Zenith® Iliac Branch

P020018S064 · Cook, Inc. · MIH · May 30, 2025 · Cardiovascular

Device Facts

• Record ID: P020018S064
• Device Name: Zenith® Iliac Branch
• Applicant: Cook, Inc.
• Product Code: MIH · Cardiovascular
• Decision Date: May 30, 2025
• Decision: APPR
• Device Class: Class 3
• Attributes: Therapeutic

Indications for Use

The Zenith® Iliac Branch, when used with the necessary additional components (Zenith AAA devices and a covered bridging stent), is indicated for endovascular treatment of aortoiliac or iliac aneurysms to preserve internal iliac arterial blood flow when the distal sealing site in the common iliac artery is insufficient for the AAA device alone and when the vessel morphology is suitable for repair, including: Common iliac artery diameter at the level of the internal iliac artery (luminal diameter) ≥16 mm; Adequate iliac/femoral access compatible with a 20 French (7.7mm O.D.) introduction system; Non-aneurysmal external iliac artery fixation segment distal to the aneurysm: With a length of at least 20mm; With a diameter measured outer wall to outer wall of no greater than 11mm and no less than 8mm; Non-aneurysmal internal iliac artery segment distal to the aneurysm: With a length of at least 10mm (with 20-30mm being preferred); With a diameter measured outer wall to outer wall no greater than 10mm and no less than 7mm.

Device Story

Zenith® Iliac Branch (ZBIS) is a bifurcated endovascular graft designed to preserve internal iliac artery (IIA) perfusion during aortoiliac or iliac aneurysm repair. It functions as a modular component used with Zenith AAA main body grafts, iliac leg grafts, and a bridging covered stent (e.g., Getinge iCAST). The device is delivered via the H&L-B One-Shot Introduction System (20 Fr), which allows for precise positioning and sidebranch cannulation. The graft consists of woven polyester fabric on self-expanding stainless steel and nitinol Z-stents. Radiopaque gold markers facilitate fluoroscopic visualization. Used in hospital settings by vascular surgeons, the device provides a minimally invasive alternative to open surgery or IIA occlusion. By maintaining IIA flow, it aims to reduce ischemic complications like buttock claudication and sexual dysfunction. Clinical success is monitored via CT/angiography to ensure graft patency, absence of endoleaks, and aneurysm exclusion.

Clinical Evidence

Pivotal prospective, non-randomized, single-arm, multi-center study (PRESERVE, n=40) evaluated ZBIS with iCAST stent. Primary endpoint: 6-month freedom from patency-related intervention (100% success, 39/39). Secondary safety endpoint: 30-day freedom from morbidity (85% success, 34/40). Technical success was 100%. No aneurysm-related deaths, ruptures, or conversions occurred through 5 years. Adverse events included thrombosis, embolization, and secondary interventions (9 patients, 15 interventions). Continued access cohort (n=30) confirmed safety/effectiveness with 100% 6-month patency and no aneurysm-related deaths through 5 years.

Technological Characteristics

Bifurcated graft of woven polyester fabric with self-expanding stainless steel and nitinol Z-stents. Radiopaque gold markers for visualization. Delivery system: 20 Fr (6.7 mm I.D.) H&L-B One-Shot Introduction System with hydrophilic-coated Flexor sheath. Sterilization: Ethylene Oxide (EtO) to SAL 10^-6. MRI compatible. Modular design for use with Zenith AAA components and bridging covered stents.

Indications for Use

Indicated for endovascular treatment of aortoiliac or iliac aneurysms in adult patients requiring preservation of internal iliac arterial blood flow where common iliac artery distal sealing is insufficient for standard AAA devices. Requires specific anatomical morphology: common iliac luminal diameter ≥16mm, external iliac fixation segment ≥20mm length (8-11mm diameter), and internal iliac segment ≥10mm length (7-10mm diameter). Contraindicated in patients with systemic infection, uncorrected bleeding disorders, inability to receive antiplatelet/anticoagulation therapy, or known hypersensitivity to device materials (stainless steel, polyester, nitinol, polypropylene, urethane, gold, ePTFE).

Reference Devices

• Zenith Flex® AAA Endovascular Graft (P020018)
• Zenith® Fenestrated Endovascular Graft (P020018)
• Zenith Spiral-Z AAA Iliac Leg (ZSLE)
• Getinge iCAST Covered Stent

Submission Summary (Full Text)

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# SUMMARY OF SAFETY AND EFFECTIVENESS DATA (SSED)

# I. GENERAL INFORMATION

| Device Generic Name: | Endovascular Graft |
| --- | --- |
| Device Trade Name: | Zenith® Iliac Branch |
| Device Procode: | MIH |
| Applicant's Name and Address: | William A. Cook Australia Pty. Ltd. 95 Brandl Street, Eight Mile Plains Queensland 4113, Australia |
| Date(s) of Panel Recommendation: | None |
| Premarket Approval Application (PMA) Number: | P020018/S064 |
| Date of FDA Notice of Approval: | May 30, 2025 |

The original PMA for the Zenith Flex® AAA Endovascular Graft with Z-Trak Introduction System and Ancillary Components (P020018) was approved on 23 May 2003 and is indicated for the endovascular treatment of patients with abdominal aortic or aorto-iliac aneurysms having morphology suitable for endovascular repair.

The SSED to support the indication is available on the CDRH website and is incorporated by reference here. The current supplement was submitted to obtain premarket approval for the Zenith® Iliac Branch for use in conjunction with the Zenith Flex AAA Endovascular Graft or the Zenith Fenestrated Endovascular Graft in the treatment of patients with aortoiliac or iliac aneurysms.

# II. INDICATIONS FOR USE

The Zenith® Iliac Branch, when used with the necessary additional components (Zenith AAA devices and a covered bridging stent), is indicated for endovascular treatment of aortoiliac or iliac aneurysms to preserve internal iliac arterial blood flow when the distal sealing site in the common iliac artery is insufficient for the AAA device alone and when the vessel morphology is suitable for repair, including:

- Common iliac artery diameter at the level of the internal iliac artery (luminal diameter) ≥16 mm
- Adequate iliac/femoral access compatible with a 20 French (7.7mm O.D.) introduction system
- Non-aneurysmal external iliac artery fixation segment distal to the aneurysm:
- With a length of at least 20mm

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○ With a diameter measured outer wall to outer wall of no greater than 11mm and no less than 8mm.
• Non-aneurysmal internal iliac artery segment distal to the aneurysm:
○ With a length of at least 10mm (with 20-30mm being preferred)
○ With a diameter measured outer wall to outer wall no greater than 10mm and no less than 7mm

### III. CONTRAINDICATIONS

The Zenith® Iliac Branch is contraindicated in:

• Patients with known sensitivities or allergies to stainless steel, polyester, solder (tin silver) nitinol (nickel, titanium), polypropylene, urethane, gold or ePTFE.
• Patients with a systemic infection who may be at increased risk of endovascular graft infection.
• Patients with uncorrected bleeding disorders.
• Patients who cannot receive recommended antiplatelet and/or anticoagulation therapy.

### IV. WARNINGS AND PRECAUTIONS

The warnings and precautions can be found in the Zenith® Iliac Branch labeling (Instructions for Use).

### V. DEVICE DESCRIPTION

The Zenith® Iliac Branch (ZBIS) is intended to be used in conjunction with the Zenith Flex AAA Endovascular Graft (i.e., a Flex AAA main body and two iliac leg graft components) or Zenith® Fenestrated AAA Endovascular Graft (i.e., a fenestrated proximal body and a bifurcated distal body), Zenith Spiral-Z AAA Iliac Leg (ZSLE) and a bridging stent. The final configuration of the deployed endovascular components is provided in Figure 1.

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Figure 1. Final Configuration of the Zenith® Iliac Branch System

### ZBIS Graft (implant)

The ZBIS is a bifurcated branch vessel graft with openings to connect the common iliac, internal iliac (sidebranch), and external iliac arteries (Figure 1 and Figure 2).

The graft is constructed of full-thickness, woven polyester fabric sewn to self-expanding stainless steel and nitinol Cook Z-Stents with braided polyester and monofilament polypropylene suture providing integrity and allowing exclusion of blood flow to the aneurysm and through the graft lumen. The graft is fully stented to provide stability and the expansile force necessary to open the lumen of the graft during deployment.

At the distal graft margin of the external iliac graft segment, the stainless-steel Z-Stent is attached to the inner lumen of the stent graft to achieve sealing with the vessel. Elsewhere, the Z-Stents are sutured on the external surface. The nitinol reinforcement rings are sutured to the most proximal graft edge, to the sidebranch proximal to the nitinol Z-Stent, and to the most distal aspect of the sidebranch. These rings help maintain lumen patency during access. Additionally, the Cook Z-Stents are intended to provide the necessary seal of the graft to the vessel wall (Figure 2). To facilitate fluoroscopic visualization of the stent graft, four radiopaque gold markers are positioned along the internal iliac side of the proximal portion of the graft to indicate the position of the sidebranch segment.

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Figure 2. Zenith® Iliac Branch implant

Table 1 details the available lengths and diameters of the ZBIS. The component diameters should be selected as described in Table 1. The length of the ZBIS is chosen to extend from the proximal portion of the common iliac artery to the external iliac artery. All lengths and diameters of the devices necessary to complete the procedure should be available to the physician, especially when pre-operative case planning measurements (treatment diameters/lengths) are not certain. This approach allows for greater intraoperative flexibility to achieve optimal procedural outcomes.

