Anticoagulation in the Cardiac Catheterization …

1 Anticoagulation in the Cardiac Anticoagulation in the Cardiac Catheterization LaboratoryCatheterization LaboratoryJonathan D. Marmur, MD, FACCP rofessor of MedicineDirector, Cardiac Catheterization and Interventional CardiologyHealth Science Center at BrooklynState University of New YorkLimitations of HeparinLimitations of HeparinLimitationConsequenceNon-specific binding to plasma proteins and endothelial cellsVariability in anticoagulant effect, especially in seriously ill patientsRelease of Platelet factor 4 and vWFfrom platelets during clottingResults in heparin resistance and a need for higher levels of heparinInability of heparin to inactivate fibrin-bound thrombinThrombin remains active when bound to fibrin and continues to activate plateletsHeparin induces platelet activationHeparin induces platelet activationFurther activates the clotting cascade Further activates the clotting cascade and release of heparinand release of heparin--binding proteinsbinding proteinsForms heparin antibodiesCan result in heparin-induced thrombo-cytopenia and thrombosis syndromeDose-dependent

2 Half-lifeNon-linear increase in half-life as dose increasesAnand S and Marmur JD SE (4,000X) Micrographs of Platelet MorphologySE (4,000X) Micrographs of Platelet Morphologynormal resting plateletnormal resting platelet12 g/mLof bivalirudin12 g/mLof bivalirudinplatelets treated with UFHplatelets treated with UFHloss of the normal discoid shape and formation of distinct pseudopodiarelease of platelet micro-particles (arrows)release of platelet micro-particles (arrows)Enhanced Platelet Enhanced Platelet Activation on UFHA ctivation on UFHU nstable angina patientsSamples drawn before and after heparin infusionLight transmission aggregometryMaximum (max) platelet aggregation in PRP from volunteers after adding saline, UFH, enoxaparin, or argatrobanXiao and Theroux Circulation1998;97:251-256( M)EnoxaparinEnoxaparinUF heparinUF heparinn~10,000 hi-risk ACS committed to an invasive strategyJAMA 2004;292 TIMI major bleeding(non-CABG)TIMI major bleeding(non-CABG)p= Prerandom.

3 Txn=2440 UFHn=2939 Enoxn=4293 Bothn~300 Pre-randomization TxRandomizationCrossover (n=798)UFHEnoxUFHEnoxUFHEnoxUFHEnoxEnoxE noxUFHUFHEnoxUFHEnoxUFHDean Kereiakes, MD3%24%29%43%16% RR in death/MIat 30 daysMetaMeta--analysis of analysis of EnoxaparinEnoxaparinvsvsUFH in ACSUFH in ACSN ~ 22,000 patients from 6 randomized controlled trials comparing Enox vsUFH in ACSN ~ 22,000 patients from 6 randomized controlled trials comparing EnoxvsUFH in ACSP etersen JL et al JAMA 2004;292:89-96 Intention-to-treat popIntention-to-treat popNo prerandomizationtxNo prerandomizationtxLesson of SYNERGY: Avoid SwitchingLesson of SYNERGY: Avoid SwitchingnewsACCSYNERGY: Enoxaparin as effective as heparin but bleeding may be an issueMar 10, 2004 / Updated with interviews / with slides /While experts are arguing over the clinical implications of the data, they agree on one clear message--that switching antithrombotic therapy worsens outcome and patients should remain on the first drug started whether they go to the cathlab or not.

4 (American College of Cardiology 2004 Scientific Sessions.) [ HeartWire > News ] sEnoxaparin sMajor Problem in the Major Problem in the CathCathLab: TimingLab: Timing--Based DosingBased DosingTIME of PCIE noxaparinUFH< 8 hrs since last doseNo IV dose neededTarget ACT ~250 sec8-12 hrs since last IVTarget ACT ~250 sec>12 hrs since last doseNobody knowsTarget ACT ~250 secDalteparin SQ IVDalteparin SQ IV1001201401601802001234567891011121314 Time points ACT 20 U/Kg IVDalteparin 120 U/kg SQ 60 U/kg IV1001201401601802001234567891011121314 Time points ACT 20 U/Kg IVDalteparin 120 U/kg SQ 60 U/kg IVMarmur et al J Am CollCardiol2003;41:394 402 Both IV dalteparin and Both IV dalteparin and enoxaparinenoxaparincan be can be monitored with the ACTmonitored with the Post Bolus (minutes)Anti-Xa (u/ml)140160180200 ACT (seconds)Anti-Xa Post Bolus (minutes)Anti-Xa (u/ml)140160180200 ACT (seconds)Anti-Xa u/mlACT-LRCavusoglu, Lakhani, and Marmur (Journal of Invasive Cardiol2005;17:416-421)Cavusoglu, Lakhani, and Marmur (Journal of Invasive Cardiol2005.)

5 17:416-421)14015016017018019020021005101 5306090120 Time (minutes)ACT (seconds)1401501601701801902002100510153 06090120 Time (minutes)ACT (seconds) mg/kg mg/kg IVDalt50 IU/kg IVDalt50 IU/kg mg/kg mg/kg IVTarget ACT for LMWH: >175 secTarget ACT for LMWH: >175 secy = 89x + 32y = 37x + 96100150200250300350400 ACT (sec)UFHLMWH175 conversion of UFH targets of 200 and 300 sec (with and without adjunctive IIb/IIIa) to theoretic values for enoxaparin or dalteparin. Assuming similar levels of drug concentration, the intersection of a vertical line drawn from the 300 (or 200) sec UFH-intercept will yield a corresponding target LMWH ACT on the y-axis.

