 18.1 19.5 N.S.

Syncope 4.8 3.9 0.04

Fatigue 35.4 36.5 N.S.

Angioedema 0.1 0.2 N.S*A patient may be in more than one category

Page 54: © Continuing Medical Implementation ® …...bridging the care gap Vascular Protection ACE inhibitor Trials

Change in Systolic Blood Pressure

-6

-5

-4

-3

-2

-1

0

0 1 2 3 4 5 6

Time Since Randomization (Years)

Pressure Change (mm Hg)

Placebo Trandolapril

Baseline= 13317

=-1.4

=-4.4, p<0.001

Page 55: © Continuing Medical Implementation ® …...bridging the care gap Vascular Protection ACE inhibitor Trials

Change in Diastolic Blood

Pressure

-7

-6

-5

-4

-3

-2

-1

0

0 1 2 3 4 5 6

Time Since Randomization (Years)

Pressure Change (mm Hg)

Placebo Trandolapril

Baseline= 7810

=-2.3

=-3.6, p<0.001

Page 56: © Continuing Medical Implementation ® …...bridging the care gap Vascular Protection ACE inhibitor Trials

1º OutcomeCV Death, MI, CABG, or

PCI

0.00

0.05

0.10

0.15

0.20

0.25

0.30

0.35

0 1 2 3 4 5 6

Years from Randomization

Incidence of Primary Outcome

Placebo

Trandolapril

Number of Patients

Placebo 4132 3992 3722 3491 3034 1941 906

Active 4158 4019 3758 3515 3093 1981 985

HR=0.96 (95% CI, 0.88-1.06) P=0.43

Page 57: © Continuing Medical Implementation ® …...bridging the care gap Vascular Protection ACE inhibitor Trials

1º Outcome and its Components

Outcome Trandolapril n=4158

%

Placebo n=4132

%

Hazard Ratio (95% CI)

P-value

CV death, MI, CABG or PCI

21.9 22.5 0.96 (0.88-1.06)

NS

CV death 3.5 3.7 0.95 (0.76-1.19)

NS

Non-fatal MI

5.3 5.3 1.00 (0.83-1.20)

NS

Revasc 17.8 18.0 0.98 (0.88-1.08)

NS

Page 58: © Continuing Medical Implementation ® …...bridging the care gap Vascular Protection ACE inhibitor Trials

Onset of New Diabetes1

The PEACE trial investigators. Angiotensin-Converting-Enzyme Inhibition in Stable Coronary Artery Disease (the PEACE trial). N Engl J Med 2004;351:2-58-68

†The analysis included 3432 patients in the trandolapril group and 3472 patients in the placebo group and excluded

patients with diabetes at baseline.

Pat

ien

ts (

%)

Placebo(absolute incidence 399/3472)

Trandolapril(absolute incidence 336/3432)

p=0.01

9.8%11.5%

12

10

8

6

4

2

0

Risk Reduction

17%

Page 59: © Continuing Medical Implementation ® …...bridging the care gap Vascular Protection ACE inhibitor Trials

CHF as a primary cause of

hospitalization or death1

The PEACE trial investigators. Angiotensin-Converting-Enzyme Inhibition in Stable Coronary Artery Disease (the PEACE trial). N Engl J Med 2004;351:2-58-68

p=0.02

Placebo(absolute incidence 1529/4132)

Trandolapril(absolute incidence 115/4158)

3.7%

2.8%

Pat

ien

ts (

%)

4.0

3.5

3.0

2.5

2.0

1.5

1.0

0.5

0.0

Risk Reduction

25%

Page 60: © Continuing Medical Implementation ® …...bridging the care gap Vascular Protection ACE inhibitor Trials

PEACE Compared with EUROPA, HOPE

studiesACE Inhibitor

Quantitative LVEF assessment

Inclusion criteria

Exclusion criteria

Primary endpoint

No. of patients

Mean follow-up

Industry sponsored

HOPE

Ramipril

No

Age > 55 with one of the following:

• Documented CAD (> 1 month post-MI, CABG or PTCA, > 50% stenosis on > 2 arteries or positive stress)

• Peripheral vascular disease

• Stroke• Diabetes associated with

one other cardioascular risk factor

LVEF known to be < 40%

Combined: MI, stroke, cardiovascular death

9,297

4.5 years

EUROPA

Perindopril

No

Age > 18 and:•Documented CAD (> 3

months post-MI, > 6 months post-PTCA or CABG, > 70% stenosis)

