Background Venous thromboembolism is a frequent complicationof total hip replacement. The pentasaccharide Org31540/SR90107A,a highly selective, indirect inhibitor of activated factor X,is the first of a new class of synthetic antithrombotic agents.To determine the optimal dose for phase 3 studies, we conducteda dose-ranging study in which Org31540/SR90107A was comparedwith a low-molecular-weight heparin, enoxaparin, in patientsundergoing total hip replacement.
Methods In a double-blind study, patients were randomly assignedto postoperative administration of one of five daily doses ofOrg31540/SR90107A, given once daily, or to 30 mg of enoxaparin,given every 12 hours. Treatment was continued for 10 days oruntil bilateral venography was performed after a minimum of5 days.
Results Of 933 patients treated, 593 were eligible for the efficacyanalysis. With Org31540/SR90107A a dose effect was observed(P=0.002), with rates of venous thromboembolism of 11.8 percent,6.7 percent, 1.7 percent, 4.4 percent, and 0 percent for thegroups assigned to 0.75 mg, 1.5 mg, 3.0 mg, 6.0 mg, and 8.0mg of the drug, respectively, as compared with a rate of 9.4percent in the enoxaparin group. The reduction in the risk ofvenous thromboembolism was 82 percent for the 3.0-mg Org31540/SR90107Agroup (P= 0.01) and 29 percent for the 1.5-mg group (P=0.51).Enrollment in the 6.0-mg and 8.0-mg Org31540/SR90107A groupswas discontinued because of bleeding complications. Major bleedingoccurred 3.5 percent less frequently in the 0.75-mg group (P=0.01)and 3.0 percent less frequently in the 1.5-mg group (P=0.05)than in the enoxaparin group (in which the rate was similarto that in the 3.0-mg group).
Conclusions Org31540/SR90107A, a synthetic pentasaccharide,has the potential to improve significantly the risk–benefitratio for the prevention of venous thromboembolism, as comparedwith low-molecular-weight heparin.
Venous thromboembolism remains an important complication ofhip-replacement surgery, despite the use of preventive measures.The challenge is to reduce the incidence of this potentiallyfatal but preventable disease further. Current prophylactictreatments include low-molecular-weight heparins, adjusted-dosesubcutaneous heparin, and warfarin.1,2 Standard heparin andlow-molecular-weight heparins are heterogeneous compounds, derivedfrom animals, that have the potential to induce antiplateletantibodies and associated thrombotic events and to impair hemostasisthrough complex effects on platelet function. Org31540/SR90107A,the first compound in a new class of synthetic oligosaccharideswith antithrombotic effects, is a selective, antithrombin-dependent,indirect inhibitor of activated factor X (factor Xa).
Org31540/SR90107A consists of five saccharide units with sulfategroups strategically positioned to bind strongly and exclusivelyto antithrombin (dissociation constant, 50 nM), the primaryendogenous regulator of blood coagulation.3,4 Org31540/SR90107Ais not neutralized by platelet factor 4 and is highly unlikelyto cause thrombocytopenia.5,6,7,8,9,10 By selectively bindingto antithrombin, Org31540/SR90107A modifies the conformationof the antithrombin molecule; this conformational change specificallypotentiates (by a factor of about 300) the natural neutralizationof factor Xa by antithrombin.5 Neutralization of factor Xa interruptsthe blood-coagulation cascade and thus inhibits thrombin generationand development of thrombus without inactivating thrombin itself(Figure 1).10,11,12,13
Figure 1. Mechanism of Anticoagulant Action of Org31540/SR90107A.
The red X indicates that the inhibition of activated factor X leads to interruption of the coagulation cascade by preventing the activation of factor II (prothrombin) to factor IIa (thrombin). Org31540/SR90107A binds with high affinity to the pentasaccharide binding site on antithrombin, producing an irreversible conformational change in antithrombin; an arginine residue is exposed, which binds to and inhibits activated factor X, a key factor in the activation of coagulation. Org31540/SR90107A is then released and made available to bind to other antithrombin molecules.
In our preliminary studies of the prevention of thrombosis,a prophylactic dose of 8.0 mg of Org31540/SR90107A was determinedto be the highest dose that did not cause a significant increasein bleeding, whereas doses as low as 2.0 mg showed efficacy.We studied five doses of Org31540/SR90107A (0.75, 1.5, 3.0,6.0, and 8.0 mg) to determine the effect of the various doseson the safety and efficacy of the drug for the prevention ofvenous thromboembolism in patients undergoing total hip replacement.The randomized and parallel control group was given 30 mg ofsubcutaneous enoxaparin, a low-molecular-weight heparin, every12 hours.
