Emerging Options for Thromboprophylaxis After Orthopedic Surgery: A Review of Clinical Data

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1 Emerging Options for Thromboprophylxis After Orthopedic Surgery: A Review of Clinicl Dt Bob L. Lobo, Phrm.D. In four rndomized, controlled studies of ptients undergoing orthopedic surgery, the ntithrombotic efficcy nd sfety of subcutneous fondprinux 2.5 mg once/dy were compred with those of subcutneous enoxprin regimens tht were pproved by the United Sttes Food nd Drug Administrtion. In ptients undergoing elective hip replcement surgery, fondprinux significntly reduced the frequency of venous thromboembolism (VTE). However, in second tril tht compred fondprinux with enoxprin 30 mg twice/dy beginning hours fter surgery, 26% risk reduction in fvor of fondprinux ws not sttisticlly significnt. In ptients undergoing elective knee replcement surgery, fondprinux significntly reduced the risk of VTE compred with enoxprin without incresing the risk of cliniclly relevnt bleeding, lthough the risk of mjor bleeding defined by the bleeding index ws significntly higher with fondprinux. Fondprinux ws superior to enoxprin 40 mg once/dy in the setting of hip frcture surgery, with no incresed risk of mjor bleeding. Met-nlysis of the four studies confirms the superior ntithrombotic efficcy of fondprinux over enoxprin in orthopedic surgery nd suggests tht the risk of mjor bleeding is similr to tht of enoxprin when the first dose of fondprinux is given t lest 6 hours fter surgery. Key Words: thromboprophylxis, orthopedic surgery, fondprinux, enoxprin, efficcy, sfety. (Phrmcotherpy 2004;24(7 Pt 2):66S 72S) The efficcy nd sfety of thromboprophylxis with fondprinux were estblished in n interntionl phse III clinicl tril progrm consisting of four rndomized, prllel-group, double-blind studies. 1 4 Since mny experts considered low-moleculr-weight heprin (LMWH) to be the most effective option for prophylxis ginst venous thromboembolism (VTE) in ptients undergoing orthopedic surgery, 5 ll four studies compred fondprinux hed-to-hed with enoxprin. Ptients in these studies received either subcutneous fondprinux 2.5 mg/dy or subcutneous enoxprin in From the Deprtment of Clinicl Phrmcy, University of Tennessee College of Phrmcy, nd the Deprtment of Phrmcy, Methodist Helthcre University Hospitl, Memphis, Tennessee. Address reprint requests to Bob L. Lobo, Phrm.D., Deprtment of Phrmcy, Methodist Helthcre University Hospitl, 1265 Union Avenue, Memphis, TN regimen tht ws pproved by the United Sttes Food nd Drug Administrtion (FDA), tht is, either 40 mg/dy or 30 mg twice/dy. 6 (These enoxprin regimens re pproved for hip or knee replcement surgeries. Enoxprin is not pproved for hip frcture surgery.) All four studies in the clinicl tril progrm 1 4 used identicl outcome mesures for thromboprophylctic efficcy nd sfety (Tble 1) to fcilitte combined nlysis. The primry efficcy outcome of djudicted VTE ws defined s composite of both symptomtic nd symptomtic deep vein thrombosis (DVT) nd symptomtic pulmonry embolism. Efficcy outcomes were confirmed through the use of routine scending bilterl contrst venogrphy of the legs between dys 5 nd 11, or erlier if thrombosis ws suspected by the investigtor. Any suspected pulmonry embolism ws

