Intracoronary Eptifibatide Bolus Intracoronary Eptifibatide Bolus Administration During Percutaneous Administration During Percutaneous

Coronary Revascularization for Acute Coronary Revascularization for Acute Coronary Syndromes With Evaluation of Coronary Syndromes With Evaluation of Platelet Glycoprotein IIb/IIIa Receptor Platelet Glycoprotein IIb/IIIa Receptor Occupancy and Platelet Function. The Occupancy and Platelet Function. The Intracoronary Eptifibatide (ICE) TrialIntracoronary Eptifibatide (ICE) Trial

Albert J. Deibele MD, Lisa K. Jennings PhD, Albert J. Deibele MD, Lisa K. Jennings PhD, James E. Tcheng MD, Cathy Neva RN, James E. Tcheng MD, Cathy Neva RN,

Angela D. Earhart BS, C. Michael Gibson MS, MDAngela D. Earhart BS, C. Michael Gibson MS, MD

BackgroundBackgroundDistal embolization of thrombotic debris occurs Distal embolization of thrombotic debris occurs during PCI for acute coronary syndromesduring PCI for acute coronary syndromesImpaired microvascular perfusion, myonecrosis Impaired microvascular perfusion, myonecrosis and increased mortality may resultand increased mortality may resultGlycoprotein IIb/IIIa inhibitors have improved Glycoprotein IIb/IIIa inhibitors have improved outcomes during PCI for acute coronary outcomes during PCI for acute coronary syndromes by reducing major adverse cardiac syndromes by reducing major adverse cardiac eventseventsIn VitroIn Vitro studies suggest that very high local studies suggest that very high local concentrations of GP IIb/IIIa inhibitors are concentrations of GP IIb/IIIa inhibitors are effective in disaggregating thrombuseffective in disaggregating thrombus

Higher levels of GP IIb/IIIa receptor occupancy Higher levels of GP IIb/IIIa receptor occupancy has led to improved myocardial perfusion in has led to improved myocardial perfusion in myocardial infarctionmyocardial infarction

Intracoronary administration of eptifibatide may Intracoronary administration of eptifibatide may result in higher local concentrationresult in higher local concentration

High local concentration of eptifibatide may lead High local concentration of eptifibatide may lead to increased GP IIb/IIIa receptor occupancy to increased GP IIb/IIIa receptor occupancy thereby promoting thrombus disaggregation and thereby promoting thrombus disaggregation and improved myocardial perfusion improved myocardial perfusion

Background (cont.)Background (cont.)

Intracoronary (IC) administration of Intracoronary (IC) administration of eptifibatide will result in higher local levels of eptifibatide will result in higher local levels of platelet Glycoprotein IIb/IIIa Receptor platelet Glycoprotein IIb/IIIa Receptor Occupancy (RO), reduced thrombus burden Occupancy (RO), reduced thrombus burden and improved measures of coronary flow and improved measures of coronary flow than intravenous (IV) administration during than intravenous (IV) administration during PCI for acute coronary syndromes.PCI for acute coronary syndromes.

HypothesisHypothesis

Non ST Elevation Myocardial InfarctionNon ST Elevation Myocardial InfarctionUnstable Angina with either ST segment shifts, Unstable Angina with either ST segment shifts, elevated biomarkers or visible thrombuselevated biomarkers or visible thrombusST Elevation Myocardial Infarction > 24 hours ST Elevation Myocardial Infarction > 24 hours from treatment with thrombolyticsfrom treatment with thrombolyticsStenosis > 70% by visual estimateStenosis > 70% by visual estimateLesion suitable for coronary stentLesion suitable for coronary stentInformed consentInformed consentAge > 18 years oldAge > 18 years old Negative pregnancy test for women of child Negative pregnancy test for women of child bearing potentialbearing potential

