IFU Pulsar-18 US rev C 18.05.2017 11:49 Seite 1

Pulsar-18

Peripheral self-expanding Nitinol stent system

English

Caution: Federal (USA) law restricts this device to sale by or on the order of a physician. IFU Pulsar-18 US rev C 18.05.2017 11:49 Seite 2

Device Description Contraindications The Pulsar-18 stent system (Figure 1) is a self-expanding stent loaded on an • Patients with known hypersensitivity to nickel or amorphous silicon carbide. over-the-wire (OTW) delivery system. The stent (1) is laser-cut from a Nitinol • Patients with uncorrected bleeding disorders and contraindication to tube. It carries 6 radiopaque marker extensions at each end (1a, 1b) and is antiplatelet and/or anti-coagulation therapy. completely coated with amorphous silicon carbide (a-SiC:H). The delivery system consists of two coaxially arranged elements: the inner shaft () and the Warnings outer shaft (3). The central guide wire lumen within the inner shaft begins with a radiopaque tip • In patients with poor kidney function, contrast agents may precipitate kidney (7) at the distal wire exit and ends with a Luer port (6) at the proximal guide wire failure. exit. The stent is loaded between the inner shaft and the outer shaft proximal to • Persons with known hypersensitivities to the following substances may suffer the tip, between two radiopaque markers (8), which facilitate fluoroscopic an allergic reaction to this implant: visualization, and positioning of the stent system towards and across the lesion. - nitinol and / or its components (e.g. nickel, titanium) The outer shaft begins proximally within the handle (9) and extends towards the - amorphous silicon carbide distal tip, covering the stent. A hydrophobic coating is applied to the outside of • DO NOT use after the “use by” date specified on the label. the inner shaft and the inside and the outside of the entire outer shaft. The guide • Device is supplied STERILE and for single use only. DO NOT re-sterilize and/or wire lumen of the inner shaft and the annular space between the inner shaft reuse. Reuse of single use devices creates potential risks including infections. and the outer shaft are flushed simultaneously through the Luer port at the Contamination of the device may lead to serious injury or patient harm. proximal guide wire exit. The guide wire lumen permits the use of 0.018" (0.46 mm) guide wires to facilitate advancement of the stent system toward and • Appropriate anticoagulation and antiplatelet therapy should be administered through the lesion to be treated. pre- and post-procedure in accordance with standard practices. The outer shaft is covered proximally with a blue colored tube (13) that indicates • If using to treat a previously stented lesion, long-term outcomes following the progress and completion of stent deployment and a transparent tube (1) to repeat dilatation of endothelialized stents have not been studied. protect from kinking. • DO NOT use if the sterile package is opened or damaged or any information Prior to deployment, the locking tab (4) must be removed and discarded. The provided is obscured. DO NOT use if the device is damaged or if the stent is stent is deployed with the trigger (5). In case the trigger release mechanism partially deployed. fails, partial stent deployment can be completed as follows: first, open the • DO NOT use in patients after failed guide wire or balloon catheter access. handle using the secondary release ring (10) and button (14), then pull directly • DO NOT use guide wires with 0.014” (0.36 mm) diameter. on the blue tube. Pulsar-18 features an “Easy Release” (11) fitted over the • If unusual resistance is experienced during the introduction of the delivery proximal outer shaft. The “Easy Release” is intended to be inserted into the system or deployment, or if stent cannot be deployed, remove the entire stent hemostatic valve of the introducer to reduce friction between the stent system system (a partially deployed stent may require surgical removal). and the hemostatic valve during stent release. • Advancement of the stent system without the guide wire extended beyond the tip may lead to vessel damage. Figure 1: Pulsar-18 stent system • DO NOT advance a partially deployed stent proximally or distally. Dragging or repositioning the stent may cause injury to the patient. • Once the stent is partially deployed it cannot be recaptured using the stent system. • Limited data exists on use of two overlapping stents. If multiple stents are required to treat a lesion, it is only recommended to use stents of same metal type and a maximum of two stents. The risk of corrosion increases when stents of differing metals contact one another. Overlapping of more than two stents has not been investigated. Precautions • Only physicians thoroughly trained and educated in the performance of PTA and stent implantation should use this device. • Stenting across a bifurcation or side branch could compromise future diagnostic or therapeutic procedures. The stent system and the “Easy Release” are compatible with an appropriately • The minimum introducer sheath size is indicated on the label. If the device is sized introducer sheath according to the indications on the label. used in conjunction with long and/or braided introducer sheaths, a larger The stent is advanced to the intended implantation location by means of the French size than indicated on the label may be necessary to reduce friction. over-the-wire delivery system and is deployed by means of the handle and • Use only guide wires with a 0.018” (0.46 mm) diameter. trigger mechanism. The stent remains in the vessel as a permanent implant. • Verify that the distal end of the outer shaft is flush against the tip. If a gap exists between the outer shaft and the tip, do not use the device. How Supplied • Exercise care during handling to reduce the possibility of releasing the stent Sterile. Non-pyrogenic. Device is sterilized with ethylene oxide. prematurely, accidental breakage, bending or kinking of the catheter shaft. • Exposure of the stent system to organic solvents, e.g. alcohol, may cause Contents damage to the stent system. • The delivery system is not designed for use with power injection systems. • One (1) Pulsar-18 self-expanding stent system in a sealed, peel-open pouch. • Always keep the device filled with sterile heparinized isotonic saline while it • One (1) Patient Implant Card. is in the vascular system. • One (1) Instruction Card. • Avoid manipulation of the stent release mechanism during removal from packaging and flushing of the stent system. Storage • If more than one stent is planned to treat a lesion, it is recommended to place Store in a dark, dry location between 10°C (50°F) and 30°C (86°F). the more distal stent first. Allow for sufficient overlap between the stents. • Recrossing a stent with adjunct devices must be performed with caution. Indications • The use of mechanical atherectomy devices or laser catheter is not recommended within the stented area. The Pulsar-18 stent system is indicated for use to improve luminal diameter in patients with symptomatic de novo, restenotic or occlusive lesions located in the superficial femoral or proximal popliteal arteries, with reference vessel diameters from 3.0 to 6.0 mm and total lesion lengths up to 190 mm.