Table 1. Zenith® Iliac Branch Size Matrix

| Reorder number^{a} | Proximal diameter mm | Distal diameter mm | Sidebranch diameter^{b} mm | Introduction sheath | | Iliac segment length | | Total graft length mm |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | | | | French size Fr | (I.D. / O.D.) mm | Common mm | External mm | |
| ZBIS-10-45-41-US | 12 | 10 | 8 | 20 | (6.7 / 7.7) | 45 | 41 | 86 |
| ZBIS-10-61-41-US | 12 | 10 | 8 | 20 | (6.7 / 7.7) | 61 | 41 | 102 |
| ZBIS-10-45-58-US | 12 | 10 | 8 | 20 | (6.7 / 7.7) | 45 | 58 | 103 |
| ZBIS-10-61-58-US | 12 | 10 | 8 | 20 | (6.7 / 7.7) | 61 | 58 | 119 |
| ZBIS-12-45-41-US | 12 | 12 | 8 | 20 | (6.7 / 7.7) | 45 | 41 | 86 |
| ZBIS-12-61-41-US | 12 | 12 | 8 | 20 | (6.7 / 7.7) | 61 | 41 | 102 |
| ZBIS-12-45-58-US | 12 | 12 | 8 | 20 | (6.7 / 7.7) | 45 | 58 | 103 |

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| Reorder number^{a} | Proximal diameter mm | Distal diameter mm | Sidebranch diameter^{b} mm | Introduction sheath | | Iliac segment length | | Total graft length mm |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | | | | French size Fr | (I.D. / O.D.) mm | Common mm | External mm | |
| ZBIS-12-61-58-US | 12 | 12 | 8 | 20 | (6.7 / 7.7) | 61 | 58 | 119 |

$^{a}$ZBIS-XX-YY-ZZ-US is the ZBIS where XX is distal diameter, YY is the Common Iliac Segment Length (length from the proximal graft edge to the tip of the internal iliac segment), and ZZ is the External Iliac Segment Length (length from the tip of the internal iliac segment to distal edge of the graft).

$^{b}$Internal iliac segment contains a 6 mm diameter nitinol z-stent, but should be expanded to at least 8 mm during bridging stent system deployment.

The choice of ZBIS diameter is determined from the outer wall to outer wall vessel diameter and not the lumen diameter. Undersizing or oversizing may result in incomplete sealing or compromised flow. Table 2 is a sizing guide for the external iliac segment.

Table 2. Zenith® Iliac Branch Diameter Sizing Guide (External Iliac Segment)

| Intended external iliac vessel diameter^{a,b} mm | Branch external iliac leg diameter^{c} mm | Introduction Sheath | |
| --- | --- | --- | --- |
| | | French size Fr | (I.D. / O.D.) mm |
| 8 | 10 | 20 | (6.7 / 7.7) |
| 9 | 10 | 20 | (6.7 / 7.7) |
| 10 | 12 | 20 | (6.7 / 7.7) |
| 11 | 12 | 20 | (6.7 / 7.7) |

$^{a}$Maximum diameter along the distal fixation site.

$^{b}$Round measured iliac diameter to nearest mm.

$^{c}$Additional considerations may affect choice of diameter.

*All dimensions are nominal.

### ZBIS Delivery System

The ZBIS is shipped pre-loaded onto the H&L-B One-Shot Introduction System (Figure 3). It has a sequential deployment method with built-in features to provide continuous control of the endovascular graft throughout the deployment procedure. The proximal end of the graft is attached to the delivery system by two nitinol trigger-wires. The distal end of the graft is also attached to the delivery system and held by an independent stainless-steel trigger-wire. The H&L-B One-Shot Introduction System enables precise positioning and allows readjustment of the final graft position before full deployment.

The delivery system uses a 20 Fr (6.7 mm I.D.) H&L-B One-Shot Introduction System that includes both a pre-loaded catheter, used to facilitate cannulation of the side branch, and wire guide, used to ensure that the lumen of the catheter is preserved during loading and shipping. The pre-loaded catheter is curved in order to enhance the positioning capability of the wire guide during the snaring process. All systems are compatible with a 0.035-inch (0.89 mm) wire guide.

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For added hemostasis, the Captor Hemostatic Valve can be loosened or tightened during introduction and/or the removal of ancillary devices into and out of the sheath. The ZBIS delivery system features a Flexor introducer sheath which resists kinking and is hydrophilically coated. Both features are intended to enhance trackability in the iliac arteries and abdominal aorta.


Figure 3. Zenith® Iliac Branch (implant) and H&L-B One-Shot Introduction System (delivery system)

### Additional Components - Proximal Main Body, Iliac Leg, and Covered Stent

The Zenith® Iliac Branch (ZBIS) must be used with an appropriate Zenith proximal device (i.e., Zenith® Flex AAA Endovascular Graft (TFFB) or Zenith® Fenestrated AAA Endovascular Graft (ZFEN)), Zenith Spiral-Z AAA Iliac Leg (ZSLE), and appropriate bridging stent. The common iliac section of the Zenith® Iliac Branch, positioned in the common iliac artery, will be connected to the short (contralateral) limb of a Zenith proximal device (TFFB or ZFEN) by a ZSLE graft of suitable length and with a distal diameter of 16 mm (i.e., ZSLE-16-YY-ZT).

The Zenith® Iliac Branch has been studied with the Getinge iCAST covered stent as the bridging stent – see Sections IX and X below for non-clinical and clinical information on this device combination.

The Instructions for Use (IFU) for the Zenith® Iliac Branch includes information regarding required materials, patient selection, anatomical requirements, recommended device sizing, and the step-by-step implant procedure. Similar details are available in the IFU for each commercially available device listed in Table 2.

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## **VI. ALTERNATIVE PRACTICES AND PROCEDURES**

There are several alternatives used for the treatment of iliac or aortoiliac aneurysms, including endovascular repair using other iliac branched endovascular grafts, medical management, open surgical repair, or internal iliac artery coverage or occlusion. Each alternative has its own advantages and disadvantages. The physician should fully discuss these alternatives with the patient to select the method that best meets expectations and lifestyle.

## **VII. MARKETING HISTORY**

The Zenith® Iliac Branch has been commercially available outside the United States since 2006. It was first marketed in the European Union and later commercialized in the Middle East/Africa, Asia, and South America. The device has not been withdrawn from marketing for any reason related to its safety or effectiveness.

## **VIII. POTENTIAL ADVERSE EFFECTS OF THE DEVICE ON HEALTH**

Below is a list of the potential adverse effects (e.g., complications) that may be associated with the use of the device:

- Allergic reaction and/or anaphylactoid response to x-ray contrast dye, anti-platelet therapy, device materials
- Amputation
- Anesthetic complications and subsequent attendant problems (e.g., aspiration)
- Aneurysm enlargement
- Aneurysm rupture and death
- Aortic damage, including perforation, dissection, bleeding, rupture and death
- Arterial or venous thrombosis and/or pseudoaneurysm
- Arteriovenous fistula
- Bleeding, hematoma or coagulopathy
- Bowel complications (e.g., ileus, transient ischemia, infarction, necrosis)
- Cardiac complications and subsequent attendant problems (e.g., arrhythmia, myocardial infarction, congestive heart failure, hypotension, hypertension)
- Claudication (e.g., buttock, lower limb)
- Death
- Edema
- Embolization (micro and macro) with transient or permanent ischemia or infarction
- Endoleak
- Endoprosthesis: improper component placement; incomplete component deployment; component migration; suture break; occlusion; infection; stent fracture; graft material wear; dilatation; erosion; puncture; endoleak; barb separation and corrosion

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- • Fever and localized inflammation
- • Genitourinary complications and subsequent attendant problems (e.g., ischemia, erosion, fistula, incontinence, hematuria, infection)
- • Graft or native vessel occlusion
- • Hepatic failure
- • Impotence
- • Infection of the aneurysm, device or access site, including abscess formation, transient fever and pain
- • Lymphatic complications and subsequent attendant problems (e.g., lymph fistula)
- • Multi-system organ failure
- • Neurologic local or systemic complications and subsequent attendant problems (e.g., stroke, transient ischemic attack, paraplegia, paraparesis, paralysis)
- • Post-implant syndrome
- • Pulmonary/respiratory complications and subsequent attendant problems (e.g., pneumonia, respiratory failure, prolonged intubation)
- • Renal complications and subsequent attendant problems (e.g., artery occlusion, contrast toxicity, insufficiency, failure)
- • Surgical conversion to open repair
- • Vascular access site complications, including infection, pain, hematoma, pseudoaneurysm, arteriovenous fistula
- • Vessel damage
- • Wound complications and subsequent attendant problems (e.g., dehiscence, infection)
- • Vascular spasm or vascular trauma (e.g., iliofemoral vessel dissection, bleeding, rupture, death)

For the specific adverse events that occurred in the clinical study, please see Section X, *Safety and Effectiveness Results* below.

## IX. SUMMARY OF NON-CLINICAL STUDIES

### A. Biocompatibility Testing

A thorough panel of biocompatibility testing was performed on the Zenith® Iliac Branch and delivery system in accordance with ISO 10993-1, *Biological evaluation of medical devices – Part 1: Evaluation and testing*, the FDA Guidance for Industry and Food and Drug Administration Staff, *Use of International Standard ISO 10993-1, Biological evaluation of medical devices – Part 1: Evaluation and testing within a risk management process* (September 2023), and 21 CFR 58 Good Laboratory Practice (GLP) requirements. Specifically, the Zenith® Iliac Branch was assessed by tests considered appropriate for devices categorized as an implant medical device contacting blood for long term contact duration (i.e., > 30 days). The H&L-B One-Shot Introduction System (delivery system) was assessed by tests considered appropriate for devices categorized as an external communicating medical device contacting circulating blood for limited contact duration (i.e., ≤ 24 hours).

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Tables 3 summarizes the test results for the Zenith® Iliac Branch (implant) and H&L-B One-Shot Introduction System (delivery system). The biocompatibility test results demonstrate that the Zenith® Iliac Branch (implant) and H&L-B One-Shot Introduction System (delivery system) are safe and acceptable for clinical use.