Methods
Patients
Consecutive patients at the 69 study centers were eligible ifthey had no childbearing potential, were 18 years of age orolder, and had undergone elective hip-replacement surgery (primaryor revision). The most important criteria for exclusion weremajor orthopedic surgery within the 3 months before enrollment,a body weight of less than 45 kg or more than 135 kg, a knowncongenital or acquired tendency to bleed, renal impairment,uncontrolled hypertension, stroke or myocardial infarction withinthe 3 months before enrollment, a contraindication to heparintherapy, treatment with anticoagulant and antiplatelet drugsduring the week before enrollment, venous thromboembolism withinthe previous 12 months, and unusual difficulties during theadministration of epidural or spinal anesthesia. The use ofnonsteroidal antiinflammatory drugs was discouraged. These exclusioncriteria were consistent with the contraindications to therapywith enoxaparin.14
Study Design
We conducted a multicenter, randomized, parallel, double-blind,dose-ranging study comparing subcutaneous Org31540/SR90107Awith subcutaneous enoxaparin for the prevention of deep-veinthrombosis and symptomatic pulmonary embolism after total hipreplacement. The study was conducted according to the provisionsof the revised Declaration of Helsinki15 and the Guidelinesfor Good Clinical Practice.16 The research protocol was approvedby an institutional review board at each center. Written informedconsent was obtained from each patient before enrollment inthe trial. A central, independent adjudication committee reviewedboth safety and efficacy outcomes. An independent efficacy andsafety monitoring committee reviewed adjudicated data throughoutthe study, using the following predefined rules for stoppingthe administration of drugs to one or more of the dose groups:if the lower limit of the 95 percent confidence interval ofthe observed rate of major bleeding exceeded 3 percent, andif the lower limit of the 95 percent confidence interval ofthe observed rate of venous thromboembolism exceeded 15 percent.In addition, the efficacy and safety monitoring committee couldstop the study at any time if it thought that patients wereput at undue risk for any adverse event. The members of allcommittees were unaware of the patients' treatment assignments.
Treatment Regimens and Trial Drugs
Org31540/SR90107A was obtained by chemical synthesis (and suppliedby Sanofi–Synthelabo, Paris) and was administered oncedaily by subcutaneous injection. The target time for the firstinjection to patients in the study groups was six hours afterthe end of surgery (range, four to eight), followed by dailyinjections at 8 a.m.; the doses tested were 0.75 mg, 1.5 mg,3.0 mg, 6.0 mg, and 8.0 mg. A 30-mg dose of enoxaparin (Lovenoxor Clexane, Aventis Pharmaceutical, Bridgewater, N.J.) was givento patients in the control group every 12 hours by subcutaneousinjection. As recommended by the manufacturer, the first doseof enoxaparin was given 12 to 24 hours after the end of surgery,and the subsequent doses were given at 8 a.m. and 8 p.m. Allstudy drugs were given either for a maximum of 10 days or untilthe predischarge venogram was obtained after a minimum of 5days.14
Thromboembolic Events
Both the efficacy analysis and the regular update to the efficacyand safety monitoring committee were based exclusively on theincidence of venous thromboembolism as determined by the adjudicationcommittee. A clinically suspected episode of venous thromboembolismhad to be followed by adequate confirmatory testing to be acceptedas a confirmed venous thromboembolism.17,18 Bilateral venographywas performed according to the method of Rabinov and Paulin19at day 10 or at discharge (whichever came first), but not beforeday 5. Any intraluminal filling defect above or within the trifurcationof the calf veins was considered proximal deep-vein thrombosis.Each patient was categorized by the adjudication committee ashaving no deep-vein thrombosis, any deep-vein thrombosis, proximaldeep-vein thrombosis, or distal deep-vein thrombosis or wasconsidered unable to be evaluated.
In cases of clinical suspicion of pulmonary embolism, the centralindependent adjudication committee considered any of the followingdiagnostic results conclusive: a lung scan indicating a highprobability of pulmonary embolism; a lung scan indicating aprobability of pulmonary embolism that was not high combinedwith proof of deep-vein thrombosis; and an abnormal pulmonaryangiogram. All deaths were classified as either related or unrelatedto venous thromboembolism or bleeding.
Safety
Bleeding was defined as major if it was clinically overt andfatal, intracranial, or retroperitoneal, involved a criticalorgan, or led to reoperation for bleeding or hematoma at theoperative site. Overt bleeding was also defined as major ifhemoglobin levels declined more than 2 g per deciliter, if morethan 2 units of packed red cells or whole blood was transfused,or if the number of units transfused plus the decline in thehemoglobin level in grams per deciliter was greater than 2.Minor bleeding was defined as clinically overt bleeding thatdid not meet the criteria for major bleeding.
Statistical Analysis
A logistic-regression analysis was used to determine the existenceof a dose effect of Org31540/SR90107A on the primary outcomevariables. We made pairwise comparisons between the 0.75-mgdose of Org31540/SR90107A and the 1.5-mg and 3.0-mg doses, andbetween these doses and enoxaparin treatment, using Fisher'sexact tests with 95 percent confidence intervals. Relative riskswere calculated in secondary analyses. Bleeding events wereanalyzed during the treatment period (from the first dose to48 hours after the last dose) and follow-up period (until day42). The analyses of the incidence of major bleeding eventsduring the treatment period were similar to the analyses performedfor venous thromboembolism. All treated patients were includedin the safety analysis, and all patients with adequate datawith regard to the presence or absence of venous thromboembolismwithin the specified interval were considered in the efficacyanalysis. A stringent per-protocol analysis was performed toincrease the reliability of an observed dose effect and to strengthenthe results with regard to dose selection.