2 EMERGING OPTIONS FOR THROMBOPROPHYLAXIS AFTER ORTHOPEDIC SURGERY Lobo 67S Tble 1. Outcome Mesures for Efficcy nd for Sfety nd Exclusion Criteri in the Four Phse III Trils of Fondprinux 1 4 Efficcy Mesures Sfety Mesures Exclusion Criteri Primry outcome Primry outcome Pregnncy Adjudicted VTE to dy 11 Mjor bleeding Active bleeding (DVT, pulmonry Ftl bleeding Acute bcteril endocrditis embolism, or both) Bleeding into criticl orgn Congenitl or cquired bleeding disorder Secondry outcomes Bleed leding to repet surgery Hemorrhgic stroke in previous 3 mo Any DVT Bleed with bleeding index 2 Ulcertive or ngiodysplstic gstrointestinl Proximl DVT Secondry outcomes disese Distl DVT Minor bleeding Brin, spinl, or ophthlmologic surgery in Symptomtic VTE to dy 11 Trnsfusions previous 3 mo Symptomtic VTE to dy 49 Units trnsfused (replcing volume) Plnned indwelling intrthecl or epidurl Deth (ny cuse) ctheter for > 6 hrs fter surgery Ptients who required or received nticogultion within 2 dys of study Hypersensitivity to heprin, LMWH, pork, or iodinted contrst medi Serum cretinine level > 2 mg/dl despite hydrtion Pltelet count < 100 x 10 3 /mm 3 Contrindiction to nticogultion Concurrent ddictive disese VTE = venous thromboembolism; DVT = deep vein thrombosis; LMWH = low-moleculr-weight heprin. confirmed by high-probbility lung scnning, pulmonry ngiogrphy, spirl computed tomogrphy, or utopsy. The primry sfety outcome of mjor bleeding ws defined s composite of ftl bleeding, bleeding into criticl orgn (retroperitonel, intrcrnil, intrspinl, or into other criticl orgns), bleed leding to repet surgery, nd overt bleeding with bleeding index of 2 or higher. The bleeding index ws defined s the number of whole blood or pcked red blood cell units trnsfused plus the difference between the prebleeding nd postbleeding hemoglobin vlues in grms/deciliter. Results of the clinicl tril progrm of fondprinux for thromboprophylxis in orthopedic surgery re summrized below. Elective Hip Replcement Surgery Venous thromboembolism is common compliction fter totl hip replcement surgery. Despite prophylxis with recommended mesures such s LMWH, wrfrin, or intermittent pneumtic compression, pproximtely 16 22% of ptients undergoing elective hip replcement surgery will experience venogrphiclly proved DVT. 5 Moreover, symptomtic DVT or pulmonry embolism occurs before hospitl dischrge in pproximtely 1% of ptients in United Sttes hospitls who undergo totl hip replcement. 7 Ptients who experience VTE fter orthopedic surgery hve incresed morbidity nd mortlity, hve longer length of sty, nd incur significntly greter costs thn those who do not experience this compliction. 7 More effective thromboprophylxis would be expected to reduce the frequency of these complictions nd thus improve the qulity of cre of ptients undergoing elective hip replcement surgery. The Europen Pentscchride Hip Elective Surgery Study (EPHESUS) 1 nd the Pentscchride in Totl Hip Replcement Surgery Study (PENTATHLON 2000) 2 compred the efficcy nd sfety of fondprinux with two FDApproved enoxprin regimens in the prevention of VTE in ptients undergoing elective hip replcement surgery. Ptients were eligible if they were ged 18 yers or older nd were scheduled for primry elective totl hip replcement surgery or revision of t lest one component of previously implnted totl hip prosthesis. Exclusion criteri for these phse III clinicl trils re listed in Tble 1. In EPHESUS, the first dose of fondprinux 2.5 mg ws given 6 hours (rnge 4 8 hrs) fter surgery, with the second dose given no sooner thn 12 hours fter the first dose. Fondprinux then ws dministered once/dy for 5 9 dys fter surgery. The ptients who were rndomly ssigned to the enoxprin rm received 40 mg once/dy in ccordnce with FDA-pproved lbeling. In 78% of these ptients, the first dose

