Recently, the FDA approved Medtronic’s paclitaxel-coated balloon IN.PACT AV for the management of failing arteriovenous fistulae (AVF). Approval for the device was based on data from the IN.PACT AV Access trial, which showed the device to significantly increase primary patency compared with standard percutaneous transluminal angioplasty. Andrew Holden (Department of Interventional Radiology, Auckland, New Zealand), the principal investigator of IN.PACT AV Access, says having a treatment that improves access circuit patency is a “huge gain”.
According to Holden, ensuring the patency of arteriovenous fistulae is an ongoing concern. He notes that while haemodialysis is the most common method of renal replacement therapy, “dialysis access circuits are prone to high rates of dysfunction” and this is primarily because of access circuit stenotic lesions. Furthermore, he says, these lesions are “often refractory” to standard percutaneous transluminal angioplasty and “require high pressure or specialty balloons to adequately dilate”. “Of more concern is the extremely high rate of restenosis, with many studies reporting a primary patency rate below 50% at six months,” Holden observes.
Therefore, given outcomes seen with drug-coated balloons for treating femoropopliteal lesions, interest in the use of these devices to treat failing arteriovenous fistulae has been considerable. However, until recently, the efficacy of drug-coated balloons in this context had not been definitively demonstrated. Holden explains: “Although many studies reported a trend towards better patency with drug-coated balloons compared with plain balloon angioplasty, the confidence intervals were wide and some studies failed to showed a benefit. Not surprisingly, there was considerable heterogeneity in technique in the papers, particularly the requirement and quality of vessel preparation prior to drug-coated balloon deployment.” He adds these studies reinforced the need for larger, multicentre, randomised trials.
The Lutonix AV Access investigational device exemption (IDE) trial was the first such randomised trial, and it evaluated the drug-coated balloon Lutonix 035 (BD). Scott Trerotola (Department of Radiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, USA) and others recently reported the two-year results of this study (285 patients with dysfunctional arteriovenous fistulae) in the Journal of Vascular and Interventional Radiology. They note that the study did not meet its primary endpoint—superior target lesion primary patency (TLPP) at six months compared with control therapy (standard percutaneous transluminal angioplasty)—but did show statistically significant TLPP at nine months (58%±4 vs. 46%±4 for control therapy; p=0.02). Lutonix AV was not associated with better TLPP at any other time point (12 months, 18 months, and 24 months). Trerotola et al conclude that the data represent “an important step forward in the development of novel therapies that improve the quality of life of patients undergoing haemodialysis”. “We hope the further introduction of other such therapies, as well as the analysis of more patients treated with drug-coated balloons, will result in a future precision-based approach to arteriovenous fistulae stenosis,” they add.
Unlike the Lutonix AV Access IDE trial, Holden reports, IN.PACT AV Access trial (330 patients) “well and truly met its primary efficacy endpoint”. At 210 days, per Kaplan-Meier estimates, the primary patency of the target lesion was 81.4% in the IN.PACT AV arm vs. 59% in the control arm (p<0.01). Additionally, patients in the IN.PACT AV arm required 56% fewer reinterventions to maintain target lesion patency through 210 days compared with those in the control arm. Holden observes: “It is highly likely that this reduced reintervention rate will make a primary drug-coated balloon angioplasty approach to arteriovenous access circuit stenoses a very cost-effective treatment.” He adds that a detailed cost-effectiveness analysis of the IN.PACT AV Access Study will be presented early 2020.
The six-month data were reported at the 2019 Cardiovascular and Interventional Radiological Society of Europe (CIRSE; 7–11 September, Barcelona, Spain) and subsequent data were presented at the recent VIVA meeting (2–7 November, Las Vegas, USA). Holden comments that these data show “a significant patency advantage for the drug-coated balloon in de novo and restenotic lesions and all anatomic locations, particularly for the arteriovenous anastomosis and cephalic arch”.
As Holden puts it, the possible relationship between paclitaxel exposure and all-cause mortality in claudicants (for the management of femoropopliteal lesions) “is a hotly debated issue” at present. However, he says that there “should be great caution” about extrapolating these data to the use of paclitaxel devices for “other arterial devices and for different clinical indications.” “The life-expectancy of haemodialysis patients may be very different to a claudicant population and the benefits of a patent vessel even more profound. In the USA, it is estimated the two-year mortality for haemodialysis patients is 33.2%, more than twice that of a claudicant population,” Holden observes.
Additionally, none of the studies evaluating drug-coated balloons for haemodialysis patients have identified any safety concerns (so far). For example, there were no significant differences in mortality between the IN.PACT AV group and the control group at 12 months—90.6% vs. 90.4%, respectively—in the IN.PACT AV Access trial. Also, Holden notes: “A recently published meta-analysis of mortality after paclitaxel-coated devices in arteriovenous access showed no difference in short to mid-term mortality for drug-coated balloon compared to plain balloon angioplasty”.
Merit Medical is hoping to following Medtronic in having a FDA-approved device for the management of failing arteriovenous fistulae. On the same day that Medtronic announced that it had received FDA approval for the IN.PACT AV (21 November 2019), Merit announced that it had received FDA Breakthrough Device Designation for its Wrapsody endovascular graft system. According to a press release, the system is a flexible, self-expanding endoprothesis for use in haemodialysis patients for the treatment of stenosis within the central veins of the outflow circuit of arteriovenous fistula (up to the superior vena cava).
Concept Medical also has FDA Breakthrough Device Designation (as of August 2019) for a device for treating dysfunctional arteriovenous fistulae—the MagicTouch AVF sirolimus-coated catheter. A press release reports that the proposed indications for the catheter are “for use in percutaneous transluminal angioplasty, after appropriate vessel preparation, for the treatment of stenosis lesions of dysfunctional native arteriovenous dialysis fistula or graft”.
Whether or not Merit Medical and Concept Medical get a device onto the US market, Holden believes, just having IN.PACT on the market is good news for all concerned. He says: “It is well recognised by clinicians, funders and—most importantly—patients that a technology that significantly improves access circuit patency and reduces reinterventions is a huge gain. Haemodialysis patients have a challenging quality of life and will be delighted at a more effective treatment with reduced reintervention.”
Of note, in Europe, the MagicTouch AVF received CE mark approval in November this year and the IN.PACT Admiral was CE-marked approved for treating arteriovenous fistulae in 2016. Furthermore, the Lutonix 035 received FDA approval for this indication in 2017.