Inclusion CriteriaInclusion Criteria

Planned PCI within 30 days of index PCIPlanned PCI within 30 days of index PCISevere coronary calcificationSevere coronary calcificationAcute ST elevation Myocardial InfarctionAcute ST elevation Myocardial InfarctionOccluded target vesselOccluded target vesselSVG as the target vesselSVG as the target vesselLeft main stenosis > 50%Left main stenosis > 50%INR > 1.4INR > 1.4Previous stent at the target lesionPrevious stent at the target lesionContraindication to GP IIb/IIIa Inhibitor therapyContraindication to GP IIb/IIIa Inhibitor therapyDVTDVTPresence of an IVC FilterPresence of an IVC Filter

Exclusion CriteriaExclusion Criteria

43 patients with acute coronary syndromes 43 patients with acute coronary syndromes randomized to IC vs IV bolus of eptifibatide randomized to IC vs IV bolus of eptifibatide during coronary stentingduring coronary stenting2 boluses of 180 mcg/Kg of eptifibatide 2 boluses of 180 mcg/Kg of eptifibatide administered over 2 minutesadministered over 2 minutesSecond bolus administered 10 minutes after the Second bolus administered 10 minutes after the initial bolusinitial bolusA continuous infusion of eptifibatide 2 A continuous infusion of eptifibatide 2 mcg/Kg/min started with the initial bolusmcg/Kg/min started with the initial bolusIC eptifibatide buffered to pH 7.0-7.4 with 2 cc IC eptifibatide buffered to pH 7.0-7.4 with 2 cc 8% sodium bicarbonate8% sodium bicarbonate

MethodsMethods

2 boluses of eptifibatide either administered IC over 2 boluses of eptifibatide either administered IC over 2 minutes via guide catheter or over 2 minutes via 2 minutes via guide catheter or over 2 minutes via peripheral IVperipheral IVA Castillo catheter seated in the coronary sinusA Castillo catheter seated in the coronary sinusCoronary sinus samples obtained for GP IIb/IIIa RO Coronary sinus samples obtained for GP IIb/IIIa RO during the bolus of eptifibatide – IC at 30 secs and during the bolus of eptifibatide – IC at 30 secs and IV at 60 secsIV at 60 secsPeripheral samples obtained for GP IIb/IIIa RO Peripheral samples obtained for GP IIb/IIIa RO immediately after the CS sample during the bolusimmediately after the CS sample during the bolusPeripheral studies of the inhibition of platelet Peripheral studies of the inhibition of platelet aggregation obtained at time 0, 15, 30 and 60 aggregation obtained at time 0, 15, 30 and 60 minutesminutesPCI performed after both boluses of eptifibatide PCI performed after both boluses of eptifibatide were administeredwere administered

Methods (cont.)Methods (cont.)

TTaabbllee 11.. BBaasseelliinnee CChhaarraacctteerriissttiiccss IICC ((NN==2222)) IIVV ((NN==1199)) pp--vvaalluuee

AAggee** 5599..99 ++ 1111..88 5588..55 ++ 1133..33 00..773344

MMaallee†† 1144 ((6633..66)) 1144 ((7733..77)) 00..449911

WWeeiigghhtt** 8877..44 ++ 2211..33 9911..33 ++ 1199..44 00..554444

CCuurrrreenntt SSmmookkeerr†† 77 ((3311..88)) 99 ((4477..44)) 00..330099

DDiiaabbeetteess MMeelllliittuuss‡‡ 33 ((1133..66)) 55 ((2266..33)) 00..443366

HHyyppeerrtteennssiioonn†† 1144 ((6633..66)) 99 ((4477..44)) 00..229955

HHyyppeerrlliippiiddeemmiiaa†† 1155 ((6688..22)) 1100 ((5522..66)) 00..330099

CCaarrddiiaacc CCaatthheetteerriizzaattiioonn IInnddiiccaattiioonn†† 00..220033

UUnnssttaabbllee AAnnggiinnaa 1100 ((4455..55)) 44 ((2211..11))