3 68S Supplement to PHARMACOTHERAPY Volume 24, Number 7, 2004 Tble 2. Efficcy Outcomes to Dy 11: EPHESUS 1 Event Fondprinux Enoxprin p Vlue Adjudicted VTE 37/908 (4) 85/919 (9) < Any DVT 36/908 (4) 83/918 (9) < Proximl DVT 6/922 (1) 23/927 (2) < Distl DVT 30/909 (3) 67/917 (7) < Symptomtic VTE 5/1129 (0.4) 3/1123 (0.3) 0.73 EPHESUS = Europen Pentscchride Hip Elective Surgery Study; VTE = venous thromboembolism; DVT = deep vein thrombosis. Dt re no. of ptients with event/no. of evluble ptients (%). ws dministered 12 hours before surgery, with the second injection given hours fter surgery; subsequent dosing ws once/dy. In the other 22% of ptients, the first dose of enoxprin ws dministered fter rther thn before surgery minly becuse of the use of regionl nesthesi during surgery. Like fondprinux, enoxprin ws continued for 5 9 dys fter surgery. The proportion of ptients who developed VTE in EPHESUS ws significntly lower in the fondprinux rm thn in the enoxprin rm (Tble 2). The reltive risk reduction in the primry end point (djudicted VTE) ws 55.9% with fondprinux compred with enoxprin. Significnt risk reductions in some secondry end points (ny DVT, proximl DVT, nd distl DVT) were lso seen. Tretment of VTE ws left up to the discretion of the investigtor, nd mny ptients with DVT detected with venogrphy received tretment. Significntly fewer ptients in the fondprinux group thn in the enoxprin group were treted for VTE by dy 11 (4% vs 9%, p<0.001). No significnt difference in symptomtic VTE ws observed. The low rte of symptomtic VTE by dy 49 (1% in both groups) my reflect the erly dignosis nd tretment of venogrphiclly detected symptomtic DVT nd the reltively lrge number of ptients (52% in both groups) who received extended prophylxis fter dy 11. No significnt differences were noted in ny of the sfety outcomes during the study or up to dy 49. The number of ptients who experienced mjor or minor bleeding ws low in both groups (Tble 3). In the PENTATHLON 2000 tril, 2 ptients ssigned to the enoxprin rm received 30 mg twice/dy beginning hours fter surgery, in ccordnce with FDA-pproved lbeling. The efficcy outcomes of PENTATHLON 2000 re displyed in Tble 4. A trend to superiority of fondprinux over enoxprin ws observed in the primry end point of djudicted VTE; Tble 3. Sfety Outcomes to Dy 11: EPHESUS 1 Fondprinux Enoxprin Outcome (n=1140) (n=1133) Primry Ftl bleeding 0 (0) 0 (0) Bleeding into criticl orgn 0 (0) 0 (0) Repet surgery due to bleed 5 (< 1) 3 (< 1) Bleeding index 2 42 (4) 29 (3) Secondry Minor bleeding 44 (4) 38 (3) Trnsfusions fter surgery 714 (63) 690 (61) Units trnsfused 2 2 Deth 0 (0) 2 (0.2) EPHESUS = Europen Pentscchride Hip Elective Surgery Study. Dt re no. (%) of ptients for ll outcomes except units trnsfused, which re the men no. of units/ptient. however, unlike in EPHESUS, this difference did not rech sttisticl significnce. Significnt differences fvoring fondprinux were observed in rtes of some secondry outcome mesures (such s ny DVT nd distl DVT), nd nonsignificntly lrger number of ptients in the enoxprin rm thn in the fondprinux rm were treted for VTE (7% vs 5%, p=0.086). A curious finding in PENTATHLON 2000 ws the difference in symptomtic VTE fvoring enoxprin over fondprinux (1% vs 0.1% t dy 11, p=0.006; 3% vs 1% t dy 49, p=0.01). The reson for the observed difference in symptomtic VTE t 49 dys is uncler but could reflect the higher rte of extended prophylxis (for ptients who were not treted for thrombotic event) tht occurred in the enoxprin rm compred with the fondprinux rm (28% vs 25%, p=0.186). It hs been estblished tht extended prophylxis reduces the risk of lteoccurring symptomtic VTE, so the difference in lte-occurring symptomtic VTE should be interpreted with cution. 8 Furthermore, since DVT ws detected t venogrphy more frequently in ptients ssigned to enoxprin thn to fondprinux, more ptients in the enoxprin

