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Presenter Disclosure
No conflict of interest
Anthony Fung
The BRIEF-PCI Trial
BrBrief ief IInfusion of nfusion of EEptifibatide ptifibatide
FFollowing ollowing PCIPCI
The BRIEF-PCI Trial
AY Fung, J Saw, A Starovoytov, C Densem,P Jokhi, SJ Walsh, RS Fox, KH Humphries,
E Aymong, DR Ricci, JG Webb, JN Hamburger,RG Carere, CE Buller.
Vancouver General Hospital & St. Paul’s Hospital, University of British Columbia, Vancouver, Canada
BackgroundBackground
• 2b3a inhibitors are widely used in PCI to prevent ischemic complications
• EPIC* (1994) showed that abciximab bolus plus 12 hr infusion reduced ischemic complications of PTCA, while bolus alone did not
• ESPRIT** (2000) established the standard eptifibatide regimen: – double boluses 180 mcg/Kg, 10 min apart– 18 - 24 hr infusion @ 2 mcg/Kg/min
*EPIC. N Engl J Med 1994; 330: 956.
**ESPRIT. Lancet 2000; 356: 2037.
Disadvantages of an 18-hourDisadvantages of an 18-hourInfusion of EptifibatideInfusion of Eptifibatide
• Full dose cost ~$ 450 US
• Prohibits same day discharge
• Prolongs hospital stay
• Increases nursing time
• May promote bleeding complications
Contemporary PCIContemporary PCI
• Dual anti-platelet oral therapy with aspirin and clopidogrel
• High dose clopidogrel loading is well tolerated and has rapid onset of action
• Routine use of coronary stents reduces abrupt vessel closure
• Prolonged 18-hour eptifibatide infusion may not be necessary
Hypothesis• Following non-emergent uncomplicated
PCI with coronary stenting, the infusion of eptifibatide can be abbreviated to less than 2 hours without adverse ischemic outcome
Trial Design• A prospective, randomized, double-
blinded, placebo-controlled study
Primary End-pointPrimary End-point• The incidence of post procedural myonecrosis
within 24 hours:– Troponin-I elevation > 0.26 mcg/L (99th
percentile of upper reference limit, and coefficient of variation <10%)*; or
– CK-MB > 3 X upper reference limit if baseline troponin-I is elevated
• Biomarkers measured at baseline, 6 hr & 18 hr in core lab
*Joint ESC/ ACC Committee on MI Definition. JACC 2000; 36: 959.
Adjudicated Secondary End-pointsAdjudicated Secondary End-points
1. Composite triple end-points: – Incidence of death, MI, or target vessel
revascularization (TVR) at 30 days
2. Composite quadruple end-points: – Triple end-points plus in-hospital major
bleeding (*REPLACE – 2 criteria)
* REPLACE-2. JAMA 2003;289:853.
Key Entry CriteriaKey Entry Criteria
• ACS, STEMI > 48 hrs or stable angina,
• No visible thrombus pre-procedure
• Uncomplicated PCI with stenting, performed under the coverage of eptifibatide
• TIMI-3 flow, no dissection, no major side branch loss, no thrombus post procedure
• Randomize after successful PCI
Sample SizeSample Size
• Non-inferiority design
• Estimated reference rate* – 50%
• Upper margin – 10%
• Power 80%
• One sided α 0.05
• N = 620 (310 per group)
*Bonz AW, et al. J Am Coll Cardiol 2002; 40: 662.
