title: Factor XI antisense oligonucleotide for prevention of venous thrombosis.
abstract: BACKGROUND
  Experimental data indicate that reducing factor XI levels attenuates thrombosis without causing bleeding, but the role of factor XI in the prevention of postoperative venous thrombosis in humans is unknown. FXI-ASO (ISIS 416858) is a second-generation antisense oligonucleotide that specifically reduces factor XI levels. We compared the efficacy and safety of FXI-ASO with those of enoxaparin in patients undergoing total knee arthroplasty.
  
  
  METHODS
  In this open-label, parallel-group study, we randomly assigned 300 patients who were undergoing elective primary unilateral total knee arthroplasty to receive one of two doses of FXI-ASO (200 mg or 300 mg) or 40 mg of enoxaparin once daily. The primary efficacy outcome was the incidence of venous thromboembolism (assessed by mandatory bilateral venography or report of symptomatic events). The principal safety outcome was major or clinically relevant nonmajor bleeding.
  
  
  RESULTS
  Around the time of surgery, the mean (±SE) factor XI levels were 0.38±0.01 units per milliliter in the 200-mg FXI-ASO group, 0.20±0.01 units per milliliter in the 300-mg FXI-ASO group, and 0.93±0.02 units per milliliter in the enoxaparin group. The primary efficacy outcome occurred in 36 of 134 patients (27%) who received the 200-mg dose of FXI-ASO and in 3 of 71 patients (4%) who received the 300-mg dose of FXI-ASO, as compared with 21 of 69 patients (30%) who received enoxaparin. The 200-mg regimen was noninferior, and the 300-mg regimen was superior, to enoxaparin (P<0.001). Bleeding occurred in 3%, 3%, and 8% of the patients in the three study groups, respectively.
  
  
  CONCLUSIONS
  This study showed that factor XI contributes to postoperative venous thromboembolism; reducing factor XI levels in patients undergoing elective primary unilateral total knee arthroplasty was an effective method for its prevention and appeared to be safe with respect to the risk of bleeding. (Funded by Isis Pharmaceuticals; FXI-ASO TKA ClinicalTrials.gov number, NCT01713361.).
authors.affiliation: From the Department of Vascular Medicine, Academic Medical Center, University of Amsterdam (H.R.B.), and International Trial Expertise Advisory and Services (ITREAS) (A.S.) - both in Amsterdam; Isis Pharmaceuticals, Carlsbad, CA (C.B., S.B., B.P.M.); Department of Pathology, Microbiology and Immunology, Vanderbilt University, Nashville (D.G.); University of Oklahoma Health Sciences Center, College of Public Health, Oklahoma City (G.E.R.); KU Leuven Department of Cardiovascular Sciences, Vascular Medicine and Hemostasis, Leuven, Belgium (P.V.); and the Thrombosis and Atherosclerosis Research Institute and McMaster University, Hamilton, ON, Canada (J.I.W.).
authors.forename: Harry R
authors.initials: HR
authors.lastname: Büller
authors.forename: Claudette
authors.initials: C
authors.lastname: Bethune
authors.forename: Sanjay
authors.initials: S
authors.lastname: Bhanot
authors.forename: David
authors.initials: D
authors.lastname: Gailani
authors.forename: Brett P
authors.initials: BP
authors.lastname: Monia
authors.forename: Gary E
authors.initials: GE
authors.lastname: Raskob
authors.forename: Annelise
authors.initials: A
authors.lastname: Segers
authors.forename: Peter
authors.initials: P
authors.lastname: Verhamme
authors.forename: Jeffrey I
authors.initials: JI
authors.lastname: Weitz
mesh_terms: D000328:Adult; D000368:Aged; D000925:Anticoagulants / Q000008:administration & dosage* / Q000009:adverse effects; D019645:Arthroplasty, Replacement, Knee; D001777:Blood Coagulation / Q000187:drug effects / Q000502:physiology; D002985:Clinical Protocols; D017984:Enoxaparin / Q000008:administration & dosage / Q000009:adverse effects; D005172:Factor XI / Q000032:analysis / Q000037:antagonists & inhibitors*; D005260:Female; D006470:Hemorrhage / Q000139:chemically induced; D006801:Humans; D007902:Length of Stay; D008297:Male; D008875:Middle Aged; D009841:Oligonucleotides / Q000008:administration & dosage* / Q000009:adverse effects; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage* / Q000009:adverse effects; D010314:Partial Thromboplastin Time; D011183:Postoperative Complications / Q000517:prevention & control*; D020246:Venous Thrombosis / Q000517:prevention & control*
chemical_list: D000925:Anticoagulants; D017984:Enoxaparin; C572197:ISIS 416858; D009841:Oligonucleotides; D016376:Oligonucleotides, Antisense; D005172:Factor XI