Oral anticoagulant therapies: Balancing the risks

Transcription

1 Orl nticogulnt therpies: Edith A. Nutescu Firin clot formtion (i.e., clotting) is the result of the conversion of firinogen to firin, the lst step in the finl common pthwy of the clotting cscde, which is ctlyzed y fctor X (FX) nd then fctor II (thromin). The intrinsic nd extrinsic pthwys oth led to ctivtion of fctor X nd the finl common pthwy. Currently ville orl nticogulnts in the United Sttes differ in their mechnisms of ction (Figure ). The vitmin K ntgonist wrfrin hs multiple trgets in the intrinsic nd extrinsic pthwys; it inhiits heptic production of the vitmin K-dependent clotting fctors II, VII, IX, nd X. Newer orl nticogulnts hve more specific ctivity on single clotting fctor. These gents include the direct thromin inhiitor digtrn nd direct FX inhiitors (rivroxn nd pixn nd the investigtionl gent edoxn). Wrfrin Wrfrin hs een ville for more thn 60 yers, nd until recently it ws the only orl nticogulnt ville in the United Sttes. The drug is widely used to prevent nd Purpose. To descrie the mechnisms of ction, phrmcokinetics, nd rte of leeding complictions from wrfrin nd trget-specific orl nticogulnts; methods for ssessing the risk for thromoemolism nd leeding in ptients receiving orl nticogulnts or temporrily interrupting such therpy to undergo elective invsive procedures or surgery; therpeutic strtegies for lncing these risks; nd cogultion ssys used to monitor orl nticogultion therpy. Summry. The trget-specific orl nticogulnts hve more specific mechnism of ction nd shorter elimintion hlf-lives thn wrfrin, ut the hlf-lives of these trget-specific gents my e prolonged in ptients with renl impirment or elderly ptients, resulting in the potentil for drug ccumultion nd leeding complictions. The rte of leeding complictions in the community setting my e higher thn in the clinicl tril setting. In ptients receiving orl nticogulnts or temporrily interrupting orl nticogulnt therpy to undergo elective invsive procedures or surgery, the risks for thromoemolism nd leeding should e ssessed y using vlidted risk scoring systems nd ptient strtifiction schemes. The time during which n orl nticogulnt should e withheld efore n invsive procedure or surgery nd the time until resumption of therpy fter the procedure depend on the drug, risk of thromosis, type of procedure (i.e., risk for leeding), nd ptient-specific vriles, especilly renl function for the trget-specific gents. New cogultion ssys re in development for use in monitoring orl nticogulnt therpy. Conclusion. An individulized pproch is needed to lnce the risks for thromoemolism nd leeding in ptients receiving orl nticogulnts. Am J Helth-Syst Phrm. 03; 70(Suppl ):S3- tret rteril nd venous thromoemolism, ut it requires frequent lortory monitoring ecuse of its nrrow therpeutic index, nd it lso intercts with numerous drugs nd foods. Wrfrin is the most commonly implicted mediction in emergency hospitliztions of elderly Americns. Bleeding is more likely to occur within the first month of therpy thn lter in tretment. 3 Risk fctors for leeding include high intensity of nticogultion (Interntionl Normlized Rtio [INR] >4.0), ge 65 yers or older, Edith A. Nutescu, Phrm.D., FCCP, is Clinicl Professor, College of Phrmcy, University of Illinois t Chicgo, nd Director, Antithromosis Center, University of Illinois Hospitl nd Helth Sciences System, Chicgo, IL. Address correspondence to Dr. Nutescu t University of Illinois t Chicgo, 833 South Wood Street, MC 886, Chicgo, IL 606 (enutescu@uic.edu). Bsed on the proceedings of symposium held Decemer 3, 0, during the 47th ASHP Midyer Clinicl Meeting nd Exhiition in Ls Vegs, Nevd, nd supported y n eductionl grnt from CSL Behring. Dr. Nutescu received n honorrium for prticipting in the symposium nd prepring this rticle. Dr. Nutescu reports tht she hs served s consultnt for Diichi-Snkyo Inc. nd hs received reserch grnt nd served s consultnt for Jnssen Phrmceuticls, Inc. The ssistnce of Crl J. Brink, M.S., B.S.Phrm., nd Susn R. Domrowski, M.S., B.S.Phrm., in developing the mnuscript is cknowledged. Ms. Brink nd Ms. Domrowski hve declred no potentil conflicts of interest. Copyright 03, Americn Society of Helth-System Phrmcists, Inc. All rights reserved /3/050-00S3$ DOI 0.46/jhp30040 Am J Helth-Syst Phrm Vol 70 My 5, 03 Suppl S3

