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original articleT h e n e w e ngl a nd j o u r na l o f m e dic i n en engl j med 363;13 nejm.org september 23, 2010 1222Fondaparinux for the Treatmentof Superficial-Vein Thrombosis in the LegsHerv Decousus, M.D., Paolo Prandoni, M.D., Ph.D., Patrick Mismetti, M.D., Ph.D.,Rupert M. Bauersachs, M.D., Zoltn Boda, M.D., Benjamin Brenner, M.D.,

Silvy Laporte, Ph.D., Lajos Matyas, M.D., Saskia Middeldorp, M.D., Ph.D.,German Sokurenko, M.D., and Alain Leizorovicz, M.D.,for the CALISTO Study Group*From INSERM CIE3, F-42055 (H.D.),EA3065 Universit Jean-Monnet (H.D.,P.M., S.L.), and Service de Mdecine etThrapeutique (H.D., P.M.) and Unit dePharmacologie Clinique (P.M., S.L.), Cen-tre Hpitalier Universitaire Saint-Etienne,Hpital Nord all in Saint-Etienne, France;and Unit Mixte de Recherche 5558, Fac-ult Ren Thomas Hyacinthe Laennec,

Lyon, France (A.L.); the ThromboembolismUnit, University of Padua, Padua, Italy(P.P.); the Department of Vascular Medi-cine, Medical Department IV, KlinikumDarmstadt, Darmstadt, Germany (R.M.B.);the 2nd Department of Medicine, Univer-sity of Debrecen, Debrecen (Z.B.), and theDepartment of Vascular and Endovascu-lar Surgery, University Teaching HospitalMiskolc, Miskolc (L.M.) both in Hunga-ry; the Thrombosis and Hemostasis Unit,Rambam Health Care Campus, Technion,Israel Institute of Technology, Haifa, Is-

rael (B.B.); the Departments of ClinicalEpidemiology and General Internal Med-icine, Leiden University Medical Center,Leiden, the Netherlands (S.M.); and CityHospital 26, St. Petersburg, Russia (G.S.).Address reprint requests to Dr. Decoususat Service de Mdecine et Thrapeutique,Hpital Nord, CHU Saint-Etienne, 42055Saint-Etienne, CEDEX, France, or at [email protected].*Investigators participating in the Com-parison of Arixtra in Lower Limb Super-

ficial Vein Thrombosis with Placebo(CALISTO) trial are listed in the Supple-mentary Appendix, available at NEJM.org.N Engl J Med 2010;363:1222-32.Copyright 2010 Massachusetts Medical Society.A BS T R AC TBackgroundThe efficacy and safety of anticoagulant treatment for patients with acute, symptom-atic superficial-vein thrombosis in the legs, but without concomitant deep-veinthrombosis or symptomatic pulmonary embolism at presentation, have not been es-tablished.Methods

In a randomized, double-blind trial, we assigned 3002 patients to receive eitherfonda-parinux, administered subcutaneously at a dose of 2.5 mg once daily, or placebo

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for45 days. The primary efficacy outcome was a composite of death from any cause orsymptomatic pulmonary embolism, symptomatic deep-vein thrombosis, or symp-tomatic extension to the saphenofemoral junction or symptomatic recurrence ofsuperficial-vein thrombosis at day 47. The main safety outcome was major bleeding.

The patients were followed until day 77.ResultsThe primary efficacy outcome occurred in 13 of 1502 patients (0.9%) in the fonda-parinux group and 88 of 1500 patients (5.9%) in the placebo group (relative riskreduction with fondaparinux, 85%; 95% confidence interval [CI], 74 to 92; P

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Lyon, France (A.L.); the ThromboembolismUnit, University of Padua, Padua, Italy(P.P.); the Department of Vascular Medi-cine, Medical Department IV, KlinikumDarmstadt, Darmstadt, Germany (R.M.B.);the 2nd Department of Medicine, Univer-sity of Debrecen, Debrecen (Z.B.), and the

Department of Vascular and Endovascu-lar Surgery, University Teaching HospitalMiskolc, Miskolc (L.M.) both in Hunga-ry; the Thrombosis and Hemostasis Unit,Rambam Health Care Campus, Technion,Israel Institute of Technology, Haifa, Is-rael (B.B.); the Departments of ClinicalEpidemiology and General Internal Med-icine, Leiden University Medical Center,Leiden, the Netherlands (S.M.); and CityHospital 26, St. Petersburg, Russia (G.S.).Address reprint requests to Dr. Decousus

at Service de Mdecine et Thrapeutique,Hpital Nord, CHU Saint-Etienne, 42055Saint-Etienne, CEDEX, France, or at [email protected].*Investigators participating in the Com-parison of Arixtra in Lower Limb Super-ficial Vein Thrombosis with Placebo(CALISTO) trial are listed in the Supple-mentary Appendix, available at NEJM.org.N Engl J Med 2010;363:1222-32.Copyright 2010 Massachusetts Medical Society.A BS T R AC TBackground

