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