A Safety and Efficacy Study of Integrilin Facilitated PCI versus Primary PCI in ST Elevation Myocardial Infarction Principal Investigator: Michel Le May,

A Safety and Efficacy Study of Integrilin Facilitated PCI versus

Primary PCI in ST Elevation Myocardial Infarction

Principal Investigator: Michel Le May, MD

ClinicalTrials.gov Identifier: NCT00251823

Disclosure Statementof Financial Interest

Within the past 12 months, I or my spouse/partner have had a financial Within the past 12 months, I or my spouse/partner have had a financial interest/arrangement or affiliation with the organization(s) listed below.interest/arrangement or affiliation with the organization(s) listed below.

Affiliation/Financial RelationshipAffiliation/Financial Relationship CompanyCompany

Grant/Research SupportGrant/Research Support Investigator initiated trial

with financial support from

Schering- Plough of Canada Inc., &

Medtronic of Canada Ltd.

Consulting Fees/HonorariaConsulting Fees/Honoraria

Major Stock Shareholder/EquityMajor Stock Shareholder/Equity

Royalty IncomeRoyalty Income

Ownership/FounderOwnership/Founder

Intellectual Property RightsIntellectual Property Rights

Other Financial BenefitOther Financial Benefit

Investigators

Michel R. Le May MD, George A. Wells, PhD, Chris A. Glover, Derek Y. Michel R. Le May MD, George A. Wells, PhD, Chris A. Glover, Derek Y. So, MD, MD, Michael P. Froeschl, MD, Jean-François Marquis, MD, So, MD, MD, Michael P. Froeschl, MD, Jean-François Marquis, MD, Edward R. O'Brien, MD, Michele Turek, MD, Marino Labinaz, MDEdward R. O'Brien, MD, Michele Turek, MD, Marino Labinaz, MD

Research Nurses/Staff

Allyson Thomas, Tanya. Abarbanel, Julie Finnigan Allyson Thomas, Tanya. Abarbanel, Julie Finnigan

Adjudication Committee

Cathy McLellan (chair), Waytak. Kong , Paul MalikCathy McLellan (chair), Waytak. Kong , Paul Malik

Data Safety Monitoring

Jean-Claude Tardif (chair), Philippe L'Allier Jean-Claude Tardif (chair), Philippe L'Allier

Participating Hospitals

University of OUniversity of Ottawa Heart Institute (on-site cath lab)ttawa Heart Institute (on-site cath lab)

Ottawa Hospital (Alta Vista campus)Ottawa Hospital (Alta Vista campus)

Ottawa Hospital (Civic campus)Ottawa Hospital (Civic campus)

Background

Randomized trials have shown that abciximab is a useful adjunct in pts referred for primary PCI.

Observational studies have shown that eptifibatide yields similar results to abciximab.

No study has examined clinical outcomes by directly comparing eptifibatide to a control group in primary PCI.

Studies with high clopidogrel loading dose are limited in primary PCI.

Trial Design

Aspirin 160 mg chewableClopidogrel 600 mg

Heparin 60 units/kg (max 4,000)

201 were assigned to PCI with heparin plus eptifibatide

199 were assigned to PCI with heparin alone

201 were included in the 30 day follow-up and were included in the

intention to treat analysis

199 were included in the 30 day follow-up and were included in the

intention to treat analysis

400 patients with STEMI and symptom onset ≤ 12 hr

Primary endpointPrimary endpoint Death, Reinfarction, Recurrent Severe Ischemia at 30 Days.Death, Reinfarction, Recurrent Severe Ischemia at 30 Days.

Primary endpointPrimary endpoint Death, Reinfarction, Recurrent Severe Ischemia at 30 Days.Death, Reinfarction, Recurrent Severe Ischemia at 30 Days.

Reinfarction

Recurrent ischemic symptoms at rest lasting at least 30 min and accompanied by New or recurrent ST-segment elevation of ≥1 mm

(0.1 mV) in any contiguous leads or New left bundle branch block or Re-elevation in serum CK level > twice the upper

limit of normal and at least 50% above the lowest level measured post-infarction.

Recurrent Severe Ischemia

Recurrent symptoms of ischemia at rest associated with any one of the following

New ST-segment deviation (elevation at least 0.1 mV or depression > 0.05 mV measured 80 ms after the J-point in at least 2 contiguous leads).