The efficacy and safety of anticoagulant treatment for patients with acute, symptom-atic superficial-vein thrombosis in the legs, but without concomitant deep-veinthrombosis or symptomatic pulmonary embolism at presentation, have not been es-tablished.MethodsIn a randomized, double-blind trial, we assigned 3002 patients to receive eitherfonda-parinux, administered subcutaneously at a dose of 2.5 mg once daily, or placebofor45 days. The primary efficacy outcome was a composite of death from any cause orsymptomatic pulmonary embolism, symptomatic deep-vein thrombosis, or symp-tomatic extension to the saphenofemoral junction or symptomatic recurrence ofsuperficial-vein thrombosis at day 47. The main safety outcome was major bleeding.The patients were followed until day 77.ResultsThe primary efficacy outcome occurred in 13 of 1502 patients (0.9%) in the fonda-parinux group and 88 of 1500 patients (5.9%) in the placebo group (relative riskreduction with fondaparinux, 85%; 95% confidence interval [CI], 74 to 92; P

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the outcome of death (0.1% in both groups). The rate of pulmonary embolism ordeep-vein thrombosis was 85% lower in the fondaparinux group than in the pla-cebo group (0.2% vs. 1.3%; 95% CI, 50 to 95; P

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Fondaparinux for Superficial-Vein Thrombosisn engl j med 363;13 nejm.org september 23, 2010 1223Superficial-vein thrombosis of thelegs is a common condition,1,2 with an es-timated incidence that may exceed that ofdeep-vein thrombosis.3,4 Patients with isolated su-

perficial-vein thrombosis that is, without con-comitant deep-vein thrombosis or symptomaticpulmonary embolism at presentation are at riskfor subsequent symptomatic venous thromboem-bolic complications.1-7 In a large, prospective, ob-servational study, the 3-month risk of such com-plications was 8.3%, with a 3.3% risk of deep-veinthrombosis or pulmonary embolism.8The treatment of this disease has not beenadequately addressed in randomized trials. Ac-cordingly, the recommendations in various guide-lines are weak, and in practice, therapeutic strate-

gies vary, ranging from no treatment to the useof antiinflammatory agents or anticoagulant drugsor surgery.8-14 The few randomized studies thathave been performed did not clarify the circum-stances under which surgery is required or thevalue or optimal dose and duration of anticoagu-lant or antiinflammatory therapy.6,15-19 The resultsof the two largest studies, evaluating low-molecu-lar-weight heparin, suggest that high-dose (ther-apeutic) or intermediate-dose regimens do notprovide substantial benefits over low-dose (pro-phylactic) regimens and that a treatment periodof 12 days or of 30 days is too short, with most

symptomatic thromboembolic complications oc-curring after the treatment period.6,17 None ofthe published studies showed a clinically rele-vant benefit of any treatment as compared withplacebo.6,7 Thus, the aim of our study was todetermine whether there is a well-defined treat-ment that could provide a benefit.We conducted the Comparison of Arixtra inLower Limb Superficial Vein Thrombosis withPlacebo (CALISTO) trial to evaluate the efficacyand safety of fondaparinux, a specific factor Xainhibitor, in reducing symptomatic venous throm-boembolic complications or death from any causein patients with acute, isolated superficial-veinthrombosis of the legs. For the active treatment,we selected the prophylactic dose of 2.5 mg offondaparinux once daily, because this dose hasbeen shown to be reasonably effective and to havean acceptable side-effect and adverse-event pro-file in a broad range of conditions.20-23 Treatmentwas to be administered for 45 days.Me t hodsPatientsHospitalized or nonhospitalized patients 18 yearsof age or older, with acute, symptomatic lower-

limb superficial-vein thrombosis at least 5 cm long,as confirmed by standardized compression ultra-sonography, were eligible to undergo randomiza-

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tion. Patients were excluded if the interval betweenthe onset of their symptoms and planned random-ization was more than 3 weeks; if they had beentreated for cancer within the previous 6 months;if they presented with symptomatic or asymptom-atic deep-vein thrombosis, symptomatic docu-mented pulmonary embolism, or superficial-vein

thrombosis associated with sclerotherapy or place-ment of an intravenous catheter or located within3 cm of the saphenofemoral junction; or if they hada documented history of superficial-vein throm-bosis within the previous 3 months or deep-veinthrombosis or pulmonary embolism within theprevious 6 months. Patients were also excludedfrom randomization if they had received an anti-thrombotic agent for more than 48 hours (otherthan aspirin at a dose =325 mg per day) or a non-steroidal antiinflammatory drug for more than72 hours as treatment for the current episode of

superficial-vein thrombosis or if, in the investiga-tors opinion, they required ligation of the sa-phenofemoral junction or stripping of varicoseveins. Other exclusion criteria were major surgerywithin the previous 3 months and conditions thatcould confer a predisposition to bleeding, includ-ing severe hepatic impairment, a creatinine clear-ance of less than 30 ml per minute, and a plateletcount of less than 100,000 per cubic millimeter.Finally, women of childbearing age were excludedif they were pregnant or were not using a reliablecontraceptive method.Study Design

