Zenith TX2 TAA Endovascular Graft (P716) Annual Clinical Update (216) Page i Annual Clinical Update Abstract Cook is pleased to provide you with this clinical update on the Zenith TX2 TAA Endovascular Graft, which was commercially approved by FDA on May 21, 28. Section I provides the results from the completed multi-center clinical trial, reflecting final data received as of February 23, 212. Briefly, the study was designed to compare thoracic aneurysm/ulcer treatment with the Zenith TX2 TAA Endovascular Graft in 16 patients to open surgical repair in 7 control patients. All patients reached a study endpoint. Five-year follow-up data were collected from 93% (68/73) of endovascular patients and 48% (12/25) control patients. Survival from aneurysm-related mortality at 6 months was 88.7% in the endovascular treatment group and 76.7% in the open surgical control group. No death in the endovascular treatment group was found to be related to failure of a component of the device. The percent of patients with new endoleak at yearly follow-up was at 12 months, 1.1% at 24 months, 1.2% at 36 months, 6.7% at 48 months, and 1.9% at 6 months. There were 14 patients with an increase in aneurysm/ulcer size at one or more time points. Device integrity observations during follow-up included stent fracture (4 patients), barb separation (18 patients), component separation (1 patient), and bare stent entanglement (1 patient). There was one report of clinically significant migration during follow-up, which occurred at 48 months. The percent of patients requiring at least one reintervention subsequent to the initial aneurysm/ulcer repair procedure was 6.9% for the endovascular treatment group and 8.6% in the open surgical control group. There were no ruptures or conversions to open surgical repair in the endovascular treatment group. Results from the additional patients enrolled during continued access (n=25) and the post-approval study (n=115) are also described. Section II summarizes worldwide commercial experience through March 31, 216. A total of 75,224 components have been sold worldwide (including 26,827 sold in the US) since May 21, 28. There have been 344 procedural and follow-up complaints reported since approval. Section III summarizes the findings from explant analysis. To date, six explants have undergone analysis. Section IV is reserved for any new notes or general instructions to clinicians, of which there are none at this time beyond those already covered as part of the indications, warnings, and precautions from the IFU. Section V provides a brief summary of the indications, warnings, and precautions from the IFU.
Zenith TX2 TAA Endovascular Graft (P716) Annual Clinical Update (216) Page ii Device Description The Zenith TX2 TAA Endovascular Graft is a two-piece cylindrical endovascular graft consisting of proximal and distal components. The proximal component can be either non-tapered or tapered and may be used alone or in combination with a distal component. The stent-grafts are constructed of woven polyester fabric sewn to self-expanding stainless steel Cook-Z stents with braided polyester and monofilament polypropylene sutures. The covered stent at the proximal end of the proximal component contains barbs, which protrude through the graft material. In addition, the bare stent at the distal end of the distal component contains barbs. Ancillary endovascular components (proximal and distal body extensions) are also available. Please refer to the IFU for a more detailed description of the components and the delivery system, as well as the indications, warnings, and precautions (also summarized in Section V). Introduction One of the conditions of approval of the Zenith TX2 TAA Endovascular Graft was to provide a clinical update to physician users annually. This update has been formatted in accordance with a template that was agreed upon by FDA, industry, and clinicians during a meeting at FDA in October 28. Accordingly, the clinical update is comprised of the following sections: Clinical Study Experience (Section I); Worldwide Commercial Experience (Section II); Explant Analysis (Section III); Notes to Clinicians (Section IV); and Brief Summary of Indications, Warnings, and Precautions from IFU (Section V).