Results
A total of 950 consecutive patients were enrolled between November1996 and December 1997 in 70 centers in the United States, Canada,and Australia. Seventeen potential patients who were registeredwith the central randomization office were subsequently foundto be ineligible and were not treated. Thus, 933 eligible patientswere treated and included in the safety analysis. There wereno statistically significant differences among the six treatmentgroups with regard to demographic variables, surgical characteristics,or risk-factor profiles (Table 1). The median duration of treatmentwas similar in the six treatment groups (six days for patientsreceiving 0.75 mg of Org31540/SR90107A, 3.0 mg of Org31540/SR90107A,or enoxaparin and seven days for all other patients).
Table 1. Base-Line Characteristics of All Treated Patients.
On the advice of the efficacy and safety monitoring committee,additional patients were not assigned to the 8.0-mg dose ofOrg31540/SR90107A after 6 of 52 patients receiving this treatmentreported major bleeding episodes. Three weeks later, assignmentto the 6.0-mg dose of Org31540/SR90107A was stopped after 9of 72 patients receiving this treatment reported major bleedingepisodes. Six additional bleeding episodes in the 6.0-mg and8.0-mg groups (three in each) were reported shortly after theprespecified stopping rule was applied, and all were classifiedas major.
A total of 593 patients who could be evaluated were includedin the efficacy analysis, which used an intention-to-treat approach.The main reasons for exclusion from the efficacy analysis werethat bilateral venography was not performed; that the assessmentwas inadequate for conclusive adjudication; and that the assessmentwas performed before day 5, after day 10, or more than 24 hoursafter the last dose of study medication (Table 2). The higherpercentage of patients in the 8.0-mg group who were excludedfrom the efficacy analysis for having venography outside theallowed interval is explained by the cessation of treatmentbefore day 5 due to bleeding.
Table 2. Patients Excluded from and Included in the Intention-to-Treat and per-Protocol Analyses.
The incidence of venous thromboembolism in patients includedin the intention-to-treat analysis and the per-protocol analysisis summarized in Table 3. In the three Org31540/SR90107A treatmentgroups included in the safety and efficacy assessments, theobserved rates of venous thromboembolism in the intention-to-treatanalysis were 11.8 percent, 6.7 percent, and 1.7 percent forthe 0.75-mg, 1.5-mg, and 3.0-mg doses, respectively, demonstratinga clear dose effect. The proportions of patients with venousthromboembolism in the various Org31540/SR90107A groups wereanalyzed with the use of a logit model20 (Figure 2). No lackof fit was detected, and the proportion of patients with venousthromboembolism decreased as the dose of Org31540/SR90107A increased(P=0.002).
Figure 2. Dose–Response Curves for Org31540/SR90107A.
The observed rates of venous thromboembolism in the intention-to-treat population are depicted with solid squares, the observed rates of major bleeding in all patients with solid circles, dose–response curves as solid lines, and 95 percent confidence limits as dotted lines. The observed rates of venous thromboembolism and major bleeding in the enoxaparin group are depicted as an open square and an open circle, respectively, with I bars indicating the 95 percent confidence intervals. The curves indicate clear dose effects on both the rate of venous thromboembolism, which decreased with increasing doses (P=0.002), and the rate of major bleeding, which increased with increasing doses (P<0.001). The lower rate of venous thromboembolism in the 3.0-mg Org31540/SR90107A group, as compared with the 0.75-mg group (P=0.003) and the enoxaparin group (P=0.01), and the lower rates of major bleeding in the 0.75-mg and 1.5-mg groups, as compared with the enoxaparin group and the 3.0-mg group, indicate that a dose of 1.5 to 3.0 mg of Org31540/SR90107A has the potential to improve significantly the risk-to-benefit ratio for venous thromboembolism.
The 3.0-mg group had a lower rate of venous thromboembolism(1.7 percent) than both the 0.75-mg group (11.8 percent, P=0.003)and the enoxaparin group (9.4 percent, P=0.01) (Table 3). Thesedifferences were statistically significant in both the intention-to-treatanalysis and the per-protocol analysis. The observed reductionin the risk of venous thromboembolism was 29 percent for the1.5-mg group as compared with the enoxaparin group (6.7 percentvs. 9.4 percent, P=0.51) and 82 percent for the 3.0-mg group(1.7 percent vs. 9.4 percent, P=0.01). Two patients in the 0.75-mggroup had a pulmonary embolism during the treatment period.
The frequency of major or minor bleeding events and the 95 percentconfidence intervals are presented according to treatment groupin Table 4. All bleeding events occurred during the treatmentperiod, except in one patient who had a minor bleeding eventthree days after the last injection of enoxaparin. The proportionsof patients with major bleeding events in the various Org31540/SR90107Agroups were analyzed with the use of a logit model20 (Figure 2).No lack of fit was detected, and a statistically significantdose-dependent effect of Org31540/SR90107A was observed (P<0.001).The risk of a major bleeding event was correlated with increasingdoses of Org31540/SR90107A and was significantly lower in the0.75-mg, 1.5-mg, and 3.0-mg groups than in the 6.0-mg group(P<0.001, P<0.001, and P=0.001, respectively) and the8.0-mg group (P<0.001, P<0.001, and P=0.005, respectively).Furthermore, the proportion of patients with a major bleedingevent was significantly higher in the enoxaparin group thanin the 0.75-mg group (by 3.5 percent, P=0.01) and the 1.5-mggroup (by 3.0 percent, P=0.05) and was not significantly differentfrom the proportion in the 3.0-mg group.