NNoonn--SSTT EElleevvaattiioonn MMII 88 ((3366..44)) 88 ((4422..11))

SSTT EElleevvaattiioonn MMII 44 ((1188..22)) 77 ((3366..88))

** -- MMeeaann ++ SSDD:: ssttuuddeenntt’’ss tt--tteesstt ((22--ssiiddeedd)) †† -- nn ((%%)):: PPeeaarrssoonn’’ss cchhii--ssqquuaarree tteesstt ‡‡ -- nn ((%%)):: FFiisshheerr’’ss eexxaacctt tteesstt ((22--ssiiddeedd))

RESULTSRESULTS

No adverse events occurred during IC No adverse events occurred during IC administration of eptifibatideadministration of eptifibatide

No arrhythmias occurred.No arrhythmias occurred.

No occurrences of pericardial effusion, No occurrences of pericardial effusion, cardiac tamponade or myocardial rupture.cardiac tamponade or myocardial rupture.

Figure 1. Peripheral % IPA with ADP

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110

Baseline 15 min post bolus 30 min post bolus 60 min post bolus*

%IP

A

IV Rx administration (n=19)IC Rx administration (n=22)

p = 0.670

* 21 IC Rx samples

Figure 2. Peripheral % IPA with TRAP

0

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50

60

70

80

90

100

110

Baseline 15 min post bolus 30 min post bolus 60 min post bolus*

%IP

A

IV Rx administration (n=13)IC Rx administration (n=17)

p = 0.124

* 17 IC Rx samples

Figure 3. % GP IIIb/IIIa RO by Collection Site and Bolus

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110

Bolus 1 Bolus 2 Bolus 1 Bolus 2

% R

O

IV Rx administration (n=19)

IC Rx administration (n=21)

Peripheral Blood Collection Coronary Sinus Blood Collection

p = 0.013 p = 0.995 p < 0.001 p = 0.001

Figure 4. % GP IIIb/IIIa RO by Type of Administration and Bolus (Paired samples)

0

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110

Bolus 1 Bolus 2 Bolus 1 Bolus 2

% R

O

Peripheral Coronary Sinus

IV RX Administration (n = 19) IC RX Administration (n = 21)

p = 0.003 p = 0.029 p < 0.001 p < 0.001

Figure 5. Five-number Summary: Corrected TIMI Frame Count (cTFC) with Mann-Whitney Test

0

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130

IV (n = 18; mean rank = 19.1) IC (n = 20; mean rank = 19.8) IV (n = 18; mean rank = 24.6) IC (n = 20; mean rank = 14.9)

cT

FC

(3

0 F

r/S

ec

)

Pre-PCI: U = 173.5; Z = -0.19 p = 0.849 Post-PCI: U = 87.5; Z = -2.71 p = 0.007

Figure 6. Post-PCI TIMI Myocardial Perfusion Grade

1111

710

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

IV Rx administration (n=18) IC Rx administration (n=21)

% P

ati

en

ts

TMPG 2/3

TMPG 0/1

p = 0.58

TTaabbllee 22 AAnnggiiooggrraapphhiicc aanndd CClliinniiccaall OOuuttccoommeess

IICC ((NN==2222)) IIVV ((NN==1199)) pp--vvaalluuee AAnnggiiooggrraapphhiicc DDaattaa

CCuullpprriitt VVeesssseell†† 00..553333

LLeefftt MMaaiinn 11 ((44..55)) 00 ((00..00))

LLeefftt AAnntteerriioorr DDeesscceennddiinngg 1100 ((4455..55)) 66 ((3311..66))

LLeefftt CCiirrccuummfflleexx 44 ((1188..22)) 66 ((3311..66))

RRiigghhtt CCoorroonnaarryy 77 ((3311..88)) 77 ((3366..88))

PPrreesseennccee ooff VViissiibbllee TThhrroommbbuuss†† 66 ((2277..33)) 77 ((3366..88)) 00..551111 ((YYeess//PPoossssiibbllee))