Zenith TX2 TAA Endovascular Graft (P716) Annual Clinical Update (216) Page iii Table of Contents Section I Clinical Study Experience... 1 Description of Studies... 1 Patient Availability... 2 Aneurysm-Related Mortality... 6 Continued Access... 7 All-Cause Mortality... 8 Endoleak... 9 Change in Size... 11 Rupture... 13 Device Integrity... 14 Migration... 17 Secondary Interventions... 18 Conversion... 21 Summary... 21 Section II Worldwide Commercial Experience... 23 Section III Explant Analysis... 26 Clinical Study Experience... 26 Worldwide Commercial Experience... 27 Summary... 27 Section IV Notes to Clinicians... 28 Section V Brief Summary of Indications, Warnings, and Precautions from IFU. 29 Indications... 29 Warnings and Precautions... 29
Zenith TX2 TAA Endovascular Graft (P716) Page 1 Annual Clinical Update (216) Section I Clinical Study Experience Description of Studies Pivotal The STARZ-TX2 Clinical Trial is a non-randomized, controlled, multi-center, multinational study that was conducted to evaluate safety and effectiveness of the Zenith TX2 TAA Endovascular Graft in the elective treatment of patients with descending thoracic aortic aneurysms or ulcers, as compared with open surgical repair. The study consisted of an endovascular treatment group and an open surgical control group. The open surgical control group was comprised of both prospectively enrolled and retrospectively enrolled patients. The same inclusion/exclusion criteria applied to both the endovascular treatment group and the open surgical control group, except that patients in the open surgical control group were not required to have anatomy amenable to endovascular repair with the Zenith TX2 TAA Endovascular Graft. The clinical study device is the same as the device that is commercially available, with the only exception pertaining to the delivery system all patients enrolled in the clinical study were treated using the H&L-B One-Shot Introduction System, which has been replaced with the now commercially-approved Pro-Form and Z-Trak Plus Introduction System. Forty-two (42) institutions enrolled a total of 16 endovascular treatment patients and 7 open surgical control patients. The study follow-up schedule for patients enrolled in the endovascular treatment group consisted of radiographic (CT scan and X-ray) and clinical assessments at pre-discharge, 3 days, 6 months, 12 months, and yearly thereafter through 5 years. The study follow-up schedule for patients enrolled in the open surgical control group consisted of radiographic (CT scan) and clinical assessments at predischarge (or 3 days) and 12 months, with an interim telephone contact at 6 months, and additional optional follow-up at yearly intervals through 5 years. The study was designed to assess two primary and two secondary hypotheses regarding the endovascular treatment group as compared with the open surgical control group. The primary hypothesis for safety was non-inferior 3-day survival, and the primary hypothesis for effectiveness was non-inferior 3-day rupture-free survival (i.e., freedom from rupture). The secondary hypotheses were superior clinical utility in the endovascular treatment group and non-inferior 3-day morbidity, expressed as a composite morbidity score including 57 pre-specified events. All study hypotheses were met. In addition, the study assessed survival, morbidity, and device performance through 12 months, and continued these assessments at yearly intervals through 5 years. Study
Zenith TX2 TAA Endovascular Graft (P716) Page 2 Annual Clinical Update (216) follow-up is complete, and the reported results reflect final data received as of February 23, 212. Continued Access Subsequent to completion of enrollment in the pivotal study and prior to commercial availability, continued access to the Zenith TX2 TAA Endovascular Graft was offered to investigators under a study expansion that followed the same inclusion/exclusion criteria, follow-up schedule, definitions, and data collection as for the pivotal study. A total of 25 patients were enrolled between July 5, 26 and August 11, 28. Follow-up for the continued access cohort is complete, and the reported results reflect final data received as of October 23, 213. Post-Approval A post-approval study of 3 patients with a primary endpoint of 5-year aneurysmrelated mortality was agreed upon as a condition of approval of the Zenith TX2 TAA Endovascular Graft. Patients enrolled pre-approval (16 pivotal + 25 continued access) will be combined with 115 additional patients to be enrolled post-approval. Patient enrollment is complete and follow-up is on-going; the reported results reflect data received as of March 14, 216. Patient Availability Patient availability for completed follow-up in the pivotal study is summarized in Table 1. Patient availability for completed follow-up in continued access is summarized in Table 2. Patient availability for on-going follow-up of the patients enrolled postapproval is summarized in Table 3.
Zenith TX2 TAA Endovascular Graft (P716) Page 3 Annual Clinical Update (216) Table 1: Follow-up Availability (Pivotal) Time point Subjects with submitted data Adequate imaging to assess parameter by core lab b Events occurring before next visit Number Clinical CT X-ray Size increase Endoleak Migration Integrity Death Conversion LTF Not due for eligible for % % % % % % % next visit follow-up (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) Endovascular Pre-discharge 158 a 1 1 99% 85% 96% n/a n/a (158) (158) (157) (135) (152) 3 3-day 95% 95% 95% 78% 81% 72% 88% 155 (147) (148) (148) (121) (126) (112) (136) 5 4 6-month 89% 94% 93% 8 78% 77% 87% 146 (13) (137) (136) (117) (114) (112) (127) 5 5 12-month 95% 95% 93% 84% 77% 8 91% 136 (129) (129) (126) (114) (15) (19) (124) 14 5 24-month 89% 9 88% 77% 77% 77% 85% 117 (14) (15) (13) (9) (9) (9) (1) 8 6 36-month 88% 92% 89% 81% 81% 85% 87% 13 (91) (95) (92) (83) (83) (88) (9) 7 8 48-month 88 86% 91% 84% 74% 68% 81% 85% 9 6 (76) 6-month 73 93% (68) Pre-discharge/ 3-day 6-month 12-month 24-month 36-month 48-month 6-month 7 62 6 32 31 3 25 1 (7) 6 (37) 72% (43) 59% (19) 58% (18) 6 (18) 48% (12) (8) 92% (67) (74) 82% (6) (65) 7 (51) (6) 73% (53) Open Surgical (71) 88% (64) (75) 9 (66) n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a 8 n/a n/a n/a n/a n/a n/a n/a 2 n/a n/a n/a n/a n/a n/a n/a 1 n/a 3 24 c n/a n/a n/a n/a n/a n/a 1 n/a n/a n/a n/a n/a n/a n/a 1 n/a n/a n/a n/a n/a n/a n/a 4 n/a 1 n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a not applicable. a Device insertion was not achieved in two patients. b Includes only adequate imaging with completed analysis, not received imaging awaiting analysis. c IRB/EC-approved follow-up was limited to 12 months at 11 sites that enrolled open surgical control patients (n=24).
