低分子肝素(英文)課件

5/00MedS1Low-Molecular-WeightHeparin

and

UnfractionatedHeparin5/00MedS1Low-Molecula5/98MedS2TheCoagulationCascadeCentraltothecoagulationcascadeisthegenerationofthrombin(factorIIa)thrombinisgeneratedfromprothrombinbytheactionofactivatedfactorX(Xa)thrombinthenactsonfibrinogentogeneratefibrinclot5/98MedS2TheCoagulat5/98MedS3CoagulationCascadeXIIaXIaIXaIntrinsicPathway(surfacecontact)XaExtrinsicPathway(tissuefactor)VIIaThrombin(IIa)Thrombin-FibrinClotaPTTPTHeparin/LMWH

(AT-IIIdependent)Hirudin/Hirulog

(directantithrombin)CourtesyofVTI5/98MedS3Coagulation5/98MedS4THROMBOSISCollagenXIa TissueFactorIXaPlateletClumpingThrombusFormationThrombusGrowthHEMOSTASISTissueFactor& CollagenPlateletAggregationPlatelet-richHemostaticPlugXaFluidThrombinHEPHEP&HIRHeparinInhibitsHemostasis5/98MedS4THROMBOSISHE5/98MedS5TheProcoagulantStateinThrombolysisAmplificationVascularInjuryActivationofPlateletsAndCoagulationXaThrombin(IIa)5/98MedS5TheProcoagu5/98MedS6Low-molecular-weightheparinUH(mw3k-30k)isaheterogeneousmixtureofpolysacchridechains(glycosaminoglycans)LMWH(mw5k)isobtainedbyalkalinedegradationofheparinbenzylesterLMWHmoleculesareenrichedwithshortchainswithhigheranti-Xa:IIaratio5/98MedS6Low-molecula5/98MedS7MechanismofActionBothUHandLMWHexerttheiranticoagulationactivitybycatalyzingantithrombin

(ATorATIII)catalyzedATisacceleratedinitsinactivationofthecoagulationenzymesthrombin(factorIIa)andfactorXlongsaPTT5/98MedS7Mechanismof5/98MedS8Therearetwoheparin-cofactors,Antithrombin(AT)andHeparinCo-factorII(HCII).ATisaneffectiveantithrombinbutHCIIisaveryweakantithrombinATHCII++++----InteractionofHeparinCo-FactorswithThrombinThrombinHFSCThrombinHFSC5/98MedS8Therearetw5/98MedS9ATHCII++++----InteractionofHeparinCo-FactorswithThrombinThrombinHFSCThrombinHFSCHeparinhasahigheraffinityforATthanforHCIIandthereismoreATinplasmathanHCII5/98MedS9ATHCII++++I5/98MedS10ATFreeThrombinAntithrombinandFreeThrombinATalonedoesnotinactivate

free-thrombinThrombinHFSC5/98MedS10ATFreeThro5/98MedS11HeparinbindstoantithrombinandincreasestherateofthrombininactivationATHeparinInactivationofThrombinby

Heparin-ATComplexesThrombinHFSC5/98MedS11Heparinbin5/98MedS12ATFibrin-BoundThrombinTherateatwhichATinactivatesfibrin-boundthrombinisreduced50-foldEffectofAntithrombinon

Fibrin-BoundThrombinThrombinHFSC5/98MedS12ATFibrin-Bo5/98MedS13InactivationofThrombinby

Heparin-ATComplexesWhenthrombinbindstofibrin,itbecomesresistanttoinactivationbyheparin.ATHeparinFibrinThrombinHFSC5/98MedS13Inactivatio5/98MedS14MechanismofActionSummaryCatalyzesATIIISpecificforfluid-phasethrombinProlongsaPTTbyinactivatingthrombinandblockingXageneration5/98MedS14Mechanismo5/98MedS15Differencesin

MechanismofActionAnysizeofheparinchaincaninhibittheactionoffactorXabybindingtoantithrombin(AT)Incontrast,inordertoinactivatethrombin(IIa),theheparinmoleculemustbelongenoughtobindbothantithrombinandthrombin<halfthechainsofLMWHarelongenough5/98MedS15Differences5/98MedS16ATUnfractionatedHeparinDifferentialinhibitoryactivityagainst

factorXaandIIaactivityThrombin(IIa)HFSCATLMWHThrombin(IIa)HFSCBybindingtoAT,mostUHandLMWHcaninhibitXaactivity.