2 Figure. Mode of ction of nticogulnts. history of highly vrile INRs, history of gstrointestinl (GI) leeding, hypertension, cererovsculr disese, nemi, mlignncy, trum, renl impirment, certin genetic fctors (e.g., ctivity of cytochrome P-450 isozymes C9 nd 4F nd vitmin K oxide reductse complex suunit ), certin concomitnt drugs, nd long durtion of wrfrin therpy. 3 The time to onset nd offset of the nticogulnt effect of wrfrin is influenced y the elimintion hlf-life of the R- nd S-isomers of the drug (45 hours nd 9 hours, respectively) nd the four vitmin K-dependent clotting fctors: 4 II: 4 7 hours VII: 4 6 hours IX: 30 hours X: 7 48 hours The hlf-life of fctor II is considerly longer thn those of the other three vitmin K-dependent fctors nd the two isomers of the drug. This long hlf-life contriutes to the lg etween the time when the drug is initited, the dosge is chnged, or the drug is discontinued nd the time when clinicl effect is oserved. It cn tke up to 0 hours fter the initition of wrfrin (or longer in slow metolizers of the drug) to chieve stedy-stte concentrtion of the drug (Figure ). 5 Conversely, it cn tke up to five dys fter wrfrin discontinution efore the drug is completely eliminted. The nticogulnt effect of wrfrin is mesured y the prothromin time (PT), which reflects reduced heptic production of fctors II, V, VII, nd X. Becuse the regents used for PT nd their sensitivity vry mong clinicl lortories, the INR is used to stndrdize nd express the PT results. 6 The resumption of norml INR vlue fter wrfrin discontinution requires the production of ctive vitmin K-dependent clotting fctors. Severl vriles cn cuse dely in recovery of norml INR. In retrospective cohort study of 633 multory ptients with n INR greter thn 6.0 nd vrious indictions for wrfrin therpy, 3 ptients (37%) hd n INR of 4.0 or higher fter two doses were withheld. 7 Risk fctors for this dely in reduction of INR included dvnced ge (odds rtio [OR] per decde of life,.8; 95% confidence intervl [CI],.0.38; p = 0.04), high index INR (OR per unit,.5; 95% CI,.4.37; p < 0.00), decompensted congestive hert filure (OR,.79; 95% S4 Am J Helth-Syst Phrm Vol 70 My 5, 03 Suppl

3 Figure. Phrmcokinetics of wrfrin nd vitmin K-dependent clotting fctors. Reproduced, with permission, from reference 5. CI, ; p = 0.009), nd ctive cncer (OR,.48; 95% CI,. 5.57; p = 0.03). A high weekly mintennce wrfrin dose ws ssocited with low risk for dely in reduction of INR (djusted OR per 0 mg of wrfrin, 0.87; 95% CI, ; p = 0.009). Trget-specific orl nticogulnts The shortcomings of wrfrin prompted reserch to develop new orl nticogulnts. Digtrn ws pproved y the Food nd Drug Administrtion (FDA) for stroke prevention in tril firilltion (AF) in Octoer Rivroxn ws pproved for this indiction in Novemer 0 fter first receiving FDA pprovl in July 0 for prophylxis of venous thromoemolism (VTE) in ptients undergoing knee or hip replcement surgery. 9 Rivroxn ws lso pproved y FDA for tretment of VTE (deep venous thromosis [DVT] nd pulmonry emolism [PE]) in Novemer 0. An ppliction for the indiction of cute coronry syndrome (ACS) hs een sumitted to FDA; pprovl is pending, s the gency requested dditionl dt from the mnufcturer. 