Intraoperative perianastomotic delivery of sirolimus is feasible, according to Sriram Iyer (Lenox Hill Hospital, New York, USA). Based on preliminary data from 56 arteriovenous fistula (AVF) patients treated with intraoperative perivascular sirolimus, there are no safety concerns, and, using hard clinical endpoints, there is a strong efficacy signal measured by maturation success and suitability for dialysis at six months. In addition, the data show some consistency, with minimal variability and durability of treatment effect.
According to Iyer, “The reason why you want to use sirolimus is because the molecular rationale is very well understood”. He adds: “Unlike sirolimus, paclitaxel is a cytotoxic drug. Sirolimus is cytostatic, and that difference may translate into a useful effect on the safety profile which we can successfully harness.”
Iyer mentioned that there is also a clinical rationale behind a stent-based endovascular sirolimus delivery. “Over six million coronary stents have been sold worldwide using the sirolimus molecule and we have very long-term longitudinal follow up,” he said.
Iyer described that 30 patients were studied in a Phase 2 trial, involving two sites and two surgeons. Twenty-two of the patients were radio-cephalic, and eight of them were brachio-cephalic. Safety, efficacy and pharmacokinetics were the endpoints and patients were followed up at two, four, six, and eight weeks, and three, six, nine and 12 months.
He then went on to describe the current, ongoing, Phase 3 prospective randomised single-blind trial that is being conducted in multiple centres across the USA. He commented: “The first patient enrolled by every surgeon at every site definitely got the drug product and is termed an open-label subject. Once that subject is enrolled the trial enters the randomised phase which is where it is right now. The patients were randomised 1:1, with controls receiving a plain AV fistula, and the treatment patients getting a local sirolimus delivery.”
Thirty patients were included in Phase 2. These patients had a mean age of 51 (25–77) and 60% were male. Twenty per cent had diabetes, and all patients were on dialysis. In Phase 3, there were 26 patients, with a slightly higher mean age of 62 (30–91). Seventy seven of these patients were male, and 69% were diabetic. Ninety five per cent of these patients were on dialysis.
In the composite cohort of 56 patients, the mean age was 56 (25–91), 58% were male, 43% were diabetic, and 98% were on dialysis. “Importantly, this [last figure] is a key strength of the trial as it shows how almost all of these patients were on dialysis at the time the fistula was created except one so that allows us to assess the success of the treatment using hard clinical endpoints.”
Iyer commented: “The maturation success using very robust clinical definitions was more than 80%.” Indeed, the figure was 87% in the Phase 2 group, 85% in the Phase 3 open label group, and therefore 86% across all patients.
Additionally, he explained that “use at six months comes close to about 80% as well,” based on figures of 76% in the Phase 2 group, 81% in the Phase 3 group, and 78% overall.
Iyer presented the outcomes of 56 AVF patients treated with sirolimus—30 from the Phase 2 and 26 from the Phase 3. In terms of safety, he noted that there was no risk of systemic immunosuppression, and that were were no problems with wound healing and no risk of infection. Finally, he noted that there was no increase in fistula thrombosis within six weeks.
“By day 90, 69% of the sirolimus-treated fistulae could be used for two-needle dialysis. The usual number in the USA by 90 days is 20–25% and that is important because 80% of all patients in the USA start dialysis on a catheter and the quicker you can use the fistula the quicker you can get rid of the catheter”, Iyer commented. He concluded: “There are two things I want to point out here. One is the internal consistency of the data and two, these 26 patients in the open label represent the output of 26 separate surgeons across the USA addressing also the issue of variability.”
Iyer recently presented these data at the Charing Cross Symposium (CX; 15–18 April, London, UK), where he revealed that the US Phase 3 randomised AVF trial is “nearing enrolment completion,” adding, “we should have results on this trial next year.”