No deaths occurred during the treatment period. Four patients(three in the 0.75-mg group and one in the enoxaparin group)died during the follow-up period. One patient in the enoxaparingroup died from a pulmonary embolism confirmed by autopsy. Theother three deaths (from myocardial infarction, intestinal necrosis,and dyspnea) were reported by the investigator to be unrelatedto the study drug and were determined by the adjudication committeeto be unrelated to bleeding or venous thromboembolism. Therewere no cases of clinically relevant drug-induced thrombocytopeniain any of the treatment groups.
Discussion
In this study, doses of the pentasaccharide Org31540/SR90107Awere administered in a double-blind fashion, and doses of enoxaparinwere administered in an open-label fashion. We accomplishedthe main objective of the study, which was to establish accuratedose–response curves for safety and efficacy and to determinethe optimal dose of Org31540/SR90107A for future clinical trialsof prophylaxis against venous thromboembolism in patients undergoingmajor orthopedic surgery. The statistically significant dose–responseeffect on both efficacy and safety was also supported by a cleardose–plasma level relation. All outcomes were evaluatedby members of an independent adjudication committee, who wereunaware of the patients' treatment assignments. The risk ofclinically suspected venous thromboembolism was very low inall treatment groups except for the 0.75-mg group, in whichtwo symptomatic cases of pulmonary embolism were confirmed.It is therefore unlikely that the blinded design of the studyhad a significant effect on the results.
The rates of exclusion from the efficacy analysis were similarfor all the groups in the study except for the 8.0-mg group,in which more patients were excluded who had adequate outcomeassessments outside the allowed interval. The finding of a significantdose response persisted when these patients were included inthe analysis. The proportion of patients with adequate venogramswithin the time allowed (80 percent) was similar to that reportedin earlier studies.21,22,23
Patients who undergo total hip replacement are at considerablerisk for venous thromboembolic complications, a risk reportedto be as high as 20 to 50 percent.1 All doses of Org31540/SR90107A,including the lowest dose of 0.75 mg, reduced this risk substantially,with low rates of major bleeding in the 0.75-mg and 1.5-mg groups.These observations are compatible with selective, potent inhibitionof factor Xa, which leads to a strong inhibition of thrombingeneration and thrombus formation and growth. In contrast toheparin, Org31540/SR90107A is highly selective and does notinteract with platelets or platelet factor 4, eliminating theneed to monitor the platelet count. Org31540/SR90107A is 100percent bioavailable and is not metabolized. The linear pharmacokineticsof Org31540/SR90107A show low variability and highly reproducibleand predictable effects. The half-maximal plasma concentrationis reached in 25 minutes, with a dose-independent half-lifeof 15 hours, characteristics that ensure that each daily doseis effective for 24 hours.
The rate of venous thromboembolism was lower with the well-toleratedonce-daily 1.5-mg and 3.0-mg doses than with 30 mg of enoxaparingiven every 12 hours. A dose of 1.5 to 3.0 mg of Org31540/SR90107Aadministered daily has the potential to improve significantlythe risk–benefit ratio for the prevention of venous thromboembolism,and it is currently being evaluated in patients undergoing majororthopedic surgery.
These findings suggest that selective inhibition of factor Xaby potentiation of the effects of antithrombin may be highlyeffective in the prevention of venous thromboembolism in patientsundergoing total hip replacement, and this prophylactic treatmentis associated with less bleeding at a level of protection similarto that of low-molecular-weight heparins.
Supported by Sanofi–Synthelabo Research, Malvern, Pa.
Dr. Hoek is an employee of Sanofi–Synthelabo Research.Drs. Turpie and Gallus have received grants from and servedas consultants to Sanofi–Synthelabo Research and othercompanies that develop treatments for venous thromboembolicdisease.
Source Information
From McMaster University, Hamilton, Ont., Canada (A.G.G.T.); Flinders Medical Centre, Adelaide, Australia (A.S.G.); and Sanofi–Synthelabo Research, Malvern, Pa. (J.A.H.).
Address reprint requests to Dr. Turpie at Hamilton Health Sciences, General Division, 237 Barton St. E., Hamilton, ON L8L 2X2, Canada, or at turpiea{at}mcmaster.ca.