Zenith TX2 TAA Endovascular Graft (P716) Page 4 Annual Clinical Update (216) Table 2: Follow-up Availability (Continued Access) Subjects with submitted data Adequate imaging to assess parameter by core lab Events occurring before next visit Eligible for Size Time point follow-up a Clinical CT X-ray Endoleak Migration Integrity Not due for increase Death Conversion LTF % % % % % % next visit (n) % (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) Endovascular Pre-discharge 1 1 96% 8 88% 25 () n/a n/a (25) (25) (24) (2) (22) 1 3-day 96% 96% 96% 79% 79% 71% 96% 24 () (23) (23) (23) (19) (19) (17) (23) 3 6-month 9 95% 95% 76% 86% 86% 9 21 () (19) (2) (2) (16) (18) (18) (19) 12-month 86% 9 9 71% 81% 76% 81% 21 () (18) (19) (19) (15) (17) (16) (17) 3 24-month 78% 1 1 72% 78% 89% 89% 18 () (14) (18) (18) (13) (14) (16) (16) 1 36-month 82% 88% 82% 53% 65% 71% 94% 17 () (14) (15) (14) (9) (11) (12) (16) 2 1 48-month 14 () 64% 71% 64% 57% 57% 64% 71% 2 1 6-month Pre-discharge/ 3-day 6-month 12-month 24-month 36-month 48-month 6-month 11 () 1 () 1 () 1 () 1 () 1 () 1 () 1 () (9) 55% (6) 1 (1) 1 (1) 1 (1) 1 (1) () 1 (1) 1 (1) (1) 64% (7) (9) 64% (7) (8) 45% (5) (8) 27% (3) Open Surgical (9) 45% (5) (1) 45% (5) n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a not applicable. a Number in parentheses within the Eligible for follow-up column indicates the number without submitted data that are still eligible.
Zenith TX2 TAA Endovascular Graft (P716) Page 5 Annual Clinical Update (216) Table 3: Follow-up Availability (Post-approval) Follow-up not yet done, but Subjects with submitted data Adequate imaging to assess parameter Events occurring before next visit Eligible patients still Not for within Size Withdrawal Clinical CT X-ray Endoleak Migration Integrity Conversio due for Time point followup window to % (n) LTF suggested increase Death or % % % % % % n next (n) (n) (n) (n) (n) (n) (n) visit (n) complete the (n) (n) (n) visit (n) Pre-discharge 1 115 (115/115) n/a a n/a a n/a a n/a a n/a a n/a a 2 3-day 89.4% 82.3% 113 n/a a n/a a 73.5% (11/113) (93/113) (83/113) n/a a n/a a 6 5 6-month 82.4% 78.4% 12 n/a a 61.8% 69.6% 67.6% 78.4% (84/12) (8/12) (63/12) (71/12) (69/12) (8/12) 3 2 12-month 76.3% 76.3% 64.9% 61.9% 63.9% 74.2% 76.3% 97 11 (74/97) (74/97) (63/97) (6/97) (62/97) (72/97) (74/97) 4 7 11 24-month 77.3% 69.3% 54.7% 6. 5.7% 65.3% 68. 75 14 (58/75) (52/75) (41/75) (45/75) (38/75) (49/75) (51/75) 7 2 16 36-month 82. 74. 64. 58. 54. 72. 74. 5 7 (41/5) (37/5) (32/5) (29/5) (27/5) (36/5) (37/5) 3 11 48-month 36 4 75. 77.8% 72.2% 69.4% 58.3% 75. 75. 3 1 7 6-month 25 1 (27/36) 6. (15/25) (28/36) 56. (14/25) (26/36) 44. (11/25) (25/36) 56. (14/25) (21/36) 48. (12/25) (27/36) 52. (13/25) (27/36) 6. (15/25) n/a n/a n/a b n/a n/a not applicable. a CT and X-rays are no longer required per new protocol amendment. b Patient 36181 was reported to be lost to follow-up 1,951 days post-procedure and did not complete the 6-month follow-up visit. Since there is no interval for events occurring after the 5-year follow-up visit, this event is being reported as a footnote, rather than providing a number within the compliance table.
