title: The von Willebrand inhibitor ARC1779 reduces cerebral embolization after carotid endarterectomy: a randomized trial.
abstract: OBJECTIVE
  Inhibition of von Willebrand factor offers a novel approach to prevention of stroke and myocardial ischemia but has not yet been demonstrated to show efficacy on clinically relevant end points. ARC1779 is an aptamer that inhibits the prothrombotic function of von Willebrand factor by binding to the A1 domain of von Willebrand factor and thereby blocking its interaction with glycoprotein. Phase 1 studies suggest it inhibits platelet aggregation with less increase in bleeding than conventional antiplatelet agents. The effect of ARC 1779 on cerebral emboli immediately after carotid endarterectomy was investigated in a randomized clinical trial.
  
  
  METHODS
  Patients undergoing carotid endarterectomy were randomized double-blind to ARC1779 or placebo administered intravenously. Transcranial Doppler recording, to detect cerebral embolic signals, was performed in the first 3 hours postoperatively. The primary end point was time to first embolic signals.
  
  
  RESULTS
  Thirty-six patients were recruited, 18 in each arm. The Kaplan-Meier median time to first embolic signals was 83.6 minutes for ARC1779 compared with 5.5 minutes for placebo. Using Cox proportional hazards embolic signals occurred statistically significantly later on ARC1779 (P=0.007). Reduced embolic signals counts were correlated with inhibition of von Willebrand factor activity (P=0.03). Increased perioperative bleeding and anemia were seen with ARC1779.
  
  
  CONCLUSIONS
  von Willebrand factor inhibition reduces thromboembolism in humans. It may play a role in treatment of stroke and myocardial ischemia. The extent to which bleeding complications occur in nonoperated patients needs to be assessed in further studies. Clinical Trial Registration- URL: http://clinicaltrials.gov. Unique identifier: NCT00742612.
authors.affiliation: Clinical Neuroscience, St George's University of London, London SW170RE, UK. hmarkus@sgul.ac.uk
authors.forename: Hugh S
authors.initials: HS
authors.lastname: Markus
authors.forename: Charles
authors.initials: C
authors.lastname: McCollum
authors.forename: Chris
authors.initials: C
authors.lastname: Imray
authors.forename: Michael A
authors.initials: MA
authors.lastname: Goulder
authors.forename: Jim
authors.initials: J
authors.lastname: Gilbert
authors.forename: Alice
authors.initials: A
authors.lastname: King
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D052157:Aptamers, Nucleotide / Q000627:therapeutic use*; D016893:Carotid Stenosis / Q000601:surgery; D004311:Double-Blind Method; D016894:Endarterectomy, Carotid / Q000009:adverse effects*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D057194:Intention to Treat Analysis; D020766:Intracranial Embolism / Q000209:etiology / Q000517:prevention & control*; D008297:Male; D008875:Middle Aged; D010974:Platelet Aggregation / Q000187:drug effects; D016896:Treatment Outcome; D014841:von Willebrand Factor / Q000037:antagonists & inhibitors*
chemical_list: C526287:ARC 1779; D052157:Aptamers, Nucleotide; D014841:von Willebrand Factor