FewerthanhalfthechainsofLMWHareofsufficientlengthtoalsobindfactorIIa,thereforehasdecreasedanti-IIaactivity.5/98MedS16ATUnfractio5/98MedS17Low-Molecular-WeightHeparins

Anti-FacotrXa:Anti-FactorIIaRatiosAgent Trade Xa:IIa MolWt(d)Enosaparin Lovenox 3.8:1 4,200Dalteparin Fragmin 2.7:1 6,000Ardeparin Normiflo 1.9:1 6,000Nadroparin 3.6:1 4,500Reviparin 3.5:1 4,000Tinzaparin 1.9:1 4,5005/98MedS17Low-Molecul5/98MedS18AdvantagesofLMWHoverUHDecreased“heparinresistance”pharmacokineticsofUHareinfluencedbyitsbindingstoplasmaprotein,endothelialcellsurfaces,macrophages,andotheracutephasereactantsLMWHhasdecreasedbindingtononanticoagulant-relatedplasmaproteins5/98MedS18Advantages5/98MedS19AdvantagesofLMWHoverUHNoneedforlaboratorymonitoringwhengivenonaweight-adjustedbasis,theLMWHanticoagulantresponseispredictableandreproducibleHigherbioavailability-90%vs30%Longerplasmahalf-life4to6hoursvs0.5to1hourrenal(slower)vshepaticclearance5/98MedS19Advantages5/98MedS20AdvantagesofLMWHoverUHLessinhibitionofplateletfunctionpotentiallylessbleedingrisk,butnotshowninclinicaluseLowerincidenceofthrombocytopeniaandthrombosis(HITsyndrome)lessinteractionwithplateletfactor4fewerheparin-dependentIgGantibodies5/98MedS20Advantages5/98MedS21MonitoringofLMWHUnnecessaryinmajorityofpatientsMaybeusefulinspecificinstancesrenalinsufficiency(creatinine>2.0mg/dl)obesepatientswithaltereddrugpKmajorbleedingriskfactorsaPTTnotuseful-lowanti-IIaactivityanti-factorXaassayismoreappropriate,butnotwidelyavailable5/98MedS21Monitoring5/98MedS22ESSENCETrial

EfficacyandSafetyofSubcutaneous

Enoxaparininnon-Q-WaveCoronaryEventsStudyArandomizedstudycomparingtheclinicalefficacyofUFHvsenoxaparinLMWHin3171patientswithrestanginaornon-Q-waveMIat30days,therewasarelativeriskreductionof15%-16%intherateofdeath,MI,orrefractoryischemiaascomparedtostandardheparinNEngJMed1997;337:447-4525/98MedS22ESSENCETri5/98MedS23ESSENCEEnoxaparin1.0mg/kgq12hsubcutaneousUFH

5,000Ubolus+inf

aPTT55-85secUnstableAnginaNon-QWaveMIAcutePhasemin48h,max8Days30days

Enox HepIncidenceofdeath,MI,angina

14d 16.6%19.8%p=.019

30d 19.8%23.3%p=.016Minorbleeding

30d13.8%8.8%p<.001Majorbleeding

30d 6.5%7.0%NSDeathalone

14d2.2%2.3%NS

30d 2.9%3.6%NS5/98MedS23ESSENCEEno5/98MedS24TIMI11B-StudyDesignEnoxaparin30mgIVbolus+1.0mg/kgq12hsubcutaneousUFH70U/kgIVbolus+15U/Kg/hUFHIVUnstableAnginaNon-QWaveMIAcutePhasemin72h,max8DaysChronicPhaseFixedDose<65kg >65kg40mg 60mgq12hFixedDoseplaceboq12h43days5/98MedS24TIMI11B-5/98MedS25TIMI11B

LMWHinUnstableAngina4,021ptswithacutecoronarysyndromeTwotreatmentgroups:

UFH:70U/kgbolus15u/kg/hriv

LMWH:30mgbolus1mg/kgs.q.bidPrimaryendpoint

(death,MI,urgentrevascularization)

48-72hr 26%

14days 15% p<0.03Circulation1999;100:1593-16015/98MedS25TIMI11B

LM5/98MedS26Meta-Analysis

ESSENCEandTIMI11BPrimaryendpoint

Death/MI/UrgentRevscularizationOddsratio RiskReduction p-valDay80.71 21% 0.02Day140.79 21% 0.0005Day430.80 20% 0.0006EuropeanSocietyofCardiology-August19985/98MedS26Meta-Analys5/98MedS27PrimaryEndpoint:Day43