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Potential Adverse Events/Complications Introduction and delivery of the stent system Possible complications include, but are not limited to: 07. Thread the distal tip of the stent system over the proximal end of the guide wire and advance the system until the wire exits the Luer port at the • Allergic reactions to contrast media, antiplatelet aggregation or anticoagulant proximal end of the delivery system. Take care to keep the delivery system medications, amorphous silicon carbide and nitinol and/or its components as straight as possible. (e.g. nickel, titanium) 08. Carefully insert the stent system through the introducer while immobilizing • Bleeding events: Access site bleeding or hemorrhage, hemorrhage requiring the guide wire. transfusion or other treatment 09. Carefully advance the stent system over the guide wire just distal to the • Death lesion to be treated. • Embolization of air, thrombotic or atherosclerotic material 10. Insert the "Easy Release" into the introducer (to reduce friction between the • Emergency surgery to correct vascular complications hemostatic valve and the outer shaft of the delivery system during stent • Infection and sepsis deployment). Blood loss may increase when the “Easy Release” is used. • Stent system events: Failure to deliver stent to intended site, stent 11 While pressing the trigger (5) with the thumb (figure A1) gently twist (45°) misplacement, stent deformation, stent embolization, stent thrombosis or and pull out the locking tab (4) (figure A and A3). occlusion, stent fracture, stent migration, inadequate apposition or 1. Lift thumb to release pressure off the trigger and allow it to extend out of the compression of stent/s, withdrawal difficulties, embolization of catheter handle (figure A4). material • Tissue necrosis and limb loss due to distal embolization • Vascular events: Access site hematoma, hypotension/ hypertension, pseudoaneurysm, arteriovenous fistula formation, retroperitoneal hematoma, vessel dissection or perforation, restenosis, thrombosis or 45° occlusion, vasospasm, peripheral ischemia, dissection, distal embolization (air, tissue debris, thrombus)

Directions for use A1 A2 Patient preparation and stent system selection PTA and placement of a self-expanding nitinol stent should be performed in an angiography equipped room. Patients are to be prepared in accordance with hospital or local procedures. It is recommended to pre-dilate the lesion using standard PTA techniques before stenting. Maintain lesion access with the guide wire when removing the PTA balloon catheter from the patient. 01. Select the appropriate stent size based on the diameter of the artery A3 A4 adjacent to the lesion and the length of the segment to be stented. The (unconstrained) stent diameter in relation to the target artery reference Figure A diameter can be seen in Table 1. The length of the stent should overlap the lesion by at least 5 mm on either side. 13. Withdraw the stent system back across the lesion, positioning the stent system markers on either side of the lesion. Table 1: 14. Maintain the stent system and guide wire as straight as possible outside the Pulsar-18 Stent Size Selection and Foreshortening Table body (figure B1). Percent Stent Free 15. Immobilize the handle and guide wire. Unconstrained Vessel Foreshortening [%] Area Caution: While deploying, any slack in the delivery system outside the patient Stent Diameter Diameter % at max. to min. (figure B) could result in incorrect stent placement, potential stent (mm) [mm] Min. Mean Max. oversizing compression or elongation.