References
Clagett GP, Anderson FA Jr, Geerts W, et al. Prevention of venous thromboembolism. Chest 1998;114:Suppl:531S-560S-531S-560S. [Free Full Text]
Nurmohamed MT, Rosendaal FR, Buller HR, et al. Low-molecular-weight heparin versus standard heparin in general and orthopaedic surgery: a meta-analysis. Lancet 1992;340:152-156. [CrossRef][Web of Science][Medline]
Petitou M, Lormeau JC, Choay J. Chemical synthesis of glycosaminoglycans: new approaches to antithrombotic drugs. Nature 1991;350:Suppl:30-33. [Medline]
van Boeckel CAA, Petitou M. The unique antithrombin III binding domain of heparin: a lead to new synthetic antithrombotics. Angew Chem Int Ed Engl 1993;32:1671-1690. [CrossRef]
Olson ST, Björk I, Sheffer R, Craig PA, Shore JD, Choay J. Role of the antithrombin-binding pentasaccharide in heparin acceleration of antithrombin-proteinase reactions: resolution of the antithrombin conformational change contribution to heparin rate enhancement. J Biol Chem 1992;267:12528-12538. [Free Full Text]
Herbert JM, Herault JP, Bernat A, et al. Biochemical and pharmacological properties of SANORG 32701, comparison with the "synthetic pentasaccharide" (SR 90107/ORG 31450) and standard heparin. Circ Res 1996;79:590-600. [Free Full Text]
Walenga JM, Jeske WP, Bara L, Samama MM, Fareed J. Biochemical and pharmacologic rationale for the development of a synthetic heparin pentasaccharide. Thromb Res 1997;86:1-36. [CrossRef][Web of Science][Medline]
Walenga JM, Fareed J. Relative contribution of factor Xa and factor IIA: inhibition in the mediation of the antithrombotic actions of LMWHs and synthetic heparin pentasaccharides. Thromb Haemorrhagic Disord 1991;3/2:53-9.
Lormeau JC, Herault JP. Comparative inhibition of extrinsic and intrinsic thrombin generation by standard heparin, a low molecular weight heparin and the synthetic ATIII-binding pentasaccharide. Thromb Haemost 1993;69:152-6, 176. [Web of Science][Medline]
Lormeau JC, Herault JP. The effect of the synthetic pentasaccharide SR90107/ORG 31540 on thrombin generation ex vivo is uniquely due to ATIII-mediated neutralization of factor Xa. Thromb Haemost 1995;74:1474-1477. [Web of Science][Medline]
Wessler S, Yin ET. On the antithrombotic action of heparin. Thromb Diath Haemorrh 1974;32:71-78. [Web of Science][Medline]
Wessler S. Small doses of heparin and a new concept of hypercoagulability. Thromb Diath Haemorrh 1975;33:81-86. [Web of Science][Medline]
Walenga JM, Bara L, Petitou M, Samama M, Fareed J, Choay J. The inhibition of the generation of thrombin and the antithrombotic effect of a pentasaccharide with sole anti-factor Xa activity. Thromb Res 1988;51:23-33. [CrossRef][Web of Science][Medline]
Lovenox (enoxaparin sodium injection). In: Physicians' desk reference. 54th ed. Montvale, N.J.: Medical Economics, 2000:2560.
World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. JAMA 2000;284:3043-3045. [Free Full Text]
Good clinical practice for trials on medicinal products in the European community. Good Clin Pract J 1994;1:Suppl.
Kearon C, Julian JA, Newman TE, Ginsberg JS. Noninvasive diagnosis of deep venous thrombosis: McMaster Diagnostic Imaging Practice Guideline Initiative. Ann Intern Med 1998;128:663-77. [Erratum, Ann Intern Med 1998;129:425.]
Ginsberg JS. Management of venous thromboembolism. N Engl J Med 1996;335:1816-1828. [Free Full Text]
Rabinov K, Paulin S. Roentgen diagnosis of venous thrombosis in the leg. Arch Surg 1972;104:134-144. [Free Full Text]
Patel HI. Sample size for a dose-response study. J Biopharm Stat 1992;2:1-8. [Erratum, J Biopharm Stat 1994;4:127.]
Eriksson BI, Wille-Jørgensen P, Kälebo P, et al. A comparison of recombinant hirudin with a low-molecular-weight heparin to prevent thromboembolic complications after total hip replacement. N Engl J Med 1997;337:1329-1335. [Free Full Text]
Planes A, Samama MM, Lensing AWA, et al. Prevention of deep vein thrombosis after hip replacement -- comparison of two low-molecular weight heparins, tinzaparin and enoxaparin. Thromb Haemost 1999;81:22-25. [Web of Science][Medline]
Turpie AGG, Kher A. Prevention of venous thrombosis after elective hip surgery. Orthopedics 1998;21:1275-1281. [Web of Science][Medline]
Appendix
