PAVE-2, paclitaxel and sirolimus-coated balloons for AVF

Michael Robson and Narayan Karunanithy (King’s College London, London, UK) write to explore the range of options in drug-coated balloons (DCBs) for stenosis in arteriovenous fistulas (AVFs). Highlighting the upcoming PAVE-2 trial, they assess the evidence from a range of studies.

Plain balloon fistuloplasty is an effective treatment for a dysfunctional arteriovenous fistula. However, restenosis is common, leading to a need for repeat intervention. To reduce this need, drug-coated balloons have been extensively studied to determine if they prolong the time to retinervention and provide benefit. The PAVE-2 trial, which promises to further illuminate the subject by assessing two types of DCB, will come as the latest in a line of trials exploring their efficacy.

Paclitaxel-coated balloons allow local delivery of paclitaxel to the site of stenosis. Paclitaxel is a drug which inhibits the cellular proliferation that leads to restenosis following fistuloplasty. Since 2015, there have been many studies published assessing their effectiveness in preserving patency following angioplasty of an AVF. There have been several systematic reviews and the general conclusion has been that there is no overall evidence of an effect for paclitaxel-coated balloons on target lesion primary patency rates. Many of the studies included in these meta-analyses had small sample sizes and there was considerable heterogeneity. There have been three multicentre, randomised controlled trials (RCTs) with more than 200 participants, which is significantly more participants than other studies, and it is useful to consider these in more detail.

The first was from Scott O Trerotola (Hospital of the University of Pennsylvania, Philadelphia, USA) et al with 285 participants and had a primary endpoint of target lesion patency at six months. There was no significant difference between groups treated with a paclitaxel-coated balloon compared with a control group receiving treatment with a non-coated balloon.¹  A second study by Robert A Lookstein (Ichan School of Medicine at Mount Sinai, New York City, USA) et al with 330 participants, using the same binary primary endpoint but a different paclitaxel-coated balloon, did find a difference between groups.²

However, the National Institute for Health and Care Research (NIHR) funded the investigator-led Paclitaxel-assisted balloon angioplasty of venous stenosis in haemodialysis access (PAVE) trial with 212 participants, which failed to show an effect on time to end of target lesion primary patency after treatment with the Lutonix (BD) paclitaxel-coated balloon compared with a non-coated balloon.³

The reason that the PAVE trial and the study by Trerotola et al did not show a benefit whereas the study by Lookstein et al did is not entirely clear. If the PAVE trial and the IN.PACT AV study are considered, there were differences in patient demography. In the PAVE trial, fistulas that had not been used for dialysis were included. It seems unlikely that these factors accounted for the differing results of the trials. Another possible explanation is that the two negative trials used the Lutonix balloon, whereas the Lookstein study used the IN.PACT AV balloon, which delivers a higher dose of paclitaxel. In summary, despite extensive study, experts in the field are uncertain about the benefit of paclitaxel-coated balloons for AVFs.

Sirolimus is another anti-proliferative drug that may be of benefit in this setting. Several strands of evidence suggest that sirolimus may be effective in preventing the neointimal hyperplasia that causes AVF restenosis. Firstly, sirolimus is an anti-proliferative drug and has been shown to inhibit both proliferation and migration in vascular smooth muscle cells in vitro and there is also supportive evidence from preclinical models of AVFs suggesting a benefit for sirolimus. Sirolimus-coated balloons have now been developed and are therefore an alternative to paclitaxel-coated balloons.

The MagicTouch (Concept Medical) balloon has been assessed in the single arm MATILDA study.⁴ Target lesion primary patency rates at three, six and 12 months were encouraging at 98, 83 and 58%. Selution (MedAlliance) is another sirolimus-coated balloon that has been reported in the ISABELLA study⁵, which was also uncontrolled. Patency rates of 95, 72 and 44% were found. Although these results are promising, proper assessment requires an RCT. The Magic Touch balloon is being assessed in the IMPRESSION industry-sponsored trial of 170 patients at three sites in Singapore.⁶

The investigator-led Paclitaxel or sirolimus coated balloons for ArterioVEnous fistulas (PAVE-2) trial has been funded by NIHR. This will be a three-armed trial including over 600 patients from around the UK. Both the IN.PACT AV and MagicTouch balloons will be compared to a control group, with a primary endpoint of time to end of treatment segment primary patency. Inclusion criteria will allow either one or two treatment segments, in contrast to PAVE where only one was allowed. The trial is currently in set-up, and we hope it will significantly advance our understanding of the efficacy of both paclitaxel and sirolimus coated balloons for AVFs.

Narayan Karunanithy is an honorary senior lecturer at the School of Biomedical Engineering and Imaging Sciences, King’s College London.

Michael Robson is a reader in Nephrology in the Faculty of Life Sciences and Medicine, King’s College London.

Disclosures:

Robson was the chief investigator for the PAVE trial

Karunanithy consults for BD, Medtronic, Boston Scientific and Penumbra

References:

1. Trerotola, SO, Lawson J, Roy-Chaudhury P, Saad TF, Trial LAC. Drug Coated Balloon Angioplasty in Failing AV Fistulas: A Randomized Controlled Trial. Clin J Am Soc Nephro 2018;13(8):1215-24
2. Lookstein, RA, Haruguchi H, Ouriel K, Weinberg I, Lei L, Cihlar S et al. Drug-Coated Balloons for Dysfunctional Dialysis Arteriovenous Fistulas. N Engl J Med 2020;383(8):733-42
3. Karunanithy, N, Robinson EJ, Ahmad F, Burton JO, Calder F, Coles S et al. A multicenter randomized controlled trial indicates that paclitaxel-coated balloons provide no benefit during angioplasty of arteriovenous fistulas. Kidney Int 2021;
4. Tang, TY, Soon SXY, Yap CJQ, Chan SL, Choke ETC, Chong TT. Utility of Sirolimus Coated Balloons for Salvaging Dysfunctional Arteriovenous Fistulae: One Year Results From the MATILDA trial. Eur J Vasc Endovasc 2021;62(2):316-17
5. Tang, TY, Yap CJ, Soon SX, Tan RY, Pang SC, Patel A et al. Utility of the selution SLR sirolimus eluting balloon to rescue failing arterio-venous fistulas – 12 month results of the ISABELLA Registry from Singapore. Cvir Endovasc 2022;5(1):8
6. Pang, SC, Tan RY, Choke E, Ho J, Tay KH, Gogna A et al. SlroliMus coated angioplasty versus plain balloon angioplasty in the tREatment of dialySis access dysfunctION (IMPRESSION): study protocol for a randomized controlled trial. Trials 2021;22(1)