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A universal drug delivery catheter for the treatment of infrapopliteal arterial disease using liquid therapy

Abstract Objective The objective of this study was to investigate the safety and feasibility of treating infrapopliteal lesions using a novel drug delivery catheter locally delivering liquid paclitaxel. Background Balloon angioplasty is currently the Gold Standard to treat below‐the‐knee disease; however, restenosis continues to be a great challenge following these percutaneous revascularization procedures. Methods The Occlusion Perfusion Catheter for Optimal Delivery of Paclitaxel for the Prevention of Endovascular Restenosis (COPPER‐A) study—Below‐the‐Knee Cohort was a prospective, nonrandomized, multicenter, feasibility, and safety study that enrolled 35 patients at 11 participating sites. The safety endpoints at 1, 3, and 6 months were freedom from thrombosis, major amputation in the target limb and target limb related death. The efficacy endpoints were primary patency and freedom from clinically driven target lesion revascularization at 6 months. Results All patients tolerated the procedure well with no reports of adverse procedural events. Thirty‐five patients were treated with a mean lesion length of 112 ± 81.2 mm with the lesion length range of 20–286 mm. At 6‐month follow‐up, primary patency was 89.3% and freedom from clinically driven target lesion revascularization was 96.4%. No patients demonstrated thrombosis, major amputation in the target limb and target limb related death at the 1‐, 3‐ and 6‐months follow‐up intervals. Conclusions The results of this multi‐center study demonstrated that infrapopliteal arteries can be safely and effectively treated with liquid paclitaxel using the occlusion perfusion catheter.


| Study design
The Occlusion Perfusion Catheter for Optimal Delivery of Paclitaxel for the Prevention of Endovascular Restenosis (COPPER-A study)-Belowthe-Knee Cohort was a prospective, non-randomized multicenter trial, at 11 sites, designed to assess the safety and efficacy of paclitaxel administration using the OPC for the prevention of restenosis in infrapopliteal de novo and restenotic lesions. The protocol was approved by a national institutional review board and individual site institutional review boards.
All patients provided written informed consent prior to enrollment. The study was conducted in accordance with good clinical practice and applicable regulations for non-significant risk studies.

| Study population
Patients eligible for enrollment had a Rutherford classes 2-5, infrapopliteal lesions ≥20 mm in length, age ≥18 years and able to tolerate dual anti-platelet therapy for a minimum of 1 month. General angiographic inclusion criteria included reference vessel diameter ≥2 mm and ≤4 mm, single or multiple lesions in the infrapopliteal arteries, lesion location in the region between the trifurcation of vessels to the ankle, minimum of one vessel run-off, pre-intervention diameter stenosis ≥70% and successful pre-treatment therapy to achieve residual stenosis to ≤30%.
Major exclusion criteria included previous intervention of the target vessel with a stent, DCB or other drug delivery catheter, pregnancy or lactating, known allergies to study medication and materials, planned amputation prior to procedure, and acute limb ischemia. Angiographic exclusion criteria included flow limiting dissection requiring stent placement, significant inflow lesion or occlusion left untreated in the ipsilateral iliac, superficial femoral artery, or popliteal artery proximal to the target lesion and visible thrombus within or proximal to the target artery.

| Study device: The OPC
The FDA 510(k) cleared OPC is a 5 Fr device (0.014 00 guidewire compatible) with an outer diameter of 1.67 mm. The catheter has three balloons; two compliant occlusion balloons (one proximal and one distal) which define the treatment chamber, and a center spaceoccupying balloon (Figure 1). The compliant occlusion balloons are sized to minimize trauma to the vessel wall during treatment. Treatment chamber pressure is measured real-time via a sensor located within the treatment chamber which is connected to an external pressure monitor for the purpose of monitoring the pressure inside the treatment chamber during infusion of the therapeutic agent. Therapeutic agents are infused through the treatment inflow under continuous pressure injection. Radiopaque markers are located on both sides of the occlusion balloons to define the treatment chamber to assist in catheter placement under fluoroscopy. The size of the F I G U R E 1 The occlusion perfusion catheter (OPC) universal drug delivery catheter. (a) The OPC, a multi-lumen balloon catheter, is designed to temporarily occlude the target lesion from blood flow, flush the blood from the treatment chamber, and then locally deliver the therapeutic agents into the artery. A built-in fiber optic pressure sensor continuously monitors the treatment chamber during delivery. (b) The distal end of the OPC catheter demonstrating the space occupying balloon, outflow port and distal occlusion balloon. (c) A cross-section of the catheter showing the 5 lm that correspond to 1-proximal and distal balloons, 2-space occupying balloons, 3-inflow port, 4-outflow port, and 5guidewire

