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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 plus Eptifibatide
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)
Heparin plus eptifibatide n = 201
Heparin alone n = 199
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
Heparin plus Eptifibatide
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
Heparin plus eptifibatide n = 201
Heparin alone n = 199
p = 0.14 p = 0. 21 p = 0.04
% pts
RevascularizationInitial Hospitalization
Heparin plus Eptifibatide
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 plus Eptifibatide
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)
Any Revascularization, % 23.9 21.1 0.51 1.17 (0.7, 1.9)
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)
Any Revascularization, % 24.4 22.6 0.68 1.10 (0.7, 1.8)
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.