Death/MI/UrgentRevasc5/98MedS27PrimaryEnd5/98MedS28DifferenceBetweenLovenoxandHeparin Lovenox Heparin

Half-life(hr) 4.5 dose-dependent Anti-Xa:IIa 14:1 1:1 Molecularwt(avg) 4,500 15,000

Timetopeakactivity 3-5 2-4

Dosingunits mg IU5/98MedS28Difference4/00MedS29EnoxaparininDVTProphylaxis

DOSAGE DURATION

inpatientsundergoing 30mgq12hSC averageduration:7to10days

hip-replacementsurgery initiate12-24hpostop upto14days 40mgqdSC

initiated12h(3)preop

extendedprophylaxisin 40mgqdSC 3weekspostdischarge

hipreplacement

inpatientsundergoing 30mgq12hSC averageduration:7to10days

knee-replacementsurg initiate12-24hpostop

inpatientsundergoing 40mgqdSC averageduration:7to10days

abdominalsurgery initiate2hpreop 4/00MedS29Enoxaparin4/00MedS30EnoxaparininTreatmentof

inacuteDVTwithorwithoutPE

DOSAGE DURATION

Forpatientswhocanbe 1mgq12hSC continueLOVENOXfora

treatedathomeforacute initiatewarfarinsodium minimalof5daysanduntil

DVTwithoutPE therapywhenappropriate atherapeuticoralanticoagulant (usuallywithin72hof effecthasbeenachieved(INR

Lovenoxadministration) 2.0to3.0).

averageduration:7days

Forhospitalizedpatients 1.5mg/kgqdSCatthe

withacuteDVTwithor sametimeeverydayor

withoutPE 1mg/kgq12hSC

4/00MedS30Enoxaparin4/00MedS31EnoxaparinforUAandnon-QMI

DOSAGE DURATION

Forthepreventionof 1mg/kgq12hSC minimum2days;usualduration

ischemiccomplications withoralaspirintherapy oftherapy:2to8days

ofunstableanginaand (100to325mgoncedaily)

non-Q-wavemyocardial

infarction(MI)when

concurrentlyadministered

withaspirin4/00MedS31Enoxaparin5/98MedS32EconomicAssessmentofLMWHvsUFH

ResultsfromtheESSENCETrail

enoxaparinheparin

Needfor

coronaryangioplasty(initial) 15% 20% p=.04

coronaryangioplasty(30d) 18% 22% p=.08

diagnosticcath(30d) 57% 63% p=.04

Initialhospitalization

meandrugcostinU.S.* $155 $80

meantotalcostofcare $11,857 $12,620

meandurationoftreatment2.3days

mutidosevialenoxaparin-1mg/kgat$0.38/mgCirculation1998;97:1702-17075/98MedS32EconomicAs5/98MedS33ReferencesLow-molecularweightheparins.

WeitzJI.NEngJMed1997;337:688-698.Biochemistryandpharmacologyoflowmolecularweightheparin.

RosenbergRD.SeminHematol1997;34(suppl4):2-8.Heparin-inducedthrombocytopeniainpatientstreatedwithlow-molecular-weightheparinorunfractionaedheparin.

WarkentinTE,LevineMN,HirshJ,HorsewoodP,RobertsRS,GentM,etal.NEnglJMed1995;332:1330-1335.UseofLMWHinthetreatmentofvenousthromboembolicdisease.

LitinSC,HeitJA,MeesKA,fortheThrombophiliaCenterInvestigators.

MayoClinProc1998;73:545-551.5/98MedS33ReferencesL5/00MedS34Low-Molecular-WeightHeparin

and

UnfractionatedHeparin5/00MedS1Low-Molecula5/98MedS35TheCoagulationCascadeCentraltothecoagulationcascadeisthegenerationofthrombin(factorIIa)thrombinisgeneratedfromprothrombinbytheactionofactivatedfactorX(Xa)thrombinthenactsonfibrinogentogeneratefibrinclot5/98MedS2TheCoagulat5/98MedS36CoagulationCascadeXIIaXIaIXaIntrinsicPathway(surfacecontact)XaExtrinsicPathway(tissuefactor)VIIaThrombin(IIa)Thrombin-FibrinClotaPTTPTHeparin/LMWH