| Study procedure
Interventions were performed mainly by the contralateral femoral approach and with the use of 6F sheaths. Prior to treatment, atherectomy and pre-dilatation of the target lesion with standard balloon(s) were performed before paclitaxel was delivered using the OPC. Radiopaque rulers were used to ensure that the zone treated with the OPC consistently exceeded the area treated with atherectomy and standard balloons by at least 10 mm. If more than one OPC treatment was used per lesion, the overlap zone was at least 10 mm. Once placement of the OPC was confirmed using the radiopaque markers, an inflation device was utilized to inflate the occlusion balloons using a mixture of contrast and saline to visualize and to define the treatment chamber. Varying contrast agents used in this study included Isovue 320 and 370 (Bracco, Monroe Township, NJ), Visipaque 270 and 320 (GE Healthcare, Chicago, IL), Omnipaque 350 (GE Healthcare, Chicago, IL), and Ultravist 300 (Bayer, Whippany, NJ). Paclitaxel diluted in contrast agent and saline at a concentration of 1.2 mg/ml was delivered, using an inflation device, into the treatment chamber through the inflow port. The column of the paclitaxel mixture filling the vessel was observed under fluoroscopy ( Figure 2).
Once blood exits the outflow port, the outflow port was closed, and the paclitaxel mixture was maintained in the treatment chamber under pressure for 2 min as measured by the pressure monitor attached to the OPC. Following the 2-min dwell time, the paclitaxel was aspirated using an inflation device, the outflow port opened, and the treatment chamber flushed with saline to minimize systemic release of paclitaxel.
The occlusion balloons were then deflated and the catheter was either removed safely from the patient or re-positioned to deliver another dose of paclitaxel.
All patients were taking 81 mg of aspirin daily. Post-procedural medical therapy included aspirin 81 mg/day and clopidogrel 75 mg/ day for a minimum of 4 weeks and aspirin therapy was continued with a dose of 81 mg/day thereafter.

| Follow-up, study end points and definitions
Follow-up for each patient occurred at 1, 3, and 6 months. The primary efficacy endpoint in this study was patency, defined as freedom from target lesion occlusion, as determined by the ultrasound core laboratory and freedom from clinically driven target lesion revascularization (CD-TLR) at 6 months. CD-TLR was defined as lack of any TLR associated with deterioration of Rutherford classification and/or increasing size of pre-existing wounds and/or occurrence of new wounds. Analysis of the TLR was done using the Kaplan-Meier survival analysis method. The primary safety endpoint in this study was freedom from major adverse events (MAEs) at 1 month, defined as TLR within 1 month, major amputation in the target limb (amputation above the metatarsals), and target limb related death. Secondary efficacy endpoints included device success defined as the ability to deliver paclitaxel to the interventional treatment area as intended, improvement in Rutherford category, Walking Impairment Questionnaire Scores at 6 months compared to baseline, and freedom from target vessel revascularization. Secondary safety endpoints were MAEs defined as target limb related death or major amputation in the target limb (amputation above the metatarsals) within the 3-and 6-months post-procedure.

| Statistical analysis
Continuous data are presented as mean ± standard deviation. No comparative statistical analyses were performed; however, primary patency and target lesion revascularization rates were analyzed using Kaplan-Meier method.  Table 2.

| Procedural outcomes
Device success, defined as the ability to deliver liquid paclitaxel to the interventional treatment area as intended was successful in zero bailout stent placement. The observed Grade A dissection was observed following atherectomy and pre-dilatation of the target lesion, prior to OPC placement. Table 3 summarizes the procedural data for all treated patients. An example of pre-and post-angiogram of a treated lesion is shown in Figure 3.

