Enoxaparin in ACS

Enoxaparin in ACSWhen evidence meets real world practiceProf. Adel lElEt EtribyAin Shams Universityo DefinitionsAgendao Is UFH w/o disadvantageso High risk combination of anticoagulants inthe management of ACSo SKo Fibrinolyticso IIb/IIIa Inhibitorso When evidence meets real world practice

o DefinitionsAgendao Is UFH w/o disadvantageso High risk combination of anticoagulants inthe management of ACSo SKo Fibrinolyticso IIb/IIIa Inhibitorso When evidence meets real world practiceAcute Coronary Syndrome (ACS) Defined …ACUTE CORONARY SYNDROMENo ST ElevationST ElevationNSTEMIUnstable Angina NQMIQwMIMyocardial Infarction

o DefinitionsAgendao Is UFH w/o disadvantageso High risk combination of anticoagulants inthe management of ACSo SKo Fibrinolyticso IIb/IIIa Inhibitorso When evidence meets real world practiceIs UFH withoutdisadvantages?

Disadvantages of UFHo Unpredictable anticoagulant effect• Significant protein binding• Inactivation by platelet factor 4

Superiority ofEnoxaparin over UFHEvidence-basedo DefinitionsAgendao Is UFH w/o disadvantageso High risk combination of anticoagulants inthe management of ACSo SKo Fibrinolyticso IIb/IIIa Inhibitorso When evidence meets real world practice

Is UFH the choice when using SK?o SK + S.C. Heparin didn’t improve outcomecompared with heparinoGISSI- 2oISIS- 3o SK + I.V. Heparin didn’t improve outcomeoGUSTO- 1o SK + I.V. Heparin increase the tendency formajor bleedingAMI-SK Study designSTEMI(n=496)SK1.5 MU i.v.1 h+ aspirin(30 days)(n=491)Enoxaparin30 mgbolus Angiography Follow-upi.v., thenday 8day 301 mg/kg s.c.q 12 h(3–8 days)(n=252)Placebo(3–8 days)(n=239)Angiographyday 8Follow-upday 30SK: StreptokinaseTreatment phaseFollow-up phase

Coronary patency (TIMI flow 2 or 3) at 8 dayssignificantly better with ClexanePa atients (% %)P

AMI-SK Conclusionso Clexane as adjunct to streptokinaseo facilitates early coronary reperfusiono reduces the risk of reocclusiono improved clinical outcome (death, MI, RA at 30days)o no significant increase in major bleedso DefinitionsAgendao Is UFH w/o disadvantageso High risk combination of anticoagulants inthe management of ACSo SKo Fibrinolyticso IIb/IIIa Inhibitorso When evidence meets real world practice

Enoxaparin versus UFH for STEMIOne Year Results fromExTRACT-TIMI 25E M. Antman, D. Morrow, C. McCabe, S. Murphy, H. White, K A A. Fox, and E.BraunwaldOn Behalf of the ExTRACT-TIMI 25 InvestigatorsProtocol DesignN = 20,506674 sites48 countriesSTEMI < 6 hLytic eligibleASALytic choice by MD(TNK, tPA, rPA, SK)Double-blind, blind, double-dummydummyENOX STRATEGY< 75 y: 30 mg IV bolusSC 1.0 mg / kg q 12 h (Hosp DC)≥ 75 y: No bolusSC 0.75mg / kg q 12 h (Hosp DC) )CrCl < 30: 1.0 mg / kg q 24 hUFH STRATEGY60 U / kg bolus (4000U)Inf 12 U/kg/h(1000/ U/h)Duration: at least 48 hCont’d at MD discretion1° Efficacy Endpoint: Death or Nonfatal MI at 30 daysAdditional F/U at 6 mo and 1 yr

1ry Results at 30 DaysPrimary Endpoint:Death or non-fatal re-MI by 30 daysMain Secondary Endpoint:Death, non-fatal re-MI, urgentrevascularization by 30 days%RR = 0.83p