This trial was an international, multicenter, ran-domized, double-blind, placebo-controlled study;the protocol, including the statistical analysis plan,is available with the full text of this article atNEJM.org. With the use of a central telephone sys-tem and a computer-generated randomization list,consecutive patients were randomly assigned, ina 1:1 ratio, to fondaparinux at a dose of 2.5 mg ormatching placebo, administered subcutaneouslyThe New England Journal of MedicineDownloaded from nejm.org on June 6, 2011. For personal use only. No other uses without permission.Copyright 2010 Massachusetts Medical Society. All rights reserved.Me t hodsPatientsHospitalized or nonhospitalized patients 18 yearsof age or older, with acute, symptomatic lower-limb superficial-vein thrombosis at least 5 cm long,as confirmed by standardized compression ultra-sonography, were eligible to undergo randomiza-tion. Patients were excluded if the interval betweenthe onset of their symptoms and planned random-ization was more than 3 weeks; if they had beentreated for cancer within the previous 6 months;if they presented with symptomatic or asymptom-

atic deep-vein thrombosis, symptomatic docu-mented pulmonary embolism, or superficial-veinthrombosis associated with sclerotherapy or place-

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ment of an intravenous catheter or located within3 cm of the saphenofemoral junction; or if they hada documented history of superficial-vein throm-bosis within the previous 3 months or deep-veinthrombosis or pulmonary embolism within theprevious 6 months. Patients were also excludedfrom randomization if they had received an anti-

thrombotic agent for more than 48 hours (otherthan aspirin at a dose =325 mg per day) or a non-steroidal antiinflammatory drug for more than72 hours as treatment for the current episode ofsuperficial-vein thrombosis or if, in the investiga-tors opinion, they required ligation of the sa-phenofemoral junction or stripping of varicoseveins. Other exclusion criteria were major surgerywithin the previous 3 months and conditions thatcould confer a predisposition to bleeding, includ-ing severe hepatic impairment, a creatinine clear-ance of less than 30 ml per minute, and a platelet

count of less than 100,000 per cubic millimeter.Finally, women of childbearing age were excludedif they were pregnant or were not using a reliablecontraceptive method.Study DesignThis trial was an international, multicenter, ran-domized, double-blind, placebo-controlled study;the protocol, including the statistical analysis plan,is available with the full text of this article atNEJM.org. With the use of a central telephone sys-tem and a computer-generated randomization list,consecutive patients were randomly assigned, ina 1:1 ratio, to fondaparinux at a dose of 2.5 mg or

matching placebo, administered subcutaneouslyThe New England Journal of MedicineDownloaded from nejm.org on June 6, 2011. For personal use only. No other uses without permission.Copyright 2010 Massachusetts Medical Society. All rights reserved.

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Copyright 2010 Massachusetts Medical Society. All rights reserved.

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Fondaparinux for Superficial-Vein Thrombosisn engl j med 363;13 nejm.org september 23, 2010 1225primary efficacy outcome, assuming an incidenceof the primary efficacy outcome of 8.0% in theplacebo group,6,8,17 at a two-sided 5% level of sig-nificance. As planned, the independent steering

committee, whose members were unaware of thegroup assignments, monitored the overall eventrate for the primary efficacy outcome. On No-vember 5, 2008, on the basis of an observed rate ofthe primary efficacy outcome of 3.1%, the com-mittee decided to increase the sample to 3000 pa-tients in order to preserve at least 90% power todetect a 50% reduction in the rate of the primaryefficacy outcome in the fondaparinux group.Efficacy analyses were performed on data fromthe intention-to-treat population, which includedall the patients who had undergone randomiza-

tion. Patients for whom a primary efficacy assess-ment was lacking (i.e., those with no events andno information on their status with respect to ef-ficacy at day 452) were assumed not to have hadany event. Safety analyses were performed on datafrom the as-treated population, which comprisedall patients who had undergone randomizationand who had received at least one dose of thestudy drug.A two-sided Fishers exact test at the 5% sig-nificance level was performed for efficacy evalu-ations, and the resulting P values are reported.Absolute differences and relative risks, with 95%

