The Santreva™-Above the Knee (ATK) Endovascular Revascularization Catheter (AngioSafe, Inc., San Jose, CA) or study device is intended to facilitate the intraluminal placement of guidewires beyond stenotic lesions, including CTOs, in the FP peripheral arteries. The study device comprises an outer catheter shaft, a proximal handle with an integrated rotation wheel and luer fitting for guidewire insertion, and an inner torque cable tube containing the guidewire lumen ( Figure 1 ). The distal portion of the catheter features a rotating tip with an integrated cutting loop designed to puncture, displace, and compress plaque during CTO crossing. This mechanism operates in conjunction with a centering system component engineered to maintain luminal position during advancement. The centering system consists of 3 collapsible wings that expand within the CTO segment and the open vascular lumen, helping stabilize the catheter which may facilitate formation of an intraplaque and angiographically visible channel. These wings are sloped bidirectionally to provide a tapered interface with both the CTO body plaque and adjacent devices such as guide catheters or sheaths during advancement and retraction of the catheter. The estimated tip load can be >1,500 g, largest crossing profile of approximately 7.3 F and device length of 150 cm. The study device exhibited none to minimal vascular endothelial damage in porcine arterial vessels comparable to its profile when evaluated against a comparator device during delivery and intraplaque advancement ( Supplementary Figure 1 ); data on file with sponsor and included in submissions for regulatory approvals in the U.S. and the European Union.

Description of study device.

After delivery of the Santreva ^TM distal tip to the target CTO lesion using standard support catheters, the operator advances the device by grasping the outer shaft and rotating the handle wheel. This simultaneous axial advancement and rotational motion allows the distal tip and cutting loop assembly to penetrate the proximal cap of the CTO. As the catheter progresses through the occlusion, continuous rotation of the tip facilitates controlled puncture, radial displacement, and compression of the plaque, while the centering system wings maintain coaxial alignment and exert lateral compression to promote intraluminal recanalization. Upon reaching and penetrating the distal cap of the occlusion, the operator can advance a guidewire through the device into the distal true lumen, enabling subsequent definitive treatment of the CTO lesion. The study device requires a minimum 6F sheath. It should preferably be introduced through a guiding catheter, or a long sheath, with careful attention to avoid covering the device’s centering assembly, as this may inhibit the device’s unique crossing mechanism. The pivotal study allowed exclusively antegrade use of the study device.

RESTOR-1 was a prospective, single-arm, multicenter pivotal study conducted at 14 U.S. sites to evaluate the safety and effectiveness of the AngioSafe™ Peripheral CTO Crossing System (Santreva™). The study was designed to demonstrate that the device safely and effectively facilitates the crossing of CTOs in the FP arteries of the lower limbs.

Patients with symptomatic PAD, classified as Rutherford Clinical Category (RCC) 2 to 5, who were referred for clinically indicated endovascular revascularization, were eligible for enrollment. Target lesions were required to be de novo CTOs located in the common femoral, superficial femoral, and/or popliteal arteries, collectively referred to as the femoropopliteal segment, with a total lesion length of ≤300 mm. Only a single target lesion per subject was permitted for enrollment. Detailed inclusion and exclusion criteria are provided in Table 1 .

The primary endpoint was clinical success, defined as successful facilitation of guidewire placement into the distal true lumen of a FP CTO using the study device, in the absence of device-related major adverse events (MAEs) through hospital discharge or within 24 hours postprocedure, whichever occurred first. Secondary endpoints included technical and procedural success. Technical success was defined as the ability of the catheter to facilitate guidewire placement into the distal true lumen, while procedural success was defined as technical success achieved without a procedural complication within 30 days. A procedural complication was defined as the need for open or repeat endovascular repair in the treated limb, or a major bleeding event classified as Bleeding Academic Research Consortium (BARC) type 3–5. Additional assessments included evaluation of intraluminal CTO crossing by intravascular ultrasound (IVUS) and subgroup analysis of the primary endpoint according to the degree of calcification (none-mild, moderate-severe). Operators were encouraged to perform angiography of the CTO segment and outflow arteries to the foot and IVUS of the traversed occluded arterial segment immediately after successful crossing without additional intervention to evaluate channel formation through the CTO and plaque compression or atheroplasty effects of the study device. posthoc IVUS analysis of intraplaque crossing (within the external elastic lamina) was performed.

