title: Safety and efficacy of local periadventitial delivery of sirolimus for improving hemodialysis graft patency: first human experience with a sirolimus-eluting collagen membrane (Coll-R).
abstract: BACKGROUND
  Neointimal hyperplasia causes a high rate of hemodialysis synthetic graft failure. Thus, therapies that inhibit neointimal hyperplasia are urgently needed. The Coll-R is a sirolimus-eluting collagen matrix designed for intra-operative perivascular implantation around the graft-venous anastomosis. Sirolimus is an anti-proliferative drug that has proven clinical utility in suppressing neointimal tissue growth in coronary artery disease when delivered locally to the vascular wall by an endovascular drug eluting stent.
  
  
  METHODS
  A cohort of 12 chronic hemodialysis patients underwent surgical placement of 13 polytetrafluoroethylene grafts + Coll-R and were followed for up to 24 months. The primary endpoint was safety (freedom from device related adverse events). Secondary endpoints were pharmacokinetics of sirolimus release, success of Coll-R implantation and primary unassisted graft patency.
  
  
  RESULTS
  There were no technical failures, infections, vascular anastomotic or wound-healing problems. Whole blood sirolimus levels rose to a mean peak of 4.8 ng/mL at 6 h and fell to <1 ng/mL at 1 week (n = 5). Twelve and 24-month primary unassisted patencies were 76 and 38%, respectively, and the thrombosis rate was 0.37/patient-year.
  
  
  CONCLUSIONS
  Perivascular implantation of the Coll-R during graft surgery safely delivered sirolimus to the vascular wall. Systemic sirolimus levels were sub-therapeutic for immunosuppression. This small first-in-human study supports the concept that the Coll-R can safely deliver sirolimus to the graft-venous anastomosis. Safety and patency in this small study were sufficiently encouraging to justify randomized controlled trials to further test the efficacy of the Coll-R.
authors.affiliation: Specialty Care, Charlie Norwood VA Medical Center, Augusta, GA, USA. wpaulson@georgiahealth.edu
authors.forename: William D
authors.initials: WD
authors.lastname: Paulson
authors.forename: Nicholas
authors.initials: N
authors.lastname: Kipshidze
authors.forename: Konstantine
authors.initials: K
authors.lastname: Kipiani
authors.forename: Nutsa
authors.initials: N
authors.lastname: Beridze
authors.forename: Maria V
authors.initials: MV
authors.lastname: DeVita
authors.forename: Surendra
authors.initials: S
authors.lastname: Shenoy
authors.forename: Sriram S
authors.initials: SS
authors.lastname: Iyer
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D019917:Blood Vessel Prosthesis Implantation; D020099:Coated Materials, Biocompatible; D003094:Collagen / Q000378:metabolism; D016503:Drug Delivery Systems; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D006973:Hypertension / Q000188:drug therapy* / Q000401:mortality; D008297:Male; D008855:Microscopy, Electron, Scanning; D008875:Middle Aged; D011138:Polytetrafluoroethylene; D006435:Renal Dialysis; D012449:Safety; D020123:Sirolimus / Q000008:administration & dosage*; D015996:Survival Rate; D013927:Thrombosis / Q000517:prevention & control; D014654:Vascular Patency / Q000187:drug effects*; D055815:Young Adult
chemical_list: D020099:Coated Materials, Biocompatible; D011138:Polytetrafluoroethylene; D003094:Collagen; D020123:Sirolimus