Table 3. Biological testing supporting the biological safety of the ZBIS (implant) and H&L-B One-Shot Introduction System (delivery system)

| Biological Evaluation | Test Purpose | Acceptance Criteria | Results |
| --- | --- | --- | --- |
| **ZBIS (Implant)** | | | |
| **Cytotoxicity** *MEM Elution Test* | Determine the potential for the test article to cause cytotoxicity | The test article met the requirements of the test if the biological response was ≤ grade 2 (mild). | **NON-CYTOTOXIC** |
| **Sensitization** *Magnusson and Kligman Maximization Test* | Investigate the potential for delayed dermal contact sensitization | None of the test extract injection sites show a greater biological reaction than the control injection sites, with the difference in mean scores for test and control being ≤ 1.0. | **NON-SENSITIZER** |
| **Irritation** *Intracutaneous Injection Test* | Determine if the test article causes local dermal irritation following intracutaneous injection in rabbits | None of the test extract injection sites show a greater biological reaction than the control injection sites, with the difference in mean scores for test and control being ≤ 1.0. | **NON-IRRITANT** |
| **Acute Systemic Toxicity** *Systemic Injection* | Determine if the test article causes systemic toxicity following injection in mice | The test article met the standard requirements if treated animals did not show significantly greater reactions than control animals, but failed if two or more animals died, displayed abnormal behavior, or if three or more animals experienced body weight loss over 2 grams. | **NON-TOXIC** |
| **Pyrogenicity** *Rabbit Pyrogen Test (Material Mediated)* | Determine if the test article induces a pyrogenic response following intravenous injection in rabbits | If no individual animal exhibited a temperature increase of 0.5°C or more above its baseline, the extract was considered nonpyrogenic. | **NON-PYROGENIC** |

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| Biological Evaluation | Test Purpose | Acceptance Criteria | Results |
| --- | --- | --- | --- |
| **Systemic Toxicity** *Subcutaneous Implantation, 13 Weeks* | Determine the potential for systemic toxicity of the test article following subcutaneous implantation in the rat for up to 13 weeks. | The test and control groups were compared using separate analyses for male and female animals, evaluating body weight, organ weight, ratios, hematology, and clinical chemistry with parametric or nonparametric tests, considering p-values < 0.05 as statistically significant. | **MINIMAL TO NO LOCAL REACTION and NON-TOXIC** |
| **Genotoxicity** *Bacterial Reverse Mutation* | Evaluate the mutagenic potential of the test article (or its metabolites) by measuring its ability to induce back mutations at selected loci of several strains of bacteria in the presence and absence of microsomal enzymes. | A test is considered positive for strains TA98, TA100 and WP2uvrA when there is a 2-fold or greater increase in the number of revertant colonies, or a 3-fold increase in revertants for strains TA1535 and TA1537 when compared to the controls. | **NON-GENOTOXIC** |
| **Genotoxicity** *Mouse Lymphoma Assay* | Determine the ability of a test article to induce forward mutations at the thymidine kinase (TK) locus as assayed by colony growth of L5178Y mouse lymphoma cells. | The test article was considered mutagenic if a two-fold or greater increase in mutant frequency of the L5178Y/TK^{+/-} cell line over the negative control was observed. | **NON-GENOTOXIC** |
| **Implantation** *Local Tissue Response, 4 Weeks* | Determine if the test article causes a local tissue response after 4 weeks implantation into muscle tissue of rabbits | A microscopic evaluation of representative implant sites from each rabbit was conducted, grading cellular changes on a severity scale of 0 to 4 and compared to the control. A difference in scores up to 0.5 is considered not significant. | **MINIMAL TO NO LOCAL REACTION** |
| **Implantation** *Local Tissue Response, 12 Weeks* | Determine if the test article causes a local tissue response after 12 weeks implantation into muscle tissue of rabbits | | **MINIMAL TO NO LOCAL REACTION** |
| **Hemocompatibility** *Hemolysis – Direct and Extract* | Determine if the test article causes hemolysis | The mean blank corrected % hemolysis above the negative control of the test article must be < 2 % to be non-hemolytic. | **NON-HEMOLYTIC** |
| **Hemocompatibility** *Complement Activation* | Evaluate the test article's potential to activate the C3a and SC5b-9 complement system | The concentration of C3a and SC5b-9 in the test article must not be significantly higher than in the untreated or negative control plasma. | **NOT A COMPLEMENT ACTIVATOR** |
| **Hemocompatibility** *Platelet Leukocyte Count* | Evaluate the test article's potential to activate or damage platelets and leukocytes. | The test article passes if the test article platelet mean percentage value is between 80 to 120% and the test article platelet mean percentage value is at least 30% above the positive control. | **NON-THROMBOGENIC** |

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| Biological Evaluation | Test Purpose | Acceptance Criteria | Results |
| --- | --- | --- | --- |
| **Hemocompatibility** *Partial Thromboplastin Time (PTT)* | Determine the potential induction of coagulation of human plasma via measurement of the PTT in response to the test article. | The test article or Sponsor Provided Control (SPC) was considered to pass if the final average clotting time of the test article or SPC was not statistically lower than either the negative reference material or the negative control. | **NON-THROMBOGENIC** |
| **Carcinogenicity** | The patient contacting materials in the ZBIS graft underwent a thorough qualitative risk assessment, and biocompatibility testing included 13-week systemic toxicity testing in rats, and genotoxicity testing through bacterial reverse mutation and mouse lymphoma assays, confirming the absence of potent systemic toxicants and genotoxic carcinogens. Additionally, all patient-contacting materials and processing aids were evaluated and found to have been used in other devices under this PMA which were previously evaluated for systemic toxicity and carcinogenicity, ensuring negligible risks of systemic toxicity and carcinogenicity. | In adult patient populations, demonstration of acceptable margins of safety (MOS) and TTC evaluations for all exhaustively extractable chemical groups and chemicals from the test article. | **ACCEPTABLE** |
| **Reproductive and Developmental Toxicity** | | | |
| **H&L-B OneShot Introduction System (Delivery System)** | | | |
| **Cytotoxicity** *MEM Elution Test* | Determine the potential for the test article to cause cytotoxicity | The test article met the requirements of the test if the biological response was ≤ grade 2 (mild). | **NON-CYTOTOXIC** |
| **Sensitization** *Magnusson and Kligman Maximization Test* | Investigate the potential for delayed dermal contact sensitization | None of the test extract injection sites show a greater biological reaction than the control injection sites, with the difference in mean scores for test and control being ≤ 1.0. | **NON-SENSITIZER** |

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| Biological Evaluation | Test Purpose | Acceptance Criteria | Results |
| --- | --- | --- | --- |
| **Irritation** *Intracutaneous Injection Test* | Determine if the test article causes local dermal irritation following intracutaneous injection in rabbits | None of the test extract injection sites show a greater biological reaction than the control injection sites, with the difference in mean scores for test and control being ≤ 1.0. | **NON-IRRITANT** |
| **Acute Systemic Toxicity** *Systemic Injection* | Determine if the test article causes local dermal irritation following injection in mice | The test article meets the requirements if treated animals do not exhibit significantly greater biological reactivity than control animals, and if no group of five animals experiencing two or more deaths, abnormal behavior in two or more animals, or body weight loss exceeding 10%. | **NON-TOXIC** |
| **Pyrogenicity** *Rabbit Pyrogen Test (Material Mediated)* | Determine if the test article induces a pyrogenic response following intravenous injection in rabbits | If no individual animal exhibited a temperature increase of 0.5°C or more above its baseline, the extract was considered nonpyrogenic. | **NON-PYROGENIC** |
| **Hemocompatibility** *Hemolysis – Direct and Extract* | Determine if the test article causes hemolysis | The mean blank corrected % hemolysis above the negative control of the test article must be < 2 % to be non-hemolytic. | **NON-HEMOLYTIC** |
| **Hemocompatibility** *Complement Activation* | Evaluate the test article's potential to activate the C3a and SC5b-9 complement system | The concentration of C3a and SC5b-9 in the test article must not be significantly higher than in the untreated or negative control plasma. | **NOT A COMPLEMENT ACTIVATOR** |
| **Hemocompatibility** *Platelet Leukocyte Count* | Evaluate the test article's potential to activate or damage platelets and leukocytes. | The test article passes if the test article platelet mean percentage value is between 80 to 120% and the test article platelet mean percentage value is at least 30% above the positive control. | **NON-THROMBOGENIC** |
| **Hemocompatibility** *Partial Thromboplastin Time (PTT)* | Determine if the placement of the test article would cause thrombosis during simulated clinical use | The test article or Sponsor Provided Control (SPC) was considered to pass if the final average clotting time of the test article or SPC was not statistically lower than either the negative reference material or the negative control. | **NON-THROMBOGENIC** |

The Zenith® Iliac Branch has not been fully evaluated to establish potential for chronic toxicity and carcinogenicity. Prolonged exposure to systemic or carcinogenic toxicants may lead to long term tissue harm and long-term carcinogenic effects. The risks of these potential harms from this specific product have not been established. However, the available information from clinical use and animal study data appropriately leveraged from the previously approved Zenith components on with identical materials does not suggest chronic toxicity or carcinogenicity concerns.

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## **B. Animal Studies**

No animal testing was conducted on the Zenith® Iliac Branch. Information from clinical use and animal study data from the previously approved Zenith components was appropriately leveraged based on the similarities in the device design and materials. Additionally, a validated bifurcated iliac animal model is not available to address delivery and deployment. These attributes were assessed in simulated use testing, as described below.

## **C. Non-clinical Bench Testing**

Comprehensive non-clinical bench testing was conducted as part of the design verification and validation to support the safety and effectiveness of the Zenith® Iliac Branch (ZBIS) and is summarized in Table 4. The test plan was developed in accordance with appropriate guidance documents and international standards, including FDA's Guidance for Industry and Staff, *Non-clinical tests and recommended labeling for intravascular stents and associated delivery systems* (2005, 2010, supplemented in 2015), and ISO 25539-1, *Cardiovascular implants – Endovascular devices – Part 1: Endovascular Prostheses*. All testing was conducted on devices representative of the final device intended for commercial use. The Zenith® Iliac Branch was evaluated with appropriate Zenith AAA proximal components and the Getinge iCAST™ Covered Stent System as the bridging stent. The test results verified that the Zenith® Iliac Branch met product performance and design specifications. Table 4 indicates which tests were performed on both non-aged and aged devices to support the product shelf life.