4 EMERGING OPTIONS FOR THROMBOPROPHYLAXIS AFTER ORTHOPEDIC SURGERY Lobo 69S Tble 4. Efficcy Outcomes: PENTATHLON Event Fondprinux Enoxprin p Vlue Adjudicted VTE 48/787 (6) 66/797 (8) Any DVT 44/784 (6) 65/796 (8) Proximl DVT 14/816 (2) 10/830 (1) 0.42 Distl DVT 34/796 (4) 54/800 (7) Symptomtic VTE 10/1126 (1) 1/1128 (0.1) PENTATHLON = Pentscchride in Totl Hip Replcement Surgery Study; VTE = venous thromboembolism; DVT = deep vein thrombosis. Dt re no. of ptients with event/no. of evluble ptients (%). rm received nticogultion fter surgery. This too would be expected to reduce the rte of lteoccurring symptomtic VTE complictions. Thus, the finding of decresed symptomtic events up to dy 49 in the enoxprin rm of PENTATHLON 2000 is unlikely to represent cliniclly meningful dvntge of enoxprin over fondprinux in prctice. The more frequent use of extended prophylxis nd therpeutic nticogultion in the enoxprin rm likely chnged the nturl history of the disese nd probbly ccounts for the difference in symptomtic events seen up to dy 49. No significnt differences in ny of the primry or secondry sfety outcomes were observed in PENTATHLON 2000 (Tble 5). Elective Mjor Knee Surgery Filure to provide thromboprophylxis in ptients undergoing totl knee replcement surgery is ssocited with prevlence of venogrphiclly proved VTE of 40 84%. 5 Commonly recommended ntithrombotic mesures, such s LMWH, wrfrin, nd intermittent pneumtic compression, reduce this rte to 28 47%. 5 In fct, pproximtely 1% of ptients in the United Sttes experience symptomtic VTE during hospitliztion for their orthopedic procedure. 7 These complictions re ssocited with incresed morbidity nd mortlity, longer length of sty, nd significntly greter costs thn when VTE does not occur. 7 Thus, more effective thromboprophylxis should improve the qulity of cre of ptients who undergo elective mjor knee surgery. The Pentscchride in Mjor Knee Surgery Study (PENTAMAKS) 3 compred the efficcy nd sfety of fondprinux 2.5 mg/dy beginning 6 hours (rnge 4 8 hrs) fter surgery with enoxprin 30 mg twice/dy beginning hours fter surgery, in ccordnce with FDApproved lbeling. The design of PENTAMAKS Tble 5. Sfety Outcomes to Dy 11: PENTATHLON Fondprinux Enoxprin Outcome (n=1128) (n=1129) Primry Ftl bleeding 0 (0) 0 (0) Bleeding into criticl orgn 0 (0) 1 (0.1) Repet surgery due to bleed 2 (0.2) 2 (0.2) Bleeding index 2 18 (2) 8 (0.7) Secondry Minor bleeding 17 (2) 24 (2) Trnsfusions fter surgery 593 (53) 555 (49) Units trnsfused 2 2 Deth 3 (0.3) 1 (0.1) PENTATHLON = Pentscchride in Totl Hip Replcement Surgery Study. Dt re no. (%) of ptients for ll outcomes except units trnsfused, which re the men no. of units/ptient. ws similr to tht of the other phse III studies in the clinicl tril progrm. Efficcy nd sfety outcomes, s well s exclusion criteri, were identicl for ll of the trils (Tble 1). The efficcy outcomes for PENTAMAKS re presented in Tble 6. Compred with enoxprin, fondprinux reduced the reltive risk of djudicted VTE by 55.2%. Fondprinux lso significntly reduced the reltive risk of the secondry end points of ny DVT (by 54.1%) nd distl DVT (by 55.9%) compred with enoxprin. There ws trend towrd reduced proximl DVT with fondprinux compred with enoxprin (reltive risk reduction 54.5%, p=0.06). As ws seen in EPHESUS, significntly more ptients were treted for VTE in the enoxprin group (25.1%) thn in the fondprinux group (15.1%, p<0.001). In ddition, 19% of ptients ssigned to fondprinux nd 20% of those ssigned to enoxprin received extended prophylxis. It is likely tht the frequent use of extended prophylxis nd the erly detection nd tretment of DVT ccount for the lck of significnt difference in the rte of symptomtic VTE seen