Zenith TX2 TAA Endovascular Graft (P716) Page 6 Annual Clinical Update (216) Aneurysm-Related Mortality Aneurysm-related mortality was defined as death occurring within 3 days of the initial implant procedure or a secondary intervention, or any death adjudicated to be aneurysmrelated by the independent clinical events committee (CEC). Pivotal The following data summarize survival from aneurysm-related mortality in the endovascular treatment and open surgical control groups. As illustrated in Figure 1 and presented in Table 4, survival from aneurysm-related mortality at 1825 days was 88.7% in the endovascular treatment group and 76.7% in the open surgical control group. No death in the endovascular treatment group was found to be related to failure of a component of the device. Figure 1: Survival from Aneurysm-related Mortality
Zenith TX2 TAA Endovascular Graft (P716) Page 7 Annual Clinical Update (216) Table 4: Kaplan-Meier Aneurysm-related Mortality Survival Estimates Arm Days Kaplan-Meier estimate Standard error Cumulative events Cumulative censored Patients remaining Endovascular 1.. 16 3.981.17 3 1 156 365.942.187 9 a 15 136 73.927.214 11 b 32 117 195.918.229 12 c 46 12 146.898.264 14 f 61 85 1825.887.283 15 h 86 59 Surgical 1.. 7 3.943.277 4 66 365.883.388 8 d 6 56 73.883.388 8 32 3 195.883.388 8 36 26 146.848.58 9 e 38 23 1825.767.712 11 g 45 14 a Reported cause for aneurysm-related deaths occurring between 3 and 365 days as follows: septicemia and respiratory failure (procedure-related); multi-system organ failure (procedure-related); unable to be determined (therefore counted as aneurysm-related); respiratory failure (procedure-related); multi-system organ failure (procedure-related); cardiopulmonary arrest secondary to pneumonia (procedure-related). b Reported cause for aneurysm-related deaths occurring between 365 and 73 days as follows: removal of ventilator support following stroke after secondary intervention (procedure-related); unable to be determined (therefore counted as aneurysm-related). c Reported cause for aneurysm-related death occurring between 73 and 195 days as follows: unable to be determined (therefore counted as aneurysm-related). d Reported cause for aneurysm-related deaths occurring between 3 and 365 days as follows: asystole (procedure-related); cardiopulmonary arrest (procedure-related); unknown (procedure-related); respiratory failure (procedure-related). e Reported cause for aneurysm-related death occurring between 195 and 146 days as follows: unable to be determined (therefore counted as aneurysm-related). f Reported causes for aneurysm-related deaths occurring between 195 and 146 days as follows: both unable to be determined (therefore counted as aneurysm-related). g Reported causes for aneurysm-related deaths occurring between 146 and 1825 days as follows: sudden cardiac arrest (unable to determine if procedure- or aneurysm-related, therefore counted as aneurysmrelated mortality); sudden shock (suspected leaking/rupture of AAA or TAA, but unable to determine which, therefore counted as aneurysm-related mortality). h Reported cause for aneurysm-related death occurring between 146 and 1825 days as follows: unable to be determined (therefore counted as aneurysm-related). Continued Access There were two TAA-related deaths according to the CEC. The causes of death were stroke (4 days post-procedure) in one and acute renal failure/care withdrawn (41 days post-procedure) for the other. Post-approval There have been two TAA-related deaths according to the CEC. The causes of death were respiratory failure (3 days post-procedure) and aortic rupture (626 days post-
Zenith TX2 TAA Endovascular Graft (P716) Page 8 Annual Clinical Update (216) procedure). The death from rupture occurred in association with a possible proximal Type I endoleak despite a decrease in aneurysm size and lack of endoleak per core lab analysis of the 12-month follow-up CT. All-Cause Mortality Pivotal The following data summarize survival from all-cause mortality in the endovascular treatment and open surgical control groups. As illustrated by Figure 2 and presented in Table 5, survival from all-cause mortality at 1825 days was 62.9% in the endovascular treatment group and 62.8% in the open surgical control group. Figure 2: Survival from All-cause Mortality
Zenith TX2 TAA Endovascular Graft (P716) Page 9 Annual Clinical Update (216) Table 5: Kaplan-Meier All-cause Mortality Survival Estimates Arm Days Kaplan-Meier estimate Standard error Cumulative events Cumulative censored Patients remaining Endovascular 1.. 16 3.981.17 3 1 156 365.916.223 13 11 136 73.82.315 27 16 117 195.762.353 35 23 12 146.75.386 42 33 85 1825.629.42 51 47 62 Surgical 1.. 7 3.943.277 4 66 365.856.42 1 4 56 73.83.485 11 29 3 195.8.551 12 32 26 146.768.615 13 34 23 1825.628.87 17 39 14 Note: One endovascular patient died at 1855 days following the procedure of unknown cause, without having undergone 5-year follow-up exams. Independent clinical events committee adjudication determined the death to be unrelated to TAA repair. If counted amongst the all-cause mortality, the adjusted Kaplan- Meier survival estimate is 61.1%. Continued Access There have been 11 total deaths (2 adjudicated as related, 6 adjudicated as unrelated by the CEC, and 3 in which the CEC was unable to adjudicate). Post-approval There have been 26 total deaths (2 adjudicated as related by the CEC, 2 adjudicated as unrelated by the CEC, and 4 in which the CEC was unable to adjudicate). Endoleak Pivotal Table 6 reports the percent of patients with endoleak (by type) at each follow-up time point based on the results from core lab analysis. Patients who underwent a secondary intervention for endoleak or who had associated aneurysm size increase are indicated by footnotes. The percent of patients with new endoleak at yearly follow-up was at 12 months, 1.1% at 24 months, 1.2% at 36 months, 6.7% at 48 months, and 1.9% at 6 months.