(AT-IIIdependent)Hirudin/Hirulog

(directantithrombin)CourtesyofVTI5/98MedS3Coagulation5/98MedS37THROMBOSISCollagenXIa TissueFactorIXaPlateletClumpingThrombusFormationThrombusGrowthHEMOSTASISTissueFactor& CollagenPlateletAggregationPlatelet-richHemostaticPlugXaFluidThrombinHEPHEP&HIRHeparinInhibitsHemostasis5/98MedS4THROMBOSISHE5/98MedS38TheProcoagulantStateinThrombolysisAmplificationVascularInjuryActivationofPlateletsAndCoagulationXaThrombin(IIa)5/98MedS5TheProcoagu5/98MedS39Low-molecular-weightheparinUH(mw3k-30k)isaheterogeneousmixtureofpolysacchridechains(glycosaminoglycans)LMWH(mw5k)isobtainedbyalkalinedegradationofheparinbenzylesterLMWHmoleculesareenrichedwithshortchainswithhigheranti-Xa:IIaratio5/98MedS6Low-molecula5/98MedS40MechanismofActionBothUHandLMWHexerttheiranticoagulationactivitybycatalyzingantithrombin

(ATorATIII)catalyzedATisacceleratedinitsinactivationofthecoagulationenzymesthrombin(factorIIa)andfactorXlongsaPTT5/98MedS7Mechanismof5/98MedS41Therearetwoheparin-cofactors,Antithrombin(AT)andHeparinCo-factorII(HCII).ATisaneffectiveantithrombinbutHCIIisaveryweakantithrombinATHCII++++----InteractionofHeparinCo-FactorswithThrombinThrombinHFSCThrombinHFSC5/98MedS8Therearetw5/98MedS42ATHCII++++----InteractionofHeparinCo-FactorswithThrombinThrombinHFSCThrombinHFSCHeparinhasahigheraffinityforATthanforHCIIandthereismoreATinplasmathanHCII5/98MedS9ATHCII++++I5/98MedS43ATFreeThrombinAntithrombinandFreeThrombinATalonedoesnotinactivate

free-thrombinThrombinHFSC5/98MedS10ATFreeThro5/98MedS44HeparinbindstoantithrombinandincreasestherateofthrombininactivationATHeparinInactivationofThrombinby

Heparin-ATComplexesThrombinHFSC5/98MedS11Heparinbin5/98MedS45ATFibrin-BoundThrombinTherateatwhichATinactivatesfibrin-boundthrombinisreduced50-foldEffectofAntithrombinon

Fibrin-BoundThrombinThrombinHFSC5/98MedS12ATFibrin-Bo5/98MedS46InactivationofThrombinby

Heparin-ATComplexesWhenthrombinbindstofibrin,itbecomesresistanttoinactivationbyheparin.ATHeparinFibrinThrombinHFSC5/98MedS13Inactivatio5/98MedS47MechanismofActionSummaryCatalyzesATIIISpecificforfluid-phasethrombinProlongsaPTTbyinactivatingthrombinandblockingXageneration5/98MedS14Mechanismo5/98MedS48Differencesin

MechanismofActionAnysizeofheparinchaincaninhibittheactionoffactorXabybindingtoantithrombin(AT)Incontrast,inordertoinactivatethrombin(IIa),theheparinmoleculemustbelongenoughtobindbothantithrombinandthrombin<halfthechainsofLMWHarelongenough5/98MedS15Differences5/98MedS49ATUnfractionatedHeparinDifferentialinhibitoryactivityagainst

factorXaandIIaactivityThrombin(IIa)HFSCATLMWHThrombin(IIa)HFSCBybindingtoAT,mostUHandLMWHcaninhibitXaactivity.

FewerthanhalfthechainsofLMWHareofsufficientlengthtoalsobindfactorIIa,thereforehasdecreasedanti-IIaactivity.5/98MedS16ATUnfractio5/98MedS50Low-Molecular-WeightHeparins

