Chief Scientific Officer Vascular Therapies NEW YORK, New York
Objectives: Anastomotic/peri-anastomotic site flow limiting stenosis resulting from neointimal hyperplasia are important determinants of patency and functional outcomes following surgically constructed dialysis vascular access (AVF, AVG) and bypass grafts for PAD. Following anastomosis creation, adventitial cells quiescent at baseline, show heightened proliferative activity for ~ 8 weeks and contribute to neointimal tissue. There are no approved systems for intraoperative drug delivery to address this prophylactically. The development, testing and outcomes of an anti-proliferative formulation intended for intraoperative periadventitial delivery are outlined.
Methods: Highly lipophilic sirolimus entrained in collagen sheets that self-curl when hydrated and terminally sterilized (SirogenTM); collagen bioresorbed in ~12 weeks. Pre-clinical testing using sheep AV graft model (Fig1) yielded histology and tissue sirolimus levels. Clinically evaluated in: AVG (N=12; Sirogen around venous anastomosis); above knee femoral-popliteal PTFE grafts (N=10; Sirogen around distal arterial anastomosis); AVF (RCT; Sirogen around anastomosis/Juxta anastomosis N=125 vs. controls without placebo collagen N=118). Blood Sirolimus levels were obtained until day 7 (Pharmacokinetics; PK).
Results: Self-curling made implantation intuitive and obviated need for sutures to keep collagen free edges approximated. There were no anastomosis suture line dehiscence or other safety concerns. Sirolimus was detected in local tissue for at least 8wks. Fig1 shows suppression of neointimal tissue following periadventitial Sirogen delivery. Clinical outcomes substantiated safety; systemic sirolimus levels were subtherapeutic for immunosuppression. 12-month primary patency for AVG and PAD grafts were 76% and 88%, respectively. The completed randomized Phase 3 AVF trial (n=243) was negative. There was, however, an unequal distribution (favoring controls) of two known hazards for AVF maturation - patients ≥65y and those with CAD. This risk imbalance could have biased outcomes and may explain trial failure. Post hoc subgroup analysis of patients ≥65y with radio-cephalic AVF showed Sirogen treatment doubled maturation success without compromising 12-month durability. An ongoing randomized Phase 3 trial (ACCESS-2) is testing benefit in this elderly high-risk group which represents 50% of incident ESKD patients.
Conclusions: Periadventitial sirolimus delivery is feasible and safe. Rationale for delivering an anti-proliferative locally via the adventitia is supported by histology, presence of sirolimus in target tissue during the vulnerable first 8 weeks post anastomosis creation and minimal systemic levels (PK data) providing freedom from systemic effects. Collagen bioresorbability ensures sirolimus is delivered without leaving a residual implant. Single intraoperative dosing eliminates patient compliance. Clinical outcomes provide a strong efficacy signal. Positive ACCESS-2 outcomes could support Regulatory approval for an unmet clinical need using this novel drug formulation.