Zenith TX2 TAA Endovascular Graft (P716) Page 1 Annual Clinical Update (216) Table 6: Percent of Endovascular Treatment Patients with Endoleak Based on Core Lab Analysis Time point Type Predischarge 3 days 6 months 12 months 24 months 36 months 48 months 6 months Any (new only) 14.1% (19/135) 1.6% (2/126) (/114) (/15) 1.1% (1/9) 1.2% (1/83) 6.7% (4/6) 1.9% (1/53) Any (new and persistent) 14.1% (19/135) 4.8% (6/126) 2.6% (3/114) 3.8% (4/15) 2.2% (2/9) 2.4% (2/83) 8.3% (5/6) 5.7% (3/53) Multiple.7% (1/135) a.8% (1/126) a.9% (1/114) a (/15) (/9) (/83) (/6) (/53) Proximal Type I (/135) (/126) (/114) (/15) (/9) (/83) 1.7% (1/6) 3.8% (2/53) Distal Type I.7% (1/135) a.8% (1/126) a.9% (1/114) a (/15) 1.1% (1/9) b 1.2% (1/83) b 1.7% (1/6) 1.9% (1/53) Type IIa 1.5% (2/135).8% (1/126) (/114) (/15) (/9) (/83) 1.7% (1/6) (/53) Type IIb 7.4% (1/135) a,c 3.2% (4/126) a 2.6% (3/114) a 1.9% (2/15) 1.1% (1/9) (/83) (/6) (/53) Type III 1.5% (2/135).8% (1/126) (/114) 1. (1/15) (/9) (/83) 1.7% (1/6) c (/53) Type IV 1.5% (2/135) (/126) (/114) (/15) (/9) (/83) (/6) (/53) Unknown 2.2% (3/135) d,e (/126) (/114) 1. (1/15) (/9) 1.2% (1/83) 1.7% (1/6) b (/53) a Patient 26121: Site reported distal Type I endoleak requiring two secondary interventions (one after the 1-month exam, and one after the 6-month exam); patient also had aneurysm increase first noted by core lab at 12-month exam, but with no change in size between 12-month and 6-month exams. b Patient 41214: Site reported distal Type I endoleak requiring secondary intervention following 36- month exam. Unknown endoleak type by core lab analysis of 48-month follow-up exam, not confirmed by site, and with no increase in aneurysm diameter at any time point. c Patient 41218: Site reported distal Type I endoleak requiring secondary intervention (placement of two distal extensions) following pre-discharge exam. Additional secondary intervention (placement of additional main body component) reported by site following 48-month exam for treatment of Type III endoleak (between separated main body component and previously placed extensions) in setting of aortic elongation. No associated increase in aneurysm diameter noted at any time point. d Patient 41216: Site reported proximal Type I endoleak requiring secondary intervention prior to predischarge exam. e Patient 25121: Secondary intervention (angiogram) performed to rule out endoleak following predischarge exam no endoleak detected. Continued Access Core lab reported endoleaks were as follows: Type III endoleak (n=3, all at predischarge), proximal Type I endoleak (n=1, at 24 months), distal Type I endoleak (n=1, at 6 months). One patient with core lab reported endoleak (proximal Type I) required a secondary intervention. Patient 4154 had a proximal extension placed 825 days postprocedure due to site reported proximal Type I endoleak with no associated aneurysm enlargement. The patient also had caudal migration of the proximal edge of the proximal component with no associated increase in aneurysm size through 6-month follow-up. Insufficient device oversizing relative to the location of actual graft placement may have been a contributing factor to migration.