No Increase in ICHents% Ev10UFHENOX86420ARD 0.7%RR 1.53ARD 0.4%RR 1.39ARD 0.1%RR 1.27P

Antithrombin therapy with a strategy of ENOXis superior to the standard strategy of UFH inSTEMI patients undergoing pharmacologicreperfusion across the spectrum of lytics usedin ExTRACT-TIMI 25

New Data from ExTRACT-TIMI 251YEAR FOLLOW UPESC 2007To determine if the benefits of theENOX strategy over the UFHstrategy were sustained through 1 yr.Methods• Telephone Tl follow-up fll at 6 and 12 monthsDeath from any causeRecurrent MIStroke→ 1yrfollow-up available on 99% of ITT cohort• CRF documentationSame endpoint pages as main trial Investigator-reported• Statistical Analysis:Intention-to-treat, treat, Log Rank

Primary End Point (ITT)Death/MI at 1 Year18 UFH17.0%Point (%%)Primaary End1614121012.0%9.9%8 RR0.836 (0.77to 0.90)P

Net Clinical BenefitDeath/MI/Disabling Stroke at 1 yrEnd Pooint (%)181614 12.3%1210 10.1%8 RR0.826 (0.76to 0.89)4 P

Elements of 1ry Endpoint at 1 Year%)Point (%End P12108642All Cause MortalityUFH 10.6%ENOX 10.5%HR0.98(0.90to 1.0707)P=0.776Non-fatal MIUFH6.8%5.7%5 ENOX43 HR0.822(0.73to 0.9292)1P=0.0006000600 50 100 150 200 250 300 350Days00 50 100 150 200 250 300 350DaysSummary-11. The benefits of the ENOX strategytover the UFH strategy in reducingDeath/MI was sustained at 1 yr2. The 1 yr benefit of the ENOXstrategy is driven by the earlyreduction in reMI

Summary-23. Net clinical benefit significantlyfavors the ENOX strategy both at 30days and 1 yr.Clinical Implications for Managementof fSTEMIThe ENOX strategy to support fibrinolysisis preferable to that of UFH:Early superiority in reducing death/MIDurable treatment benefit

o DefinitionsAgendao Is UFH w/o disadvantageso High risk combination of anticoagulants inthe management of ACSo SKo Fibrinolyticso IIb/IIIa Inhibitorso When evidence meets real world practiceEnoxaparin incombination withGPIIb/IIIa inhibitors

Enoxaparin and GP IIb/IIIa inhibitors inUA/NSTEMI‣ ACUTE II: second Antithrombotic Combination UsingTirofiban and EnoxaparinCohen M et al. Am Heart J 2002‣ INTERACT: Integrilin and EnoxaparinRandomizedAssessment of Acute Coronary Syndromes TreatmentGoodman S et al. Circulation 2003‣ SYNERGY: SuperiorYield of the New strategy of Enoxaparin,Revascularization & GlYcoprotein IIb/IIIa InhibitorsACUTE II: TIMI Bleeding EventsTirofiban + UFH (n=210)Tirofiban + enoxaparin (n=315)TIMI-major0.31.0P=NSTIMI-minor2.54.3P=NSTIMI-“lossno site”3.54.8P=NS0 1 2 3 4 5Patients (%)

%1098765432104.8%INTERACT(Aspirin + Integrilin)UHEnoxaparinP = 0.03031.8%MB 96 hrs25.4%P = 0.030314.3%Death/MI 30dNICE - 3NationalInvestigatorsCollaborating on Enoxaparin