An episode of acute pulmonary edema, sustained ventricular arrhythmias or hemodynamic instability.

The need for urgent revascularization. Recurrent myocardial infarction.

Exclusion Criteria

Active bleeding Stroke within 90 days or intracranial bleeding at any time Major surgery or trauma within six weeks Systolic blood pressure > 200 mm Hg Diastolic blood pressure > 110 mm Hg Prolonged CPR (>10 min) PCI within 30 days Fibrinolytic or GP 2b/3a within 7 days Coagulation disorder / warfarin therapy

Exclusion Criteria (2)

Known severe renal impairment (creatinine > 200 mol/L) Contrast allergy LMWH within 12 hrs Cardiogenic shock Intolerance to aspirin or clopidogrel Medical condition likely to result in death within 12 months Participation in another study Pregnancy

Sample Size

Estimated the incidence of the primary endpoint at 30 days in pts assigned to PCI with heparin alone at 15% and in pts assigned to PCI with heparin plus eptifibatide at 5%.

-level: 0.05 (two-sided); -error: 0.10 Anticipated a loss to follow-up rate of 5%. The number of pts required was 200 per group.

Timeline

Open label study design

400 pts were randomly assigned:

201 to PCI with heparin plus 201 to PCI with heparin plus eptifibatideeptifibatide

199 to PCI with heparin alone199 to PCI with heparin alone Enrollment started August 2005 Enrollment completed March 2008 Final 6-month follow-up September 2008

Baseline CharacteristicsHeparin plus

Eptifibatide

Heparin

Alone

(n = 201) (n = 199)

Age, yr 60.4 ± 12.1 60.6 ± 11.8

Age ≥ 75, % 15.4 12.6

Male sex, % 80.6 71.9

Hypertension, % 45.8 49.8

Diabetes mellitus, % 14.4 18.1

Current smoker, % 44.8 38.2

History of hyperlipidimia, % 33.3 38.7

Prior myocardial infarction, % 10.5 13.6

Prior angioplasty, % 8.0 8.0

Baseline Characteristics (2)Heparin plus

Eptifibatide

Heparin

Alone

(n = 201) (n = 199)

Prior bypass surgery, % 5.0 4.0

Anterior MI, % 36.3 37.7

Heart rate, beats/min 74 ± 16 76 ± 18

Systolic blood pressure, mm Hg 130 ± 23 134 ± 24

Diastolic blood pressure, mm Hg 77 ± 14 80 ± 15

Killip class 1, % 90.6 86.4

Body mass index, kg/m2 28 ± 5 28 ± 5

Creatinine clearance, ml/min 93 ± 35 87 ± 31

Peak CK, units/L 2009 ± 1879 2047 ± 1627

Initial Medications

Heparin plus

Eptifibatide

Heparin

Alone

(n = 201) (n = 199)

Aspirin, % 100 100

Clopidogrel, % 100 100

Eptifibatide, % 100* 3.0

Abciximab, % 0.5 4.5

* Duration of eptifibatide infusion > 16 hrs in 82% pts;

94% received eptifibatide before cardiac catheterization.

Median Time Intervals (min)

Heparin plus Eptifibatide

HeparinAlone

(n = 201) (n = 199)

Symptoms to hospital arrival 90 88

Hospital arrival to randomization 46 31

Randomization to balloon inflation 48 50

Hospital arrival to balloon inflation 96 95

Clopidogrel to balloon inflation 75 75

Eptifibatide to balloon inflation 43 -

Symptoms to eptifibatide 144 -

Symptoms to balloon inflation 196 194

Angiographic Results


Heparin

Alone

(n = 201) (n = 199)

Coronary angiography, % 100 100

Diseased coronary arteries

Left main, % 0.5 0.5

One vessel, % 48.8 46.2

Two vessel, % 30.8 28.6

Three vessel, % 19.4 24.6

No significant disease, % 0.5 0.0

Infarct-Related Artery

Heparin plus

Eptifibatide

Heparin

Alone

(n = 201) (n = 199)

Left main, % 0.5 0.5

Left anterior descending, % 36 37

Left circumflex, % 14 12

Right coronary, % 46 48

Bypass graft, % 3 1

Unknown, % 0 2

PCI ProcedureHeparin plus Eptifibatide

Heparin Alone

(n = 201) (n = 199)