| Safety and efficacy outcomes
Through the 6-month follow-up, there were two deaths, unrelated to the procedure, one patient withdrawal and four patients lost to followup. The two unrelated deaths were due to acute myocardial infarction and coronary artery disease with diabetic complications. There were no incidences of target limb related thrombosis or major amputations (

| DISCUSSION
This multicenter study clinically demonstrates the safety and efficacy of liquid paclitaxel administered using the OPC delivery catheter for the prevention of restenosis in infrapopliteal de novo and restenotic lesions. Although our previous first-in-human study found encouraging safety and initial feasibility, this more elaborate study provides further evidence into this novel approach with larger number of patients and more stringent evaluation of the treated lesion. 13 The primary safety outcome demonstrated no treatment related deaths, thrombosis or major amputation. Primary patency was 89.3% and freedom from clinically driven target lesion revascularization rate was 96.4% in lesions treated with a mean length of 119.1 ± 81.2 mm. Together, these results provide encouragement in the interventional treatment of the heavy atherosclerotic disease burden in BTK arteries and provide further insight into the local liquid therapy approach.
Treatment of BTK disease remains a major hurdle in endovascular therapy; in particular, as the majority of these patients suffer from CLI with increased risk of cardiovascular disease. Historically, balloon angioplasty provided poor patency outcomes in these vessels with restenosis rates of 35% at 6 months and increasing to 46%-58% at 1 year. 14-16 The use of DCBs was seen as a better alternative to balloon angioplasty, in particular for diffuse and long lesions of the periphery. However, the benefit of DCB to treat BTK disease remains controversial, primarily due to safety concerns. 9 has been suggested to correlate with distal coating embolization as shown in pre-clinical animal studies. 17 More recently, a systematic review and meta-analysis of randomized controlled trials investigating paclitaxelcoated devices for peripheral applications showed an increased risk of death. 18 The authors postulate late paclitaxel toxicity, associated with crystallinity of paclitaxel coating, may be the reason for the observed increased in death rate. 18 Additionally, the long-term impact of excipients on paclitaxel safety in DCBs remain relatively unknown. The fundamental delivery approach of the OPC also differs from DCBs. In liquid delivery using the OPC, pressure in the treatment chamber uniformly delivers liquid paclitaxel into the vessel wall regardless of the cross-sectional shape of the vessel. In DCB however, successful delivery of drug coated on the surface of the balloon is highly dependent on the cross-sectional shape of the vessel, with a preference toward a circular cross-sectional area to maximize balloonto-artery contact area. DCB places finite paclitaxel deposits onto the luminal surface, with the goal that these paclitaxel deposits will solubilize and diffuse into the vessel wall. The OPC device directly delivers liquid paclitaxel into the arterial wall following the two-minute delivery time during treatment as previously shown. 26 Overall the use of liquid oncological paclitaxel reduces safety concerns associated with crystalline paclitaxel form and long-term paclitaxel toxicity. Additionally, the design of the OPC system ensures little to no loss of paclitaxel during tracking of the device to the lesion   This current study shows the potential benefit of such a universal catheter to treat BTK arterial revascularization, however, the study does suffer from certain limitations. Long term outcomes are not known as the COPPER-A BTK study included a small number of patients with a 6-month follow-up. As this was a feasibility and safety analysis, this study included patients ranging from claudication to critical limb ischemia. While most patients had CLI (51.4%), future studies will need to investigate its role in Rutherford six patients. Furthermore, while the OPC device can be utilized to treat multiple BTK vessels of varying lengths, the safety and feasibility of this treatment approach will need to be investigated as patients in this cohort had one vessel treated with drug delivery. Finally, all patients were treated with atherectomy. The role of debulking heavily diseased BTK vessels and its effect on local liquid paclitaxel pharmacokinetics and subsequent patency/TLR will need to be further elucidated in future research. The study also lacked DCB and balloon angioplasty comparative groups. Future studies should include angiographic follow-up to assess binary restenosis at the treatment site and wound care assessment.

| CONCLUSION
Treatment of infrapopliteal arteries remains unresolved and associated with a high restenosis rates and poor long-term clinical patency.
The results from this multi-center study shows the potential of the OPC catheter to safely and effectively treat de novo and restenotic BTK lesions. The delivery of liquid paclitaxel using the OPC catheter under controlled pressure was technically achievable without procedural complications. These results provide encouragement for local liquid delivery as an alternative approach for infrapopliteal revascularization. In particular, the ability to treat very long or multiple lesions with a single device, provides a more economical option. The safety profile in this study is particularly favorable in view of recent concerns regarding adverse events with crystalline-paclitaxel coated devices. Longer term follow-up and larger clinical studies will be needed to support our findings of this technology with head-to-head comparisons with DCB and balloon angioplasty.