5 70S Supplement to PHARMACOTHERAPY Volume 24, Number 7, 2004 Tble 6. Efficcy Outcomes to Dy 11: PENTAMAKS 3 Event Fondprinux Enoxprin p Vlue Adjudicted VTE 45/361 (12.5) 101/363 (27.8) <0.001 Any DVT 45/361 (12.5) 98/361 (27.1) <0.001 Proximl DVT 9/368 (2.4) 20/372 (5.4) 0.06 Distl DVT 35/372 (9.4) 78/366 (21.3) <0.001 Symptomtic VTE 3/517 (0.6) 7/517 (1.4) 0.34 PENTAMAKS = Pentscchride in Mjor Knee Surgery Study; VTE = venous thromboembolism; DVT = deep vein thrombosis. Dt re no. of ptients with event/no. of evluble ptients (%). by dy 49 (1.0% vs 1.9%, p=0.3). A significnt difference in mjor bleeding between fondprinux nd enoxprin ws observed in the PENTAMAKS tril. Overll, mjor bleeding occurred in 11 ptients ssigned to fondprinux nd 1 ptient ssigned to enoxprin (p=0.006). This difference cn be ttributed to nine cses of mjor bleeding ssocited only with bleeding index of 2 or more in ptients receiving fondprinux (Tble 7). In these cses, bleeding ws t the surgicl site in seven ptients, nd the study drug ws discontinued in three of the nine ptients. Since the drug ws continued in most of the ptients with bleeding index of 2 or more, the clinicl relevnce of this finding is open to question. The rtes of minor bleeding, need for trnsfusion, nd other dverse events did not differ significntly between the two groups. Hip Frcture Surgery The rte of venogrphiclly proved DVT is 24 27% in ptients undergoing hip frcture surgery, despite recommended thromboprophylctic options. Ftl pulmonry embolism occurs in 4 13% of ptients undergoing surgery for hip frcture repir who do not receive ny thromboprophylxis. Symptomtic VTE occurs in pproximtely 1.3% of ptients in the United Sttes who re hospitlized for hip frcture surgery. 7 These events re ssocited with incresed morbidity nd mortlity, longer length of sty, nd significntly greter costs of treting the ptient who is hospitlized with hip frcture. 7 More effective thromboprophylxis would be expected to improve outcomes in ptients who undergo hip frcture surgery. The Pentscchride in Hip-Frcture Surgery Study (PENTHIFRA) 4 compred fondprinux 2.5 mg/dy with enoxprin 40 mg/dy. In the enoxprin group, the first dose ws given 12 hours before surgery nd the second hours Tble 7. Sfety Outcomes to Dy 11: PENTAMAKS 3 Fondprinux Enoxprin Outcome (n=517) (n=517) Primry Ftl bleeding 0 (0) 0 (0) Bleeding into criticl orgn 0 (0) 0 (0) Repet surgery due to bleed 2 (0.4) 1 (0.2) Bleeding index 2 9 (1.7) 0 (0) Secondry Minor bleeding 14 (2.7) 19 (3.7) Trnsfusions fter surgery 222 (42.9) 197 (38.1) Units trnsfused Deth 2 (0.4) 3 (0.6) PENTAMAKS = Pentscchride in Mjor Knee Surgery Study. Dt re no. (%) of ptients for ll outcomes except units trnsfused, which re the men no. of units/ptient. fter surgery, wheres the first fondprinux dose ws dministered 6 hours (rnge 4 8 hrs) fter surgery. However, if surgery ws to be delyed hours fter dmission, fondprinux ws dministered 12 hours before surgery. In ddition, if spinl or epidurl nesthesi ws plnned, preopertive injections were omitted. Fondprinux ws given preopertively to 11% of ptients, wheres enoxprin ws given preopertively to pproximtely 25% of ptients. Study design, exclusion criteri, nd efficcy nd sfety mesures were identicl to those of the previously mentioned trils (Tble 1). However, ptients in PENTHIFRA were excluded if they presented with trum ffecting more thn one orgn system, if more thn 24 hours hd elpsed between trum nd hospitliztion, or if surgery would be performed more thn 48 hours fter dmission. The risk of the primry end point of djudicted VTE ws reduced by 56.4% with fondprinux compred with enoxprin (Tble 8). The risks of the secondry end points of ny DVT, proximl DVT, nd distl DVT were reduced by 58.2%, 78.7%, nd 55.4%, respectively, with fondprinux compred with enoxprin