4 3.0 – 3.5 0 1  77 - 81

5 3.0 – 4.0 0 1 1 77 - 83

6 4.0 – 5.0 0 1  83 - 86

7 5.0 – 6.0 0 1 4 86 - 89 B1 Stent system preparation 0. Open the outer packaging and remove the sterile pouch. 03. After careful inspection of the pouch for damage to the sterile barrier, peel open the pouch, and remove the tray. First pick up the handle and then pull the catheter out of the spiral loop holder and place it onto the sterile field. Take care not to kink the catheter. 04. Examine the stent system for damage. Ensure that the stent is contained within the outer shaft. Do not use if the stent is partially deployed.

Flushing of the stent system B2 05. Attach a 10 ml syringe filled with sterile heparinized saline to the Luer port at the proximal guide wire exit and inject at least 5 ml saline into the guide wire lumen until the fluid exits the catheter tip and also between the end of Figure B the outer shaft and the tip. 06. Remove the syringe. Note: Whenever the stent system is in the body it should be manipulated while under fluoroscopy.

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Stent deployment Note: Correctly deployed stent length (not compressed or elongated) can be checked by matching the delivery system markers with the respective stent Caution: During stent deployment, do not hold the “Easy Release“ in place. If the markers following deployment. “Easy Release“ comes out of the introducer do not reinsert it. Blockage or high friction during stent deployment may occur. Caution: If unusual resistance is experienced during deployment, stop the procedure and determine the cause of the resistance before proceeding. If 16. Ensure that the position of distal and proximal stent ends relative to the necessary follow “Description of secondary release” as described below. lesion is still correct (figure C1). 17. Begin stent deployment under fluoroscopic guidance by pushing the trigger 0. Obtain angiographic visualization of the stented vessel segment. with the thumb while holding the handle in a fixed position (figure C). Delivery system removal Caution: The first press of the trigger removes any slack from the delivery system and could change the stent position within the lesion (figure C3). 1. After full stent deployment, carefully remove the delivery system under Always realign and ensure proper stent position (figure C4 and C5) before fluoroscopic guidance while observing the radiopaque tip, leaving the guide continuing to trigger (figure C6). wire in place. Note: If the tip encounters any resistance during delivery system removal, free Note: Stent begins deploying approximately between the second and fourth the tip by carefully moving the delivery system in the distal direction and trigger. then re-attempt removal. . After use, dispose the product and packaging in accordance with hospital, administrative and/or local government policy. C1 Overlapping stents For placing a second stent, repeat steps 0 to  with a new device. The stent overlap area must be at least 10 mm and not more than 0 mm. To position the second stent, use the radiopaque markers of the already implanted stent and delivery system.

1x C2 Post-procedural 3. If the stent is incompletely expanded along the lesion, post deployment balloon dilatation can be performed. Select a PTA balloon whose inflated diameter matches the reference diameter of the target vessel. 4. Obtain angiographic visualization of the stented vessel segment. ! C3 Description of secondary release 01. In case the trigger release mechanism fails before releasing the stent, remove the complete system from the patient. C4 0. If the trigger release mechanism fails with a partially released stent: turn the handle over as in figure E1; while keeping the handle stable, push button (14) on underside of the handle then pull and lift on the secondary release ring (10) to break open the handle (figure E). 03. Firmly hold the cutting unit with the thumb (figure E3) and pull directly on C5 the blue tubing (see arrow in figure E3) parallel to the proximal end of the guide wire until the stent is completely deployed Note: It may occur that parts of the handle mechanism drop out. They are not necessary for this method of stent release.

C6

Figure C E1

18. Once the distal end of the stent has been deployed, always observe and maintain the -3 mm gap between the distal stent markers and the distal delivery system markers to ensure a uniform stent deployment (as shown in figure D below).