The principal investigators who recruited patients for the studywere J. Muntz and G. Landon, Houston; P. Comp and T. Whitsett,Oklahoma City; J. McCutchen, Orlando, Fla.; D. Anderson, Halifax,N.S., Canada; P. Wells, Ottawa, Ont., Canada; S. Duffin, FortGordon, Ga.; L. Vickars, Vancouver, B.C., Canada; M. Holt, Herston,Australia; M. Mant, Edmonton, Alta., Canada; T.G. Schwaderer,Grand Rapids, Mich.; H. Salem, Box Hill, Australia; D. MacDonald,East Lansing, Mich.; B. L'Esperance and J. Kassis, Montreal;K. Duane, Tampa, Fla.; T. Brighton, Kogarah, Australia; D. Ma,Darlinghurst, Australia; P. Peters and G. Raj, Dallas; R. Ennis,Hollywood, Calif.; J. Christian, Augusta, Ga.; L. Desjardins,Ste. Foy, Que., Canada; I. Ziv, Buffalo, N.Y.; S. Dunitz, Tulsa,Okla.; F.A. Burke, Lexington, Ky.; K. Beer, Toledo, Ohio; A.Gallus, Bedford Park, Australia; S.M. Bates, Hamilton, Ont.,Canada; S.B. Lowe, Winston-Salem, N.C.; J. Cade, Parkville,Australia; M. Cruickshank, London, Ont., Canada; W.J. Kennedy,Sarasota, Fla.; D. Butler, Sacramento, Calif.; M. Koren andN. Abramson, Jacksonville, Fla.; C. Simons, Pendell, Pa.; R.Zimmerman, Portland, Oreg.; R.B. Sorrells, Little Rock, Ark.;C. Kollmer, South Daytona, Fla.; B. Richards, Southport, Australia;T.J. Chippendale, Oceanside, Calif.; J. Ohar and T. Hyers, St.Louis; C.W. Colwell, La Jolla, Calif.; R. Emerson, Plano, Calif.;R. Friedman, Charleston, S.C.; G.S. Kantor, Palm Beach Gardens,Fla.; B. Evans, Salt Lake City; W.J. Hopkinson, Maywood, Ill.;J. Karrasch, Kippa-Ring, Australia; G. Paiemont, San Francisco;M. Ward, Covina, Calif.; C. Chesterman, Randwick, Australia;R. Zann, Boca Raton, Fla.; G. Johnson, Minneapolis; P. Clagett,Dallas; D.G. Bramlet, St. Petersburg, Fla.; T. Shery, CulverCity, Calif.; T. Kneidel, Wichita, Kans.; H. Garewal, Tucson,Ariz.; N. Abramson, Jacksonville, Fla.; D. Eckhoff, Denver;C. Demers, Quebec, Que., Canada; T.V. Swanson, Las Vegas; D.Green and J. Chediak, Chicago; L. Kirkegaard, Tacoma, Wash.;C. Walker, Whittier, Calif.; E. Gan, Clayton, Australia; andB. Spetzler, Salem, Oreg.; central independent adjudicationcommittee: M. Gent, J. Hirsh, J. Ginsberg, C. Kearon, and J.Weitz, Hamilton, Ont., Canada; Efficacy and Safety MonitoringCommittee: M. Samama, Paris; H. Kwaan, Chicago; and A. Planes,Paris.
Lassen, M. R., Dahl, O., Mismetti, P., Zielske, D., Turpie, A. G.G.
(2008). SR123781A: A New Once-Daily Synthetic Oligosaccharide Anticoagulant for Thromboprophylaxis After Total Hip Replacement Surgery: The DRIVE (Dose Ranging Study in Elective Total Hip Replacement Surgery) Study. J Am Coll Cardiol
51: 1498-1504
[Abstract][Full Text]
Turpie, A. G.G.
(2008). Selective factor Xa inhibition with fondaparinux: from concept to clinical benefit. Eur Heart J Suppl
10: C1-C7
[Abstract][Full Text]
Stark, J. E., Vesta, K. S.
(2006). A Pharmacist-Initiated Method to Improve Venous Thromboembolic Prophylaxis Rates in Medically Ill Patients. Journal of Pharmacy Practice
19: 275-279
[Abstract]
Piazza, G., Goldhaber, S. Z.
(2006). Acute Pulmonary Embolism: Part II: Treatment and Prophylaxis. Circulation
114: e42-e47
[Full Text]
Wiles, N, Hunt, B J
(2006). Anticoagulation via anti-Factor Xa inhibition. Lupus
15: 167-171
[Abstract]
Bauer, K. A.
(2006). New Anticoagulants. ASH Education Book
2006: 450-456
[Abstract][Full Text]
Rowlingson, J. C., Hanson, P. B.
(2005). Neuraxial Anesthesia and Low-Molecular-Weight Heparin Prophylaxis in Major Orthopedic Surgery in the Wake of the Latest American Society of Regional Anesthesia Guidelines. Anesth. Analg.
100: 1482-1488
[Abstract][Full Text]
Mehta, S. R., Steg, P. G., Granger, C. B., Bassand, J.-P., Faxon, D. P., Weitz, J. I., Afzal, R., Rush, B., Peters, R. J.G., Natarajan, M. K., Velianou, J. L., Goodhart, D. M., Labinaz, M., Tanguay, J.-F., Fox, K. A.A., Yusuf, S., for the ASPIRE Investigators,
(2005). Randomized, Blinded Trial Comparing Fondaparinux With Unfractionated Heparin in Patients Undergoing Contemporary Percutaneous Coronary Intervention: Arixtra Study in Percutaneous Coronary Intervention: A Randomized Evaluation (ASPIRE) Pilot Trial. Circulation
111: 1390-1397
[Abstract][Full Text]
Savi, P., Chong, B. H., Greinacher, A., Gruel, Y., Kelton, J. G., Warkentin, T. E., Eichler, P., Meuleman, D., Petitou, M., Herault, J.-P., Cariou, R., Herbert, J.-M.
(2005). Effect of fondaparinux on platelet activation in the presence of heparin-dependent antibodies: a blinded comparative multicenter study with unfractionated heparin. Blood
105: 139-144
[Abstract][Full Text]
Turpie, A. G. G., Eriksson, B. I., Bauer, K. A., Lassen, M. R.