**Table 4. Summary of Non-clinical Bench Testing for the Zenith® Iliac Branch**

| Test | Test Purpose | Acceptance Criteria | Results |
| --- | --- | --- | --- |
| Dimensional verification of the endovascular system* | Characterize the largest diameter encountered along the section of the delivery system to be inserted into the vasculature. | Delivery system nominal outer diameter shall be ≤ 7.7 mm. Length of sheath must be ≥ 30 +1/- 1.5 cm. | PASS |
| Force to Deploy* | Evaluate the force required to deploy and withdraw the ZBIS in a clinically relevant anatomical model. | The maximum force to deploy and withdraw the ZBIS will meet design requirements. | PASS |
| Delivery System Tensile Bond Strength* | Establish the tensile bond strength of delivery system joints and verify that the strength of the bond joints is adequate for the intended use | The tensile bond strength of delivery system bonds will meet design requirements. | PASS |
| Delivery System Torsional Bond Strength* | Establish the torsional bond strength of delivery system joints and verify that the strength of the bond joints is adequate for the intended use | The torsional bond strength of delivery system bonds will meet design requirements. | PASS |
| Simulated Use - Deployment accuracy* | Confirm delivery, deployment, and retraction of the ZBIS under simulated use conditions. | ZBIS shall be deployed within a representative anatomical model in accordance with the IFU. | PASS |

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| Test | Test Purpose | Acceptance Criteria | Results |
| --- | --- | --- | --- |
| Hemostasis | Measure leak flow through a physiologically pressurized test article. | Fluid loss from the Captor valve shall be ≤ the fluid loss from the valve on the existing commercially available Zenith AAA endovascular graft delivery system. | PASS |
| Visibility | Evaluate the visibility of the ZBIS/iCAST and the delivery system under fluoroscopy. | The device must be visible under fluoroscopy. | PASS |
| **ZBIS (implant)** | | | |
| Corrosion | Evaluate the corrosion resistance of metallic components in the ZBIS and iCAST. | Corrosion must not affect the functional integrity of the implant. | PASS |
| Fatigue and Durability (FEA) | Evaluate longitudinal and pulsatile fatigue performance of ZBIS and iCAST stents for 400 million cycles (equivalent to 10 years). | Analyses must result in a fatigue safety factor > 1.0 | PASS |
| Pulsatile Fatigue and Durability | Assess the fatigue durability of ZBIS and iCAST through exposure to time-accelerated, physiologically modeled, controlled displacement pulsatile loading through 400 million cycles (equivalent to 10 years). | The devices must withstand loading conditions and there must be no clinically relevant material wear, abrasion, or stent fracture. | PASS |
| Axial Fatigue and Durability | Assess durability of compressive and tensile forces along the longitudinal axis of the ZBIS and iCast to evaluate its durability and structural integrity over 400 million cycles (equivalent to 10 years). | The devices must withstand loading conditions and there must be no clinically relevant material wear, abrasion, or stent fracture. | PASS |
| Separation force for overlapping endovascular prostheses | Establish the forces required to separate the modular components of an endovascular graft prosthesis or to separate overlapping endoprostheses in the deployed state. | The force required to separate the overlapping components must be greater than the force induced by blood flow, acting on those components. • The force required to separate the bifurcated graft from the iliac leg graft must be > 1.7 N • The force required to separate the balloon expandable covered bridging stent from the internal iliac branch must be > 0.8 N. | PASS |
| Radial force (self-expanding endovascular prostheses) | Demonstrate that when grafts are sized correctly, the z-stents are expected to exert a radial force sufficient to maintain graft patency and apposition to the vessel wall without causing vessel damage | The radial force for each stent will meet design requirements. | PASS |

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| Test | Test Purpose | Acceptance Criteria | Results |
| --- | --- | --- | --- |
| Resistance to kinking (flexibility) | Determine the minimum radius that the endovascular prosthesis can accommodate without kinking. | Graft body components must have a kink radius ≤ 34.7 mm | PASS |
| Integral Water Permeability | Assess the integral water permeability of a test article. | Permeability of graft material after the addition of sutures should not be greater than 550 mL/min/cm². | PASS |
| Dimensional verification of the endovascular prosthesis* | Evaluate the final stent dimension and ensure design specifications were met. | The graft diameters and lengths meet device specifications. | PASS |
| Burst strength | Determine the circumferential tensile strength of a tubular test article. | Circumferential tensile strength of the graft material must be ≥ 2.7 N/mm. | PASS |
| Factory anastomotic strength (endovascular grafts with seams in the graft material) | Evaluate the durability and integrity of the device seams to withstand the forces encountered during implantation and long-term use. | Circumferential tensile strength of the graft material seam must be ≥ 1.7 N/mm. | PASS |
| Longitudinal tensile strength | Assess the ability of the device to withstand tension and measure its maximum strength before breaking or deforming. | The longitudinal tensile strength of the implant fabric must be > 100 N. | PASS |
| MRI safety and compatibility | To evaluate the MRI safety and compatibility | The measured magnetically induced deflection force and torque shall be < 29.4 N/cm². The measured RF induced temperature rise shall be appropriately low as to not induce tissue damage. The measured magnetically induced force shall be less than the force required to cause the device to separate. | PASS |

Note: The specific engineering tests completed to support the two-year shelf life for the ZBIS are denoted by an asterisk (*).

#### **D. Sterilization, Packaging and Shelf Life**

The Zenith® Iliac Branch is sterilized by a validated Ethylene Oxide (EtO) sterilization process to achieve a minimum Sterility Assurance Level (SAL) of 10⁻⁶. The methods used to validate the sterilization cycle are in accordance with ISO 11135-1, “*Sterilization of health-care products – Ethylene oxide – Requirements for the development, validation and routine control of sterilization process for medical devices.*” Additionally, the EO residual and bacterial endotoxin was verified to be within acceptable ranges in accordance with ISO 10993-7 “*Biological Evaluation of Medical Devices – Part 7: Ethylene Oxide Sterilization Residuals.*”

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Product and packaging testing of the Zenith® Iliac Branch was performed and validated to support the device’s 2-year shelf life. The packaging was demonstrated to protect the product and to maintain a sterile barrier through simulated distribution and shelf life. Non-clinical functional testing of the device after aging was performed as indicated in Table 4. Together, the data supports a 2-year shelf life for the Zenith® Iliac Branch.

## **X. SUMMARY OF THE PRIMARY CLINICAL STUDY**

The applicant performed a clinical study to establish a reasonable assurance of safety and effectiveness of endovascular treatment with the Zenith® Iliac Branch (formerly branded under the clinical investigation as the Zenith Branch Endovascular Graft-Iliac Bifurcation) in combination with the Getinge iCAST™ Covered Stent System (formally branded as the Atrium iCAST Covered Stent and referred herein as the iCAST stent) for the treatment of patients with aortoiliac or iliac aneurysms. The clinical study was conducted in the United States under an Investigational Device Exemption (IDE# G070241; NCT02571907). Data from this clinical study were the basis for the PMA approval decision. A summary of the clinical study is presented below.

### **A. Study Design**

The PRESERVE-Zenith Iliac Branch Clinical Study (conducted under the previous brand name PRESERVE Zenith Branch Endovascular Graft-Iliac Bifurcation Clinical Study) was a prospective, non-randomized, single-arm, multi-center clinical study intended to assess the safety and effectiveness of endovascular treatment with the ZBIS in combination with the iCAST stent for the treatment of patients with aortoiliac or iliac aneurysms with an unsuitable distal sealing site for a Zenith iliac leg component proximal to the common iliac bifurcation to maintain internal iliac artery patency during endovascular aneurysm repair.

A total of 40 patients were treated with ZBIS and iCAST between 01 April 2014 and 06 May 2015. The database for this PMA reflects data locked on 10 February 2021. Study patients were enrolled across 18 investigational sites in the United States.

This study evaluated safety and effectiveness through comparison to performance goals. The primary endpoint was 6-month freedom from patency-related intervention of the Internal Iliac Artery (IIA) (further defined below). The performance goal for the primary endpoint was established through a review of data from reports on the complications rates associated with coil embolization and stent graft coverage of the IIA in endovascular repair of aortoiliac aneurysms. The secondary safety endpoint was 30-day freedom from morbidity (i.e., the morbidity index defined below). The performance goal for the secondary safety endpoint was established through a review of safety data from the Zenith AAA Endovascular Graft Clinical Study (P020018). The secondary effectiveness endpoint for the study was branch vessel patency at 6 months. This endpoint was assessed for descriptive purposes only and therefore a performance goal for this endpoint was not established.

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An independent data safety monitoring board (DSMB) monitored the clinical trial according to an established safety monitoring plan. An independent clinical events committee (CEC) adjudicated predefined clinical events reported during the study in accordance with the CEC charter. An independent core laboratory analyzed all patient imaging.

1. Clinical Inclusion and Exclusion Criteria

Enrollment in the study was limited to patients who met the following inclusion criteria:

1) An aortoiliac or iliac aneurysm
2) An unsuitable distal sealing site for a Zenith iliac leg graft within the common iliac artery on the intended side of ZBIS implantation (e.g., fixation/seal length < 10 mm or diameter > 20 mm)

Patients were not permitted to enroll in the study if they met any of the following exclusion criteria:

General Exclusion Criteria

1) Age < 18 years
2) A medical condition or disorder that may limit life expectancy to less than 2 years or that may cause non-compliance with the protocol
3) Pregnant, breast-feeding, or planning on becoming pregnant prior to completion of the study
4) Unwilling or unable to comply with the follow-up schedule
5) Unable or unwilling to give informed consent
6) Simultaneously participating in another investigative device or drug study (patient must have completed the follow-up phase for the primary endpoint of any previous study at least 30 days prior to enrollment in this study)

Medical Exclusion Criteria

1) Pre-procedure creatinine > 2.0 mg/dl and not on dialysis (patient must be able to undergo contrast-enhanced CT)
2) Cultural objection to receipt of blood or blood products
3) Known hypersensitivity or contraindication to study device materials (i.e., stainless steel, polyester, polytetrafluoroethylene, gold, or nitinol)
4) Known hypersensitivity or contraindication to contrast material that, in the opinion of the investigator, cannot be adequately premedicated
5) Leaking, ruptured, or symptomatic aneurysm
6) Uncorrectable coagulopathy
7) Systemic infection (i.e., sepsis)
8) Previous treatment (e.g., endovascular or surgical AAA graft, stents in the common iliac artery or external iliac artery) below the aortic bifurcation that precludes the use of the Zenith Branch Endovascular Graft-Iliac Bifurcation
9) Previously placed stent in internal iliac artery on side of intended implantation
10) Planned significant interventional or surgical procedure that is unrelated to AAA repair within 30 days before or after AAA repair

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# *Anatomical Exclusion Criteria*

Patients were excluded from the study if they were unsuitable for implantation of a Zenith Flex AAA Endovascular Graft (physicians will determine suitability of a patient based on their clinical experience) or if any of the following are true:

On the intended side of ZBIS implantation:

1) A non-aneurysmal external iliac segment (fixation site) distal to the aneurysm:
a. with a length of < 20 mm, or
b. with an outer wall diameter < 8 mm
2) Common iliac artery length < 50 mm
3) Occluded or > 50% stenosed internal iliac artery
4) Aneurysmal disease distal to intended internal iliac artery landing zone
5) A non-aneurysmal main internal iliac artery trunk segment (fixation site):
a. with a length of < 10 mm, or
b. with an inner wall diameter > 10 mm or < 7 mm
6) Common iliac artery diameter at the level of the internal iliac artery (luminal) < 16 mm

On the side opposite of intended ZBIS implantation:

1) Inadequate common iliac fixation for a Zenith iliac leg graft
2) > 70% stenosis of the internal iliac artery (unresolved at the time of index procedure)

[Note: These criteria for the side opposite of intended ZBIS implantation did not apply if the patient was considered unsuitable for open surgical repair in the opinion of the investigator, in which case the investigator could treat the side opposite of intended ZBIS implantation per standard practice.]