925 - Consented
168 - PCI not done
133 – Excluded *
624 - Randomized
*Reasons for exclusion
•51 unsatisfactory angiographic results•42 eptifibatide not given•15 logistics & other issues •14 femoral puncture site complications•4 filling defect•4 withdrew consent•3 PTCA only (no stenting)
ClopidogrelPre-treatment
AdequateStop Eptifibatide
Not adequateClopidogrel 600 mg
Stop eptifibatide 2 hrs later
Placebo Eptifibatide
75 mg ≥ 4 days;300 mg ≥ 6 hrs; 600 mg ≥ 2 hrs
EptifibatidePlacebo
624 - Randomized
312 – Brief
20 - stopped earlydue to bleeding
312 - Standard
19 - stopped earlydue to bleeding
Biomarkers Baseline, 6 H, 18 HFU at 30 days 100%
Baseline CharacteristicsBaseline CharacteristicsBrief (< 2 H) Standard (18 H)
Age 62 ± 10 63 ± 10
Male 80% 84%
Diabetes on Rx 12% 15%
Stable angina 47% 51%
ACS (88% TnI+) 39% 35%
STEMI > 48 H 15% 14%
Clopidogrel Pretreat 71% 66%
Procedural CharacteristicsProcedural CharacteristicsBrief (< 2H) Standard (18 H)
Femoral access 97% 96%
6 French 88% 88%
Multi-vessel 52% 51%
≥ 2 stents 41% 42%
Stent length mm 29.4 ± 18 28.6 ± 17
B2 or C lesions 63% 62%
Closure device 26% 25%
Post-PCI Myonecrosis @ 24 hrsPost-PCI Myonecrosis @ 24 hrs
30.1% 28.3%
0%
10%
20%
30%
40%
Brief
Standard
∆ 1.8%; 95% CI 7.8%;
p< 0.012 for non inferiority
1° end-point
Incidence of Myonecrosis in Subgroups Incidence of Myonecrosis in Subgroups
Composite Triple End-points @ 30 DaysComposite Triple End-points @ 30 Days
0.6 0.6
4.8
0
4.84.5 4.5
00
2
4
6
8
Death MI TVR Triple
BriefStandard
P=NS
%
2° end-point
Bleeding & Quadruple End-pointsBleeding & Quadruple End-points
1
5.44.2
21.2
17.6
8.7
0
5
10
15
20
25
Major Minor Quadruple
BriefStandard
P=0.02
P=NS
%
REPLACE-2 criteria
P = NS
2° end-point
ConclusionConclusion• Eptifibatide infusion can safely be
abbreviated to < 2 hours following successful non-emergent coronary stenting without an increase in post procedural myonecrosis
• We observed less major bleeding when the eptifibatide infusion is abbreviated
Funded by:VGH & UBC Hospital FoundationVGH Cardiology Research
AcknowledgementAcknowledgement
• Cardiac science nursing staffs and research coordinators
• Data & Safety Monitoring Board– Dr. W. Douglas Weaver (Detroit, MI), Chair– Dr. Simon Dixon (Royal Oak, MI)– Dr. Krishnan Ramanathan (Vancouver, BC)
• Events Committee– Dr. Graham Wong (Vancouver, BC), Chair
• Chemistry Core Lab– Dr. Morris Pudek (Vancouver, BC)
624 Randomized
319 Acute presentation
305 Stable angina
90 STEMI
229 ACS178 TnI Pos
140 Stable, inadequate clopidogrel
165 Stable, adequate clopidogrel(ISAR-REACT like)
ISAR-REACT Ineligible SubgroupsISAR-REACT Ineligible Subgroups
Brief Standard
BRIEF-PCI
(N = 624)30.1% 28.3%
ISAR-REACT
Ineligible
(N = 455)
28.7% 28.9%
Definition of MI & Definition of MI & Incidence of MyonecrosisIncidence of Myonecrosis
• 99th percentile = 0.11; 10% CV = 0.26;• ESC / ACC (2007) definition: 0.11 X 3 = 0.33
TnI cut-off Brief Standard
> 0.26
Brief - PCI30.1% 28.3%
> 0.33
ESC / ACC28.4% 25.1%
REPLACE – 2 Major BleedingREPLACE – 2 Major Bleeding
• Results in death• Retroperitoneal, intracranial or intraocular • Results in hemodynamic compromise • Requiring surgical intervention • Any transfusion > 2 units • Decrease in hemoglobin ≥ 4 g/dL• Clinically overt bleeding resulting in a
decrease in hemoglobin ≥ 3 g/dL