(2004). Fondaparinux. J Am Acad Orthop Surg
12: 371-375
[Full Text]
Young, G., Yonekawa, K. E, Nakagawa, P., Nugent, D. J
(2004). Argatroban as an alternative to heparin in extracorporeal membrane oxygenation circuits. Perfusion
19: 283-288
[Abstract]
Turpie, A. G.G., Bauer, K. A., Eriksson, B. I., Lassen, M. R.
(2004). Superiority of Fondaparinux Over Enoxaparin in Preventing Venous Thromboembolism in Major Orthopedic Surgery Using Different Efficacy End Points. Chest
126: 501-508
[Abstract][Full Text]
Simoons, M. L., Bobbink, I. W. G., Boland, J., Gardien, M., Klootwijk, P., Lensing, A. W. A., Ruzyllo, W., Umans, V. A. W. M., Vahanian, A., Van De Werf, F., Zeymer, U., PENTUA Investigators,
(2004). A dose-finding study of fondaparinux in patients with non-ST-segment elevation acute coronary syndromes: The Pentasaccharide in Unstable Angina (PENTUA) study. J Am Coll Cardiol
43: 2183-2190
[Abstract][Full Text]
Tonnessen, B. H., Money, S. R.
(2004). Low-Molecular-Weight Heparin Versus Coumarin for the Prevention of Recurrent Venous Thromboembolism in Patients With Cancer. PERSPECT VASC SURG ENDOVASC THER
16: 144-146
[Abstract]
Kahn, S. R., Ginsberg, J. S.
(2004). Relationship Between Deep Venous Thrombosis and the Postthrombotic Syndrome. Arch Intern Med
164: 17-26
[Abstract][Full Text]
Stark, J. E, Kilzer, W. J
(2004). Venous Thromboembolic Prophylaxis in Hospitalized Medical Patients. The Annals of Pharmacotherapy
38: 36-40
[Abstract][Full Text]
Nutescu, E. A, Wittkowsky, A. K
(2004). Direct Thrombin Inhibitors for Anticoagulation. The Annals of Pharmacotherapy
38: 99-109
[Abstract][Full Text]
Bauer, K. A.
(2003). New Pentasaccharides for Prophylaxis of Deep Vein Thrombosis: Pharmacology. Chest
124: 364S-370S
[Abstract][Full Text]
Turpie, A. G. G., Eriksson, B. I., Bauer, K. A., Lassen, M. R.
(2003). New Pentasaccharides for the Prophylaxis of Venous Thromboembolism: Clinical Studies. Chest
124: 371S-378S
[Abstract][Full Text]
Raskob, G. E., Hirsh, J.
(2003). Controversies in Timing of the First Dose of Anticoagulant Prophylaxis Against Venous Thromboembolism After Major Orthopedic Surgery. Chest
124: 379S-385S
[Abstract][Full Text]
Davidson, B. L., Sullivan, S. D., Kahn, S. R., Borris, L., Bossuyt, P., Raskob, G.
(2003). The Economics of Venous Thromboembolism Prophylaxis: A Primer for Clinicians. Chest
124: 393S-396S
[Abstract][Full Text]
Dewerchin, M., Herault, J.-P., Wallays, G., Petitou, M., Schaeffer, P., Millet, L., Weitz, J. I., Moons, L., Collen, D., Carmeliet, P., Herbert, J.-M.
(2003). Life-Threatening Thrombosis in Mice With Targeted Arg48-to-Cys Mutation of the Heparin-Binding Domain of Antithrombin. Circ. Res.
93: 1120-1126
[Abstract][Full Text]
Tran, A. H, Lee, G.
(2003). Fondaparinux for Prevention of Venous Thromboembolism in Major Orthopedic Surgery. The Annals of Pharmacotherapy
37: 1632-1643
[Abstract][Full Text]
Wiebe, E. M., Stafford, A. R., Fredenburgh, J. C., Weitz, J. I.
(2003). Mechanism of Catalysis of Inhibition of Factor IXa by Antithrombin in the Presence of Heparin or Pentasaccharide. J. Biol. Chem.
278: 35767-35774
[Abstract][Full Text]
Eriksson, B. I., Lassen, M. R.
(2003). Duration of Prophylaxis Against Venous Thromboembolism With Fondaparinux After Hip Fracture Surgery: A Multicenter, Randomized, Placebo-Controlled, Double-blind Study. Arch Intern Med
163: 1337-1342
[Abstract][Full Text]
Hyers, T. M.
(2003). Management of Venous Thromboembolism: Past, Present, and Future. Arch Intern Med
163: 759-768
[Abstract][Full Text]
Cohen, M.
(2003). The role of low-molecular-weight heparin in the management of acute coronary syndromes. J Am Coll Cardiol
41: 55S-61S
[Abstract][Full Text]
Bates, S. M., Ginsberg, J. S.
(2002). How we manage venous thromboembolism during pregnancy. Blood
100: 3470-3478
[Abstract][Full Text]
Bijsterveld, N. R., Moons, A. H., Boekholdt, S. M., van Aken, B. E., Fennema, H., Peters, R. J.G., Meijers, J. C.M., Buller, H. R., Levi, M.