Zenith TX2 TAA Endovascular Graft (P716) Page 11 Annual Clinical Update (216) Post-approval Core lab reported endoleaks thus far are as follows: distal Type I endoleak (n=5, one at 1 month and 6 months; one at 6 months; one at 1 month, 6 months, and 12 months; one at 12 months and 24 months; and one at 36 months), proximal Type I endoleak (n=2, one at 6 months and one at 12 months), Type III endoleak (n=1, at 6 months), Type IV (n=1, at 6 months; Type IIb was also reported for this patient). One patient with core lab reported endoleak (Type III) required a secondary intervention. Patient 47188 had a proximal extension placed 287 days post-procedure to treat site reported proximal Type I endoleak with no associated aneurysm growth reported. Change in Size Pivotal Table 7 reports the percent of patients with an increase (> 5 mm), decrease (> 5 mm), or no change ( 5 mm) in aneurysm diameter (or ulcer depth) by core lab analysis at each follow-up time point subsequent to pre-discharge, which represents baseline. In total, 14 patients (12 aneurysm, 2 ulcer) have experienced an increase in size at one or more time points: 5 with detectable endoleak at one or more time points (2 requiring secondary intervention and 3 which resolved without reintervention); 3 with no detectable endoleak (or evidence of infection), but who underwent secondary intervention for a decrease in overlap between components for 1, migration for 1, and suspected endotension for 1; 5 without detectable endoleak (or evidence of infection), but with a decrease or stabilization in size at subsequent follow-up without reintervention; and 1 with no detectable endoleak (or evidence of infection), no reintervention, and has reached the final follow-up timepoint. Any patient with size increase and associated endoleak and/or requiring a secondary intervention is indicated by a footnote in Table 5. There were no reports of rupture or conversion to open surgical repair in the endovascular treatment group. Table 7: Percent of Endovascular Treatment Patients with an Increase, Decrease, or No Change in Aneurysm/Ulcer Size Based on Core Lab Analysis Time point Combined % (n) Aneurysm % (n) Ulcer % (n) 3-day Increase (> 5 mm) Decrease (> 5 mm) No change ( 5 mm) 6-month Increase (> 5 mm) Decrease (> 5 mm) No change ( 5 mm).8% (1/121) 5.8% (7/121) 93.4% (113/121) 3.4% (4/117) 32.5% (38/117) 64.1% (75/117).9% (1/16) 5.7% (6/16) 93.4% (99/16) 3. (3/99) a 33.3% (33/99) 63.6% (63/99) (/15) 6.7% (1/15) 93.3% (14/15) 5.6% (1/18) e 27.8% (5/18) 66.7% (12/18)
Zenith TX2 TAA Endovascular Graft (P716) Page 12 Annual Clinical Update (216) Time point Combined % (n) Aneurysm % (n) Ulcer % (n) 12-month Increase (> 5 mm) Decrease (> 5 mm) No change ( 5 mm) 24-month Increase (> 5 mm) Decrease (> 5 mm) No change ( 5 mm) 36-month Increase (> 5 mm) Decrease (> 5 mm) No change ( 5 mm) 48-month Increase (> 5 mm) Decrease (> 5 mm) No change ( 5 mm) 6-month Increase (> 5 mm) Decrease (> 5 mm) No change ( 5 mm) 7. (8/114) 47.4% (54/114) 45.6% (52/114) 3.3% (3/9) 52.2% (47/9) 44.4% (4/9) 4.8% (4/83) 59. (49/83) 36.1% (3/83) 4.6% (3/65) 61.5% (4/65) 33.8% (22/65) 5.9% (3/51) 62.7% (32/51) 31.4% (16/51) 7.1% (7/99) a,b,c,d 5.5% (5/99) 42.4% (42/99) 2.6% (2/78) c,f 55.1% (43/78) 42.3% (33/78) b,d 5.6% (4/71) b,f,g 63.4% (45/71) 31. (22/71) c,d 5.5% (3/55) b,c,h 65.5% (36/55) d 29.1% (16/55) f 7. (3/43) b,h 67.4% (29/43) d 25.6% (11/43) f 6.7% (1/15) 26.7% (4/15) 66.7% (1/15) e 8.3% (1/12) 33.3% (4/12) 58.3% (7/12) e (/12) 33.3% (4/12) e 66.7% (8/12) (/1) 4. (4/1) 6. (6/1) (/8) 37.5% (3/8) 62.5% (5/8) a Patient 9123: Patient underwent two secondary interventions after the 12-month exam for continued increase without detectable endoleak or evidence of graft infection and expired within 3 days of the latter secondary intervention (after removal of ventilator support following a stroke), prior to the 24-month exam. b Patient 261211: Patient underwent two secondary interventions (one after the 1-month exam, and one after the 6-month exam) for distal Type I endoleak; there was no change in size between the 12-month and 6-month exams. c Patient 361212: Patient presented with flank pain and underwent secondary intervention between the 12-month and 24-month exams because of decreasing overlap between components from device alignment with greater curve over time (without associated junctional Type III endoleak). Type IIa endoleak was reported at 48-month follow-up without reintervention, and the patient died prior to 6-month follow-up. d Patient 41121: Patient presented with flank pain and underwent secondary intervention between the 12-month and 24-month exams to treat symptoms due to junctional Type III endoleak from component separation retrospective review of procedural imaging suggests the length of overlap achieved between components at the time of initial deployment was less than the minimum recommended amount. e Patient 321211: Patient was noted to have a Type IIb endoleak at pre-discharge, but not on subsequent follow-up and was without secondary intervention. f Patient 36126: Patient underwent secondary intervention between 48- and 6-months for CECconfirmed migration. No endoleak has been noted at any follow-up timepoint. No change in aneurysm size at last follow-up. g Patient 41121: Patient was noted to have endoleak of unknown type at pre-discharge, but not on subsequent follow-up and was without secondary intervention. h Patient 41213: Patient was noted to have a Type IIb endoleak at pre-discharge, but not on subsequent follow-up and was without secondary intervention. Continued Access Core lab reported increase in aneurysm size (> 5 mm) occurred in 2 patients (one at 24 months and one at 36 months that was reported again at 6 months). Neither patient underwent a secondary intervention. Patient 36153 (with aneurysm growth at 24 months) was without detectable endoleak and had an aneurysm size at 6-month followup that was unchanged from baseline. Patient 31153 (with aneurysm growth at 36- and 6-month follow-up) had Type III endoleak at pre-discharge follow-up and distal Type I
Zenith TX2 TAA Endovascular Graft (P716) Page 13 Annual Clinical Update (216) endoleak at 6-month follow-up due to cranial migration of the distal edge of the distal component in the setting of aneurysmal enlargement of the aorta distal to the study device, which per core laboratory assessment, advanced over time to include aorta surrounding the distal device component without need for secondary intervention through 6-month follow-up. Per the study site, the case was conservatively managed due to comorbid conditions, with no secondary intervention planned. Post-approval Core lab reported increase in aneurysm size (> 5 mm) occurred in 8 patients (one at 12- months; one at 12 months, 24 months, and 36 months; one at 12 months through 48 months; one at 24 months and 36-months, one at 24 months and 48 months, one at 36- months, and two at 6-months), 4 also with core lab reported endoleak, as noted below. No patients with core lab reported aneurysm growth have undergone a secondary intervention to date. Patient 57184 had a core lab reported distal Type I endoleak at 1 month, 6 months, and at 36 months; the core lab also reported presence of a Type IIA endoleak at 1 month and 6 months. In addition, the core lab reported the presence of radiographic migration and barb separation at 12-months. Patient 57188 had a core lab reported persistent Type IIB endoleak at 1 month and 6 months; in addition, the core lab reported a Type IV endoleak at 6 months. Patient 58182 had a core lab reported Type IIB endoleak at 1 month, which appears to have resolved without the need for any reintervention. Patient 58184R had a core lab reported distal Type I endoleak that persisted at both 12 months and 24 months. At 3 days, the core lab also reported barb separation. Rupture Pivotal As shown in Table 8, there have been no ruptures in either the endovascular treatment group or open surgical control group. Table 8: Kaplan-Meier for Freedom from Rupture Arm Days Kaplan-Meier estimate Standard error Cumulative events Cumulative censored Patients remaining Endovascular 1.. 16 3 1.. 4 156 365 1.. 24 136 73 1.. 43 117 195 1.. 58 12 146 1.. 75 85 1825 1.. 11 59
Zenith TX2 TAA Endovascular Graft (P716) Page 14 Annual Clinical Update (216) Arm Days Kaplan-Meier estimate Standard error Cumulative events Cumulative censored Patients remaining Surgical 1.. 7 3 1.. 4 66 365 1.. 14 56 73 1.. 4 3 195 1.. 44 26 146 1.. 47 23 1825 1.. 56 14 Continued Access There were no ruptures reported. Post-approval There has thus far been one rupture reported (the same patient died, as noted previously). Device Integrity Pivotal The percent of patients with device integrity findings at each follow-up time point based on the results from core lab analysis are presented in Table 9. Device integrity findings during follow-up included: stent fracture (4 patients), barb separation (18 patients), component separation (1 patient), and bare stent entanglement (1 patient). As indicated in the footnotes to the table, the need for associated reintervention was infrequent in patients with device integrity findings. Table 9: Percent of Patients with Device Integrity Findings Based on Core Lab Analysis (Date of First Occurrence) Time point Finding Predischarge 3 days 6 months 12 months 24 months 36 months 48 months 6 months Stent fracture (/152) (/136) (/127) (/124) 1. (1/1) c 1.1% (1/9) b 1.3% (1/75) h 1.5% (1/66) p Barb separation (/152) (/136) (/127).8% (1/124) i 4. (4/1) g,j,s,t 4.4% (4/9) d,e,k,q 6.8% (5/75) f,h,l,m,n 6.1 % (4/66) o,p,r,u Stent-tograft (/1) (/152) (/136) (/127) (/124) (/9) (/75) (/66) separation Component 1.1% (/1) separation (/152) (/136) (/127) (/124) (1/9) d (/75).7% Other (1/152) a (/1) (/136) (/127) (/124) (/9) (/75) a Patient 7124: Entanglement of neighboring struts of distal bare stent; finding not associated with migration, endoleak, increase in aneurysm size, or the need for secondary intervention. (/66) (/66)