PCI, % 95 92

Stent Insertion, % 93 92

Stents per patient, % 1.4 ± 0.9 1.5 ± 0.9

Drug eluting stent, % 19 16

Aspiration catheters, % 10 7

Final balloon size, mm 3.2 ± 0.5 3.2 ± 0.5

Maximum balloon pressure, atm 17 ± 3 17 ± 3

Maximal ACT achieved, sec 193 213

Intra-aortic balloon, % 2 2

Infarct-Related ArteryTIMI Flow Rates

TIMI 0-1TIMI 3 TIMI 2

24

13

63

25

19

55

0

20

40

60

80

100

%

Heparin pluseptifibatide

Heparin alone

Prior to PCI After PCI

91

4

94

4

0

20

40

60

80

100

Heparin pluseptifibatide

Heparinalone

%

p = 0.16 p = 0.43

Events Within 30 Days

3.5

2.01.5

0.5

3.03.5

6.5

5.5

0

2

4

6

8

Death Re-MI Recurrent SevereIschemia

Primary(composite)

Heparin plus eptifibatide n = 201

Heparin alone n = 199

p = 0.54 p = 0.62 p = 0.76 p = 0.69

% pts

Kaplan-Meier Estimates30 days

Log-Rank p = 0.70

0

1

2

3

4

5

6

7

8

9

10

0 6 12 18 24 30Days

Patie

nts

with

Pri

mar

y E

nd P

Oin

t (%

)

Heparin plus eptifibatide

Heparin alone

6.5%

5.5%

Clinical Events at 30 DaysHeparin plus Eptifibatide

Heparin

Alone p value R R (95% CI)

(n = 201) (n = 199)

Death, % 3.5 2.0 0.54 1.76 (0.51, 6.11)

Reinfarction, % 1.5 0.5 0.62 3.00 (0.31, 29.1)

Death or ReMI, % 5.0 2.5 0.49 2.03 (0.68, 6.05)

Severe Rec. Ischemia, % 3.0 3.5 0.76 0.84 (0.28, 2.56)

Primary Outcome, % 6.5 5.5 0.69 1.18 (0.52, 2.70)

C H F, % 7.5 11.0 0.22 0.65 (0.33, 1.29)

Cardiogenic Shock, % 4.0 3.0 0.60 1.33 (0.45, 3.92)

Stroke, % 0 0.5 0.50

Hemorrhagic 0 0.5

Events Within Six Months

4.5

2.0

2.01.0

4.5 4.6

8.07.1

0.0

2.0

4.0

6.0

8.0

10.0

Death Re-MI Recurrent SevereIschemia

Primary(composite)



p = 0.54 p = 0.62 p = 0.97 p = 0.75

% pts

0

1

2

3

4

5

6

7

8

9

10

0 30 60 90 120 150 180

Days

Pati

ents

wit

h Pr

imar

y

End

Poin

t (%

)

Heparin plus eptifibatide

Heparin alone

Kaplan-Meier Estimates180 days

Log-Rank p = 0.76 8.0%

7.1%

Clinical Events at Six MonthsHeparin plus Eptifibatide

Heparin Alone

p value R R (95% CI)

(n = 201) (n = 199)

Death,% 4.5 3.0 0. 45 1.49 (0.52, 4.27)

Reinfarction,% 2.0 1.0 0.68 1.98 (0.36, 10.9)

Death or ReMI,% 6.5 3.6 0.18 1.88 (0.73, 4.81)

Severe Rec. Ischemia,% 4.5 4.6 0.97 0.98 (0.38, 2.52)

Primary Outcome,% 8.0 7.1 0.89 1.13 (0.54, 2.38)

C H F,% 7.5 12.2 0.11 0.58 (0.30, 1.14)

Cardiogenic Shock,% 4.0 4.6 0.77 0.87 (0.33, 2.29)

Stroke,% 0 2.0 0.06

Hemorrhagic 0 1.0

Primary OutcomeSubgroup Analysis

Subgroup Relative Risk Risk ratio and 95% CIHeparin plus Heparin Eptifibatide Alone