0 Apixn is the newest trgetspecific nticogulnt to ecome ville. It ws pproved y FDA in Decemer 0 for reducing the risk of stroke nd systemic emolism in ptients with nonvlvulr tril firilltion. Edoxn hs een evluted for stroke prevention in AF, prevention of VTE in ptients undergoing hip replcement surgery, nd tretment of VTE. -4 It hs een pproved in Jpn for VTE prevention fter mjor orthopedic surgery, ut plns for sumission of new drug ppliction to FDA hve not yet een nnounced. All four of these trget-specific orl nticogulnts re eliminted y the kidneys nd cn ccumulte in ptients with renl impirment, lthough the gents differ in the extent to which they rely on the kidneys for elimintion (Tle ). Digtrn is the drug tht is most dependent on renl function for elimintion, nd pixn is the lest dependent. Digtrn is dilyzle; the other three trgetspecific gents re unlikely to e removed y dilysis. As cretinine clernce decreses (i.e., s renl function deteriortes), the hlf-life of ech drug nd its nticogulnt effect increse ecuse of drug ccumultion, nd this increses the potentil for leeding complictions. The mgnitude of the effect is lrgest for digtrn nd smllest for pixn. These differences re importnt in the choice mong the trget-specific orl nticogulnts for ptients with renl impirment. Clinicl trils compring digtrn, rivroxn, or pixn with wrfrin for stroke prevention in AF reveled importnt differences in the sfety profiles of these gents. In the RELY nd ROCKET-AF studies, there ws no significnt difference in mjor leeding, the primry sfety endpoint, etween digtrn (the lrger [50 mg] of two dosges evluted) or rivroxn nd wrfrin (p = 0. 3 nd p = 0.44, respectively). 7,8 In the ARISTOTLE study, the rte of mjor leeding ws 3% lower with pixn thn wrfrin, difference tht is significnt (p < 0.00). 9 Am J Helth-Syst Phrm Vol 70 My 5, 03 Suppl S5

4 Tle. Properties of Trget-Specific Orl Anticogulnts 5,6, Property Digtrn Rivroxn Apixn Edoxn Direct fctor inhiition II X X X Renl clernce (%) Hlf-life in renl impirment (hr) >80 ml/min ml/min ml/min <30 ml/min Dilyzle Yes Unlikely Unlikely Unlikely = cretinine clernce. Dt not ville. Tle. Selected Scoring Systems for Stroke Risk Assessment in Ptients with Atril Firilltion,, Risk Fctor CHA Congestive hert filure Hypertension Age 75 yers Dietes History of stroke or trnsient ischemic ttck Mximum score CHA -Vsc Congestive hert filure/left ventriculr dysfunction Hypertension Age 75 yers Dietes History of stroke, trnsient ischemic ttck, or thromoemolism Vsculr disese Age yers Femle sex Mximum score Points Ptients with tril firilltion re considered t low, intermedite, or high risk for stroke if their CHA score or CHA -Vsc score is 0,, or or higher, respectively. The rte of intrcrnil hemorrhge (ICH) ws significntly lower with ll three orl nticogulnts compred with wrfrin in these three studies (p < 0.00, p = 0.0, nd p < 0.00, respectively). However, the rte of mjor GI leeding ws significntly higher with digtrn 50 mg nd rivroxn thn with wrfrin (p < 0.00 for oth comprisons), lthough it ws not significntly different etween pixn nd wrfrin (p = 0.37). There ppered to e trdeoff etween the reduced risk for ICH nd the incresed risk for 6 9 mjor GI leeding when digtrn or rivroxn ws used insted of wrfrin. In 0, digtrn nd wrfrin were the most common prescription drugs ssocited with serious, disling, or ftl injury reported to the FDA MedWtch dverse event reporting progrm. 