confidence intervals, are also reported. Time-to-event outcomes estimated by means of the Kap-lanMeier method were compared with the useof the log-rank test. A prespecified sensitivityanalysis was performed in which patients withmissing data on the primary efficacy outcomewere excluded. Zelens exact test was used to verifythe consistency of the treatment effect across 16prespecified sets of subgroups and 1 set of sub-groups that was defined post hoc.24R e sult sStudy Populations and TreatmentsBetween March 2007 and May 2009, a total of3002 patients were enrolled at 171 centers in 17countries (see the Supplementary Appendix) 1502 in the fondaparinux group and 1500 in theplacebo group. Of the 3002 patients who under-went randomization, 18 patients in the fonda-parinux group (1.2%) and 22 in the placebo group(1.5%) did not have a primary efficacy assessment(Table 1 in the Supplementary Appendix). Overall,1481 patients in the fondaparinux group (98.6%)and 1467 in the placebo group (97.8%) completedthe follow-up visit at day 752 (Table 2 in the Sup-plementary Appendix). Of the 3002 patients who

underwent randomization, 4 patients in the fonda-parinux group and 11 in the placebo group re-ceived no study drug (as a result of the patients

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decision, in each case), and 1 patient who was ran-domly assigned to the placebo group received atleast one dose of fondaparinux in error; thus, 1499patients in the fondaparinux group (99.8%) and1488 in placebo group (99.2%) were included inthe safety analyses.The demographic and clinical characteristics of

the patients, the medications and interventionsthe patients received before their entry into thestudy (Table 1, and Table 3 in the SupplementaryAppendix), the duration of treatment, and the ad-herence to treatment, as calculated with the useof a formula that was based on the number ofsyringes used and the number returned unused(Table 2), were well balanced between the twogroups. In addition, the treatments other than thestudy drugs that patients received during thecourse of the study were well balanced betweenthe two groups, with two exceptions: patients in

the placebo group received anticoagulant drugs ororal nonsteroidal antiinflammatory drugs morefrequently than did patients in the fondaparinuxgroup (Table 2).Efficacy OutcomesThe primary efficacy outcome occurred in 13 of1502 patients (0.9%) in the fondaparinux groupand 88 of 1500 patients (5.9%) in the placebo group(relative risk with fondaparinux, 0.15; 95% confi-dence interval [CI], 0.08 to 0.26; P

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tients in order to preserve at least 90% power todetect a 50% reduction in the rate of the primaryefficacy outcome in the fondaparinux group.Efficacy analyses were performed on data fromthe intention-to-treat population, which includedall the patients who had undergone randomiza-tion. Patients for whom a primary efficacy assess-

ment was lacking (i.e., those with no events andno information on their status with respect to ef-ficacy at day 452) were assumed not to have hadany event. Safety analyses were performed on datafrom the as-treated population, which comprisedall patients who had undergone randomizationand who had received at least one dose of thestudy drug.A two-sided Fishers exact test at the 5% sig-nificance level was performed for efficacy evalu-ations, and the resulting P values are reported.Absolute differences and relative risks, with 95%

confidence intervals, are also reported. Time-to-event outcomes estimated by means of the Kap-lanMeier method were compared with the useof the log-rank test. A prespecified sensitivityanalysis was performed in which patients withmissing data on the primary efficacy outcomewere excluded. Zelens exact test was used to verifythe consistency of the treatment effect across 16prespecified sets of subgroups and 1 set of sub-groups that was defined post hoc.24R e sult sStudy Populations and TreatmentsBetween March 2007 and May 2009, a total of

3002 patients were enrolled at 171 centers in 17countries (see the Supplementary Appendix) 1502 in the fondaparinux group and 1500 in theplacebo group. Of the 3002 patients who under-went randomization, 18 patients in the fonda-parinux group (1.2%) and 22 in the placebo group(1.5%) did not have a primary efficacy assessment(Table 1 in the Supplementary Appendix). Overall,1481 patients in the fondaparinux group (98.6%)and 1467 in the placebo group (97.8%) completedthe follow-up visit at day 752 (Table 2 in the Sup-plementary Appendix). Of the 3002 patients whounderwent randomization, 4 patients in the fonda-parinux group and 11 in the placebo group re-ceived no study drug (as a result of the patientsdecision, in each case), and 1 patient who was ran-domly assigned to the placebo group received atleast one dose of fondaparinux in error; thus, 1499patients in the fondaparinux group (99.8%) and1488 in placebo group (99.2%) were included inthe safety analyses.The demographic and clinical characteristics ofthe patients, the medications and interventionsthe patients received before their entry into thestudy (Table 1, and Table 3 in the Supplementary

Appendix), the duration of treatment, and the ad-herence to treatment, as calculated with the useof a formula that was based on the number of

