Additional randomised controlled data regarding the effectiveness of drug-coated balloons (DCBs) in maintaining arteriovenous (AV) access offers new evidence, but it is freighted with uncertainty. However, specific modelling suggests fewer reinterventions could reinforce economic benefits when the IN.PACT AV device (Medtronic) is used, and sirolimus presents new directions, experts say.
“DCBs for the prevention of restenosis in haemodialysis fistulas have now undergone rigorous evaluation, arguably more than any other AV access intervention apart from stent grafts for venous stenosis,” write Scott Trerotola (University of Pennsylvania, Philadelphia, USA), Prabir Roy-Chaudhury (University of North Carolina Kidney Center, Salisbury, USA) and Theodore Saad (Christiana Care Health System, Newark, USA) in a May 8 editorial published online in the American Journal of Kidney Diseases (AJKD). They elaborate that it is “perplexing and disappointing” to see conflicting results from a host of DCB studies with similar designs—leading to their claim that more data in this space has not equalled more clarity.
Trerotola, Roy-Chaudury and Saad’s editorial follows in the wake of Yanqi Yin (Peking University First Hospital, Beijing, China) and colleagues’ publication in the same journal in January this year of a multicentre randomised controlled trial evaluating the efficacy and safety of DCBs in preventing fistula restenosis in Chinese haemodialysis patients. The triallists report that, compared to conventional high-pressure balloon angioplasty, DCB treatment achieved superior primary patency defined using ultrasound-measured peak systolic velocity ratio (PSVR) at six months, and superior intervention-free survival of both the target lesion and the target shunt at 12 months, without evidence of greater adverse events.
Importantly, Trerotola and colleagues clarify that the compound, unvalidated endpoint incorporating a “peculiar” patency measure used in this trial confounds the interpretation of the results, as do the procedural differences across the two groups, with both of these factors detracting from the positive results of the study.
These results (obtained with Cardionovum’s Aperto OTW DCB; 3μg/mm2 paclitaxel dose) sit amidst two other previously reported large pivotal trials, the Lutonix AV trial that came within striking distance of achieving its primary endpoint (with BD’s Lutonix AV DCB; 2μg/mm2 paclitaxel dose), and the IN.PACT AV Access trial (with Medtronic’s IN.PACT AV DCB; 3.5 μg/mm2 paclitaxel dose), which was the only trial to successfully do so. A third, as-yet unpublished trial, PAVE, which also used the Lutonix AV DCB, did not demonstrate a benefit to using the antiproliferative. With this conflicting evidence of efficacy, the usual suspects of drug dose, excipient, patient, procedure, fistula and lesion specifics come into the foreground to understand discrepancies in outcome, although Trerotola and colleagues use the Chinese trial results to suggest discounting dose, but not excipient, differences.
But, if the efficacy outcomes of DCBs are mined from the IN.PACT AV Access trial data alone and modelled to demonstrate economic benefit, there are savings gains for systems to be had, investigators maintain.
Robert Lookstein (Mount Sinai, New York, USA), first author of the six-month IN.PACT AV Access trial results, published in the New England Journal of Medicine and showing that DCB angioplasty was superior to standard angioplasty for the treatment of stenotic lesions in dysfunctional haemodialysis AV fistulas, has previously outlined that using the IN.PACT AV DCB can confer economic advantages to healthcare systems.
Lookstein and colleagues used 12-month reintervention rate data from the IN.PACT AV Access pivotal trial within a Budget Impact Model of the US and German healthcare systems to demonstrate cost savings almost immediately. “As those savings were projected out [from 12 months] to 36 months, each individual patient projected out a saving of over €3,000 in the German economic model and over US$3,300 in the US healthcare system”, he stated, elaborating that these numbers—when applied in conservative modelling to the entire end-stage renal disease population in both systems—would demand a lot of attention from payers.
Economic benefits to patients and health systems with DCB use accrue over time
This theme was further explored at the recent Charing Cross (CX) 2021 Digital Edition (19–22 April, online).