NICE -3Objectiveso To assess the safety yp profile (primarily withrespect to bleeding) of enoxaparin and a IIb/IIIaantagonist (abciximab, eptifibatide or tirofiban) inpatients with ACSo To assess the feasibility and safety of bringingpatients t forward to the catheterization t ti laboratoryon combination therapy (without the use of UFheparin)NICE -3Protocol661 patients enrolledAll treated t withEnoxaparin46 clinical sites inUS / CanadaStudy Initiatedt January 2000[Enoxaparinalone](n=45)Tirofiban(n=217)Eptifibatide(n=252)All IIb/IIIa patients(n=616)Abciximab(n=147)Enrollment CompletedMay 2000In-hospital, 14-day, and 30-day follow-upData availableAugust 2000

NICE - 3151214Major Bleeding910Non-CABG Major Bleeding10.6630EPICNICE-3 4.5%4.13.8CAPTURENICE-3 1.9%21.51.1 0.85.3 5.12.41.4? ?EPILOG EPISTENT RESTORE PRISM+ IMPACT II PURSUIT3NICE -3Conclusionso Combination of enoxaparin plus GPIIb/IIIaantagonists does NOT result in major non-CABGbleeding.o Patients on combination therapy may safelyundergo PCI.o Enoxaparin could be prescribed followingthrombolytics (tenecteplase, SK) withoutincrease risk of ICH.

o DefinitionsAgendao Is UFH w/o disadvantageso High risk combination of anticoagulants inthe management of ACSo SKo Fibrinolyticso IIb/IIIa Inhibitorso When evidence meets real world practiceReasons for Quitting UFH in PCI1.Anticoagulation with UFH is unpredictable–In STEEPLE, only 20% of patients were in the“official” target range2.Frequent medical errors with UFH• LaPointe NM, Jollis JG. Arch InternMed. 2003;163:1461-1466.1461 14663.Clexane is safer, more effective & easier to3.Clexane is safer, more effective & easier touse

Task Force Recommendations6 Rx studies(enoxaparin)ACS1 mg/kg SC BID 11 Rx studies(enoxaparin)PCIno add. LMWH Elective PCI 1° PCICATH LAB within 8 hours 0.5 mg/kg IV 0.5 mg/kg IV?5 non-Rx studies(enoxaparin)Definitive Evaluation of Enoxaparin AcrossCAD/ACS Spectrum > 50,000 patientsUA/NSTEMIMeta-analysisN=21,946patientsSTEMIMetaanalysisN>27,000patientstElective PCIMeta-analysisN>7,000patientsReduction in death/re-MI10% 22%Reduction in major bleeding43%Murphy SA, et al. Eur Heart J. 2007; Epub ahead of printDumaine R, et al. Arch Int Med (in press)

Clexane in ACS – My ApproachACSConservative StrategyInvasive StrategySTEMI NSTEMI • Prolonged procedure• Post CABG• No ACT availableNo Cathlab Glycoprotein• On Clexane in CCUWithin 3 hoursIIb/IIIaSK + fullFull lldoseClexane IVdose Clexane Clexane0.5 mg/kgConclusionsWhen making a a decision for propermanagement of patients with ACS weshould combine EBM with common sense.When using both,Clexane seems to be the bestchoice

Thank You..SummaryoCombining Clexane with SK or thrombolytics providesbetter ST resolution & reperfusion as well as clinicalevents suggesting less re-occlusion.o Combining Clexane with GPIIb/IIIa receptor antagonistsdid not increase major – non CABG bleeding.o Patients on combination therapy (Clexane + GPIIb/IIIa RA)may safely undergo PCI.o Clexane could be prescribed following thrombolytics(tenecteplase, SK) without increase risk of ICH.

Egyptian Guidelines for themanagement of ACSLow Molecular Weight Heparin:Enoxaparin was the only LMWH which showed benefit over UFH onhard end-pointsof death, MI or need for urgent revascularizationi(ESSENCE trial).-Dose: 1 mg/kg/12hours subcutaneously.-Duration: from 2-8days.Both Nd Nadroparine and Dlt Dalteparin did not show any advantage overUFH on hard end points (FRIC &FRAXIStrials).Most studies showed no benefit of long term treatment by LMWH’sexcept in patients with elevated Troponin (30days).