6 Based on these observations, we propose a minimum LMWH target ACT of 175 (or 200) in the presence (or absence) of GP IIb/IIIa ConcentrationTheoretic LMWH Target ACTT heoretic LMWH Target ACTP rotamine Can Neutralize LMWH (at least Protamine Can Neutralize LMWH (at least partially)partially)LMWH% Anti-Xa NeutralizedTinzaparin867454 DalteparinEnoxaparinCrowther et al Br J Haematol2002;116:178-186 80 U/kg40 10 mg45 randomized 3528 patients from 124 sites to one of two doses of IV enoxaparinor IV unfractionated heparin, with GP IIb/IIIa inhibition use at the discretion of the operator. The primary end point of the study was non-CABG major and minor bleeding out to 48 hours.

7 The primary end point of major bleeding was 57% lower in the enoxaparin arms, compared with the UFH arm. There were no significant differences in rates of death; nonfatal MI, death, or MI; or death, MI, and urgent target vessel revascularization. STEEPLE randomized 3528 patients from 124 sites to one of two doses of IV enoxaparinor IV unfractionated heparin, with GP IIb/IIIa inhibition use at the discretion of the operator. The primary end point of the study was non-CABG major and minor bleeding out to 48 hours. The primary end point of major bleeding was 57% lower in the enoxaparinarms, compared with the UFH arm. There were no significant differences in rates of death; nonfatal MI, death, or MI; or death, MI, and urgent target vessel revascularization.

8 MICHELANGELO: OASISMICHELANGELO: OASIS--5 5 FondaparinuxFondaparinuxProgramProgramTh e Creation of Man (Fragment of the Sistine Chapel) (1511-12)150 XaXIIF ibrinFibrinogenXaVaPLCa2+IIaVIIIaCa2+PLI XaIntrinsicExtrinsic (TF:VII)Inhibition of one molecule of Xa can inhibit the generation of 50 molecules of thrombinInhibition of one molecule of Xacan inhibit the generation of 50 molecules of thrombinPatients with NSTE ACS, Chest discomfort < 24 hours2 of 3: Age>60, ST Segment , Cardiac markersPatients with NSTE ACS, Chest discomfort < 24 hoursPatients with NSTE ACS, Chest discomfort < 24 hours2 of 3: Age>60, ST Segment 2 of 3: Age>60, ST Segment , , Cardiac markerscardiac mg sc once mg sc once mg sc once dailyOASISOASIS--5 Study Design: 5 Study Design: Randomized, Double BlindRandomized, Double BlindASA, Clop, GP IIb/IIIa, planned Cath/PCI as per local practice (mean days to cath: 5 2)ASA, Clop, GP IIb/IIIa, planned Cath/PCI as per local practice (mean days to cath: 5 2)RandomizeRandomizeEnoxaparin1 mg/kg sc twice dailyEnoxaparinEnoxaparin1 mg/kg sc twice daily1 mg/kg sc twice dailyPrimary:Efficacy:Death, MI, refractory ischemiaat 9 days Safety:Major bleeding at 9 daysRisk benefit:Death, MI, refractory ischemia, major bleeds 9 daysSecondary.

9 Above & each component separatelyat day 30 & 6 monthsHypothesis:First test non-inferiority, then test superiorityPrimary:Primary:EfficacyEffic acy::Death, MI, refractory ischemiaDeath, MI, refractory ischemiaat 9 days at 9 days SafetySafety::Major bleeding at 9 daysMajor bleeding at 9 daysRisk benefitRisk benefit::Death, MI, refractory ischemia, major bleeds 9 daysDeath, MI, refractory ischemia, major bleeds 9 daysSecondarySecondary::Above & each component Above & each component separatelyseparatelyat day 30 & 6 monthsat day 30 & 6 monthsHypothesisHypothesis::First test nonFirst test non--inferiority, then test superiorityinferiority, then test superiorityOutcomesPCI< 6 hPCI< 6 h,,No additional UFHNo additional UFHPCI >6 hPCI >6 h,,IV UFHIV UFHWith IIb/IIIa 65 U/kgWith IIb/IIIa 65 U/kgWithout IIb/IIIa 100 U/kgWithout IIb/IIIa 100 U/kgPCI <6 hPCI <6 h::IV Fonda mgIV Fonda mgwithout IIb/IIIa, 0 with IIb/IIIawithout IIb/IIIa, 0 with IIb/IIIaPCI> 6 hPCI> 6 h.

10 IV Fonda mg withIV Fonda mg withand mg without IIb/IIIa and mg without IIb/IIIa ExcludeAge < 21 Any contra-indto EnoxHem stroke< 12 > 3 mg/dL/265 umol/LN=20,000 DaysCumulative 95% CI Efficacy OutcomePrimary Efficacy OutcomeDeath/MI/RI at Day 9 Death/MI/RI at Day 9 Major Bleeding: 9 DaysMajor Bleeding: 9 DaysDaysCumulative 95% CI << : Day 30 Mortality: Day 30 DaysCumulative 95% CI 95% CI at 6 MonthsMortality at 6 MonthsDaysCumulative CI CI During Study Treatment Period PCI During Study Treatment Period Procedural ComplicationsProcedural ComplicationsEvents at 30 daysEnox(%)Fonda(%)HR (95% CI)P valueAny UFH during *Following institution of routine UFH prior to PCI, only one case of cath thrombus in 330 patients given ( ) Access ( )<< ( ) ( )<< * ( ) ( )No.