Clinical heart failure

Combined: CV death, non-fatal MI or, cardiac arrest

12,218

4.2 years

Yes

PEACE

Trandolapril

Yes

Age > 50 and:•Documented CAD (> 3

months post-MI, PTCA or CABG, > 50% stenosis)

•LVEF > 40 % (< 18 months before randomisation)

LVEF < 40 %

Combined: MI, cardiovascular death,need for PTCA or CABG

8,290

Yes

No

5.2 years

Page 61: © Continuing Medical Implementation ® …...bridging the care gap Vascular Protection ACE inhibitor Trials

PEACE vs. HOPE and EUROPA: Baseline Characteristics

PEACE1 HOPE2 EUROPA3

Characteristic (n = 8290) (n = 9297) (12,218)Age (y) 64 66 60

Male (%) 83 73 85

Mean ejection fraction (%) 58 NA NA

Mean BP (mmHg) 133/78 139/79 137/82

Mean BMI 28 28 NA

History of (%)

MI 56 52 65

Diabetes 17 38 12

PTCA/CABG 72 NA 59

CABG 39 26 29

PTCA 42 18 291. Pfeffer MA, et al: Am Heart J 2001; 142(3):375-7. 2. Yusuf S, et al: N Engl J Med 2000; 342(3):145-53. 3. EUROPA Investigators: Lancet 2003; 362:782–8.

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HOPE and PEACE Comparison

CV death, MI, or Stroke

0

0.05

0.1

0.15

0.2

0 1 2 3 4 5

Years from Randomization

Cumulative Failure Rate (%)

HOPE Placebo HOPE Active

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HOPE and PEACE Comparison

CV death, MI, or Stroke

0

0.05

0.1

0.15

0.2

0 1 2 3 4 5

Years from Randomization

Cumulative Failure Rate (%)

HOPE Placebo HOPE Active PEACE Placebo

Page 64: © Continuing Medical Implementation ® …...bridging the care gap Vascular Protection ACE inhibitor Trials

EUROPA and PEACE Comparison CV death, MI, or

Cardiac Arrest

0

0.02

0.04

0.06

0.08

0.1

0 1 2 3 4

Years from Randomization

Cumulative Failure Rate (%)

EUROPA Placebo EUROPA Active

Page 65: © Continuing Medical Implementation ® …...bridging the care gap Vascular Protection ACE inhibitor Trials

0

0.02

0.04

0.06

0.08

0.1

0 1 2 3 4

Years from Randomization

Cumulative Failure Rate (%)

EUROPA Placebo EUROPA Active PEACE Placebo

EUROPA and PEACE Comparison CV death, MI, or

Cardiac Arrest

Page 66: © Continuing Medical Implementation ® …...bridging the care gap Vascular Protection ACE inhibitor Trials

Annualized CV Mortality in the Placebo Arms of

HOPE, EUROPA, & PEACE1.62

0.97

0.77

0

0.2

0.4

0.6

0.8

1

1.2

1.4

1.6

1.8

HOPE

EUROPA

PEACE

An

nu

aliz

ed C

V M

ort

alit

y (%

)

The annualized all-cause mortality in the PEACE population was only 1.6%, similar to that of an age and gender matched general population.

Page 67: © Continuing Medical Implementation ® …...bridging the care gap Vascular Protection ACE inhibitor Trials

Percent of Deaths due to CV Causes in the Placebo Arms of HOPE, EUROPA, & PEACE

and in the General Population

6359

47

35

0

10

20

30

40

50

60

70

HOPE

EUROPA

PEACE

General Population*

* Age and gender matched to PEACE cohort%

of

Dea

ths

du

e to

CV

Cau

ses

Page 68: © Continuing Medical Implementation ® …...bridging the care gap Vascular Protection ACE inhibitor Trials

Baseline Concomitant Medications in Major ACE Inhibitor Studies

35

6070

91

32

62 58

92

4740

29

76

0

20

40

60

80

100

CCB Beta-blocker Lipid-lowering Antiplatelet

% of patients at baseline

PEACE EUROPA HOPE

Pfeffer MA, et al: Am Heart J 2001; 142(3):375-7. Fox KM, et al: Lancet 2003; 362(9386):782-8. Yusuf S, et al: N Engl J Med 2000; 342(3):145-53.