0 Digtrn ccounted for 378 serious dverse events, including 367 cses of hemorrhge nd 54 deths. Wrfrin ccounted for 06 serious dverse events, including 73 cses of hemorrhge nd 7 deths. The unexpectedly lrge numer of reports of hemorrhge in ptients receiving digtrn could reflect differences etween the clinicl tril setting nd the community setting, including differences in monitoring nd perhps heightened reporting ecuse of perception of greter sfety issues with the newer trget-specific orl nticogulnts thn with wrfrin nd differences in ptient popultions. Most complictions from digtrn use reported to FDA occurred in elderly ptients, mny of whom hve impired renl function. Digtrn dosge reduction is recommended for ptients with renl impirment, nd filure to mke this reduction could explin hemorrhgic complictions in these ptients. 8 The use of ny orl nticogulnt to reduce the risk for thromoemolism whether it is wrfrin or one of the trget-specific gents is ccompnied y risk for leeding. Efforts to reduce the risk for leeding my increse the risk for thromoemolism. An individulized pproch is needed to lnce these risks nd minimize relted moridity nd mortlity. Risk ssessment Severl vlidted stroke risk ssessment tools re ville for use in ptients with AF (Tle ). Use of the CHA score is dvocted in the 0 guidelines from the Americn College of Chest Physicins S6 Am J Helth-Syst Phrm Vol 70 My 5, 03 Suppl

5 (ACCP).,3 Points re ssigned to individul risk fctors, then dded to determine the CHA score. Ptients with AF re ctegorized s low, intermedite, or high risk for stroke if their CHA score is 0,, or or higher, respectively. No nticogultion is recommended y ACCP for ptients t low risk for stroke. 3 The use of digtrn insted of wrfrin is suggested when orl nticogultion is recommended in ptients t intermedite or high risk for stroke (i.e., CHA score of or higher). No recommendtions re mde in the ACCP guidelines for the use of rivroxn or pixn for stroke prevention in AF ecuse these drugs were not pproved y FDA for this indiction t the time the guidelines were eing developed. It is expected, however, tht future updtes in the guidelines will encompss these gents. Guidelines from the Americn College of Crdiology (ACC) nd Americn Hert Assocition (AHA) cll for spirin therpy for ptients with no risk fctors for stroke, spirin or orl nticogulnt therpy for ptients with one stroke risk fctor, nd orl nticogulnt therpy for ptients with two or more risk fctors. 4,5 Digtrn is n lterntive to wrfrin for orl nticogulnt therpy in ptients without contrindictions to its use, ccording to ACC nd AHA. As with the ACCP guidelines, the ACC/AHA guidelines were pulished in 0 nd thus do not mention rivroxn or pixn. Updted guidelines relesed y the Europen Society of Crdiology (ESC) in August 0 recommend use of the CHA -Vsc score (Tle ), nother point-sed system for predicting stroke in ptients with AF tht tkes into considertion the presence of vsculr disese, history of thromoemolism, ge yers (s well s 75 yers or older), nd femle sex s well s the risk fctors ssessed in the CHA scoring system.,6 The CHA -Vsc score ws developed to improve upon the predictive vlue of the CHA score nd etter identify ptients truly t low risk for stroke. 6 Ptients with AF re considered t low, intermedite, or high risk for stroke if their CHA -Vsc score is 0,, or or higher, respectively. No nticogulnt therpy is recommended y ESC for ptients with CHA -Vsc score of 0 (i.e., ptients less thn 65 yers of ge with lone AF). In ptients with CHA -Vsc score of, wrfrin, direct thromin inhiitor (i.e., digtrn), or n orl FX inhiitor (i.e., rivroxn, pixn) should e considered fter ssessing the risk of leeding complictions nd considering ptient preferences. Anticogulnt therpy is recommended unless contrindicted for ptients with CHA -Vsc score of or higher. Point-sed scoring systems for ssessing the risk for leeding from the use of orl nticogulnts in ptients with AF hve lso een developed nd vlidted (Tle 3). 