On either the intended or the opposite side of ZBIS implantation:

1) Significant occlusive disease, tortuosity, or calcification of the iliac arteries
2) Unsuitable arterial anatomy (e.g., excessive angulation between the internal and common/external iliac arteries)

# 2. Follow-up Schedule

Prior to the study procedure, patients underwent a clinical exam, blood test, and CT scan. Postoperatively, patients were scheduled to return for follow-up examinations within 7 days (pre-discharge), at 30 days, 6 months, 12 months, and then annually through 5 years postoperatively. The objective parameters measured during the study based on CT included assessment of endoleaks, migration, patency, and device integrity. Adverse events and complications were recorded at all visits. The key timepoints and data collection information are shown in Table 5.

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**Table 5. Data Collection Schedule for the PRESERVE Clinical Study**

| Data Collection | Pre-op | Intra-op | Pre-discharge | Month | | | | | | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | | | | 1 | 6 | 12 | 24 | 36 | 48 | 60 |
| CT Scan^{a} | X | | | X^{b} | X^{b} | X^{b} | X^{b} | X^{b} | X^{b} | X^{b} |
| Angiography | X^{c} | X | | | | | | | | |
| Blood tests^{d} | X | | X | X | X | X | X | X | X | X |
| Clinical Exam | X | | X | X | X | X | X | X | X | X |

$^{a}$ Selective angiography may have been performed to provide more focused imaging in instances potential device integrity issues were identified but unable to be confirmed on CT.

$^{b}$ In patients experiencing renal failure during follow-up, selective angiography (preferred) or duplex ultrasound may have been used in conjunction with non-contrast CT.

$^{c}$ Pre-procedure angiography may have been requested at discretion of film reviewer/proctor.

$^{d}$ Blood tests included creatinine.

### 3. Clinical Endpoints

#### *Primary Endpoint*

With regards to safety and effectiveness, the primary endpoint for the study was the assessment of 6-month freedom from patency-related intervention. Freedom from patency-related intervention was defined as freedom from a secondary intervention to treat a > 60% stenosis of the internal iliac artery (IIA; as identified through computed tomography [CT] scan, angiography, or duplex ultrasound and confirmed by core laboratory) associated with clinical symptoms. This endpoint definition includes patients with internal iliac artery stenosis following successful placement of the ZBIS and covered bridging stent, and any cases of technical failure resulting in occlusion of the internal iliac artery during the initial implant procedure that require secondary intervention for associated clinical symptoms.

For the power calculation of the primary hypothesis, the true patency rate of the IIA following treatment with the ZBIS was assumed to be 83% based on clinical literature describing outcomes associated with sacrificing the IIA during endovascular repair available at the time of protocol development. A performance goal of 55% for freedom from patency-related intervention was determined and a simulation study indicated that a maximum sample size of 25 patients would provide a power of approximately 88.5%, at a type I error rate of 2.5%.

The analysis required that the performance goal of 55% be met (H$_{0}$: $\pi \leq 55\%$; H$_{a}$: $\pi > 55\%$). The study device was considered to have met the primary endpoint if the 2.5$^{th}$ percentile of the Bayesian posterior distribution of $\pi$ was greater than the performance goal.

#### *Secondary Safety Endpoint*

The secondary safety endpoint for the study was freedom from 30-day morbidity (i.e., the morbidity index, a measure of 33 elements in seven categories [i.e., cardiovascular, pulmonary, renal, bowel, wound, neurologic, and vascular]) and was associated with prospective power calculations and associated hypothesis testing. For the secondary safety hypothesis, the true rate of freedom from 30-day morbidity was assumed to be 72.5%, which was derived from patients with patent IIA in the Zenith AAA Endovascular

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Graft Clinical Study who were free from 30-day morbidity (i.e., free from all 31 events in the Zenith AAA Endovascular Graft Clinical Study morbidity index [defined below] and hip/thigh/buttock claudication). With a performance goal of 46% for freedom from 30-day morbidity, the simulation study indicated that a maximum sample size of 29 patients would provide a power of 85.8%, at a type I error rate of 2.5%.

The analysis required that the performance goal of 46% be met (H₀: p ≤ 46%; Hₐ: p >46%). The study device was considered to have met the secondary endpoint if the 2.5th percentile of the Bayesian posterior distribution of p was greater than the performance goal.

# Additional Endpoints

Additional endpoints were evaluated including assessments of aneurysm-related death, conversion, rupture, 6-month branch vessel patency, success measures (i.e., technical success during the implant procedure, procedural success within 30 days, and treatment success at 12-month follow-up), clinical utility measures [i.e., duration of intensive care unit (ICU) stay, days to ambulation, days to resumption of oral fluid intake, days to resumption of regular diet, days to first bowel function, days to hospital discharge, blood replacement requirements], adverse events related to the ZBIS or iCAST stent, distal Type I endoleaks, and Type III endoleaks involving the ZBIS and iCAST stent. Summary statistics for these endpoints are provided, but no statistical inference or hypothesis testing was performed.

# B. Accountability of PMA Cohort

Enrollment in the study totaled 40 patients. Follow-up availability through 5 years is reported in Figure 1 and includes the number of patients eligible at each follow-up time point and the number of patients for whom clinical data were available.

Importantly, nearly all eligible patients (97.5%; 39/40) remained in the study at their 6-month follow-up visit which was the timepoint for the primary study endpoint. The percentage of eligible patients who completed the clinical exam and CT imaging was above 80% and above 75%, respectively, at each timepoint throughout the study. The number of patients available for analysis at each time point is shown in Table 6.

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**Table 6. Follow-up data availability - Pivotal Cohort (Through 5 Years)**

| Visit | Eligible for Follow-up | Percent of Data Available | | Adequate Imaging for Core Laboratory to Assess Parameter | | | | | Events Occurring Before Next Interval | | | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | | Clinical Exam | CT | Size Increase | Endoleak | Patency | Migration | Device Integrity | Death | Conversion | Lost to Follow-up (LTF) | Withdrawal |
| Procedure | 40 | N/A | N/A | N/A | 92.5% (37/40) | 92.5% (37/40) | N/A | N/A | 0 | 0 | 0 | 0 |
| Pre-discharge | 40 | 100% (40/40) | N/A | N/A | N/A | N/A | N/A | N/A | 0 | 0 | 0 | 0 |
| 1-month | 40 | 100% (40/40) | 100% (40/40) | N/A | 100% (40/40) | 100.0% (40/40) | N/A | 97.5% (39/40) | 1 | 0 | 0 | 0 |
| 6-month | 39 | 94.9% (37/39) | 94.9% (37/39) | 94.9% (37/39) | 94.9% (37/39) | 94.9% (37/39) | 94.9% (37/39) | 92.3% (36/39) | 0 | 0 | 2 | 0 |
| 12-month | 37 | 100% (37/37) | 100% (37/37) | 100.0% (37/37) | 97.3% (36/37) | 97.3% (36/37) | 100% (37/37) | 100% (37/37) | 0 | 0 | 0 | 0 |
| 2-year | 37 | 86.5% (32/37) | 75.7% (28/37) | 75.7% (28/37) | 73.0% (27/37) | 78.4% (29/37) | 75.7% (28/37) | 75.7% (28/37) | 0 | 0 | 0 | 2 |
| 3-year | 35 | 88.6% (31/35) | 88.6% (31/35) | 88.6% (31/35) | 82.9% (29/35) | 94.3% (33/35) | 88.6% (31/35) | 88.6% (31/35) | 1 | 0 | 0 | 1 |
| 4-year | 33 | 81.8% (27/33) | 84.8% (28/33) | 84.8% (28/33) | 87.9% (29/33) | 87.9% (29/33) | 84.8% (28/33) | 81.8% (27/33) | 2 | 0 | 1 | 0 |
| 5-year | 30 | 90.0% (27/30) | 86.7% (26/30) | 86.7% (26/30) | 83.3% (25/30) | 83.3% (25/30) | 86.7% (26/30) | 86.7% (26/30) | N/A | N/A | N/A | N/A |

Note: In patients experiencing renal failure and unable to undergo contrast-enhanced CT scan, a duplex ultrasound may be used in conjunction with noncontrast CT scan. In these cases, the core laboratory may be able to adequately assess aneurysm size change, endoleak, and patency when an ultrasound is performed in combination with a noncontrast CT scan.

N/A = Not applicable.

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### C. Study Population Demographics and Baseline Parameters

The demographics and baseline parameters of the study population are typical for a study of patients with extensive AAA disease involving the iliac arteries performed in the US.

#### Demographics

The demographics and patient characteristics, including age, sex, race, height, and weight are presented in Table 7. The mean age was $67.8 \pm 9.0$ years, with most patients being male (95.0%, 38/40) and of white ethnicity (87.5%, 38/40).

**Table 7. Demographics and patient characteristics**

| Demographic | Mean ± SD (n, range) or Percent Patients (number/total number) |
| --- | --- |
| Age (years) | 67.8 ± 9.0 (40, 48 – 86) |
| Sex | |
| Male | 95.0% (38/40) |
| Female | 5.0% (2/40) |
| Self-reported Race | |
| American Indian or Alaska Native | 0% (0/40) |
| Asian | 2.5% (1/40) |
| Black or African American | 7.5% (3/40) |
| Hispanic or Latino | 2.5% (1/40) |
| Native Hawaiian or other Pacific Islander | 0% (0/40) |
| White | 87.5% (35/40) |
| Height (in) | 69.5 ± 2.7 (40, 64 – 76) |
| Weight (lbs) | 198.4 ± 43.2 (40, 132.0 – 334.4) |
| BMI | 28.8 ± 5.4 (40, 18.6 – 47.3) |

#### Medical History and Comorbidities

Patient pre-existing comorbid medical conditions are summarized in Table 8. Common comorbidities in the population included hypertension (77.5%, 31/40) and past or current smoking (75%, 30/40).