Female sex 2 / 39 6 / 56 0.48 (0.10 - 2.25)Male Sex 11 / 162 5 / 143 1.94 (0.69 - 5.46)Age < 75 yrs 9 / 170 8 / 174 1.15 (0.45 - 2.91)Age ≥ 75 yrs 4 / 31 3 / 25 1.08 (0.26 - 4.37)No Diabetes 8 / 172 7 / 163 1.08 (0.40 - 2.92)Diabetes 5 / 29 4 / 36 1.55 (0.46 - 5.26)Location of infarct anterior 6 / 73 5 / 75 1.23 (0.39 - 3.86)Location of infarct non-anterior 7 / 128 6 / 124 1.13 (0.39 - 3.27)Killip class I 11 / 182 8 / 172 1.30 (0.54 - 3.15)Killip class > I 2 / 19 3 / 27 0.95 (0.17 - 5.14)Initial TIMI flow grade < 3 13 / 150 8 / 152 1.65 (0.70 - 3.86)Initial TIMI flow grade 3 0 / 51 3 / 47 0.13 (0.01 - 2.49)Symptom to randomization < 180 min 9 / 164 6 / 151 1.38 (0.50 - 3.79)Symptom to randomization ≥ 180 min 4 / 37 5 / 48 1.04 (0.30 - 3.60)Symptom onset to balloon < 180 min 4 / 94 4 / 97 1.03 (0.27 - 4.01)Symptom onset to balloon ≥ 180 min 9 / 107 7 / 102 1.23 (0.47 - 3.17)Hospital arrival to balloon < 90 min 5 / 96 6 / 94 0.82 (0.26 - 2.58)Hospital arrival to balloon ≥ 90 min 8 / 105 5 / 105 1.60 (0.54 - 4.73)Clopidogrel to balloon < 75 min 5 / 105 8 / 105 0.63 (0.21 - 1.85)Clopidogrel to balloon ≥ 75 min 8 / 96 3 / 94 2.61 (0.71 - 9.54)TIMI not high risk 4 / 87 2 / 70 1.61 (0.30 - 8.53)TIMI high risk 9 / 114 9 / 129 1.13 (0.47 - 2.75)

0.1 0.2 0.5 1 2 5 10


Better

Heparin Alone Better

(95%CI)

All patients 13 / 201 11 / 199 1.18 (0.52 - 2.70)

TIMI Bleeding Events During Initial Hospitalization

9.4

5.5

12.9

9.1

22.4

14.6

0

5

10

15

20

25

Major Minor Major or Minor



p = 0.14 p = 0. 21 p = 0.04

% pts

RevascularizationInitial Hospitalization


Heparin

Alone p value R R (95% CI)

(n = 201) (n = 199)

Non-protocol PCI , % 17.4 18.1 0.86 0.95 (0.6, 1.6)

PCI IRA , % 2.0 1.0 0.69 2.00 (0.4, 11.1)

Repeat TVR, % 3.5 2.0 0.54 1.76 (0.5, 6.1)

Bypass Surgery, % 4.5 3.0 0.45 1.50 (0.5, 4.3)

Any Revascularization, % 21.9 20.6 0.75 1.08 (0.7, 1.7)

Revascularization30 Days and Six Months


Heparin Alone

p value R R (95% CI)

30 Days

Non-protocol PCI, % 19.4 18.6 0.84 1.05 (0.6, 1.7)

Repeat TVR, % 4.0 2.0 0.38 1.76 (0.5, 6.1)

Bypass Surgery, % 5.0 3.0 0.32 1.68 (0.6, 4.7)


Six Months

Non-protocol PCI, % 19.9 19.1 0.84 1.05 (0.6, 1.7)

Repeat TVR, % 4.0 3.0 0.60 1.33 (0.5, 3.9)

Bypass Surgery, % 5.0 4.0 0.65 1.25 (0.5, 3.2)


Limitations

Relatively small sample size. Study was performed after the establishment of an

integrated city-wide rapid response STEMI system that resulted in relatively short ischemic time intervals.

Relatively high percentage of PCI to a non–infarct-related artery performed later during the initial hospitalization may have contributed to the low event rates.

Conclusions

In pts with acute STEMI pre-treated with high dose clopidogrel, as compared with PCI with heparin alone,

PCI with eptifibatide initiated before catheterization

1) does not improve clinical outcomes and

2) is associated with more bleeding.

A Safety and Efficacy Study of Integrilin Facilitated PCI versus Primary PCI in ST Elevation Myocardial Infarction Principal Investigator: Michel Le May,

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