2.1 Study design

The Pathfinder Registry was a prospective, single-arm, multicenter, open-label, observational clinical study assessing the safety and efficacy of the 355 nm laser system in subjects with symptomatic infrainguinal PAD at 10 sites in the United States between August 2020 and March 2021. Institution Review Board (IRB) approval was obtained from a central IRB and all subjects included in the registry signed informed consents before enrollment.

Inclusion criteria were subjects 18 years of age or older with symptomatic infrainguinal PAD. All subjects had documented symptomatic atherosclerotic PAD with claudication or CLTI (Rutherford Classification 2–5). Subjects were excluded if a target lesion was in an bypass graft; there was planned use of another atherectomy device during the same procedure; if the subject was participating in another study using an interventional device that did not have regulatory clearance; if they had comorbid condition(s), which could limit the subject's ability to participate in the trial or to comply with follow-up requirements; or if the subject had anticipated survival of <1 year.

2.2 Endpoints

The primary efficacy endpoint for the study was technical procedural success measured as the percentage of subjects with successful revascularization of target vessel following the use of the 355 nm laser System and any adjunctive treatment if required, including angioplasty and stent placement at the operator's discretion. Successful revascularization was defined as achieving ≤30% residual stenosis at the index lesion postatherectomy and adjunctive therapy as evaluated by an angiographic Core Lab. The primary safety endpoint was the percentage of subjects who did not experience periprocedural major adverse events (PPMAEs) before discharge. PPMAEs included flow-limiting dissection (National Heart, Lung and Blood Institute [NHLBI] grade > C), clinically significant distal embolization which required more than simple aspiration or a vasodilator, the need for bailout stenting defined as being due to either a flow-limiting dissection per NHLBI grade > C or residual narrowing of >30%, a major or unplanned amputation, target vessel perforation requiring endovascular or surgical repair, or death. Supporting Information S1: Table 1 lists the secondary endpoints for the study.

2.3 Device

The 355 nm laser consists of a single-use catheter containing an array of optical fibers with a blunt rounded blade at its tip to both penetrate and transmit 355 nm coherent laser energy to modify and ablate atherosclerotic plaque. The laser and the blade work in synergy and the unique laser energy delivery profile enables a higher affinity to lesional material than the endothelium of blood vessels, inherently reducing the risk for vessel injury.^{15, 16} The 355 nm laser catheter is connected to the laser generator and transmits 40 short pulses per second to the occluded or narrowed artery at preset fluency levels of 50 or 60 mJ/mm². The system has four different single-use catheters with diameters ranging from 0.9 to 2.35 mm. The 2 and 2.35 mm catheters have an aspiration feature intended for debris and thrombus collection and removal from the vessel during the atherectomy procedure. The 2.35 mm catheter also has an “off-center” feature which can facilitate debulking of eccentric lesions. All catheters are inserted over a 300 cm 0.014” guide wire that has been used to cross the lesion intraluminally.

2.4 Study methods

Baseline data were collected to characterize subjects in terms of comorbidities, disease stage, prior treatments, lesion/occlusion baseline characteristics, and details of the atherectomy procedure and the adjunctive therapy. Ankle Brachial Index (ABI) and Rutherford classification were determined, and a Walking Impairment Questionnaire (WIQ)⁸ was administered pre-procedurally and at 6, 12, and 24 (±1) months following the procedure.

2.5 Study procedure

All subjects underwent atherectomy with the 355 nm laser system. Adjunctive therapy with either standard balloon angioplasty or drug-coated balloon angioplasty and stenting were used per operator discretion.^{10, 17, 18} Stent placement was limited and at the discretion of the operator. Prospective data, including MAEs, lesion patency rate, and clinical outcomes were collected to evaluate the clinical course of the subjects during the study follow-up period. Procedural angiograms were evaluated by an independent angiographic Core Laboratory (Prairie Education and Research Cooperative d/b/a Synvacor), to determine target vessel(s), target lesion length, diameter stenosis percentage, minimal lumen diameter, and tibial run-off(s). Angiographic films that were captured and submitted in accordance with the predefined angiographic acquisition protocol were qualitatively and quantitatively analyzed using a validated QVA software program (Cardiovascular Angiographic Analysis System). The analysis was done by two different readers, except in cases when values were found inconsistent or problems were identified, then an overread by a third reader or the medical director review was required. All data were collected using an electronic data collection platform. Subjects were managed per each site's standard clinical practices and the 355 nm laser system was utilized per the manufacturer's instructions.