6 EMERGING OPTIONS FOR THROMBOPROPHYLAXIS AFTER ORTHOPEDIC SURGERY Lobo 71S Tble 8. Efficcy Outcomes to Dy 11: PENTHIFRA 4 Event Fondprinux Enoxprin p Vlue Adjudicted VTE 52/626 (8.3) 119/624 (19.1) <0.001 Any DVT 49/624 (7.9) 117/623 (18.8) <0.001 Proximl DVT 6/650 (0.9) 28/646 (4.3) <0.001 Distl DVT 42/627 (6.7) 94/626 (15.0) <0.001 Symptomtic VTE 4/831 (0.5) 4/840 (0.5) <1.00 PENTHIFRA = Pentscchride in Hip-Frcture Surgery Study; VTE = venous thromboembolism; DVT = deep vein thrombosis. Dt re no. of ptients with event/no. of evluble ptients (%). (p<0.001 for ll). Significntly more ptients in the enoxprin rm thn in the fondprinux rm were treted for VTE (11.7% vs 6.1%, p<0.001). Furthermore, of the ptients who were not treted for VTE, 58.5% of ptients in the fondprinux group nd 55.8% of ptients treted with enoxprin received prolonged thromboprophylxis. This very high rte of extended prophylxis combined with erly detection nd tretment of VTE probbly ccounts for the very low frequency nd similr symptomtic event rtes by dy 49 in the two groups. No significnt difference in the rtes of mjor bleeding ws seen in PENTHIFRA (Tble 9). However, minor bleeding occurred more commonly in the fondprinux rm (4.1% vs 2.1%, p=0.02). The PENTHIFRA tril estblished fondprinux s sfe nd efficcious gent for VTE prophylxis fter hip frcture surgery. It is currently the only product pproved by the FDA for this indiction. Met-nlysis of the Phse III Studies The very similr or identicl designs nd outcome mesures in the four phse III studies fcilitted met-nlysis of the efficcy nd sfety dt. 9 Of the 7344 ptients who were rndomized into these trils, pproximtely 25% of ptients in both groups could not be included in the efficcy nlysis, primrily becuse venogrphy could not be performed or the imges could not be evluted. There were 7237 ptients who received t lest one dose of study drug, nd their dt were therefore vilble for the nlysis of sfety. All but 36 ptients in the fondprinux group nd 34 ptients in the enoxprin group were followed up until dy 49. The overll frequency of VTE in the fondprinux-treted ptients ws 6.8%, compred with 13.7% in those ssigned to enoxprin. The common odds reduction in overll VTE of 55.2% in fvor of fondprinux ws significnt Tble 9. Sfety Outcomes to Dy 11: PENTHIFRA 4 Fondprinux Enoxprin Outcome (n=831) (n=842) Primry Ftl bleeding 0 (0) 1 (0.1) Bleeding into criticl orgn 0 (0) 0 (0) Repet surgery due to bleed 3 (0.4) 2 (0.2) Bleeding index 2 15 (1.8) 16 (1.9) Secondry Minor bleeding 34 (4.1) 18 (2.1) Trnsfusions fter surgery 421 (50.7) 422 (50.1) Units trnsfused Deth 11 (1.3) 16 (1.9) PENTHIFRA = Pentscchride in Hip-Frcture Surgery Study. Dt re no. (%) of ptients for ll outcomes except units trnsfused, which re men no. of units/ptient. (p<0.001, 95% confidence intervl %). Moreover, the common odds reduction in fvor of fondprinux for proximl DVT ws 57.4% (95% confidence intervl %). Superiority of fondprinux in the common odds reduction for VTE ws seen cross the three study popultions; specificlly, 45.3% in totl hip replcement, 61.6% in hip frcture surgery, nd 63.1% in mjor knee surgery (p<0.001 for ll 3 groups). The number of ptients who were treted for VTE ws significntly lower in the fondprinux group (5.5%) thn in the enoxprin group (9.7%, p<0.001). Approximtely 41% of both the fondprinux- nd the enoxprin-treted ptients received extended thromboprophylxis. This, combined with erly detection nd tretment of VTE, probbly ccounts for the low rte of symptomtic VTE in the fondprinux (0.6%) nd enoxprin (0.4%) groups (p=0.25). The rtes of ftl bleeding, bleeding into criticl orgn, bleed leding to repet surgery, nd minor bleeding did not differ between the two groups. However, mjor bleeding events were more common in fondprinux-treted ptients