E2

Figure D E3 19. Repeatedly push the trigger until the stent has been completely deployed, which is achieved when the blue colored proximal part of the outer shaft (13) disappears within the handle. The length of the blue part corresponds to the mounted stent length. Figure E

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Magnetic Resonance Imaging (MRI) • The primary effectiveness endpoint for the Pulsar stent group was the primary patency rate at 1 months (395 days) post-index procedure. Primary patency was defined as freedom from more than 50% restenosis based on MR conditional the duplex ultrasound peak systolic velocity ratio (PSVR) > .4, comparing data within the treated segment to the proximal normal segment or based on a clinically-indicated TLR with angiographic evidence of >50% stenosis. A clinically-indicated TLR was defined as any repeat, percutaneous intervention or bypass surgery of the target lesion driven by clinical findings (ischemic MRI Safety Information symptoms). The endpoint assessed the 1-month rate against a performance Non-clinical testing has demonstrated that the BIOTRONIK Pulsar-18 stent is goal (PG) of 66%. MR Conditional for single and overlapping lengths up to 385 mm. A patient with this device can be safely scanned in an MR system meeting the following The study included several additional secondary endpoints, but no formal conditions: hypotheses were associated with the evaluation of the secondary endpoints. • Static magnetic field of 1.5 and 3.0 Tesla Independent core laboratory analysis of study-required duplex ultrasounds • Maximum spatial gradient magnetic field of 3000 gauss/cm (30 T/m) (DUS), X-rays and angiographic images was performed. In addition, MAE and possible MAE events were reviewed by an independent Clinical Events • Maximum MR system reported, whole-body averaged specific absorption rate Committee (CEC) composed of physicians knowledgeable in the treatment of (SAR) of 1 W/kg for landmarks below the umbilicus and  W/kg (Normal peripheral artery disease (PAD). Events were evaluated as to relationship to the Operating Mode) for landmarks above the umbilicus. procedure and/or stent, as well as whether TLR events were clinically indicated. Under the scan conditions defined above, the Pulsar-18 stent is expected to produce a maximum temperature rise of 5.7°C after 15 minutes of continuous 2. Demographics and Clinical Characteristics scanning. Table  provides a summary of the subject demographics and clinical In non-clinical testing of the BIOTRONIK Pulsar-18 stent, the image artifact characteristics at the enrollment/baseline visit for all evaluable subjects in the caused by the device extends approximately 4 mm when imaged with a gradient Pulsar stent group. echo sequence or 3 mm when imaged with a spin echo pulse sequence and a 3.0 Tesla MRI system. The artifact may obscure the device lumen. Table 2: Summary of Clinical Studies Pulsar Stent Group Baseline Demographics and Clinical Characteristics BIOTRONIK collected clinical data through the BIOFLEX-I clinical trial to Pulsar Stent Group Parameter establish a reasonable assurance of safety and effectiveness of femoropopliteal Evaluable n=302 stenting with the Astron Pulsar and Pulsar 18 Stent Systems (Pulsar Stents) for the treatment of atherosclerotic lesions found in superficial femoral artery (SFA) Age in years at enrollment and proximal popliteal artery (PPA). A summary of the clinical trial is presented mean ± SD (range, min/max) 67.3 ± 10.3 (41.5, 95.9) below. Gender (%, n/n) The BIOFLEX-I Study Male Gender 67.9% (05/30) The Treatment of Atherosclerotic Lesions Using the Self-expanding Astron and Pulsar Stents (BIOFLEX-I) Study was a prospective, non-randomized, multi- Race (%, n/n) center study focusing separately on lesion treatment in the superficial femoral White 90.4% (73/30) artery or proximal popliteal and iliac artery. Only the SFA/PPA lesion treatment cohort is applicable to the Pulsar stents. Black or African American 7.3% (/30) Subjects were considered eligible for Pulsar stent group implantation if they had de novo or restenotic, atherosclerotic (≤190 mm long) or occlusive (≤100 Asian .3% (7/30) mm long) lesions in either the superficial femoral or proximal popliteal arteries, American Indian or Alaska Native 0.0% (0/30) with reference vessel diameters ranging from .5 to 6 mm. Subjects were allowed to receive treatment for one lesion per limb, however, if multiple limbs Native Hawaiian or other Pacific Islander 0.0% (0/30) were treated they could not be for the same indication; the lesions had to represent different indications (i.e. one iliac lesion and one femoropopliteal Hispanic Ethnicity (%, n/n) lesion on contralateral limbs). Only four subjects received investigational stent Hispanic 7.0% (1/30) treatment of both an iliac and SFA lesion under the BIOFLEX-I protocol. The Pulsar stent group (either the Astron Pulsar or the Pulsar 18) were used for Non-Hispanic 93.0% (81/30) the treatment of SFA or PPA lesions in 30 subjects enrolled at 38 study sites (9 in the U.S.,  in Canada and 7 in Europe). Following enrollment/baseline and General Medical History (%, n/n)* the index procedure, all evaluable subjects were to be assessed at 1, 6, 1, 4, Diabetes 40.7% (13/30) and 36 months post-index procedure. Subjects were to be prescribed dual antiplatelet therapy at the index procedure and upon discharge, for a minimum Hypertension 84.4% (55/30) of three months and then in accordance with clinical guidelines based on physician discretion. The subjects were to continue aspirin therapy for the Hyperlipidemia 81.1% (45/30) duration of study participation. Upon completion of the study, subjects were to Smoking status return to standard of care follow-up with their physician. The first subject was enrolled on July 19, 011 and enrollment was completed Current smoker 40.4% (1/30) September 15, 014. The data presented includes site-reported data collected Within last 5 years 15.% (46/30) through April 6, 016. A total of 367 stents were implanted. 1. Clinical Endpoints Never/not within last 5 years 44.4% (134/30) The primary study endpoints were as follows: History of cerebrovascular disease 15.9% (48/30) • The primary safety endpoint for the Pulsar stent group was the freedom from History of congestive heart failure 8.9% (7/30) procedure- or stent-related major adverse events (MAEs) at 30 days post- index procedure. The MAE rate was a composite of mortality, clinically-driven History of ischemic heart disease 41.1% (14/30) target lesion revascularization (TLR) and index limb amputation. Index limb amputation includes the loss of any part of the limb receiving intervention. History of coronary revascularization 36.4% (110/30) The endpoint assessed the 30-day rate against a performance goal (PG) of History of renal insufficiency 5.6% (17/30) 88%.

