© continuing medical implementation ® …...bridging the care gap vascular protection ace...
TRANSCRIPT
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© Continuing Medical Implementation ® …...bridging the care gap
Vascular Protection ACE inhibitor TrialsVascular Protection ACE inhibitor Trials
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Heart Outcomes Prevention Evaluation Study
A large, simple, randomized trial of Ramipril and vitamin E in
patients at high risk for cardiovascular events
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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Baseline characteristicsBaseline characteristics
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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
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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
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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
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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
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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
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How does Europa compare with Hope?How does Europa compare with Hope?
A closer look at the Patients….A closer look at the Patients….
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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
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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
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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.
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ResultsResults
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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
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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
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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
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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
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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
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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
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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%
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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(%)(%)
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-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
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Adherence to treatmentAdherence to treatment
0 6 12 18 24 30 36
MonthsMonths
0
20
40
60
80
100
120(%)
PlaceboPlacebo
Perindopril Perindopril 8mg8mg
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ConclusionConclusion
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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%
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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
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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
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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.
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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%
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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%
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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
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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
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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
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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
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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.
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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
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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.
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% 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%%
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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
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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
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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
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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
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© Continuing Medical Implementation ® …...bridging the care gap