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syringes used and the number returned unused(Table 2), were well balanced between the twogroups. In addition, the treatments other than thestudy drugs that patients received during thecourse of the study were well balanced betweenthe two groups, with two exceptions: patients inthe placebo group received anticoagulant drugs or

oral nonsteroidal antiinflammatory drugs morefrequently than did patients in the fondaparinuxgroup (Table 2).Efficacy OutcomesThe primary efficacy outcome occurred in 13 of1502 patients (0.9%) in the fondaparinux groupand 88 of 1500 patients (5.9%) in the placebo group(relative risk with fondaparinux, 0.15; 95% confi-dence interval [CI], 0.08 to 0.26; P

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The new england journal of medicine

Table 1. Baseline Characteristics of the Study Patients.*CharacteristicAge yrFemale sex no. (%)

Body-mass indexMean=30 no. (%)Medical conditions no. (%)Varicose veinsPrevious superficial-vein thrombosisPrevious deep-vein thrombosis or pulmonary embolismCardiovascular diseaseHeart failure or respiratory failureChronicAcuteKnown thrombophilia

Autoimmune diseaseAcute infectious diseaseHistory of cancerCurrent hospitalizationTraumaTreatment at inclusion no. (%)Graduated compression stockingsAnalgesic agentsTopical nonsteroidal antiinflammatory drugsTopical anticoagulant drugsOral nonsteroidal antiinflammatory drugs or COX-2 inhibitorsOral or parenteral anticoagulant drugsAspirin or other antiplatelet agents

GlucocorticoidsOral contraceptive or hormone-replacement therapyFondaparinux(N = 1502)57.113.3974 (64.8)29.25.2574 (38.2)1331 (88.6)178 (11.9)105 (7.0)71 (4.7)71 (4.7)5 (0.3)20 (1.3)12 (0.8)11 (0.7)32 (2.1)10 (0.7)10 (0.7)1131 (75.3)391 (26.0)598 (39.8)57 (3.8)54 (3.6)

67 (4.5)347 (23.1)34 (2.3)

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43 (2.9)Placebo(N = 1500)56.913.6944 (62.9)29.05.4536 (35.7)

1329 (88.6)178 (11.9)104 (6.9)66 (4.4)88 (5.9)1 (0.1)18 (1.2)14 (0.9)8 (0.5)29 (1.9)11 (0.7)16 (1.1)

1147 (76.5)401 (26.7)608 (40.5)50 (3.3)65 (4.3)58 (3.9)364 (24.3)25 (1.7)40 (2.7)P Value0.690.290.32

0.161.001.001.000.730.170.220.870.700.650.800.830.250.470.680.710.550.310.460.470.290.82

* Plusminus values are means SD. The P values were calculated with the use of Students t-test for continuous varia

bles and Fishers exact test for categoricalvariables. The body-mass index is the weight in kilograms divided by the square of the heig

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ht in meters. Cardiovascular disease includes myocardial infarction, ischemic stroke, and peripheral arterial occlusive disorder.Data are shown for patients in whom the condition was present at baseline or hadoccurred within the previous4 weeks.

tained at day 77 (Fig. 1 and Table 3). The treatmenteffect was consistent across all the subgroups weexamined (Fig. 2). Finally, more patients in the placebogroup than in the fondaparinux group underwentsurgery for superficial-vein thrombosis(Table 3), including ligation of the saphenofemoraljunction, which by day 77 had been performed

in 52 patients in the placebo group (3.5%), as comparedwith 8 in the fondaparinux group (0.5%).

Safety Outcomes

By day 47, major bleeding had occurred in onepatient (0.1%) in each group (P=1.00). The ratesof clinically relevant nonmajor, minor, and total

n engl j med 363;13 nejm.org september 23, 2010

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Fondaparinux for Superficial-Vein Thrombosis

Table 2. Treatment Received during the Study.*TreatmentStudy treatmentReceipt of at least one injection of study drug no. (%)

Mean days of treatmentDuration of treatment no./total no. (%)=10 days1130 days3145 days>45 daysSelf-administered treatment no. (%)Adherence to treatmentPatients who adhered no. (%)Mean adherence %Other treatmentsGraduated compression stockings no. (%)

Analgesic agents no. (%)Topical nonsteroidal antiinflammatory drugs no. (%)Topical anticoagulant drugs no. (%)Oral nonsteroidal antiinflammatory drugs or COX-2 inhibitors no. (%)Oral or parenteral anticoagulant treatment no. (%)High (therapeutic) doseIntermediate doseLow (prophylactic) doseUnknown doseAspirin or other antiplatelet agents no. (%)Fondaparinux(N = 1502)1499 (99.8)