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*Definitions: Hypertension and Hyperlipidemia: requiring treatment with a 4. Safety and Effectiveness Results prescription medication; Cerebrovascular disease: carotid artery disease and history of stroke or transient ischemic attack (TIA); Congestive heart failure: a. Primary Safety Endpoint ejection fraction < 40% or heart failure diagnosis; Ischemic heart disease: The primary safety endpoint of the freedom from procedure- or stent-related myocardial infarction, angina pectoris, percutaneous or surgical coronary MAEs at 30 days post-index procedure was 99.7%, 95% confidence interval (CI) revascularization, positive exercise test or anti-anginal therapy; Renal [98.%, 100.0%], which exceeded the performance goal, and is presented in insufficiency: creatinine ≥ 1.5 mg/dL (last measurement prior to baseline). Table 4. One procedure-related MAE was reported. Further details of the 30- 3. Lesion Characteristics Day MAE composite and component event rates are also included in the table. Table 3 summarizes the baseline lesion characteristics for all evaluable Table 4: subjects obtained from the baseline angiogram at the index procedure. Pulsar Stent Group Primary Safety Endpoint and Components (N=302)

Table 3: 30 Days PG Primary Safety Endpoint [95% CI] Pulsar Stent Group Baseline Lesion Characteristics Rate (%, n/n) (%) Pulsar Stent Group Parameter (Core laboratory) Category Evaluable 30-Day Freedom from MAEs 1 99.7% (301/30) [98.%, 100.0%] 88% n = 302