7,8,30 None of these scoring systems hve yet een recommended y ACCP, ACC, or AHA, lthough the lck of recommendtion does not suggest tht ssessment of leeding risk is not needed. The ESC recommends use of the HAS-BLED scoring system insted of the HEMORR HAGES nd Anticogultion nd Risk Fctors in Atril Firilltion scoring systems ecuse of the greter simplicity of HAS-BLED. 6,8 A forml leeding risk ssessment is recommended y ESC for ll ptients with AF who Tle 3. Selected Scoring Systems for Bleeding Risk Assessment in Ptients with Atril Firilltion Receiving Orl Anticogulnt Therpy 7-9, Risk Fctor HEMORR HAGES Heptic or renl disese Ethnol use Mlignncy Age >75 yers Reduced pltelet count or function Re-leeding Hypertension, uncontrolled Anemi Genetic fctors Elevted fll risk ± neuropsychitric disese Stroke Mximum score HAS-BLED c Hypertension, systolic lood pressure >60 mm Hg Anorml renl or liver function Stroke Bleeding history or predisposition Lile INRs Age >65 yers Antipltelet or NSAID use Alcohol use >8 servings/week Mximum score Points for ech for ech 4 for ech INR = Interntionl Normlized Rtio, NSAID = nonsteroidl ntiinflmmtory drug. The risk for leeding in ptients with HEMORR HAGES score of 0, 3, or 4 or more is low, moderte, or high, respectively. c The risk for leeding in ptients with HAS-BLED score of 0,, nd 3 or more is low, moderte, or high, respectively. Am J Helth-Syst Phrm Vol 70 My 5, 03 Suppl S7

6 re receiving orl nticogulnt (or ntipltelet) therpy. In ptients with HAS-BLED score of 3 or higher, who y definition re considered t high risk, the use of cution, periodic monitoring, nd efforts to correct reversile risk fctors for leeding (e.g., uncontrolled hypertension, lile INR vlues, concomitnt nonsteroidl nti-inflmmtory drug or lcohol use) re recommended y ESC. A high HAS-BLED score lone is not necessrily n solute contrindiction to use of orl nticogulnt therpy. The risk scoring systems in Tle nd Tle 3 were developed for ptients with AF nd re sed on clinicl dt from this ptient popultion. A similr process should e used to ssess the risk for thromoemolism nd leeding in ptients receiving orl nticogulnts for other indictions (e.g., VTE), with tools developed for those specific indictions. Periopertive mngement Orl nticogulnt therpy should e temporrily discontinued in ptients undergoing n elective invsive Tle 4. Ptient Risk Strtifiction for Periopertive Thromoemolism when Orl Anticogulnt Therpy Is Temporrily Interrupted 3 High Risk (>0% nnul risk for thromoemolism) Atril firilltion Recent (within pst three months) stroke or trnsient ischemic ttck CHA score 5 or 6 Rheumtic vlvulr hert disese Mechnicl hert vlve Any cged-ll or tilting disc vlve in mitrl or ortic position Any mitrl vlve prosthesis Recent (within pst six months) stroke or trnsient ischemic ttck Venous thromoemolism Recent (within pst three months) venous thromoemolism Severe thromophili Deficiency of protein C, protein S, or ntithromin Antiphospholipid ntiodies Multiple thromophilis Moderte Risk (5 0% nnul risk for thromoemolism) Atril firilltion CHA score 3 or 4 Mechnicl hert vlve Bileflet ortic vlve prosthesis with mjor risk fctors for stroke Venous thromoemolism Venous thromoemolism within pst 3 months Recurrent venous thromoemolism Non-severe thromophili (e.g., heterozygous fctor V Leiden or prothromin gene muttion) Active cncer (treted within pst six months or pllitive) Low Risk (<5% nnul risk for thromoemolism) Atril firilltion CHA score 0 (without prior stroke or trnsient ischemic ttck) Mechnicl hert vlve Bileflet ortic vlve prosthesis without tril firilltion nd mjor risk fctors for stroke Venous thromoemolism Venous thromoemolism more thn months go with no other risk fctors for thromoemolism procedure or surgery who hve high leeding risk, for the purpose of voiding leeding complictions; however, the risk for periopertive thromoemolism is lso mjor concern when nticogultion therpy is interrupted. The risk for periopertive thromoemolism (Tle 4) nd leeding (Tle 5) should e evluted in such ptients to determine the pproprite time to discontinue nd resume orl nticogulnt therpy. Although VTE is postopertive concern in ptients without indictions for nticogultion prior to surgery, rteril nd venous thromoemolism is the primry concern during interruption of orl nticogultion in ptients with indictions for such therpy efore surgery (e.g., AF, mechnicl hert vlve, VTE). 