43.67.335/1499 (2.3)26/1499 (1.7)1161/1499 (77.5)277/1499 (18.5)1360/1499 (90.7)1434 (95.5)98.38.91247 (83.0)416 (27.7)623 (41.5)59 (3.9)32 (2.1)17 (1.1)10 (0.7)1 (0.1)6 (0.4)2 (0.1)322 (21.4)Placebo(N = 1500)1488 (99.2)41.211.095/1488 (6.4)66/1488 (4.4)

1091/1488 (73.3)236/1488 (15.9)1364/1488 (91.7)

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1329 (88.6)98.48.71247 (83.1)428 (28.5)627 (41.8)50 (3.3)56 (3.7)

96 (6.4)62 (4.1)6 (0.4)44 (2.9)3 (0.2)339 (22.6)

* Plusminus values are means SD. Patients were considered not to have adhered to treatment if they received lessthan 80% of the scheduled study drug(i.e.,

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The new england journal of medicine

Table 3. Efficacy Outcomes.Efficacy OutcomeBy Day 47Primary composite outcome

DeathPulmonary embolismDeep-vein thrombosisExtension of superficial-vein thrombosis tothe saphenofemoral junctionRecurrence of superficial-vein thrombosisDeep-vein thrombosis or pulmonary embolismSurgery for superficial-vein thrombosisBy Day 77Composite outcomeDeathPulmonary embolism

Deep-vein thrombosisExtension of superficial-vein thrombosis tothe saphenofemoral junctionRecurrence of superficial-vein thrombosisDeep-vein thrombosis or pulmonary embolismSurgery for superficial-vein thrombosisFondaparinux(N = 1502)Placebo(N = 1500)no. with event (%)13 (0.9) 88 (5.9)2 (0.1) 1 (0.1)

0 5 (0.3)3 (0.2) 18 (1.2)4 (0.3) 51 (3.4)5 (0.3) 24 (1.6)3 (0.2) 20 (1.3)11 (0.7) 57 (3.8)18 (1.2) 94 (6.3)2 (0.1) 1 (0.1)0 6 (0.4)4 (0.3) 19 (1.3)5 (0.3) 54 (3.6)8 (0.5) 26 (1.7)4 (0.3) 22 (1.5)15 (1.0) 61 (4.1)Absolute Risk Reductionwith Fondaparinuxpercentage points (95% CI)-5.0 (-6.3 to -3.7)0.1 (-0.2 to 0.3)-0.3 (-0.6 to 0.0)-1.0 (-1.6 to -0.4)-3.1 (-4.1 to -2.2)-1.3 (-2.0 to -0.6)-1.1 (-1.8 to -0.5)-3.1 (-4.1 to -2.0)

-5.1 (-6.4 to -3.7)0.1 (-0.2 to 0.3)-0.4 (-0.7 to -0.1)

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-1.0 (-1.6 to -0.4)-3.3 (-4.3 to -2.3)-1.2 (-2.0 to -0.4)-1.2 (-1.9 to -0.5)-3.1 (-4.2 to -1.9)Relative Risk withFondaparinux

% (95% CI)0.15 (0.08 to 0.26)1.99 (0.18 to 21.87)Not calculated0.17 (0.05 to 0.56)0.08 (0.03 to 0.22)0.21 (0.08 to 0.54)0.15 (0.05 to 0.50)0.19 (0.10 to 0.37)0.19 (0.12 to 0.32)1.99 (0.18 to 21.87)Not calculated

0.21 (0.07 to 0.62)0.09 (0.04 to 0.23)0.31 (0.14 to 0.68)0.18 (0.06 to 0.53)0.25 (0.14 to 0.43)P Value*

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from close clinical monitoring, with adequate diagnosticprocedures performed in the event of newor persistent symptoms, and since an independentdata and safety monitoring committee carefullyoversaw the study outcomes.

The patients in our study are representative of

those encountered in routine practice1,2,8: almost

all were outpatients, and there was a clear predominanceof women and a substantial proportionof obese patients, most presenting with varicoseveins and superficial-vein thrombosis involvingthe great saphenous vein. The rate of symptomaticthromboembolic complications in the placebogroup at day 47 (5.9%; 95% CI, 4.7 to 7.2) wasin the low range of the expected rate of thromboembolicevents, possibly because very-high-riskpatients (e.g., those with active cancer or a recent

history of venous thromboembolism and those inwhom the thrombus was located within 3 cm ofthe saphenofemoral junction) were not enrolled inthis placebo-controlled trial. However, this rateand the corresponding rate at day 77 (6.3%; 95%CI, 5.1 to 7.6) are consistent with that observed at3 months in a prospective observational study inwhich a similar composite outcome was evaluated


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Fondaparinux for Superficial-Vein ThrombosisCumulativeHazard(%)100806040