7 72S Supplement to PHARMACOTHERAPY Volume 24, Number 7, 2004 (2.7%) thn in ptients treted with enoxprin (1.7%, p= 0.008). This finding cn be ttributed lrgely to incresed bleeding events ssocited only with bleeding index of 2 or more (in 2.3% of fondprinux-treted ptients vs only 1.5% of enoxprin-treted ptients). Mny ptients in the phse III trils received fondprinux sooner thn 6 hours fter surgery, since the recommended dosing window ws 4 8 hours fter surgery. A logistic regression model ws performed nd demonstrted significnt reltionship between the frequency of mjor bleeding nd the timing (3 9 hrs fter surgery) of the first fondprinux dose (p=0.008). This model demonstrted tht when the first dose of fondprinux ws dministered 6 or more hours fter surgery, superior efficcy of fondprinux ws mintined, yet the rte of mjor bleeding becme similr to the rte seen in the enoxprin rm. This finding underscores the importnce of witing 6 8 hours fter surgery before dministrtion of the first dose of fondprinux. The phse III clinicl tril results indicte tht fondprinux is more effective thn enoxprin, with similr mjor bleeding risks, when dosed ccording to the recommended lbeling. Further study on the efficcy of fondprinux when dosed the morning fter surgery is under wy. A study is currently under wy to exmine the efficcy of fondprinux when dosed either 6 8 hours fter surgery or on the morning of the dy fter surgery. In the mentime, fondprinux should not be dministered sooner thn 6 hours fter surgery (to minimize the risk of bleeding) nd not lter thn 8 hours fter surgery (to provide optiml ntithrombotic efficcy). Conclusion The risk of VTE fter orthopedic surgery remins high in United Sttes hospitls, with pproximtely 1% of ptients developing VTE during their hospitl sty. Efforts directed t improving the qulity of cre in this ptient popultion must include optimiztion of thromboprophylxis regimens. The evidence suggests tht fondprinux reduces the risk of VTE fter orthopedic surgery more effectively thn enoxprin, with similr sfety profile. References 1. Lssen MR, Buer KA, Eriksson BI, Turpie AGG, for the Europen Pentscchride Elective Surgery Study (EPHESUS) Steering Committee. Postopertive fondprinux versus preopertive enoxprin for prevention of venous thromboembolism in elective hip-replcement surgery: rndomised double-blind comprison. Lncet 2002;359: Turpie AGG, Buer KA, Eriksson BI, Lssen MR, for the PENTATHLON 2000 Study Steering Committee. Postopertive fondprinux versus postopertive enoxprin for prevention of venous thromboembolism fter elective hip-replcement surgery: rndomised double-blind tril. Lncet 2002;359: (Errtum in Lncet 2002;360:1102.) 3. Buer KA, Eriksson BI, Lssen MR, Turpie AGG, for the Steering Committee of the Pentscchride in Mjor Knee Surgery Study. Fondprinux compred with enoxprin for the prevention of venous thromboembolism fter elective mjor knee surgery. N Engl J Med 2001;345: Eriksson BI, Buer KA, Lssen MR, Turpie AGG, for the Steering Committee of the Pentscchride in Hip-Frcture Surgery Study. Fondprinux compred with enoxprin for the prevention of venous thromboembolism fter hip-frcture surgery. N Engl J Med 2001;345: Geerts WH, Heit JA, Clgett GP, et l. Prevention of venous thromboembolism. Chest 2001;119(suppl 1):S Aventis Phrmceuticls Inc. Lovenox (enoxprin sodium injection) pckge insert. Bridgewter, NJ; Ollendorf DA, Ver-Llonch M, Oster G. Cost of venous thromboembolism following mjor orthopedic surgery in hospitlized ptients. Am J Helth-Syst Phrm 2002;59: Eikelboom JW, Quinln DJ, Douketis JD. Extended-durtion prophylxis ginst venous thromboembolism fter totl hip or knee replcement: met-nlysis of the rndomized trils. Lncet 2001;358: Turpie AGG, Buer KA, Eriksson BI, Lssen MR. Fondprinux vs enoxprin for the prevention of venous thromboembolism in mjor orthopedic surgery: met-nlysis of 4 rndomized double-blind studies. Arch Intern Med 2002;162: