by Frank J. Criado, MD, FACS, FSVM
Dr. Frank Criado's summaries from Charing Cross 2017
Drug-coated balloons (DCBs) are regarded as the most impactful new technology in the peripheral arterial disease (PAD) market. Their superior effectiveness in achieving patency and reducing clinically-driven target-lesion revascularization over plain old balloon angioplasty is now well established in the treatment of non-complex femoro-popliteal arterial lesions. But questions remain on the best endovascular treatment strategy for long, complex/complicated lesions and chronic total occlusions – as to long-term durability particularly.
In case of complex disease, which endovascular strategy is best? DCB followed by a bail-out stenting? Or stand-alone stenting? How about atherectomy followed by DCB? We just don’t have enough data yet to answer these important questions.
But progress is being made. “Year-on-year, DCBs have clearly shown that they have a place. The question now is how much further can they go than the treatment of straightforward lesions in the peripheral vascular space?” asked Prof. Roger Greenhalgh (CX Program Chairman). Another insightful statement during this important session came from Gary Ansel: “DCBs can place drug inside a vessel; they cannot change recoil from a calcified lesion and cannot treat a dissection. Until we can get a technology that can do that without a scaffold, stents will play a big part in what we do as we get into more complex lesion lengths, and calcification.” In my view, this added needed perspective and tamped down unbridled enthusiasm on the idea that DCBs “can do it all…” Not true. Not reasonable.
When the audience was polled, 54.6% voted in favor of DCBs as an alternative to stents, another 39.9% thought these devices should be used for in-stent restenosis. Three thought they were a last resort (?)
Gary Ansel’s presentation on the 1-year results from the IN.PACT Global Study with complex lesions had been eagerly awaited. The analysis compared standard usage patients (n = 281) who met similar inclusion criteria for the IN.PACT SFA pivotal trial, an FDA investigational device exemption (IDE) study, compared with use in a broader spectrum of patients (n = 1125) who had wider inclusion criteria reflecting more real-world patients. Results in both patient subsets demonstrated consistently positive outcomes with Medtronic’s IN.PACT Admiral at 1 year. In the standard IN.PACT Global Study, clinically-driven target lesion revascularisation (CD-TLR) was 3.4%, which was comparable to 2.4% in a similar population in the IN.PACT SFA pivotal trial. CD-TLR for the group with complex lesions was 8.5%, despite the disease complexity observed in these patient types. These results were also consistent with the full clinical cohort for the IN.PACT Global Study (n = 1406), in which 1-year CD-TLR was 7.5%. There were no safety issues.
Ansel (Columbus, USA) commented that “the data in this study highlight that the IN.PACT Admiral can be safe and effective when used in our patients with complex peripheral arterial disease, such as those with challenging calcified lesions and with significant comorbidities.”
Another important contribution in the DCB universe was the podium-first presentation of a new subset analysis of patients with complex, calcified lesions from the long lesion and chronic total occlusion imaging cohort of the IN.PACT Global Study by Fabrizio Fanelli (Rome, Italy). He explained that the IN.PACT Global is a prospective, multicenter, independently adjudicated single-arm study to expand clinical evidence of IN.PACT Admiral in the treatment of real-world patients with symptomatic femoro-popliteal disease. The ad hoc analysis shared with the CX audience characterized outcomes across complex cases consisting of long lesions (≥15 cm), chronic occlusions (≥5 cm), with moderately severe and severe calcification. Fanelli reported that a total of 72 patients from the long lesion and chronic total occlusion imaging cohorts met the criteria for complex lesions including severe calcification. The mean lesion length treated was 24.73 ± 10.82 cm, with 60.3% total occlusions and 56.4% severe calcium. The provisional stent rate was 51.4% (mostly related to vessel recoil). At 12 months, primary patency by Kaplan-Meier estimate was 88.8%. CD-TLR was 8.5%. There were no device or procedure-related deaths through 30 days or major amputations at 12 months. “Results from this small cohort confirm the safe and effective performance of the IN.PACT Admiral DCB, with adjunctive stenting, in this complex lesion set,” Fanelli concluded.
The first-in-man RANGER SFA randomized trial comparing the use of DCBs (Ranger; Boston Scientific) with angioplasty was also presented. Dierk Scheinert (Leipzig, Germany) said, “There was greater patency rate at 12 months for the Ranger group than the control group. Kaplan-Meier estimates were 86% vs 56% for the two arms, respectively. The freedom from TLR was also greater for the Ranger arm than the control arm at 12 months (91% vs 70%).
Prakash Krishnan (New York) presented on evidence from the ILLUMENATE European and US trials that randomized patients to treatment with the Stellarex DCB (Spectranetics) or with POBA. Primary patency rates at 1 year were 89% in the European study and 82.3% in the US study in the DCB group. One year freedom from CD-TLR was 94.8% in the European trial and 93.6% in the US study. Both the trials met their primary safety and effectiveness endpoints and demonstrated superiority to angioplasty on both counts. Differences in the patient populations between the European trial and the US pivotal trial were noted: the patient population was described as a complex cohort in the treatment arm that included high rates of severe calcification, diabetes, renal insufficiency, and cardiovascular disease. An important issue brought to our attention during the discussion was that there was no standardized manner of measuring calcium in peripheral lesions. Fanelli noted that this was a “key point” and that there was a need for clear definition in measuring calcification and a need to use the same language among experts. There was also agreement on the importance of adapting paclitaxel dosing and improvement in DCB coating stability.
Despite hearing new data on the effectiveness and safety of DCB use in challenging lesions, the audience (and several experts) were unconvinced that DCBs alone could do the trick in all these scenarios. The audience heard Peter Gaines (Sheffield, UK) comment that when DCBs were used in real-world situations, the use of complementary stenting went up significantly, when compared to the rate of stenting seen in pivotal trials. He went so far as to say that “DCBs need stents,” highlighting that re-occlusion occurs because of vessel recoil, late negative remodeling and restenosis – none of which can be fully addressed with an anti-restenotic drug. Hence the need for scaffolding. We see that in DCB registries where, unlike pivotal trials, the overall stent rate is about 28%-35%. He said further that the stenting rate is 53% in lesions longer than 25 cm, and 47% in total occlusions.
Gaines also presented on the topic of swirling-flow stents. These devices improve outcomes to 2 years compared to straight stents. The increase in wall shear is durable and continues to be effective after the loss of the drug effect. The BioMimics 3D (Veryan Medical) is emerging (he affirmed) as the ideal stent to complement DCBs.
Paclitaxel Particle Embolization
The first late-breaking presentation was by Koen Deloose (Dendermonde, Belgium) and focused on the downstream paclitaxel particle embolization seen with various DCBs. He stated that an effective DCB formulation must deliver large quantities of the drug within seconds and that therapeutic drug levels must be maintained for more than 4 weeks. He presented data that highlighted a safety issue with particulate embolic events. “Pacitaxel (and possibly excipient) particle embolization occurs in all DCBs, but varies in extent between devices. There are differences in particulate embolization rates which do not manifest clinically in claudicants but may be clinically relevant in patients with tissue loss,” he said. Deloose noted that artificial balloon shaking and inflation tests indicate important differences between various DCBs. Shake tests, bench flow models, and animal studies have shown that IN.PACT would appear to have more particulate than Lutonix (Bard). “In vitro tests," Deloose continued, "where analyses of downstream particulates of different DCBs in polycarbonate filters are compared are indicative. Animal tests—in which a blind comparison of the effect of downstream drug-coated particulates in distal vascular territories are analyzed in a pharmacokinetic and histological way—are real eye-openers of the potential risk of major distal embolization with chronic inflammation, fibrinoid arteriolar necrosis, and crystalline deposits consequences."
“Downstream paclitaxel particulates are a real phenomenon, immediately linked to coating stability and paclitaxel-to-balloon adherence. The clinical relevance for claudicants seems irrelevant, however, it is still unknown if there is an issue for critical limb ischemia patients with poor distal vessel run-off,” Deloose explained.
Andrew Holden (Auckland, New Zealand) spoke of the current realities and future desirability of having data on head-to-head comparisons. He explained that while there are studies providing comparison between strategies and comparing devices such as drug-eluting stents, unfortunately, there are still no completed multicenter randomized trials providing head-to-head comparisons of DCBs in femoro-popliteal occlusive disease. These are eagerly awaited given the huge impact DCBs have made. “Although almost all DCBs used in the superficial femoral artery use the same drug (paclitaxel), they are otherwise very different in terms of dosimetry, drug formulation, the use and choice of excipient, coating methods, and usage methods per instructions of use. In the absence of prospective randomized trials, one method to compare devices is cross-trial comparison between high-quality trials using similar methodology. The most objective method to compare is core-laboratory defined primary patency, although patency differences may not be reflected in clinical outcomes,” Holden explained.
He compared data from the clinical programs of the IN.PACT, Lutonix, and Stellarex DCBs, explaining that all three trials investigating these devices were multicenter, randomized trials evaluating these devices in patients with claudication or rest pain. All used the same independent duplex core laboratory, with the same primary patency definition and the same primary endpoint of patency at 1 year. All trials used an independent Clinical Events Committee to adjudicate CD-TLR. “A comparison between these trials shows similar demographics, although lesions were longer in IN.PACT SFA and more severe claudicants were treated in the Stellarex ILLUMENATE EU trial. While all trials showed a highly significant patency advantage for the DCBs over plain angioplasty at 1 year, IN.PACT and Stellarex appeared to show superior patency and freedom from CD-TLR over Lutonix. Longer-term follow-up also suggests that durability of the anti-restenotic effect may differ,” Holden reported.
"Two physician-initiated head-to-head randomized controlled trials are underway, both using 12-month patency as the primary endpoint," he added. “The HEROES-DCB trial in the USA involves 275 patients randomized between IN.PACT and Lutonix, while the COMPARE 1 trial in Germany involves 414 patients randomized between IN.PACT and Ranger. Both use 12-month patency as the primary endpoint,” he added.
Holden also highlighted that a major consideration when comparing DCBs is safety. “It is intuitively appealing to select a device with a lower dose of paclitaxel if it can achieve similar patency to those using higher doses. It has been postulated that higher drug doses may be associated with increased local and systemic adverse effects. These have not been clearly identified with current DCBs used in superficial femoral artery trials for claudication or rest pain.