(2002). Ability of Recombinant Factor VIIa to Reverse the Anticoagulant Effect of the Pentasaccharide Fondaparinux in Healthy Volunteers. Circulation
106: 2550-2554
[Abstract][Full Text]
Kalodiki, E., Nicolaides, A. N.
(2002). Superficial Thrombophlebitis and Low-Molecular-Weight Heparins. ANGIOLOGY
53: 659-663
[Abstract]
Guerrini, M., Raman, R., Venkataraman, G., Torri, G., Sasisekharan, R., Casu, B.
(2002). A novel computational approach to integrate NMR spectroscopy and capillary electrophoresis for structure assignment of heparin and heparan sulfate oligosaccharides. Glycobiology
12: 713-719
[Abstract][Full Text]
Heit, J. A.
(2002). The Potential Role of Fondaparinux as Venous Thromboembolism Prophylaxis After Total Hip or Knee Replacement or Hip Fracture Surgery. Arch Intern Med
162: 1806-1808
[Full Text]
Turpie, A. G. G., Bauer, K. A., Eriksson, B. I., Lassen, M. R., for the Steering Committees of the Pentasaccharide,
(2002). Fondaparinux vs Enoxaparin for the Prevention of Venous Thromboembolism in Major Orthopedic Surgery: A Meta-analysis of 4 Randomized Double-blind Studies. Arch Intern Med
162: 1833-1840
[Abstract][Full Text]
Strebel, N., Prins, M., Agnelli, G., Buller, H. R.
(2002). Preoperative or Postoperative Start of Prophylaxis for Venous Thromboembolism With Low-Molecular-Weight Heparin in Elective Hip Surgery?. Arch Intern Med
162: 1451-1456
[Abstract][Full Text]
Dyke, C. K., Becker, R. C., Kleiman, N. S., Hochman, J. S., Bovill, E. G., Lincoff, A. M., Gerstenblith, G., Dzavik, V., Gardner, L. H., Hasselblad, V., Zillman, L. A., Shimoto, Y., Robertson, T. L., Kunitada, S., Armstrong, P. W., Harrington, R. A.
(2002). First Experience With Direct Factor Xa Inhibition in Patients With Stable Coronary Disease: A Pharmacokinetic and Pharmacodynamic Evaluation. Circulation
105: 2385-2391
[Abstract][Full Text]
Van de Werf, F.J., Antman, E.M., Simoons, M.L.
(2002). Managing ST elevation myocardial infarction. Eur Heart J Suppl
4: E15-E23
[Abstract]
Murashige, N., Kami, M., Marlovits, S., Priestley, M., Scacewater, R., Eriksson, B. I., Diuguid, D. L.
(2002). Prevention of Venous Thromboembolism with Fondaparinux. NEJM
346: 940-942
[Full Text]
Corti, R., Fuster, V., Badimon, J.J.
(2002). Strategy for ensuring a better future for the vessel wall. Eur Heart J Suppl
4: A31-A41
[Abstract]
Eriksson, B. I., Bauer, K. A., Lassen, M. R., Turpie, A. G.G., the Steering Committee of the Pentasaccharide in H,
(2001). Fondaparinux Compared with Enoxaparin for the Prevention of Venous Thromboembolism after Hip-Fracture Surgery. NEJM
345: 1298-1304
[Abstract][Full Text]
Bauer, K. A., Eriksson, B. I., Lassen, M. R., Turpie, A. G.G., the Steering Committee of the Pentasaccharide in M,
(2001). Fondaparinux Compared with Enoxaparin for the Prevention of Venous Thromboembolism after Elective Major Knee Surgery. NEJM
345: 1305-1310
[Abstract][Full Text]
Diuguid, D. L.
(2001). Choosing a Parenteral Anticoagulant Agent. NEJM
345: 1340-1342
[Full Text]
Kelly, J., Rudd, A., Lewis, R.R., Hunt, B.J.
(2001). Screening for subclinical deep-vein thrombosis. QJM
94: 511-519
[Full Text]
NURMOHAMED, M T, DIJKMANS, B A C
(2001). Prevention of post-discharge venous thromboembolism in patients with rheumatoid arthritis undergoing knee or hip arthroplasty: a continuing matter of debate. Ann Rheum Dis
60: 905-907
[Full Text]
Coussement, P.K, Bassand, J.-P, Convens, C, Vrolix, M, Boland, J, Grollier, G, Michels, R, Vahanian, A, Vanderheyden, M, Rupprecht, H.-J, Van de Werf, F
(2001). A synthetic factor-Xa inhibitor (ORG31540/SR9017A) as an adjunct to fibrinolysis in acute myocardial infarction. The PENTALYSE study. Eur Heart J
22: 1716-1724
[Abstract]
Hull, R., Pineo, G., Landow, L., Turpie, A. G.G., Gallus, A. S., Hoek, J. A.
(2001). A Synthetic Pentasaccharide for the Prevention of Deep-Vein Thrombosis. NEJM
345: 291-292
[Full Text]
(2001). A New Alternative to Heparin. Journal Watch Cardiology
2001: 11-11
[Full Text]
(2001). A New Alternative to Heparin. JWatch General
2001: 3-3
[Full Text]