2.6 Statistical analysis

Statistical analysis was performed by the study sponsor. The statistical analyses conducted for quantitative variables included frequency counts and percentages, means, SD, minimums, and maximums of each parameter. Categorical variables were summarized by frequencies and percentages. Unless explicitly stated, percentages utilized a denominator corresponding to the number of unique subjects or lesions that contributed to the endpoint. Statistical analyses were run using SAS Software version 9.4 (SAS Institute Inc.).

An α of 0.05 was used to determine statistical significance.

3.1 Patient population

One hundred and forty-two subjects were consented for enrollment in the study. Forty subjects were excluded from the study, 35 due to the absence of angiographic disease, three did not meet the inclusion/exclusion criteria, and two did not have a proper signed informed consent form. One subject inadvertently enrolled in the study was classified as Rutherford Class 6 and this data was included in the analysis since proper consent had been received and the patient underwent treatment with the 355 nm laser device and had data collected during follow-up visits.

3.2 Baseline demographics and clinical characteristics

Baseline demographics and clinical characteristics of the 102 subjects with one hundred and twenty-one 355 nm laser-treated target lesions in the intent-to-treat study population are listed in Table 1. Mean age was 68.4 ± 10.21 years, ranging from 28 to 92 years. There were more males than females (61.8% vs. 38.2%), with most subjects reported as being Caucasian (71.6%). Current and former smokers represented 28.4% and 38.2% of the study population, respectively. There was a high prevalence of one or more comorbidities, including hypertension (87.3%), hyperlipidemia (75.5%), diabetes mellitus (52.9%), and coronary artery disease (44.1%). Sixty of the 102 subjects (58.8%) had undergone a previous surgical or percutaneous intervention to treat PAD (46 [45.1%] were in the index limb). The average time since the last PAD intervention was 2.3 ± 3.28 years ago, with 39 of these 60 subjects (38.2%) having had an atherectomy; 46 (76%) of prior interventions were in the index limb. The mean ABI (or Tibial Brachial Index [TBI] if ABI was not available) was 0.73 ± 0.28 (range 0.28–1.41, n = 68). The mean Rutherford was 3.6 ± 0.92. The mean overall WIQ score at baseline for the 95 subjects with available data was 22.8 ± 22.5 (range 0.1–96.4) with 82.1% of subjects deemed to be low performers due a to overall WIQ score of 39 or less.¹⁹

3.3 Baseline angiographic variables

Baseline Core Lab data were available for 107 of the 121 (88.4%) target lesions. Treated lesion locations are shown in Table 2. De novo stenosis was the most common stenosis type (67.8%), followed by ISR (22.3%) and non-ISR (17.4%). Lesions had a mean Core Lab-reported length of 13.6 ± 11.5 cm (range 0.5–52.0 cm) and mean percent diameter stenosis of 87.1 ± 16.5 (range 17–100). Over a third of the lesions (36.5%) were reported by the Core Lab to have moderate-to-severe calcification, per Peripheral Academic Research Consortium (PARC) grading system with circumferential calcium distribution of ≥180° (both sides of vessel) and >50% of the lesion length.²⁰

3.4 Procedural data

One hundred and fifty-four lesions were treated with or without 355 nm laser system with a mean of 1.5 ± 0.77 (range 1–4) lesions treated per patient (Supporting Information S1: Table 2). This included 121 lesions treated with the 355 nm laser system and 33 lesions that were not treated with atherectomy before the use of angioplasty balloons or stents. One or more adjunctive therapies were used after atherectomy in 114 of the 120 (data were missing for one patient) lesions (95.0%), including balloon angioplasty in 104 (86.0%) and stents in (28) 23.1% of lesions. Other adjunctive therapies are available in Supporting Information S1: Table 2. Mean procedure time was 87.5 ± 39.5 min.