3 A residul nticogulnt effect is cceptle t the time of minor invsive procedures or surgery with low risk of leeding, ut miniml or no nticogulnt effect is desired t the time of mjor procedures with high risk of leeding or where the consequences of leeding re prticulrly dire (Tle 5). Aggressive nticogultion is needed for ptients t high risk for thromoemolism (Tle 4), nd therpy with short hlf-life (e.g., low moleculr weight heprin or trget-specific orl nticogulnt insted of wrfrin) should e considered in such ptients so tht it hs rpid offset of effect efore the procedure nd rpid onset fter the procedure (i.e., miniml interruption of nticogultion). The rte of decline in plsm concentrtion of drug fter discontinution depends on the hlf-life. The percentge of the plsm concentrtion remining fter one, two, three, four, nd five hlf-lives hve elpsed is 50%, 5%,.5%, 6.5%, nd 3.5%, respectively. When therpeutic concentrtions re present nd the drug is discontinued, t lest four or five hlf-lives must elpse efore the plsm concentrtion ecomes S8 Am J Helth-Syst Phrm Vol 70 My 5, 03 Suppl

7 sufficiently low to minimize the therpeutic effects. Vriles tht cn cuse dely in recovery of norml INR in ptients receiving wrfrin my increse the mount of time efore surgery during which the drug should e withheld to void leeding complictions. Impired renl function, which is common in the elderly, my require discontinution of orl nticogulnts further in dvnce of surgery thn would e necessry in ptients with norml renl function to minimize the risk for leeding. Postopertive considertions in determining when to resume orl nticogulnt therpy include the effect of the surgery, risk of leeding, nd owel motility. Therpy my e resumed once hemostsis hs een chieved. Wrfrin should e discontinued five dys efore surgery nd resumed pproximtely 4 hours fter surgery when there is dequte hemostsis. 3 To minimize the risk of over-nticogultion, generlly the preopertive wrfrin dose should e used insted of lrger dose when therpy is resumed. An lterntive pproch is to give mini-loding dose for the first few dys when therpy is reinitited to cuse more rpid nticogultion, nd then trnsition to the preopertive mintennce dose. 3 The numer of doses of trgetspecific orl nticogulnts tht should e withheld efore invsive procedures depends on the type of procedure nd the ptient s renl function (Tle 6), especilly for digtrn ecuse of the importnce of the kidneys in elimintion of the drug. 34,35 A lrger numer of doses of digtrn should e withheld efore invsive procedures in ptients with moderte or severe renl impirment thn in ptients with mild renl impirment or norml renl function. A lrger numer of doses of digtrn, rivroxn, nd pixn should e withheld efore mjor surgery thn efore minor procedure ecuse of the greter risk Tle 5. Procedure Risk Strtifiction for Periopertive Bleeding 3,33 High Risk (two-dy risk of mjor leeding 4%) Mjor crdic surgery (hert vlve replcement/coronry rtery ypss grfting) Mjor neurosurgicl procedures Mjor cncer surgery (hed nd neck/dominl/thorcic) Mjor orthopedic surgery (joint replcement/lminectomy) Mjor urologic surgery (prostte/ldder resection) Mjor vsculr surgery Kidney iopsy Polypectomy, vricel tretment, iliry sphincterectomy, pneumtic dilttion Endoscopiclly guided fine-needle spirtion Any mjor opertion (procedure durtion >45 minutes) Low Risk (two-dy risk of mjor leeding 0 %) Cholecystectomy Adominl herni repir Adominl hysterectomy Coronry ngiogrphy/percutneous coronry intervention/ electrophysiologic testing Pcemker/crdic defirilltor insertion Gstrointestinl endoscopy ± iopsy, enteroscopy, iliry/pncretic stent without sphincterotomy, endonosonogrphy without spirtion Minor plstic surgery (crpl tunnel repir) Minor orthopedic surgery/rthroscopy Minor gynecologic surgery (diltion nd curettge) Minor dentl procedures (extrctions) Minor skin procedures (cncer excision) Minor eye procedures (ctrct) Delyed initition of ridging to minimize risk for pocket hemtom. Tle 6. Interruption of Trget-Specific Orl Anticogulnt Therpy for Invsive Procedures nd Surgery 8,9,,34,35, Drug (Cretinine Clernce) Time of Lst Dose efore Minor Procedure (dys) Time of Lst Dose efore Mjor Surgery (dys) Digtrn (>50 ml/min) Digtrn (3 50 ml/min) 4 Digtrn ( 30 ml/min) 4 6 Rivroxn or pixn (>50 ml/min) Rivroxn or pixn (30 50 ml/min) 3 4 Rivroxn or pixn (<30 ml/min) 4 Therpy should generlly e resumed 4 48 hours fter minor procedure nd 48 7 hours fter mjor surgery. If unfrctionted heprin (UFH) or low moleculr weight heprin (LMWH) is used s ridging therpy in ptients with tril firilltion, mechnicl hert vlve, or venous thromoemolism who re t high risk for thromoemolism, orl nticogulnt therpy with trget-specific gent should e resumed t the time when the UFH infusion is discontinued nd t the time when the next scheduled dose of LMWH would hve een given. See Tle 5 for procedure risk strtifiction for periopertive leeding (minor procedures re ssocited with low risk of periopertive leeding, nd mjor surgery is ssocited with high risk for periopertive leeding). Am J Helth-Syst Phrm Vol 70 My 5, 03 Suppl S9

8 of leeding ssocited with mjor surgery (Tle 5). Digtrn, rivroxn, nd pixn should e resumed 4 48 hours fter minor procedure nd 48 7 hours fter mjor surgery, ssuming tht hemostsis hs een chieved. In ptients t high thromosis risk in whom dequte hemostsis is chieved shortly fter the end of the procedure nd postopertive leeding risk is stndrd, it my e resonle to resume nticogultion within 4 hours fter surgery. Some clinicins suggest resuming therpy in stepped dosing pproch. For digtrn, this would strt with hlf dose (75 mg) for the first dose nd therefter increse to the usul mintennce dose. For rivroxn, it would strt with 0 mg then increse to the usul mintennce dose. 35 In ptients with postopertive owel prlysis, ridging with n injectle nticogulnt my e required until the ptient is le to tke orl nticogulnts. The rivroxn prescriing informtion contins oxed wrning tht discontinuing rivroxn in the sence of dequte lterntive nticogultion increses the risk of thromotic events nd tht if nticogultion with rivroxn must e discontinued for reson other thn pthologicl leeding, nother nticogulnt should e dministered. 9 Mesurement of nticogulnt effect The lck of need for routine lortory monitoring is n dvntge of the trget-specific orl nticogulnts over wrfrin. Nevertheless, mesurement of nticogulnt ctivity during therpy with the trgetspecific gents is potentilly useful in ptients undergoing invsive procedures or surgery nd certin other ptients nd scenrios, such s the following: Active leeding, Progressive renl insufficiency, Possile excessive or indequte dosing, Drug interctions, Suspected nondherence, Elderly or very young, Overweight or underweight, nd Receiving thromolytic or triple ntithromotic therpy. Vrious hemtologic tests hve een used to ssess cogultion sttus, nd the usefulness of these cogultion ssys differs mong the trget-specific orl nticogulnts. The ecrin clotting time (ECT), direct mesure of thromin genertion (ecrin ctivtes prothromin), is the most useful lortory test for monitoring cogultion during digtrn therpy, ut this test is not widely ville in the clinicl setting. 