Right 47.0% (14/30) 30-Day MAE 0.3% (1/30) Target side (%, n/n) Left 53.0% (160/30) Stenosis 30-Day Mortality 0.3% (1/30) 69.9% (11/30) Lesion type (%, n/n) (Non-occlusive) 30-Day Target Limb Occlusion 30.1% (91/30) 0.0% (0/30) Amputation Ostial SFA 0.7% (/30) 30-Day Target Lesion 0.0% (0/30) Proximal SFA 1.6% (38/30) Revascularization (TLR) Lesion location (%, n/n) Mid SFA 51.7% (156/30) 1Freedom from MAE rate ≥ PG, p<0.001. Distal SFA 3.8% (99/30) b. Primary Effectiveness Endpoint Proximal popliteal .3% (7/30) Table 5 presents the results from the primary analysis of the primary patency None/Mild 7.% (8/30) at 1 months for all lesion lengths of the Pulsar stent group. Out of the 68 evaluable subjects in the Intent-to-Treat (ITT) population, for which patency Lesion calcification (%, n/n) Moderate 30.1% (91/30) could be confirmed at 1-months, 179 subjects had confirmed patency. The Severe 4.7% (19/30) overall patency rate was 66.8% (179/68), 95% CI [60.8%, 7.4%]. The observed primary patency rate was 66.8%, however the lower bound of the 95% CI was Lesion length (mm) mean ± SD (range) 8.0 ± 46.9 (9.1, 8.0) below 66%, therefore the performance goal was not met. Results of the pre- specified sub-group analysis of the primary patency rate for standard and long Pre-deployment minimum mean ± SD (range) 1.0 ± 0.9 (0.0, 3.5) lesion lengths are also included in the table. lumen diameter (mm) Post-deployment minimum Table 5: mean ± SD (range) 4.1 ± 0.7 (., 6.) lumen diameter (mm) Pulsar Stent Group Primary Effectiveness Endpoint and Lesion Length Sub-groups (N=302) Final stent minimum lumen mean ± SD (range) 4.5 ± 0.7 (.4, 6.6) 12-months diameter (mm) PG Primary Efficacy Endpoint (395 Days) [95% CI] Reference vessel diameter (%) mean ± SD (range) 5.0 ± 0.9 (3.0, 7.5) Rate (%, n/n) (mm) 1-Month Primary Patency Pre-deployment lesion mean ± SD (range) 80.4 ± 16.7 (39.0, 100.0) stenosis (%) All Lesion Lengths 66.8% (179/68) [60.8%, 7.4%] 66% Pre-deployment lesion mean ± SD (range) 89.7 ± 9.5 (70.0, 100.0) ≤ 140 mm Lesion Lengths stenosis (%) (site-reported) 68.5% (161/35) Sub-group Post-deployment lesion mean ± SD (range) 17.9 ± 9.8 (1.5, 54.5) stenosis (%) > 140 mm Lesion Lengths 54.5% (18/33) Sub-group Post-deployment lesion mean ± SD (range) 3.8 ± 7.5 (0.0, 50.0) stenosis (%) (site-reported) Final stent diameter stenosis mean ± SD (range) 11.0 ± 10.5 (0.0, 54.5) (%) 0 vessel 6.3% (19/30) 1 vessel 4.5% (74/30) Distal vessel runoff  vessel 30.8% (93/30) (%, n/n) 3 vessel 7.8% (84/30) Not Available 10.6% (3/30) Type A 55.1% (166/301) Type B 35.% (106/301) TASC II Type (%, n/n) Type C 8.6% (6/301) Type D 1.0% (3/301)

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Figure  and Table 6 present the Kaplan-Meier analysis of freedom from loss of c. Secondary Endpoints patency at 1 months (395 days) for all lesion lengths, which was 67.3%, 95% CI Secondary endpoints were assessed at the specified time points. Key secondary [61.7%, 7.9%] for the ITT population. endpoint safety and efficacy results for the ITT population are summarized in Table 7. Figure 2: Primary Patency Kaplan-Meier Analysis Table 7: Key Secondary Endpoint Safety and Effectiveness Results Effectiveness Measure Secondary Endpoints Procedure or stent-related MAEs at 1 months (%, n/n) 1.7% (36/83) Distribution of MAEs at 1 months (%, n/n) 30-day Mortality (%, n/n) 0.4% (1/83) 1-Month Target Lesion Revascularization (TLR) (%, n/n) 1.4% (35/83) 1-Month Target Limb Amputation (%, n/n) 0.4% (1/83) Stent fracture rate at 1 months post-index procedure a 3.1% (9/93) (%, n/n)

Primary assisted patency (freedom from remote TVR) rate 98.9% (7/75) at 1 months b (%, n/n)

Subjects free from repeat endovascular procedure on 98.9% (7/75) study limb outside of study lesion (%, n/n)

Subjects free from repeat surgical procedure on study 100.0% limb outside of study lesion (%, n/n) (75/75) Secondary patency rate at 1 months c (%, n/n) 98.% (71/76) Subjects free from bypass on study limb (%, n/n) 99.6% (75/76) Subjects free from amputation on study limb (%, n/n) 98.6% (7/76) Acute procedural success d (%, n/n) 98.0% (96/30)

30-day clinical success e (%, n/n) 97.7% (94/301)