**Table 8. Medical history and comorbid conditions**

| Medical History | Percent Patients (number/total number) |
| --- | --- |
| **Cardiovascular** | |
| Myocardial infarction (MI) | 25.0% (10/40) |
| Percutaneous transluminal coronary angioplasty (PTCA)/stent | 17.5% (7/40) |
| Coronary artery bypass graft surgery (CABG) | 17.5% (7/40) |
| Symptomatic congestive heart failure (CHF) | 5.0% (2/40) |
| Angina | 12.5% (5/40) |
| Cardiac arrhythmia | 17.5% (7/40) |

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| Medical History | | Percent Patients (number/total number) |
| --- | --- | --- |
| **Vascular** | Thromboembolic event | 5.0% (2/40) |
| | Peripheral vascular disease | 5.0% (2/40) |
| | Aneurysm (not subject of current study) | 30.0% (12/40) |
| | Dissection | 0% (0/40) |
| | Thoracic trauma | 0% (0/40) |
| | Stenting of iliac artery (not subject of current study) | 0% (0/40) |
| | Impotence | 42.5% (17/40) |
| | Buttock claudication | 0% (0/40) |
| | Uncorrectable coagulopathy | 0% (0/40) |
| | Endarterectomy | 0% (0/40) |
| | Hypertension | 77.5% (31/40) |
| **Pulmonary** | Chronic obstructive pulmonary disease (COPD) | 25.0% (10/40) |
| | Home oxygen | 2.5% (1/40) |
| **Renal** | Chronic renal failure | 2.5% (1/40) |
| | Dialysis | 0% (0/40) |
| | Renal insufficiency | 10.0% (4/40) |
| **Endocrine** | Diabetes | 27.5% (11/40) |
| **Infectious disease** | Systemic infection | 10.0% (4/40) |
| **Gastrointestinal** | Gastrointestinal disease | 30.0% (12/40) |
| **Hepatobiliary** | Liver disease | 15.0% (6/40) |
| **Neoplasms** | Cancer | 15.0% (6/40) |
| **Neurologic** | Stroke | 12.5% (5/40) |
| **Allergies** | | 47.5% (19/40) |
| **Smoking** | Current | 27.5% (11/40) |
| | Quit | 47.5% (19/40) |
| | Never | 25.0% (10/40) |

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### Baseline Anatomical Measurements

Patients underwent pre-procedure imaging to evaluate iliac morphology (Table 9).

Measurements provided are reported on the same side as the intended side for treatment (i.e., left or right) with ZBIS.

**Table 9. Pre-procedure anatomical measurements in the iliac arteries**

| Measurement | Mean ± SD (N, Range) |
| --- | --- |
| | Site |
| At intended distal fixation site (mm) | |
| EIA outer diameter | 10.2 ± 1.4 (40, 8.0 – 13.0) |
| EIA fixation length | 44.7 ± 29.5 (40, 20.0 – 134.0) |
| IIA inner diameter | 8.0 ± 0.9 (40, 6.9 – 10.0) |
| IIA outer diameter | 8.8 ± 0.9 (40, 7.0 – 10.0) |
| IIA fixation length | 20.5 ± 7.1 (40, 10.0 – 40.0) |
| Iliac artery diameters | |
| CIA maximum diameter (outer-wall) | 35.9 ± 10.1 (40, 20.0 – 62.9) |
| EIA minimum diameter (access) (inner-wall) | 10.6 ± 9.4 (40, 7.1 – 68.0) |
| EIA maximum diameter (outer-wall) | 10.4 ± 1.8 (40, 7.3 – 15.0) |
| CIA lumen diameter just proximal to IIA | 21.4 ± 6.4 (40, 13.9 – 42.6) |
| IIA maximum diameter (outer-wall) | 9.7 ± 3.0 (40, 6.5 – 25.0) |
| IIA lumen diameter of ostia | 8.1 ± 2.6 (40, 5.0 – 20.0) |
| Iliac artery lengths (mm) | |
| CIA length from aortic bifurcation to iliac bifurcation | 70.9 ± 14.8 (40, 50.0 – 121.0) |
| IIA length from ostia to anterior-posterior division | 33.8 ± 19.0 (40, 19.0 – 140.0) |
| Iliac artery angles and location (degrees) | |
| Angle of IIA to EIA | 55.4 ± 31.5 (39, 15.0 – 153.0) |
| Angle of right CIA to left CIA | 54.4 ± 22.2 (39, 0 – 125.0) |
| Circumferential location of IIA (degrees)^{a} | 150.8 ± 50.2 (39.0, 23.0 – 270.0) |

Note: CIA = common iliac artery; EIA = external iliac artery; IIA = internal iliac artery.

$^{a}$ Circumferential location of the IIA is measured from 0 to 360 degrees with 0 degrees being anterior, 90 degrees being left, 180 degrees being posterior, and 270 degrees being right.

The extent of calcification was defined as either none (lack of calcification), mild (less than 40% circumferential calcification), moderate (between 40% and 70% circumferential calcification), or severe (greater than 70% circumferential calcification). The extent of occlusive disease was defined as either none (lack of occlusive disease), mild (some disease, focal with less than 30% narrowing), moderate (between 30-50% narrowing), or severe (greater than 50% narrowing). Tortuosity was defined as either none (no tortuosity), mild (minimal tortuosity with less than one turn involving either external or common iliac artery), moderate (single turn involving either external or common iliac artery), or severe (compound turns involving external and common iliac arteries). Per the site assessment, most patients had none or mild calcification and occlusive disease in the iliac arteries. Mild or moderate iliac tortuosity was reported in 75% of patients.

### D. Procedural Information

Table 10 reports anesthesia and access methods used to support device placement. Most procedures were performed under general anesthesia (90.0%, 36/40). Vascular access was obtained primarily via percutaneous (52.5%, 21/40) or femoral artery cutdown (45.0%, 18/40) access technique during insertion of ZBIS.

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Table 10. Primary anesthesia type and access method

| Characteristic | Percent Patients (number/total number) |
| --- | --- |
| **Anesthesia Method** | |
| Local | 5.0% (2/40) |
| Regional | 5.0% (2/40)^{a} |
| General | 90.0% (36/40) |
| **Access Method** | |
| Percutaneous | 52.5% (21/40) |
| Cutdown | 45.0% (18/40) |
| Cutdown/Percutaneous | 2.5% (1/40) |
| Iliac conduit | 0% (0/40) |

$^{a}$ One patient received both regional and monitored anesthesia care.

Procedural measures are detailed in Table 11. The average procedure time was 210.5 ± 53.4 minutes with an average fluoroscopy time of 40.1 ± 15.7 minutes. The average total contrast volume used was 128.2 ± 63.5 cc with an average concentration of 310.0 ± 40.8 mgI/mL. Most patients (60%, 24/40) received non-ionic contrast agents. The average estimated blood loss was 275.6 ± 215.5 cc (maximum blood loss was 800 cc).

Table 11. Procedural times, monitoring, and blood loss

| Parameter | Mean ± SD (n, range) or Percent Patients (number/total number) |
| --- | --- |
| Procedure (min) | 210.5 ± 53.4 (37, 123 – 331) |
| Fluoroscopy (min) | 40.1 ± 15.7 (39, 12 – 93) |
| Total amount of contrast used (cc) | 128.2 ± 63.5 (39, 35 – 328) |
| Concentration of contrast (mgI/mL) | 310.0 ± 40.8 (40, 100 – 370) |
| Type of contrast agent^{a} | |
| Ionic | 25.0% (10/40) |
| Non-ionic | 60.0% (24/40) |
| Iso-osmolar | 17.5% (7/40) |
| Non-iso-osmolar | 12.5% (5/40) |
| Estimated blood loss (cc) | 275.6 ± 215.5 (40, 0 – 800) |
| Blood bank products received | |
| PRBC | 5.0% (2/40) |
| FFP | 0% (0/40) |
| Platelets | 0% (0/40) |
| Cryoprecipitate | 0% (0/40) |
| Cell saver | 5.0% (2/40) |
| Amount of blood products received (cc) | |
| PRBC | 350.0 ± 0 (2, 350 – 350) |
| FFP | N/A |
| Platelets | N/A |
| Cryoprecipitate | N/A |
| Cell saver | 275.0 ± 14.1 (2, 265 – 285) |

$^{a}$ Patients can receive multiple types of contrast agent and may appear on more than one row.

### Devices Placed during Index Procedure

Table 12 reports the number and size of ZBIS devices placed at the index procedure. In total, 40 ZBIS devices were placed in 40 study patients. The Reference Part Number (RPN) for the ZBIS is presented in the following format according to the lengths and diameter of the ZBIS (mm): ZBIS-XX-YY-ZZ, where XX is distal diameter, YY is the Common Iliac Segment

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Length (length from the proximal graft edge to the tip of the sidebranch), and ZZ is the External Iliac Segment Length (length from the tip of the sidebranch to distal edge of the graft). All available ZBIS RPNs were used in the study with the most common being ZBIS-12-61-58 (27.5%, 11/40) and ZBIS-12-45-58 (22.5%, 9/40).

**Table 12. ZBIS sizes used in the PRESERVE clinical study**

| Distal Diameter (mm) | 10 | 12 | 10 | 12 | 10 | 12 | 10 | 12 | Total # ZBIS |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Common Iliac Segment Length (CISL) (mm) | 45 | 45 | 45 | 45 | 61 | 61 | 61 | 61 | |
| External Iliac Segment Length (EISL) (mm) | 41 | 41 | 58 | 58 | 41 | 41 | 58 | 58 | |
| **Total** | 2 | 5 | 2 | 9 | 2 | 4 | 5 | 11 | 40 |

The number and size of iCAST stents implanted during the study procedures are shown in Table 13. In total, 47 iCAST stents were implanted in the 40 study patients. The most common iCAST stent sizes implanted were the 9 x 59 mm (29.8%, 14/47) and 9 x 38 mm (27.7%, 13/47) stents. Six patients received more than one iCAST stent deployed within the sidebranch of the ZBIS. Specifically, five patients received two iCAST stents and one patient received three iCAST stents. The use of multiple iCAST stents was to obtain either maximal seal distally within the internal iliac artery or to ensure optimal overlap within the ZBIS sidebranch.

