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Fondaparinux Versus Direct Thrombin Inhibitor Therapy for The ©2008 Schattauer GmbH,Stuttgart EditorialFocus Fondaparinux versus direct thrombin inhibitortherapyfor the management of heparin-induced thrombocytopenia(HIT)– Bridgingthe River Coumarin TheodoreE.Warkentin Department of Pathologyand Molecular Medicine,and Department of Medicine,Michael G. DeGrooteSchool of Medicine,McMaster University,Hamilton, Ontario,Canada ondaparinux is asynthetic antithrombin-binding "penta- 100kg) with thrombosis,and 2.5 mg for patients without throm- saccharide"anticoagulant with provenantithrombotic effi- bosis. All patients had HIT"confirmed" by apositiveanti-PF4/ Fcacyinavarietyofprophylactic and therapeutic settings heparin enzyme-immunoassay(EIA).The primaryobjective (1). Although its use is associatedwith formation of anti-platelet wasanevaluation of plateletcount recovery.Secondaryobjec- factor 4(PF4)/heparin antibodiesatafrequencysimilartothat tivesincludedcomparisons of variouscomplications (death, am- observedwith low-molecular-weightheparin (LMWH), fonda- putation, newthrombosis, major bleeding), as well as the fre- parinuxislesslikelytoproduce immune thrombocytopenia, quencyofachieving "successfulbridging" with warfarin,de- probablybecauseit(unlikeLMWH) formspoorlywith PF4 the fined as reaching an INRof2.0 to 3.0 for twoconsecutive days antigens recognized by HIT antibodies (2, 3). To date,asyn- while receiving fondaparinux,orafter stopping the DTI. drome resembling HITseemsrare with fondaparinux (3). Theinvestigatorsfound that the frequenciesand extents of Fondaparinux is increasinglyviewedasanattractivecandi- plateletcount recovery did not differsignificantly betweenthe date anticoagulant to manage HIT(1, 4). Manyofits properties fondaparinux and DTI treatment groups, and that no newthrom- –subcutaneous administration, long half-life,lack of inter- botic eventsoccurred in eithergroup. However, successful national normalizedratio (INR)prolongation, specificfactor Xa bridging to warfarin therapywas seen in just twoofsix (33%) inhibition –differ from thoseofthe direct thrombin inhibitors fondaparinux-treated patients, and in noneofthe eight DTI- (DTI),lepirudin and argatroban, approvedtotreat HIT.These treatedpatients whoreceivedwarfarin. Of note,the lowfrequen- pharmacologic differencesmay be useful. Forexample, DTI- cy of successful bridging in the fondaparinux-treatedpatients coumarin (warfarin) overlap posesrisk of precipitating micro- appeared to reflect in part investigator inattention to the study vascularthrombosis, particularly venous limbgangrene, in some protocol sinceintwo patients the fondaparinux wasstopped on patients with HIT(5, 6). Warfarin useduring the acute (throm- the first daythat the INRreached the therapeutic range, even bocytopenic) phase of HITisinimicalbecauseitdoes not inhibit though the protocol calledfor two days of overlap within the INR HIThypercoagulability, and it predisposestodepletion of the therapeutic range. Forthe other twobridging failures,one re- natural anticoagulant, protein C. In theory, fondaparinux-cou- sulted from deliberate interruption in coumarin therapy(to per- marinoverlap should have lowerrisk of suchcomplications. mit amputation),whereasthe other occurredbecausethe INR In this issue of Thrombosis and Haemostasis,Lobo et al. (7) abruptlyrose to 4.0 during overlap, i.e.atruebridging failure. reportthe resultsofanopen-labelprospectivepilot studyoffon- Forthe 10 DTI-treatedpatients, fourdeveloped venous limbgan- daparinux in sevenpatients with adiagnosis of HITtreated with grene, although in twopatients this complication wasassociated fondaparinux (with warfarin overlap).Unlikepreviousstudiesof with warfarin useprior to initiation of DTItherapy. However, for fondaparinux for HIT,theyalso evaluatedacomparator group, anotherpatient, limb necrosis mayhavedeveloped (orworsened) This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. consisting of ten historical controls managed at the same hospi- during attempts at DTI-warfarinbridging characterized by sev- tal with DTI (lepirudin, n=6; argatroban, n=4) and warfarin. eral episodesofstopping and restarting the DTI. Dosing of fondaparinux wasthe same as for non-HIT indi- WhyisDTI-coumarinoverlapanat-riskperiodfor warfarin- cations,i.e. 7.5 mg for patients (of body weight between 50 and induced venous limb gangrene?Factors include the prolongation Correspondence to: Financialsupport: Dr.T.Warkentin Someofthe studies describedinthiseditorial were supportedbythe Heart and Stroke Hamilton Regional Laboratory MedicineProgram Foundation of Ontario (T5207, T6157 [TEW]). Room 1–180A,HamiltonHealth Sciences (Hamilton General Site) 237 Barton St. E., Hamilton, Ontario,L8L 2X2Canada Received December3,2007 Te l.: +1 905 527 0271 (ext. 46139),Fax: +1 905 577 1421 Accepted December3,2007 E-mail: [email protected] Prepublished onlineDecember 5, 2007 doi:10.1160/TH07–12–0713 Thromb Haemost 2008; 99: 2–3 2 EditorialFocus of INR by DTI(8), especially argatroban (with potential forphys- bodiesinthe pathogenesis of HIT, the demonstration of such icians to concludeprematurely that the patient is adequatelyanti- antibodies(using sensitive plateletactivation assays) in future coagulatedwith warfarin), the prolongation of the partial throm- studiesoffondaparinux therapyisrecommended. boplastin time by warfarin (leadingtoDTI underdosing) (6), and Second,the primarystudy endpoint –plateletcount recovery theshorthalf-livesofDTI (with potential for abrupt "rebound" of –does not reliably indicatetherapeutic benefit. Afterall, platelet thrombinaction if the DTI is stoppedwhenHIT is still active). countsrecoverasquicklyinHIT patients managedwith warfarin In contrast, fondaparinux usecould minimize such risk dur- or ancrod –two discredited HITtherapies(10). ing bridging to warfarin.First, the physicianhas the optionto Third,the study of Lobo et al. wassmall, with onlyseven fon- dischargethe patient on continuing subcutaneous fondaparinux daparinux- and 10 DTI-treated patients. Many patients evaluated therapy, therebyavoiding or postponing warfarin (althoughthis for inclusionwithin the prospectivecohortstudy or its historical approachwas notstudiedbyLobo et al.).Inaddition, the subcu- controls were excluded forreasonsofrenal dysfunction and fail- taneous dosing and long half-life of fondaparinux probablyre- uretofollowthe DTI protocol, respectively.The small study size duce risk of severe thrombin "rebound" if it is stoppedpre- does not allowfor definitiveconclusions as to whether severe maturely. Further,fondaparinux does not prolong the INR, and HIT-associated hypercoagulabilitycan be reliablycontrolled so fondaparinux-warfarinoverlap should be no morecomplexto with fondaparinux. manage thansimilarbridging to warfarin performed during In summary, fondaparinux has the likelyadvantage (vs. DTI) LMWH or danaparoidtherapy. of improving bridging to warfarin,but (unlikeDTI) itsefficacy What are the limitations of this studybyLobo et al.? First,the as aprimary non-heparin anticoagulant for severe HIT-associ- authorsreliedonapositiveanti-PF4/heparin EIA to diagnose ated hypercoagulabilityisnot established. Howcan physicians HIT; however, apositiveEIA does notalways"rule in" this diag- deal with this therapeutic conundrum?One possibility–not yet nosis (9). Manypatient sera thattestEIA-positive lack platelet- describedinthe literature, buttheoreticallyattractive–istoutil- activating antibodies. Theoverall "weak" EIA reactivity in the izeaDTI during the thrombocytopenic phase of HIT;however, fondaparinux-treated patients (the medianEIA optical density once the plateletcount has substantiallyrecovered,rather than [od] wasonly0.70 units)raisesdoubt as to whether allthe pa- performing DTI-warfarin bridging, aDTI-fondaparinux transi- tients sufferedfrom HIT.(Indeed,one patient with an od of only tion canbeperformed. In this way, one circumvents the "off- 0.50 units,nothrombosis, and preceding abciximab therapymay label" use of fondaparinux as the primary treatment of HIT, well have had delayed-onsetofthrombocytopenia inducedby while at the same time avoiding the complexity (and risk) of this glycoprotein IIb/IIIa antagonist.) Givengrowing acceptance DTI-warfarinoverlap. This studybyLobo et al. provides lots of of the keyrole of heparin-dependent platelet-activating anti- ideasfor the management of HIT. References 1. BradnerJE, EikelboomJW. Emerginganticoagu- 4. EfirdLE, Kockler DR.Fondaparinux forthrom- 8. Warkentin TE,Greinacher A, CravenS,etal. Dif- lants and heparin-induced thrombocytopenia:indirect boembolictreatment and prophylaxisofheparin-in- ferencesinthe clinically effective molarconcentrations and direct factor Xa inhibitors and oral thrombinin- duced thrombocytopenia.Pharmacotherapy2006;40: of four direct thrombininhibitors explaintheir variable hibitors. In: WarkentinTE,GreinacherA, eds.Heparin- 1383–1387. prothrombin timeprolongation. Thromb Haemost Induced Thrombocytopenia, 4th ed. NewYork: In- 5. Smythe MA, Warkentin TE,Stephens JL, et al. Ve- 2005; 94: 958–964. formaHealthcare USA, Inc.; 2007:441–461. nouslimb gangrene duringoverlapping therapywith 9. Lo GK,Sigouin CS, Warkentin TE.What is thepo- 2. Warkentin TE,Cook RJ,Marder VJ,etal. Anti-pla- warfarinand adirect thrombininhibitorfor immune tential foroverdiagnosisofheparin-induced throm- teletfactor 4/heparin antibodiesinorthopedic surgery heparin-induced thrombocytopenia.AmJHematol bocytopenia?AmJHematol2007;82: 1037–1043. patients receiving antithrombotic prophylaxiswith fon- 2002; 71: 50–52. 10. Lubenow N, WarkentinTE,GreinacherA,
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