Ankle Brachial Index (ABI) Change from Baseline to 1- Table 6: 0. ± 0.1 Primary Patency in All Stents through 12 Months month Paired Data (mean ± SD), n = 66 Time from Six Minute Walk Test Change from Baseline to 1 months Primary Standard 95% Confidence 13.6 ± 41.7 Implant Events At Risk Paired Data (mean feet ± SD), n = 47 Patency Rate Error Interval (Days) Walking Impairment Questionnaire (WIQ) Score Changes 0 100.0% 0 --- 0 30 from Baseline to 1 months Paired Data 30 99.7% 0.3% [99.1%, 100.0%] 1 86 WIQ PAD Specific Score (mean ± SD), n = 65 39.1 ± 40.4

90 97.9% 0.9% [96.%, 99.6%] 6 75 WIQ Walking Distance Score (mean ± SD), n = 64 3.6 ± 37.4 WIQ Walking Speed Score (mean ± SD), n = 63 18.3 ± 8.1 180 90.4% 1.8% [86.9%, 93.9%] 7 49 WIQ Stair Climbing Score (mean ± SD), n = 55 0.1 ± 36.0 70 77.0% .6% [7.0%, 8.0%] 63 06 a) Number of stents out of total stents, based on a secondary analysis of stents 365 70.6% .8% [65.1%, 76.1%] 80 188 with an X-ray evaluation. 395 67.3% .9% [61.7%, 7.9%] 89 179 b) Freedom from a repeat procedure (endovascular or surgical) outside of the initially treated lesion to maintain patency of the target vessel (remote target vessel revascularization). The treated lesion includes the stented segment plus 5 mm proximal and distal to the stent. c) Freedom from treated lesion abandonment (bypass) or amputation of the target limb. d) Completion of the procedure and the stented lesion having less than 30% residual stenosis determined by angiography immediately after stent placement and no MAEs before hospital discharge. e) Completion of the procedure and the stented lesion having less than 30% residual stenosis determined by angiography immediately after stent placement and no MAEs within 30 days of the index procedure.

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d. Evaluation of Safety - Summary of Serious Adverse Events Rate of Subjects Number of Observed with Event Category Adverse n = 302 Table 8 summarizes the serious adverse events (SAEs) for the ITT population. Events SAEs must be site reported as having an onset within 395 days of the index % (n/N) procedure. Note that the total number for each category of adverse events is Vascular event 118 6.% (79/30) not necessarily the sum of individual events within the sub-categories, as it is a count of unique subjects with the adverse event category. Acute mesenteric ischemia 1 0.3% (1/30)

Table 8: Arterial embolization distal to puncture 1 0.3% (1/30) Summary of Serious Adverse Events at 12 Months (395 Days) site Rate of Subjects Number of Carotid stenosis 8 .3% (7/30) with Event Category Adverse n = 302 Events Contralateral iliac dissection 1 0.3% (1/30) % (n/N) Gangrene - led to amputation 1 0.3% (1/30) Any serious adverse event 450 59.6% (180/30) Hematoma - Non-index procedure 5 1.7% (5/30) Cancer 10 3.3% (10/30) related Numbness and/or tingling, lower Cardiovascular 93 19.5% (59/30) 1 0.3% (1/30) extremities

Dermatological 1 0.3% (1/30) Open or non-healing wound/ulcer 3 1.0% (3/30)

Electrolyte imbalance  0.7% (/30) Planned carotid stenting 1 0.3% (1/30)

Endocrine 11 .6% (8/30) Planned PVI in contralateral extremity 10 3.3% (10/30)

Gastrointestinal 8 5.3% (16/30) Pseudoaneurysm 1 0.3% (1/30)

Stenosis or occlusion in contralateral Genitourinary 5 1.7% (5/30) 45 14.% (43/30) extremity Hematological event 7 1.7% (5/30) Stenosis or occlusion in target 4 7.0% (1/30) extremity outside of stent segment Infection 37 9.3% (8/30) Subclavian stenosis 1 0.3% (1/30) Musculoskeletal 1 6.3% (19/30) Thrombosis 5 1.3% (4/30) Neurological/Nervous system 1 4.0% (1/30) Varicose veins  0.7% (/30) Ophthalmological event 3 1.0% (3/30) Vessel dissection or perforation during 1 0.3% (1/30) placement of thrombolysis catheter Procedure-related event 11 3.0% (9/30) Vessel dissection or perforation during 4 1.3% (4/30) Allergic reaction to contrast media or PTA  0.7% (/30) anti-thrombotic meds Vessel dissection prior to stent 1 0.3% (1/30) placement Bleeding requiring treatment 1 0.3% (1/30) Worsening claudication  0.7% (/30) Hematoma 3 1.0% (3/30) Other medical event 14 .6% (8/30) Nausea and/or vomiting 1 0.3% (1/30)