All four commercially available laser catheter sizes were used during procedures, with a mean laser duration of 123.3 ± 87.97 s.

3.5 Efficacy endpoints

Table 3 displays the angiography Core Lab-reported findings. The final residual diameter stenosis, following the use of the 355 nm laser system and any final adjunctive treatment (if required), was 24.4 ± 15.5. Sixty-nine lesions (69.0%) achieved the primary effectiveness endpoint of technical procedural success defined as ≤30% residual stenosis at the index lesion postatherectomy and adjunctive therapy, as evaluated by an angiographic Core Lab. Figure 1 shows improvements in stenosis diameter from baseline following both 355 nm laser treatment and subsequent adjunctive therapy for all subjects and in subgroup analyses of subjects with ISR, chronic total occlusion (CTO), and with Core Lab-defined severe calcification at baseline.

Although the study was not powered to assess differences in ABI, WIQ, or Rutherford classification, mean ABI (or TBI if ABI was not available) was found to be significantly increased versus baseline at both 6 months (p = 0.0180) and 12 months (p < 0.0001) following the procedure (Figure 2A). WIQ scores were also significantly increased at 6 and 12 months (p < 0.0001) (Figure 2B). Rutherford classification significantly decreased from baseline during the same time intervals (p < 0.0001) (Figure 2C) with 94% of subjects showing improvement at 12 months compared to baseline.

The percentage of subjects rated as low performers on the WIQ (overall score of ≤39) decreased from 82.1% at baseline to 37.2% at 6 months and 29.3% at 12 months (Figure 3). The percentage of subjects with duplex ultraound (DUS)assessed patency, defined as less than 50% stenosis, remained consistent from the 6-month through the 12-month follow-up periods ranging from 71.0% at 6 months to 71.6% at 12 months (Figure 4). At 6- and 12-month DUS follow-up, 17 (74.0%) and 15 (65.2%) of below the knee lesions (BTK)remained free from occlusions, whereas the rates of above the knee lesions were 43 (87.8%) and 38 (80.9%), respectively.

3.6 Safety endpoints

Ninety-seven subjects of the 102 subjects (95.1%) met the primary safety endpoint of not experiencing a PPMAE before discharge. PPMAEs occurred in five (4.9%) subjects. This included one subject who developed a clinically significant distal embolization following the use of the 355 nm laser device, which resolved intraprocedurally with thrombectomy and stenting, without further complications. Four (3.9%) subjects required bailout stenting following adjunctive therapy with balloon angioplasty. This included two (2.0%) subjects who experienced type C dissections revealed after balloon inflation and two (2.0%) who remained with residual narrowing. The need for bailout stenting occurred only after balloon angioplasty was performed with no patients requiring stenting after the initial treatment with the 355 nm laser device before angioplasty.

There were no periprocedural deaths, major or unplanned amputations, or target vessel perforations requiring endovascular or surgical repair before discharge. Only one PPMAE (drug-eluted stent[s] bailout stenting due to >30% stenosis postballoon angioplasty in the target lesion) was deemed by the physician to be related to the 355 nm laser system, resulting in 99.0% of subjects meeting the secondary safety endpoint. Among all 102 subjects, only one patient received a filter as an embolic protection device. There were 10 (11.2%) subjects with MAEs reported during the 12-month follow-up period (in 89 patients), all of which were assessed by the reporting physicians as not directly related to the use of the 355 nm laser system. This included two (2.2%) Rutherford 5 subjects who had unplanned major target limb amputations, six (6.7%) subjects who underwent a clinically driven target lesion revascularization (TLR), and two (2.2%) subjects who underwent a target vessel revascularization. There were no cardiovascular deaths reported for the study population during the 12-month follow-up period and no death associated with the use of the 355 nm laser device.