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Arteriovenous Fistula Outcomes After Local Vascular Delivery of a Sirolimus Formulation

2019; Elsevier BV; Volume: 70; Issue: 2 Linguagem: Inglês

10.1016/j.jvs.2019.06.048

1097-6809

Daniel G. Clair, Michael J. Moritz, Jason Burgess, Karl A. Illig, Stefan Moldovan, Justin Parden, John Ross, Sri Iyer,

Vascular Malformations and Hemangiomas

In the United States, 39% of arteriovenous fistulas (AVFs) fail to mature; for the remaining 61%, the median time to “first use” of the AVF is 108 days (United States Renal Data System, 2018). In the United States, on average, 25% of AVFs are functional by day 90, and approximately 50% of AVFs are functionally durable at later time points (range, 38%-65%; United States Renal Data System, 2018). Uncontrolled cell proliferation at and around the anastomosis (juxta-anastomotic segment) of an AVF causing a flow-limiting stenosis is an important cause of maturation failure. Sirolimus delivered locally to the vascular wall is a clinically proven antiproliferative. The ongoing U.S. phase 3 trial (NCT02513303) is testing the value of locally delivered sirolimus for improving AVF outcomes. A prior single-arm phase 2 study showed 87% maturation success, and ∼75% of the AVFs were suitable for dialysis at 12 months. Patients scheduled to undergo creation of a single-stage end-to-side radiocephalic or brachiocephalic fistula with baseline duplex ultrasound diameter (cephalic vein, ≥2.5 mm; artery, ≥2 mm) were eligible (Table). After successful AVF creation, sirolimus dosage units (Vascular Therapies, Cresskill, NJ) were circumferentially implanted around the anastomosis and juxta-anastomotic segment (intraoperative perivascular drug delivery). Key metrics are tabulated (Table). Overall, 50% of AVFs were suitable for two-needle dialysis supporting a dialysis pump flow of >300 mL/min on or before day 90. The sole chronic kidney disease patient initiated dialysis using the index fistula ∼4 months after surgery (zero catheter days). Compared with historical “standard of care” surgical controls, sirolimus-treated AVFs signal a clinically meaningful improvement in fistula maturation success with shortened times to first use and the potential to achieve the desired clinical benefit of a functionally durable AVF. Enrollment is ongoing in the randomized U.S. phase 3 clinical trial.TableEligible patientsPhaseNo.Age, years, mean (rangeMaleDiabetesESRDRCFBCFEarly thrombosisbTTFD,c days, medianFistula maturation success3 OLa2661.4 (30-91)77%69%2515113 (12.5%)7621/24 (87.5%)BCF, Brachiocephalic fistula; ESRD, end-stage renal disease; OL, open label; RCF, radiocephalic fistula; TTFD, time to first dialysis.aOpen label (OL): refers to the first phase 3 subject enrolled by a participating surgeon (definitely received the sirolimus product). bWithin 6 weeks of surgery. cTTFD = Time to first of three consecutive dialysis sessions using the index AVF with two needles and Q b. > 300mL/min. Excludes AVF that thrombosed early. Open table in a new tab