Safety endpoints included the incidence of device-related MAEs through discharge or within 24 hours postprocedure, and the incidence of all MAEs through 30 days postprocedure.

Device performance was evaluated based on pretreatment assembly and delivery without kinking or damage, advancement of the device-guidewirecatheter assembly to the proximal cap of the CTO, proper extension and expansion of the centering system, successful penetration of the proximal cap, and placement of the guidewire into the distal true lumen. Lesion crossing time was defined as the interval from device positioning at the proximal cap to guidewire entry into the distal true lumen. Clinical improvement was assessed by changes in Rutherford classification and pain Numeric Rating Scale (NRS) at 30 days compared with baseline.

All candidate cases were reviewed by a central screening committee, which evaluated prior lower extremity imaging obtained within 90 days of the index procedure to confirm eligibility according to the protocol-defined inclusion and exclusion criteria. On the day of the procedure, a preprocedure angiogram was performed to verify final eligibility. The CTO crossing procedure was defined to begin when the investigational device was first introduced into the vasculature. All procedures were conducted according to the Instructions for Use (IFU) and the Study Operations Manual to ensure standardization of procedural technique, imaging acquisition, and perioperative care across study sites. Other catheters (including re-entry devices) or specialized guide wires were allowed based on operator discretion; however technical success was defined when the study device facilitated placement of the guidewire in the true lumen beyond the distal CTO cap. Balloon angioplasty of the CTO track was allowed to advance the study device. Following CTO crossing, when feasible, IVUS and angiographic imaging were performed to confirm intraluminal passage of the device and atheroplasty. Subsequent lesion treatment, including balloon angioplasty, stenting, or atherectomy, was performed at the discretion of the investigator. Cine angiography was used to document the entire procedure.

postprocedure assessments, including evaluation for adverse events, were conducted before hospital discharge and at 30 days (±7 days) post-treatment. All adverse events were reviewed and adjudicated by an independent Clinical Events Committee (CEC) to determine device or procedure relatedness, seriousness, and classification as an MAE.

On-site clinical monitoring was performed by Veranex (Raleigh, NC) to ensure compliance with the study protocol, Good Clinical Practice requirements, institutional review board (IRB)/ethics committee recommendations which approved the study, and clinical study agreements. Source data verification confirmed proper informed consent and concordance between case report forms (CRFs) and source documentation. RCC and a pain numeric scale were used to report baseline and 30-days patient symptoms. Angiographic and IVUS images were independently analyzed by a core laboratory (Syntactx, New York, NY). All angiographic and IVUS datasets were processed and analyzed using CASS image analysis software (CASS Workstation, Pie Medical Imaging, Netherlands) and QIVUS Research Edition 3.1.18.0 (Medis Medical Imaging Systems Inc., Netherlands), respectively.

In Banerjee et al., the technical success rate of the CTO crossing device group was 74% (95% confidence interval or CI 68%–80%). The AngioSafe Peripheral CTO Crossing System was designed to achieve a higher rate of clinical success, defined as technical success without a device-related MAE through discharge or within 24 hours postprocedure, whichever occurred first. The expected clinical success rate for the AngioSafe system was 0.85, which would represent a meaningful improvement.

The primary hypothesis tested whether the AngioSafe Peripheral CTO Crossing System would perform better than a benchmark rate of 0.70, corresponding to the lower bound of the 95% CI reported by Banerjee et al. The null hypothesis stated that π ≤0.70, while the alternative hypothesis stated that π >0.70. Assuming a true clinical success rate of 0.85, a 1-sided significance level of 0.05, and 90% power, the required sample size based on a binomial exact test was 70 treated subjects.

Only 1 target lesion per subject was included in the analysis, regardless of whether the occlusion was contiguous or exhibited intermittent reconstituted flow. When data were available on more than 1 lesion in a subject, 1 lesion was randomly selected for inclusion. Consequently, the number of treated lesions corresponded directly to the number of treated subjects.

To evaluate the primary endpoint, a minimum of 70 subjects were to be treated at up to 14 participating U.S. sites. Approximately 75 subjects were expected to undergo treatment to ensure 70 evaluable cases in the primary analysis. Accounting for an anticipated 40% screen failure rate, up to 125 subjects were planned for enrollment. The allowance for screening failures reflected site-level differences in institutional or IRB requirements mandating consent prior to image submission for the screening committee’s review, as well as additional exclusions based on preprocedure angiographic reassessment. No individual site was permitted to enroll more than 25% of the total study population.