Post-surgical wound discomfort 1 0.3% (1/30) e. BIOFLEX-I Study Pulsar Group Sub-group Analyses Pseudoaneurysm 3 1.0% (3/30) Gender: No evidence of associations between gender and primary endpoints were observed, except for procedure- or stent-related MAE rate at 1 months, Renal 10 .6% (8/30) which showed a higher rate in females than males (19.8% vs. 9.6%). The female subjects that experienced a TLR at 1-months had higher rates of occlusive and Respiratory 7 .0% (6/30) longer lesion lengths, as well as proportion of smaller vessels than observed in the primary female cohort and overall study population. This sub-group analysis Stent event 60 16.6% (50/30) was not statistically powered. Stenosis or occlusion of target lesion Elderly: No significant differences in primary or secondary endpoint event rates 55 16.% (49/30) within stent segment were observed based on age (>75 years of age versus ≤ 75 years of age). Diabetic patients: The observed primary patency at 1 months was similar in Thrombosis or occlusion during subjects without diabetes (68.4%) compared to those with diabetes (64.6%). 1 0.3% (1/30) stenting procedure g. Applicability to Pediatric Population Vessel dissection or perforation during 4 1.3% (4/30) PAD is not typically found in pediatric populations excepting rare lipid disorders. stenting procedure Accordingly, the safety and effectiveness of the Pulsar stent systems in pediatric populations were not studied in the BIOFLEX-I study.

8 IFU Pulsar-18 US rev C 18.05.2017 11:49 Seite 9

Other Patients are advised to register the presence of an implanted stent and the Symbol Legend conditions under which it can be scanned safely with the MedicAlert Foundation (www.medicalert.org) or equivalent organization. Sterilized using Do not use if package ethylene oxide is damaged Warranty / Liability The product and each component of its system (hereinafter "the product") have Do not re-use Batch code been designed, manufactured, tested and packaged with all reasonable care. However, BIOTRONIK has no control over the conditions under which the Catalogue Caution product is used and a disturbance of the intended function of the product may number occur for various reasons. In this respect, the warnings in this product publication/ instructions for use are expressly to be considered as an integral part of this disclaimer and provide more detailed information. For this reason, Keep dry Use by BIOTRONIK disclaims all warranties, expressed or implied regarding the product, including but not limited to, any warranty of merchantability or fitness Keep away from Consult instructions for a particular purpose of the product. Product descriptions or user guidelines sunlight for use in publications do not constitute any expressed representation or any expressed or implied warranty. BIOTRONIK is not liable for any direct, incidental or Temperature MR conditional consequential damages or medical expenses caused by any use, defect, failure limitation or malfunction of the product whether the claim is based on contract, warranty, tort or otherwise. This does not apply in the case of intention or in the case of Do not Date of gross negligence of legal representatives or executive staff of BIOTRONIK. In resterilize manufacture commercial transactions relating to merchants, the liability is limited to the compensation of typical damages; compensation for any untypical or incidental damage is excluded. These limitations of liability and warranty are not intended Stent Manufacturer to contravene any mandatory provisions of law applicable in the respective country. If any clause of the disclaimer is considered by a competent court to be invalid or to be in conflict with the applicable law, the remaining part of it shall not be affected and remain in full force and effect. The invalid clause shall be substituted by a valid clause which best reflects BIOTRONIK's legitimate interest in limiting ist liability or warranty without infringing any mandatory provisions of applicable law. No person has any authority to bind BIOTRONIK to any warranty or liability regarding the product.

Table 9: Available Pulsar-18 Stent Sizes

Nominal Stent Ø 4 5 6 7 (mm)

Usable Length 90 135 90 135 90 135 90 135 (cm)

20 x x x x x x x x

30 x x x x x x x x

40 x x x x x x x x

60 x x x x x x x x

Stent 80 x x x x x x x x Length (mm) 100 x x x x x x x x 120 x x x x x x x x

150 x x x x x x x x

170 x x x x x x x x

200 x x x x x x x x

9 IFU Pulsar-18 US rev C 18.05.2017 11:49 Seite 10 5 0 -

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