PPrree--PPCCII SStteennoossiiss ((%%))** 8899..44 ++ 1111..00 9911..11 ++ 66..11 00..555533

PPrree--PPCCII TTIIMMII FFllooww GGrraaddee†† 00..558822

00..00 11 ((44..55)) 00 ((00..00))

22..00 22 ((99..11)) 11 ((55..66))

22..55 33 ((1133..66)) 11 ((55..66))

33..00 1166 ((7722..77)) 1166 ((8888..99))

PPoosstt--PPCCII TTIIMMII FFllooww GGrraaddee‡‡ 00..446622

22..55 00 ((00..00)) 11 ((55..66))

33..00 2211 ((110000..00)) 1177 ((9944..44))

CClliinniiccaall DDaattaa

PPrroocceedduurree RReellaatteedd MMII‡‡ 11 ((44..55)) 33 ((1155..88)) 00..332211

BBlleeeeddiinngg

MMiinnoorr EEvveenntt†† 00 ((00..00)) 00 ((00..00)) ------------

MMaajjoorr EEvveenntt†† 00 ((00..00)) 00 ((00..00)) ------------

AArrrrhhyytthhmmiiaa‡‡ 00 ((00..00)) 22 ((1100..55)) 00..220099

DDeeaatthh†† 00 ((00..00)) 00 ((00..00)) ------------

3300 DDaayy FFoollllooww--uupp

DDeeaatthh†† 00 ((00..00)) 00 ((00..00)) ------------

RReeiinnffaarrccttiioonn†† 00 ((00..00)) 00 ((00..00)) ------------

UUrrggeenntt RReevvaassccuullaarriizzaattiioonn‡‡ 11 ((44..55)) 00 ((00..00)) 11..0000

** -- MMeeaann ++ SSDD:: ssttuuddeenntt’’ss tt--tteesstt ((22--ssiiddeedd)) †† -- nn ((%%)):: PPeeaarrssoonn’’ss cchhii--ssqquuaarree tteesstt ‡‡ -- nn ((%%)):: FFiisshheerr’’ss eexxaacctt tteesstt ((22--ssiiddeedd))

IC vs IV administration of eptifibatide results in IC vs IV administration of eptifibatide results in similar levels of systemic inhibition of platelet similar levels of systemic inhibition of platelet aggregation.aggregation.

IC administration of eptifibatide results in higher IC administration of eptifibatide results in higher local levels of GP IIb/IIIa RO.local levels of GP IIb/IIIa RO.

IC treatment with eptifibatide was associated with IC treatment with eptifibatide was associated with improved coronary flow and microvascular improved coronary flow and microvascular perfusion by an improved cTFC.perfusion by an improved cTFC.

ConclusionsConclusions

High first bolus GP IIb/IIIa RO in the coronary High first bolus GP IIb/IIIa RO in the coronary sinus was the only factor in a multivariate analysis sinus was the only factor in a multivariate analysis associated with an improved cTFC.associated with an improved cTFC.

Further prospective, randomized studies to Further prospective, randomized studies to explore the angiographic and clinical efficacy of explore the angiographic and clinical efficacy of this strategy are warranted.this strategy are warranted.

Conclusions (cont.)Conclusions (cont.)

This study was supported by a grant from the This study was supported by a grant from the SMDC Foundation and the University of SMDC Foundation and the University of

Tennessee Vascular Biology Center of ExcellenceTennessee Vascular Biology Center of Excellence

SMDC Research StaffSMDC Research Staff

Jennifer GundersonJennifer Gunderson

Christine LeoneChristine Leone

Lezlie SwansonLezlie Swanson

Colleen RenierColleen Renier

Jeanette PalcherJeanette Palcher

University of TennesseeUniversity of Tennessee

Mary JacoskiMary Jacoski

Angela EarhartAngela Earhart

Melanie WhiteMelanie White