Presenting on the economic outcomes of DCBs in AV access at two years in the US healthcare system, professor of radiology Sanjay Misra (Mayo Clinic, Rochester, USA) reported gains over time for DCB compared to standard balloon angioplasty. The IN.PACT AV access trial one-year results underpinned the calculations used in the analysis with two approaches being used: a primary analysis involving index and reintervention-based costs, and a secondary analysis for comprehensive vascular access costs. The results from the primary analysis showed meaningful reductions in projected reintervention costs. If the DCB cost is US$1,800 or less, the strategy would break even at the two-year mark, and achieve savings of US$1,400 at the three-year horizon, said Misra, noting that “as time goes by, savings become larger.” Even earlier cost neutrality and slightly higher savings at the two-and-a-half-year mark were achieved using the secondary analysis. At a healthcare system level, Misra proposed that Medicare savings to the tune of US$160–250 million could be made at one year, growing to more than US$420 million at three years if half of the 233,000 annual procedures of standard angioplasty were converted to DCB use instead.
Misra said: “Using two independent calculation approaches, treatment with the IN.PACT AV DCB can be expected to lead to substantive per patient and health system savings.” Further, these savings vary by site of service, with the greatest savings being obtained in the in-hospital setting, he noted.
Misra’s recent research has focused on the use of stem cells to aid AV fistula maturation and prevention of venous stenosis. He attributed the patient gains with the use of DCBs to the reductions in reinterventions, which can help reduce patient morbidity and help improve quality of life, but cautioned that these findings were based specifically on data from the IN.PACT AV Access trial and may not apply to other DCB devices.
These data led session moderator Nicholas Inston (Queen Elizabeth Hospital Birmingham, Birmingham, UK) to ask whether DCBs should be rationed and reserved to maintain access in patients who were likely to survive beyond the two-year mark on a cost basis. “I think it is very difficult to determine who is going to live for two years […] so I would be a little hesitant to ration the use of this technology,” responded Misra, noting that things to look out for included determining which patients might thrombose. Co-moderator Domenico Valenti (King’s College Hospital, London, UK) intervened to clarify whether the costs of using high-pressure balloons had been accounted for in the analysis, prompting Misra to explain that these had been bundled within the costs attributed to standard angioplasty.
Exciting new direction for drug treatment accelerates with sirolimus use
The dialysis vascular access circuit is often fated for failure due to neointimal hyperplasia formation, which is widely accepted to be the main pathophysiological reason for vessel narrowing. What man tries to create, nature tries to “take back”, quipped Suai Chieh Tan (Singapore General Hospital, Singapore). The use of sirolimus as an alternative drug coating to paclitaxel to arrest neointimal hyperplasia is advancing, but is still at early stages, he said during the same CX 2021 session on access maintenance.
The two drugs, sirolimus and paclitaxel, are vastly different, Tan made abundantly clear, with the former described as being a cytostatic, immunosuppressant antiproliferative and the latter a cytotoxic, chemotherapeutic agent.
Describing the emerging evidence from Singapore using sirolimus-coated balloons to treat thrombosed AV grafts, which are plagued by abysmal results, Tan drew attention to published results in the Journal of Vascular and Interventional Radiology (JVIR) from last year showing a three-month primary patency of 65% that dropped to 55% at six months—figures he described as encouraging when compared to similar data stemming from the employment of cutting balloons or stent grafts.
Turning tack to the outcomes of sirolimus balloons with AV fistulas, he presented data from PLOS One, also from last year, showing six-month circuit access patency rates of 68% and target lesion primary patency rates in the same timeframe of 82.9% with Concept Medical’s MagicTouch device.
Spurred on by these initial data with small numbers of patients, the team at Singapore has embarked on a prospective, multicentre, double-blinded randomised controlled trial and begun enrolling patients with failing AV fistulas from January 2021. The triallists plan to enrol 170 patients who will be allocated to receive either standard angioplasty or treatment with a sirolimus-coated device.
Inston then looked back to the use of sirolimus as an immunosuppressant in renal transplants to seek reassurance that using this potent drug would not eventually lead down a path of “having our fingers burnt” due to impaired wound healing, provoking Tan to reply that these studies were an effort to harness the potential of this drug in slowing down the process of neointimal hyperplasia within the blood vessel being treated.
Tan closed his presentation by noting that the application of sirolimus-coated balloons in dialysis access appears to be safe and effective, but said that larger randomised trials were ongoing to verify these early findings.
This is essentially the same thought Trerotola and colleagues conclude their AJKD editorial on the wider topic of DCB use in failing fistulas with: “[…] nephrologists may be heartened in the knowledge that there are multiple additional large multicentre randomised controlled trials forthcoming, hopefully with commonly used and well-accepted endpoints, which will perhaps provide both more data and more clarity. Only time will tell.”