**Table 13. iCast covered stent sizes used in the PRESERVE clinical study**

| Diameter (mm) | Length (mm) | | Total |
| --- | --- | --- | --- |
| | 38 | 59 | |
| 8 | 7 | 5 | 12 |
| 9 | 13 | 14 | 27 |
| 10 | 8 | N/A^{a} | 8 |
| **Total** | 28 | 19 | 47 |

$^{a}$ 10 x 59 mm iCAST stents were not available in the United States during this study.

ZBIS is used in combination with the Zenith Flex AAA endovascular graft and Zenith iliac leg grafts (ZSLE). The number and size of these additional endovascular components used in the pivotal study are shown in Table 14. In total, 40 Zenith Flex AAA Endovascular Grafts were implanted in the 40 patients. A ZSLE is deployed into the short (contralateral) leg of the Zenith Flex AAA Endovascular Graft, connecting the lumen of the main body graft to the ZBIS stent. An additional ZSLE is deployed into the long (ipsilateral) leg of the Zenith Flex AAA Endovascular Graft. More than one ZSLE may be deployed on either side according to physician discretion. In total, 44 ZSLE stents were implanted within the contralateral leg of the Zenith Flex AAA Endovascular Graft with 4 patients receiving more than one ZSLE stent (same side as ZBIS). In total, 41 ZSLE stents were implanted within the ipsilateral leg of the Zenith Flex AAA Endovascular Graft with 2 patients receiving more than one ZSLE stent (opposite side as ZBIS).

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**Table 14. Zenith Flex AAA Endovascular Graft and ZSLE stents used**

| Zenith Flex AAA Endovascular Graft | Same side as ZBIS | | Opposite side as ZBIS | |
| --- | --- | --- | --- | --- |
| | ZSLE | Additional ZSLE | ZSLE | Additional ZSLE |
| 40 | 40 | 4 | 39^{a} | 2 |

$^{a}$ One patient did not receive a ZSLE on the opposite side as ZBIS.

Clinical utility measures are reported in Table 15. The average ICU stay was $17.1 \pm 32.7$ hours and the average length of time to hospital discharge was $2.0 \pm 2.4$ days.

**Table 15. Clinical utility measures**

| Clinical utility | Mean $\pm$ SD (range), Total |
| --- | --- |
| Duration of ICU stay (hours) | $17.1 \pm 32.7$ (38, 0 – 144) |
| Days to first ambulation | $1.0 \pm 0.8$ (40, 0 – 5) |
| Days to resumption of oral fluid intake | $0.4 \pm 0.6$ (40, 0 – 3) |
| Days to resumption of regular diet | $0.8 \pm 0.8$ (40, 0 – 4) |
| Days to first bowel movement | $2.1 \pm 1.8$ (30, 0 – 8) |
| Days to discharge | $2.0 \pm 2.4$ (40, 0 – 14) |

## **E. Safety and Effectiveness Results**

### **1. Safety and Effectiveness Results**

The primary safety and effectiveness endpoint was prospectively defined as 6-month freedom from patency-related intervention, which is defined as a secondary intervention to treat a > 60% stenosis of the internal iliac artery (as identified through computed tomography (CT) scan, angiography, or duplex ultrasound and confirmed by core laboratory) associated with clinical symptoms. Of note, this endpoint definition not only includes patients with internal iliac artery stenosis following successful placement of the ZBIS and covered bridging stent, but also any cases of technical failure resulting in occlusion of the internal iliac artery during the initial implant procedure that require secondary intervention for associated clinical symptoms. The results for 6-month freedom from patency-related intervention are presented in Table 16.

The success rate for the primary safety and effectiveness endpoint was 100% (39/39) of patients, and the 2.5th percentile of the Bayesian posterior distribution was 91.2%, surpassing the performance goal of 55%. Based on these results, the primary endpoint for the study was met.

Endpoint data were available for 39 patients due to the death of one patient prior to the 6-month follow-up visit; based on an intent-to-treat analysis, including this patient either as a success (40/40) or as a failure (39/40), the observed rate for the primary endpoint also met the established performance goal (posterior probability < 0.01).

**Table 16. 6-month freedom from patency-related intervention**

| 6-month freedom from patency-related reintervention | Performance goal | Lower bound^{a} | Posterior probability | Performance goal met |
| --- | --- | --- | --- | --- |
| 100% (39/39) | 55% | 91.2% | < 0.01 | Yes |

$^{a}$ The lower bound, per the protocol, is the 2.5th percentile of the Bayesian posterior distribution

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## 2. Secondary Safety Results

The secondary safety endpoint for the study was 30-day freedom from morbidity (i.e., the morbidity index defined in Section X.A.3 above).

The results for 30-day freedom from morbidity are presented in Table 17. Safety data through 30 days were available for all 40 patients. The success rate for the secondary safety endpoint was 85% (34/40) of patients, and the 2.5th percentile of the Bayesian posterior distribution was 70.8%, surpassing the performance goal of 46%. Based on these results, the secondary safety endpoint for the study was met.

Six patients experienced morbid events within 30 days of the procedure: distal embolization resulting in tissue loss or requiring reintervention (n = 1), inotropic support (n = 1), pneumonia requiring antibiotics (n = 1), paralytic ileus > 4 days (n = 1), impotence (n=1), and limb thrombosis on the same side as the ZBIS (n = 1).

**Table 17. 30-day freedom from morbidity**

| 30-day freedom from morbidity | Performance goal | Lower Bound^{a} | Posterior probability | Performance goal met |
| --- | --- | --- | --- | --- |
| 85% (34/40) | 46% | 70.8% | < 0.01 | Yes |

$^{a}$ The lower bound, per the protocol, is the 2.5th percentile of the Bayesian posterior distribution.

## 3. Additional Safety Outcomes

### *Death, Rupture, and Conversion*

Kaplan-Meier estimates for freedom from death, rupture, and conversion to open surgical repair are reported in Table 18. Among the 40 study patients, there was one death through 1 year; the freedom from all-cause mortality was 97.5%. In total, there were four deaths during the study; the 5-year freedom from all-cause mortality was 88.5%. There were no aneurysm-related deaths in the study. Likewise, there were no ruptures or conversions to open surgical repair during the study.

**Table 18. Kaplan-Meier estimates (freedom from death, rupture, and conversion)**

| Serious Adverse Event | Parameter | 30 Days | 180 Days | 365 Days | 730 Days | 1095 Days | 1460 Days | 1825 Days |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
| All-cause mortality | Number at risk | 40 | 39 | 37 | 37 | 35 | 33 | 18 |
| | Cumulative events | 0 | 1^{a} | 1 | 1 | 1 | 2^{a,b} | 4^{a-d} |
| | Cumulative censored | 0 | 0 | 2 | 2 | 4 | 5 | 18 |
| | Kaplan-Meier estimate | 100% | 97.5% | 97.5% | 97.5% | 97.5% | 94.6% | 88.5% |
| | Standard error | 0% | 2.5% | 2.5% | 2.5% | 2.5% | 3.8% | 5.7% |
| Aneurysm-related mortality | Number at risk | 40 | 39 | 37 | 37 | 35 | 33 | 18 |
| | Cumulative events | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| | Cumulative censored | 0 | 1 | 3 | 3 | 5 | 7 | 22 |
| | Kaplan-Meier estimate | 100% | 100% | 100% | 100% | 100% | 100% | 100% |
| | Standard error | 0% | 0% | 0% | 0% | 0% | 0% | 0% |
| Rupture | Number at risk | 40 | 39 | 37 | 37 | 35 | 33 | 18 |
| | Cumulative events | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| | Cumulative censored | 0 | 1 | 3 | 3 | 5 | 7 | 22 |
| | Kaplan-Meier estimate | 100% | 100% | 100% | 100% | 100% | 100% | 100% |
| | Standard error | 0% | 0% | 0% | 0% | 0% | 0% | 0% |

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| Serious Adverse Event | Parameter | 30 Days | 180 Days | 365 Days | 730 Days | 1095 Days | 1460 Days | 1825 Days |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Conversion | Number at risk | 40 | 39 | 37 | 37 | 35 | 33 | 18 |
| | Cumulative events | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| | Cumulative censored | 0 | 1 | 3 | 3 | 5 | 7 | 22 |
| | Kaplan-Meier estimate | 100% | 100% | 100% | 100% | 100% | 100% | 100% |
| | Standard error | 0% | 0% | 0% | 0% | 0% | 0% | 0% |

$^{a}$ Respiratory failure from CHF on POD 167; CEC adjudication was not related; related to pre-existing condition

$^{b}$ Malignant neoplasm of bladder with metastasis to liver and spine on POD 1383; CEC adjudication was not related; related to pre-existing condition

$^{c}$ Multi-factorial acute hypoxic respiratory failure on POD 1570; CEC adjudication was not related; related to fall, rib fractures, respiratory failure

$^{d}$ Unknown cause of death on POD 1723; CEC was unable to adjudicate

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# *Adverse Effects that Occurred in the PMA Clinical Study*

A total of 29 patients (72.5%) had a total of 141 adverse events. Table 19 reports Kaplan-Meier estimates for all adverse events according to category.

In particular, several types of vascular adverse events were reported during study follow-up.

- Additional aneurysms (5 events) were reported in four patients. Three of these aneurysms occurred in the iliac arteries on the side opposite the ZBIS and were all successfully treated with either stent placement (n=2) or bypass (n=1). The remaining two aneurysms occurred in the thoracic aorta, one requiring surgical replacement of the aortic root and ascending aorta and the other occurring in the ascending aorta and was not treated.
- Thrombosis events were reported in three patients, two of which had thrombosis of the external iliac segment of the ZBIS resulting in an occlusion. Both were treated with a secondary intervention involving thrombectomy and stent placement and were reported to have successfully restored patency. The third patient had thrombosis and occlusion of the iCAST stent in the IIA, on which no treatment was performed.
- Embolization with ischemia or infarction of the left gluteal area was reported in one patient on same day as the index procedure. Four surgical treatments were performed involving surgical exploration, drainage, and debridement of the left gluteal area and left buttock after which the event was considered to have resolved.
- Vascular injury was reported in 2 patients. One vascular injury was reported to be a stenosis of the external iliac artery at the distal edge of the ZBIS resulting in a secondary intervention which included balloon angioplasty and stent placement. The second vascular injury was reported to be an occlusion of the IIA (same side as ZBIS) that did not require treatment.