2000 5 10 15 20 35 40 45 50 55 60 65 70 7525 80309.008.007.006.005.004.003.002.001.00

0.000 5 10 15 20 35 40 45 50 55 60 65 70 7525 8030DaysHazard ratio at day 47,0.14 (95% CI, 0.080.26);P

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T h e n e w e ng l a n d j o u r na l o f m e dic i n en engl j med 363;13 nejm.org september 23, 2010 1230of surgery, primarily ligation of the saphenofem-oral junction, for superficial-vein thrombosis a prespecified secondary outcome. In addition,more patients in the placebo group than in the

fondaparinux group required therapeutic dosesof anticoagulant therapy.A potential limitation of our study is the dif-ficulty in applying the data to clinical practice,because a complete ultrasonographic examinationwas performed in every patient with a suspectedsuperficial-vein thrombosis first, to confirmthe condition, and second, to rule out the pres-ence of deep-vein thrombosis. However, perform-ing a complete ultrasonographic examination mayhelp physicians avoid treating patients who donot have thrombosis and allow the appropriate

0.50.20.10.050.02 1.0 5.02.0PlaceboBetterFondaparinuxBetterAge75 yrSexMaleFemaleWeight100 kg

Body-mass index

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Distance of thrombus from sapheno-femoral junction

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0.12 (0.050.25)0.22 (0.090.52)0.10 (0.010.77)0.010.06 (0.010.41)11/1031 (1.1)1/375 (0.3)

1/114 (0.9)6/528 (1.1)7/974 (0.7)0/2 (0.0)10/1313 (0.8)3/183 (1.6)7/922 (0.8)6/574 (1.0)0/68 (0.0)4/412 (1.0)9/1007 (0.9)1/105 (1.0)

12/1397 (0.9)0/178 (0.0)13/1324 (1.0)1/32 (3.1)12/1470 (0.8)10/1331 (0.8)3/171 (1.8)5/710 (0.7)8/791 (1.0)13/1399 (0.9)0/103 (0.0)1/117 (0.9)11/1235 (0.9)

13/1502 (0.9)The New England Journal of MedicineDownloaded from nejm.org on June 6, 2011. For personal use only. No other uses without permission.Copyright 2010 Massachusetts Medical Society. All rights reserved.0.50.20.10.050.02 1.0 5.02.0PlaceboBetterFondaparinuxBetterAge75 yrSexMaleFemaleWeight100 kgBody-mass index

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NoHistory of superficial-vein thrombosisYesNoHistory of cancerYesNo

Varicose veins at inclusionYesNoSuperficial-vein thrombosis locationrelative to the kneeAboveBelow onlySuperficial-vein thrombosis involvinggreat saphenous veinYesNoDistance of thrombus from sapheno-

femoral junction

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0.13 (0.070.25)0.14 (0.080.25)ND0.15 (0.080.28)0.10 (0.010.76)ND0.18 (0.100.32)

0.21 (0.100.44)0.15 (0.080.26)0.15 (0.080.26)0.15 (0.080.31)ND0.18 (0.060.51)0.16 (0.070.37)0.14 (0.060.31)0.20 (0.060.67)0.14 (0.070.27)ND0.12 (0.050.25)

0.22 (0.090.52)0.10 (0.010.77)0.010.06 (0.010.41)11/1031 (1.1)1/375 (0.3)1/114 (0.9)6/528 (1.1)7/974 (0.7)0/2 (0.0)10/1313 (0.8)3/183 (1.6)7/922 (0.8)

6/574 (1.0)0/68 (0.0)4/412 (1.0)9/1007 (0.9)1/105 (1.0)12/1397 (0.9)0/178 (0.0)13/1324 (1.0)1/32 (3.1)12/1470 (0.8)10/1331 (0.8)3/171 (1.8)5/710 (0.7)8/791 (1.0)13/1399 (0.9)0/103 (0.0)1/117 (0.9)11/1235 (0.9)13/1502 (0.9)The New England Journal of MedicineDownloaded from nejm.org on June 6, 2011. For personal use only. No other uses without permission.Copyright 2010 Massachusetts Medical Society. All rights reserved.