Page 69: © Continuing Medical Implementation ® …...bridging the care gap Vascular Protection ACE inhibitor Trials

% Death, MI, Cardiac arrest

Age, gender, previous MI, previous CABG/PCI, Age, gender, previous MI, previous CABG/PCI, PVD or stroke, hypertension, diabetes,PVD or stroke, hypertension, diabetes,

smoking, hyperchol., lipid lowering, smoking, hyperchol., lipid lowering, -blockers.-blockers.

LowLow MediumMedium High riskHigh risk

5.25.2 6.26.2 6.26.28.18.1

12.712.715.215.2%%

Page 70: © Continuing Medical Implementation ® …...bridging the care gap Vascular Protection ACE inhibitor Trials

PEACE was conducted in a population with CAD and preserved LV function who received

intensive contemporary management.— This usually included coronary revascularization, lipid lowering and blood pressure control.— The CV event rate was lower than in HOPE and EUROPA.

In this population, which represents the majority of patients with CAD, the addition of an ACE inhibitor did not reduce further clinical

atherosclerotic events.

Conclusions

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So What Can We Say About the Role of ACEi in CAD?

After PEACE, the AHA-ACC secondary prevention guidelines recommending that ACE inhibitors be considered for all patients with vascular disease remains unchanged.

Patients with vascular disease that are at low to moderate or high risk, or with LV dysfunction should routinely have an ACE inhibitor.

PEACE demonstrates that, as the absolute risk of a patient decreases, if LV function is preserved and intensive contemporary management given, with good control of all risk factors, the absolute benefits of an ACE inhibitor decrease and their routine use in these patients may not be warranted.

The role of ACE inhibitors started early post-CABG in patients with preserved LV function and intensive contemporary management remains to be determined and should get answered by the IMAGINE study.

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The IMAGINE Study

Ischemia Management with Accupril

post bypass Graft via Inhibition of

the coNverting Enzyme

Page 73: © Continuing Medical Implementation ® …...bridging the care gap Vascular Protection ACE inhibitor Trials

Comparison with Other Trials

Study Post-CABG

CV Event Rate

(%)

BP Reading at Baseline

% Diabetic % Lipid-lowering Therapy

% Beta-blocker

Use

% ASA∕

Antiplatelet Use

HOPE > 4 yrs 1.62 139/79 mmHg

38 29 40 76

EUROPA > 6 months

0.92 137/82 mmHg

12 56 63 92

PEACE > 3 months

0.77 133/78 mmHg

17 70 60 90

IMAGINE ≤ 7 days 0.46 122/70

mmHg

<10 90* 80* 98*

*average use during study

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2.4

1.61.7

0

0.5

1

1.5

2

2.5HOPE

EUROPA

PEACE

IMAGINE

An

nu

aliz

ed A

ll C

ause

Mo

rtal

ity

(%)

0.86

All Cause Mortality in Placebo Arms

Page 75: © Continuing Medical Implementation ® …...bridging the care gap Vascular Protection ACE inhibitor Trials

CV Mortality in Placebo Arms

1.62

0.97

0.77

0

0.2

0.4

0.6

0.8

1

1.2

1.4

1.6

1.8HOPE

EUROPA

PEACE

IMAGINE

An

nu

aliz

ed C

V M

ort

alit

y (%

)

0.46

Page 76: © Continuing Medical Implementation ® …...bridging the care gap Vascular Protection ACE inhibitor Trials

CV Mortality in Placebo Arms

1.62

0.97

0.77

0

0.2

0.4

0.6

0.8

1

1.2

1.4

1.6

1.8HOPE

EUROPA

PEACE

IMAGINE

An

nu

aliz

ed C

V M

ort

alit

y (%

)

0.460.38

IMAGINE After 3 months

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© Continuing Medical Implementation ® …...bridging the care gap

Role of ACE inhibitors in Vascular Health Management &

Prevention

Role of ACE inhibitors in Vascular Health Management &

Prevention

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© Continuing Medical Implementation ® …...bridging the care gap

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© Continuing Medical Implementation ® …...bridging the care gap

Page 80: © Continuing Medical Implementation ® …...bridging the care gap Vascular Protection ACE inhibitor Trials

© Continuing Medical Implementation ® …...bridging the care gap