6 The thromin time (TT), mesure of the ctivity of thromin in plsm, is less useful thn the ECT, ut it is more widely ville. The PT nd INR re less useful thn the TT for ssessing cogultion during digtrn therpy. The ctivted prtil thromoplstin time (PTT, mesure of the intrinsic nd finl common pthwys in cogultion) is frequently used in most institutions nd is sensitive to the effects of digtrn; thus, this ssy is potentil lterntive until ECT ecomes more widely ville. Chromogenic nti-fx ssys re useful for monitoring cogultion during rivroxn nd pixn therpy. 6 Although the PTT nd PT re less useful thn chromogenic ssys during rivroxn therpy, the vilility of PT mkes PT prcticl to use. The INR is not useful for monitoring cogultion during tretment with FX inhiitors (i.e., rivroxn or pixn). 6 The PTT nd PT re widely ville, lthough not idel, tests for monitoring the trget-specific orl nticogulnts. The extent to which these nticogulnts prolong the PTT nd PT vries. 36 Digtrn prolongs the PTT to greter extent nd the PT to lesser extent thn do the FX inhiitors, nd the extent of the PT prolongtion differs etween rivroxn nd pixn. The extent of prolongtion of these test vlues lso depends on the regent nd cogulometer used, nticogulnt dose, nd time since the lst dose. The PTT is useful for its negtive predictive vlue. A norml PTT suggests tht little digtrn nticogulnt ctivity my e present. However, norml PTT during digtrn therpy nd norml PT during rivroxn therpy 37 cnnot completely exclude the presence of the drug, ecuse the tests re not sufficiently sensitive. A sfe PT or PTT vlue for invsive procedures in ptients receiving trget-specific orl nticogulnts hs not een identified. The TT, since it is highly sensitive, is more pproprite for providing qulittive informtion out the presence of digtrn thn quntittive informtion out the mount of drug present. A reltionship etween cogultion ssy results nd ptient outcomes hs not een estlished. Newer cogultion ssys need to e developed, stndrdized, nd vlidted. Endogenous thromin potentil (ETP), dilute prothromin time (dpt), Heptest (Americn Dignostic, Stmford, CT), prothrominse-induced clotting time (PiCT), nd chromogenic nti-fctor II re mong the ssys in development. 6 The ETP reflects thromin genertion. The dpt is n ssy with greter sensitivity thn PT. The Heptest mesures inhiition of endogenous FX. The PiCT ssy, which is pproved y FDA for mesuring the effects of unfrctionted heprin nd low moleculr weight heprin, hs een explored for use in mesuring the nticogulnt effect of rivroxn. 6 Chromogenic nti-fctor X nd nti-fctor II ssys re potentilly useful for monitoring cogultion during tretment with FX inhiitors s well s the fctor II inhiitor digtrn. 6 S0 Am J Helth-Syst Phrm Vol 70 My 5, 03 Suppl

9 Conclusion An individulized pproch is needed to lnce the risks for thromoemolism nd leeding in ptients receiving orl nticogulnts. References. Neel S. Essentil wrfrin knowledge. In: Gulseth M, ed. Mnging nticogultion ptients in the hospitl. Bethesd, MD: Americn Society of Helth-System Phrmcists; 007: Budnitz DS, Lovegrove MC, Sheh N et l. Emergency hospitliztions for dverse drug events in older Americns. N Engl J Med. 0; 365: Coumdin (wrfrin sodium) prescriing informtion. Princeton, NJ: Bristol-Myers Squi Compny; 0 Oct. pi_coumdin.pdf (ccessed 03 Jn 4). 4. Wittkowsky AK. Wrfrin (AHFS 0:.04). In: Murphy JE, ed. Clinicl phrmcokinetics, 5th ed. Bethesd, MD: Americn Society of Helth-System Phrmcists; 0: DocLirry/Bookstore/P548/Smple- Chpter-4.spx (ccessed 03 Jn 4). 5. Eckhoff CD, DiDomenico RJ, Shpiro NL. Inititing wrfrin therpy: 5 mg versus 0 mg. Ann Phrmcother. 004; 38: Miyres MA, Dvis K. 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