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Fondaparinux for Superficial-Vein Thrombosis

Figure 2 (facing page). Rates of the Primary EfficacyOutcome at Day 47 in Prespecified Subgroups.The primary efficacy outcome was a composite ofdeath from any cause, symptomatic pulmonary embo-

lism, symptomatic deep-vein thrombosis, or symptom-atic extension to the saphenofemoral junction orsymptomatic recurrence of superficial-vein thrombo-sis. The size of each square is in proportion to thenumber of patients in the comparison. The analysis ofsubgroups according to the distance of thrombus fromthe saphenofemoral junction included only subjectswho had a thrombosis involving the great saphenousvein. No adjustment for multiple comparisons wasmade, since subgroup analyses were performed for ex-ploratory purposes only. None of the P values for inter-action were less than 0.10 (data not shown). Results

for 12 of the 16 prespecified subgroups are presented;the treatment effect was also consistent within each ofthe 4 other prespecified subgroups (defined accordingto country and status with respect to receipt of gradu-ated compression stockings, use of nonsteroidal anti-inflammatory drugs, and use of aspirin or other anti-platelet agents at baseline), as well as the subgroupdefined post hoc (defined according to whether the in-dex superficial-vein thrombosis was in a varicose veinon ultrasonographic examination). The body-mass in-dex is the weight in kilograms divided by the square ofthe height in meters. ND denotes not determined.care of patients who present with concomitant

deep-vein thrombosis.8 Our results were obtainedwithout the use of repeat systematic compressionultrasonography in contrast to clinical practicein certain countries.8 The 45-day regimen of subcutaneousinjections could also be questionedfrom a practical standpoint. However, the feasibilityof such treatment was confirmed by the highdegree of patient adherence; more than 90% ofpatients injected themselves with the study drug.The effect of the 45-day fondaparinux regimen onthe quality of life was not formally assessed in ourstudy. However, the significantly reduced risk ofsymptomatic complications and of recourse tosurgery or therapeutic doses of anticoagulantagents that we observed with fondaparinux therapyis likely to be associated with an improvedquality of life. Finally, the cost-effectiveness of a45-day regimen of fondaparinux remains to beevaluated, taking into account the clinical eventsthat may be prevented with treatment and factorsthat potentially vary across countries, such as thedirect cost of fondaparinux and the clinical management(including diagnostic and therapeuticprocedures) that is currently proposed in routinepractice when fondaparinux is not used.

Table 4. Safety Outcomes up to Day 47.Safety Outcome

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BleedingMajor*FatalSymptomatic in a critical organCausing 2 g/dl fall in hemoglobin or necessitatingtransfusion of =2 units ofpacked red cells or whole blood

Clinically relevant nonmajorMinorAnyArterial thromboembolic complicationAny adverse eventDrug-relatedNonfatal seriousLeading to discontinuation of study treatmentLeading to withdrawal from studyFondaparinux(N = 1499)Placebo

(N = 1488)no. with event (%)1 (0.1) 1 (0.1)0 01 (0.1) 00 1 (0.1)5 (0.3) 8 (0.5)9 (0.6) 6 (0.4)15 (1.0) 14 (0.9)0 3 (0.2)195 (13.0) 199 (13.4)56 (3.7) 49 (3.3)10 (0.7) 16 (1.1)

18 (1.2) 29 (1.9)2 (0.1) 1 (0.1)

* P =1.00 with the use of Fishers exact test. One patient in the fondaparinux group had retinal bleeding that resolved afterthe discontinuation of study treatment; there were no functional consequencesthat affected vision. One patient in the placebo group had epistaxis that necessitated medical interventionbut that resolved without further consequences. There were two cases of acute coronary syndrome and one of ischemic stroke

all in the placebo group.

In conclusion, patients with isolated, symptom

atic superficial-vein thrombosis in the legs are at

substantial risk for symptomatic thromboembo

lic complications. Fondaparinux administered at

a dose of 2.5 mg once daily for 45 days is effec

tive and widely applicable for the treatment of

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such patients.

Supported by a grant from GlaxoSmithKline.

Dr. Decousus reports receiving research grant support fromBayer, Boehringer Ingelheim, Bristol-Myers Squibb, and Glaxo-SmithKline and fees for board memberships from Bayer, Daiichi

Sankyo, GlaxoSmithKline, and Sanofi-Aventis; Dr. Prandoni,receiving research grant support and consulting fees fromGlaxoSmithKline; Dr. Mismetti, receiving research grant supportfrom GlaxoSmithKline and fees for board memberships orsymposia from Bayer, Boehringer Ingelheim, GlaxoSmithKline,and Sanofi-Aventis; Dr. Bauersachs, receiving consulting fees orhonoraria from Sanofi-Aventis, Pfizer, and GlaxoSmithKline;Dr. Brenner, serving on advisory boards for GlaxoSmithKline,Sanofi-Aventis, Pfizer, and Bayer Pharmaceuticals and receivinglecture fees from GlaxoSmithKline, Sanofi-Aventis, Bayer Pharmaceuticals,and Boehringer Ingelheim and grant support fromSanofi-Aventis; Dr. Laporte, receiving research grant support

from Bayer and Sanofi-Aventis and fees for board membershipsor consulting from Bayer, Boehringer Ingelheim, GlaxoSmith


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