**Table 19. Kaplan-Meier estimates (freedom from morbidity)**

| Category | Parameter | 30 Days | 180 Days | 365 Days | 730 Days | 1095 Days | 1460 Days | 1825 Days |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
| **Access site/incision** | Number at risk | 40 | 39 | 37 | 37 | 35 | 33 | 18 |
| | Cumulative events | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| | Cumulative censored | 0 | 1 | 3 | 3 | 5 | 7 | 22 |
| | Kaplan-Meier estimate | 100% | 100% | 100% | 100% | 100% | 100% | 100% |
| | Standard error | 0% | 0% | 0% | 0% | 0% | 0% | 0% |
| **Cardiovascular** | Number at risk | 39 | 38 | 36 | 33 | 30 | 28 | 16 |
| | Cumulative events | 1 | 1 | 1 | 4 | 5 | 5 | 5 |
| | Cumulative censored | 0 | 1 | 3 | 3 | 5 | 7 | 19 |
| | Kaplan-Meier estimate | 97.5% | 97.5% | 97.5% | 89.4% | 86.5% | 86.5% | 86.5% |
| | Standard error | 2.5% | 2.5% | 2.5% | 5.1% | 5.8% | 5.8% | 5.8% |

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| Category | Parameter | 30 Days | 180 Days | 365 Days | 730 Days | 1095 Days | 1460 Days | 1825 Days |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Cardiac arrhythmia | Number at risk | 39 | 38 | 36 | 35 | 32 | 30 | 17 |
| | Cumulative events | 1 | 1 | 1 | 2 | 3 | 3 | 3 |
| | Cumulative censored | 0 | 1 | 3 | 3 | 5 | 7 | 20 |
| | Kaplan-Meier estimate | 97.5% | 97.5% | 97.5% | 94.8% | 91.9% | 91.9% | 91.9% |
| | Standard error | 2.5% | 2.5% | 2.5% | 3.7% | 4.6% | 4.6% | 4.6% |
| Congestive heart failure (CHF) | Number at risk | 40 | 39 | 37 | 36 | 33 | 31 | 17 |
| | Cumulative events | 0 | 0 | 0 | 1 | 2 | 2 | 2 |
| | Cumulative censored | 0 | 1 | 3 | 3 | 5 | 7 | 21 |
| | Kaplan-Meier estimate | 100% | 100% | 100% | 97.3% | 94.4% | 94.4% | 94.4% |
| | Standard error | 0% | 0% | 0% | 2.7% | 3.9% | 3.9% | 3.9% |
| Myocardial Infarction (MI) | Number at risk | 40 | 39 | 37 | 36 | 34 | 32 | 17 |
| | Cumulative events | 0 | 0 | 0 | 1 | 1 | 1 | 1 |
| | Cumulative censored | 0 | 1 | 3 | 3 | 5 | 7 | 22 |
| | Kaplan-Meier estimate | 100% | 100% | 100% | 97.3% | 97.3% | 97.3% | 97.3% |
| | Standard error | 0% | 0% | 0% | 2.7% | 2.7% | 2.7% | 2.7% |
| Cerebrovascular/neurologic | Number at risk | 40 | 39 | 36 | 36 | 33 | 31 | 17 |
| | Cumulative events | 0 | 0 | 2 | 2 | 3 | 3 | 3 |
| | Cumulative censored | 0 | 1 | 2 | 2 | 4 | 6 | 20 |
| | Kaplan-Meier estimate | 100% | 100% | 94.8% | 94.8% | 92.0% | 92.0% | 92.0% |
| | Standard error | 0% | 0% | 3.6% | 3.6% | 4.5% | 4.5% | 4.5% |
| Transient ischemic attack | Number at risk | 40 | 39 | 36 | 36 | 34 | 32 | 18 |
| | Cumulative events | 0 | 0 | 1 | 1 | 1 | 1 | 1 |
| | Cumulative censored | 0 | 1 | 3 | 3 | 5 | 7 | 21 |
| | Kaplan-Meier estimate | 100% | 100% | 97.3% | 97.3% | 97.3% | 97.3% | 97.3% |
| | Standard error | 0% | 0% | 2.7% | 2.7% | 2.7% | 2.7% | 2.7% |
| Stroke | Number at risk | 40 | 39 | 37 | 37 | 34 | 32 | 17 |
| | Cumulative events | 0 | 0 | 1 | 1 | 2 | 2 | 2 |
| | Cumulative censored | 0 | 1 | 2 | 2 | 4 | 6 | 21 |
| | Kaplan-Meier estimate | 100% | 100% | 97.4% | 97.4% | 94.7% | 94.7% | 94.7% |
| | Standard error | 0% | 0% | 2.5% | 2.5% | 3.8% | 3.8% | 3.8% |
| Gastrointestinal | Number at risk | 39 | 38 | 36 | 36 | 34 | 32 | 18 |
| | Cumulative events | 1 | 1 | 1 | 1 | 1 | 1 | 1 |
| | Cumulative censored | 0 | 1 | 3 | 3 | 5 | 7 | 21 |
| | Kaplan-Meier estimate | 97.5% | 97.5% | 97.5% | 97.5% | 97.5% | 97.5% | 97.5% |
| | Standard error | 2.5% | 2.5% | 2.5% | 2.5% | 2.5% | 2.5% | 2.5% |

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| Category | Parameter | 30 Days | 180 Days | 365 Days | 730 Days | 1095 Days | 1460 Days | 1825 Days |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Bleeding requiring intervention | Number at risk | 40 | 39 | 37 | 37 | 34 | 32 | 18 |
| | Cumulative events | 0 | 0 | 0 | 0 | 1 | 1 | 1 |
| | Cumulative censored | 0 | 1 | 3 | 3 | 5 | 7 | 21 |
| | Kaplan-Meier estimate | 100% | 100% | 100% | 100% | 97.2% | 97.2% | 97.2% |
| | Standard error | 0% | 0% | 0% | 0% | 2.7% | 2.7% | 2.7% |
| Infection | Number at risk | 40 | 39 | 37 | 37 | 34 | 32 | 18 |
| | Cumulative events | 0 | 0 | 0 | 0 | 1 | 1 | 1 |
| | Cumulative censored | 0 | 1 | 3 | 3 | 5 | 7 | 21 |
| | Kaplan-Meier estimate | 100% | 100% | 100% | 100% | 97.2% | 97.2% | 97.2% |
| | Standard error | 0% | 0% | 0% | 0% | 2.7% | 2.7% | 2.7% |
| Ileus | Number at risk | 39 | 38 | 36 | 36 | 34 | 32 | 18 |
| | Cumulative events | 1 | 1 | 1 | 1 | 1 | 1 | 1 |
| | Cumulative censored | 0 | 1 | 3 | 3 | 5 | 7 | 21 |
| | Kaplan-Meier estimate | 97.5% | 97.5% | 97.5% | 97.5% | 97.5% | 97.5% | 97.5% |
| | Standard error | 2.5% | 2.5% | 2.5% | 2.5% | 2.5% | 2.5% | 2.5% |
| Hepatic | Number at risk | 40 | 39 | 37 | 37 | 35 | 33 | 18 |
| | Cumulative events | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| | Cumulative censored | 0 | 1 | 3 | 3 | 5 | 7 | 22 |
| | Kaplan-Meier estimate | 100% | 100% | 100% | 100% | 100% | 100% | 100% |
| | Standard error | 0% | 0% | 0% | 0% | 0% | 0% | 0% |
| Pulmonary | Number at risk | 38 | 36 | 34 | 33 | 27 | 25 | 13 |
| | Cumulative events | 2 | 3 | 3 | 4 | 8 | 8 | 8 |
| | Cumulative censored | 0 | 1 | 3 | 3 | 5 | 7 | 19 |
| | Kaplan-Meier estimate | 95.0% | 92.5% | 92.5% | 89.8% | 78.5% | 78.5% | 78.5% |
| | Standard error | 3.4% | 4.2% | 4.2% | 5.0% | 7.0% | 7.0% | 7.0% |
| Chronic obstructive pulmonary disease (COPD) | Number at risk | 40 | 39 | 37 | 37 | 32 | 30 | 15 |
| | Cumulative events | 0 | 0 | 0 | 0 | 3 | 3 | 4 |
| | Cumulative censored | 0 | 1 | 3 | 3 | 5 | 7 | 21 |
| | Kaplan-Meier estimate | 100% | 100% | 100% | 100% | 91.6% | 91.6% | 88.3% |
| | Standard error | 0% | 0% | 0% | 0% | 4.7% | 4.7% | 5.8% |
| Pneumothorax | Number at risk | 40 | 38 | 36 | 36 | 34 | 32 | 17 |
| | Cumulative events | 0 | 1 | 1 | 1 | 1 | 1 | 1 |
| | Cumulative censored | 0 | 1 | 3 | 3 | 5 | 7 | 22 |
| | Kaplan-Meier estimate | 100% | 97.5% | 97.5% | 97.5% | 97.5% | 97.5% | 97.5% |
| | Standard error | 0% | 2.5% | 2.5% | 2.5% | 2.5% | 2.5% | 2.5% |

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| Category | Parameter | 30 Days | 180 Days | 365 Days | 730 Days | 1095 Days | 1460 Days | 1825 Days |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Pulmonary embolism | Number at risk | 39 | 38 | 36 | 36 | 33 | 31 | 17 |
| | Cumulative events | 1 | 1 | 1 | 1 | 2 | 2 | 2 |
| | Cumulative censored | 0 | 1 | 3 | 3 | 5 | 7 | 21 |
| | Kaplan-Meier estimate | 97.5% | 97.5% | 97.5% | 97.5% | 94.6% | 94.6% | 94.6% |
| | Standard error | 2.5% | 2.5% | 2.5% | 2.5% | 3.8% | 3.8% | 3.8% |
| Pneumonia | Number at risk | 39 | 38 | 36 | 35 | 32 | 30 | 16 |
| | Cumulative events | 1 | 1 | 1 | 2 | 3 | 3 | 3 |
| | Cumulative censored | 0 | 1 | 3 | 3 | 5 | 7 | 21 |
|…