Anti-FacotrXa:Anti-FactorIIaRatiosAgent Trade Xa:IIa MolWt(d)Enosaparin Lovenox 3.8:1 4,200Dalteparin Fragmin 2.7:1 6,000Ardeparin Normiflo 1.9:1 6,000Nadroparin 3.6:1 4,500Reviparin 3.5:1 4,000Tinzaparin 1.9:1 4,5005/98MedS17Low-Molecul5/98MedS51AdvantagesofLMWHoverUHDecreased“heparinresistance”pharmacokineticsofUHareinfluencedbyitsbindingstoplasmaprotein,endothelialcellsurfaces,macrophages,andotheracutephasereactantsLMWHhasdecreasedbindingtononanticoagulant-relatedplasmaproteins5/98MedS18Advantages5/98MedS52AdvantagesofLMWHoverUHNoneedforlaboratorymonitoringwhengivenonaweight-adjustedbasis,theLMWHanticoagulantresponseispredictableandreproducibleHigherbioavailability-90%vs30%Longerplasmahalf-life4to6hoursvs0.5to1hourrenal(slower)vshepaticclearance5/98MedS19Advantages5/98MedS53AdvantagesofLMWHoverUHLessinhibitionofplateletfunctionpotentiallylessbleedingrisk,butnotshowninclinicaluseLowerincidenceofthrombocytopeniaandthrombosis(HITsyndrome)lessinteractionwithplateletfactor4fewerheparin-dependentIgGantibodies5/98MedS20Advantages5/98MedS54MonitoringofLMWHUnnecessaryinmajorityofpatientsMaybeusefulinspecificinstancesrenalinsufficiency(creatinine>2.0mg/dl)obesepatientswithaltereddrugpKmajorbleedingriskfactorsaPTTnotuseful-lowanti-IIaactivityanti-factorXaassayismoreappropriate,butnotwidelyavailable5/98MedS21Monitoring5/98MedS55ESSENCETrial

EfficacyandSafetyofSubcutaneous

Enoxaparininnon-Q-WaveCoronaryEventsStudyArandomizedstudycomparingtheclinicalefficacyofUFHvsenoxaparinLMWHin3171patientswithrestanginaornon-Q-waveMIat30days,therewasarelativeriskreductionof15%-16%intherateofdeath,MI,orrefractoryischemiaascomparedtostandardheparinNEngJMed1997;337:447-4525/98MedS22ESSENCETri5/98MedS56ESSENCEEnoxaparin1.0mg/kgq12hsubcutaneousUFH

5,000Ubolus+inf

aPTT55-85secUnstableAnginaNon-QWaveMIAcutePhasemin48h,max8Days30days

Enox HepIncidenceofdeath,MI,angina

14d 16.6%19.8%p=.019

30d 19.8%23.3%p=.016Minorbleeding

30d13.8%8.8%p<.001Majorbleeding

30d 6.5%7.0%NSDeathalone

14d2.2%2.3%NS

30d 2.9%3.6%NS5/98MedS23ESSENCEEno5/98MedS57TIMI11B-StudyDesignEnoxaparin30mgIVbolus+1.0mg/kgq12hsubcutaneousUFH70U/kgIVbolus+15U/Kg/hUFHIVUnstableAnginaNon-QWaveMIAcutePhasemin72h,max8DaysChronicPhaseFixedDose<65kg >65kg40mg 60mgq12hFixedDoseplaceboq12h43days5/98MedS24TIMI11B-5/98MedS58TIMI11B

LMWHinUnstableAngina4,021ptswithacutecoronarysyndromeTwotreatmentgroups:

UFH:70U/kgbolus15u/kg/hriv

LMWH:30mgbolus1mg/kgs.q.bidPrimaryendpoint

(death,MI,urgentrevascularization)

48-72hr 26%

14days 15% p<0.03Circulation1999;100:1593-16015/98MedS25TIMI11B

LM5/98MedS59Meta-Analysis

ESSENCEandTIMI11BPrimaryendpoint

Death/MI/UrgentRevscularizationOddsratio RiskReduction p-valDay80.71 21% 0.02Day140.79 21% 0.0005Day430.80 20% 0.0006EuropeanSocietyofCardiology-August19985/98MedS26Meta-Analys5/98MedS60PrimaryEndpoint:Day43

Death/MI/UrgentRevasc5/98MedS27PrimaryEnd5/98MedS61DifferenceBetweenLovenoxandHeparin Lovenox Heparin

Half-life(hr) 4.5 dose-dependent Anti-Xa:IIa 14:1 1:1 Molecularwt(avg) 4,500 15,000

Timetopeakactivity 3-5 2-4

Dosingunits mg IU5/98MedS28Difference4/00MedS62EnoxaparininDVTProphylaxis

DOSAGE DURATION

inpatientsundergoing 30mgq12hSC averageduration:7to10days

hip-replacementsurgery initiate12-24hpostop upto14days 40mgqdSC

initiated12h(3)preop

extendedprophylaxisin 40mgqdSC 3weekspostdischarge

hipreplacement

inpatientsundergoing 30mgq12hSC averageduration:7to10days

knee-replacementsurg initiate12-24hpostop

inpatientsundergoing 40mgqdSC averageduration:7to10days

abdominalsurgery initiate2hpreop 4/00MedS29Enoxaparin4/00MedS63EnoxaparininT