Zenith TX2 TAA Endovascular Graft (P716) Page 15 Annual Clinical Update (216) b Patient 6111: Single stent fracture on proximal component not associated with endoleak, migration, or need for secondary intervention increase in aneurysm size noted at 6-month and 12-month follow-ups, but with no change in size at the 24-, 36-, 48-, and 6-month follow-up, as compared with baseline. c Patient 7127: Single stent fracture on distal component not associated with endoleak, increase in size, or need for secondary intervention caudal migration noted at 24-month follow-up, but of the proximal component; no migration of the distal component. d Patient 41218: Single barb separation on proximal component not associated with endoleak, increase in size, or requiring secondary intervention. Radiographic migration of proximal component noted at 24- month follow-up. Separation between proximal component and distal main body extension in the setting of aortic elongation, resulting in Type III endoleak requiring secondary intervention (additional main body component placement) following 48-month exam; separation first noted by core lab on 36-month exam. e Patient 25111: Single barb separation on proximal component not associated with migration, increase in size, or secondary intervention Type I endoleak noted on subsequent follow-up. [but at distal seal site, not the proximal seal site] f Patient 7121: Single barb separation on distal component not associated with endoleak, migration, increase in size, or need for secondary intervention. g Patient 261211: Single barb separation on proximal component patient previously underwent two secondary interventions for distal Type I endoleak and caudal migration of the proximal component was reported at 6-month follow-up. The patient was also noted to have an increase in aneurysm size at 12 months but the diameter at 6 months had not changed in size compared with 12 months. h Patient 36129: Single barb separation on proximal component and 2 fractures of distal stent on distal component not associated with increase in size or need for secondary intervention caudal migration of the proximal component had been noted at 12-month follow-up and a proximal Type I endoleak was noted at 48- and 6-month follow-ups (the core lab noted an inverted funnel-shaped proximal neck on preprocedure imaging, and device oversizing appeared insufficient relative to the location of actual graft placement). i Patient 9129: Single barb separation on proximal component not associated with endoleak, increase in size, or the need for secondary intervention caudal migration of the proximal component and cranial migration of the distal component noted at 24-month follow-up (the core lab noted an inverted funnelshaped proximal neck with circumferential thrombus and a funnel-shaped distal neck with circumferential thrombus on pre-procedure imaging). j Patient 41213: Single barb separation on distal component not associated with endoleak (Type IIb endoleak noted at pre-discharge, but not on subsequent follow-up.), migration, or need for secondary intervention increase in aneurysm size was noted at 6-month follow-up. k Patient 26129: Single barb separation on proximal component not associated with endoleak, migration, increase in size, or need for secondary intervention. l Patient 36126: Single barb separation on proximal component not associated with endoleak or increase in size (aneurysm size increase was noted at 24- and 36-month follow-ups, but no change from baseline size at 6-month follow-up, and a decrease in size compared to 24-month follow-up) caudal migration of proximal end and cranial migration of distal end noted at 48-month follow-up and a secondary intervention (placement of proximal and distal graft extensions) was performed between 48 and 6 months (the core lab noted an inverted funnel-shaped proximal neck and funnel-shaped distal neck on pre-procedure imaging, and device oversizing at the proximal end appeared insufficient relative to the location of actual graft placement). m Patient 41216: Single barb separation from proximal component not associated with endoleak, migration, increase in size, or need for secondary intervention. n Patient 9121: Single barb separation on distal component not associated with endoleak, migration, increase in size, or need for secondary intervention. o Patient 1111: Multiple (two) barb separations on proximal component not associated with endoleak, migration, increase in size, or need for secondary intervention. p Patient 9125: Multiple (three) barb separations and one stent fracture on distal component not associated with endoleak, migration, increase in size, or need for secondary intervention. q Patient 41121: Single barb separation on proximal component not associated with endoleak, migration, increase in size (aneurysm size increase was noted at 12-month follow-up, but no change from baseline size at 24-month follow-up and decreased from baseline size at 6-month follow-up), or need for secondary intervention (intervention was performed between 12 and 24 months to treat component separation that was not verified by core lab and persistent endoleak).
Zenith TX2 TAA Endovascular Graft (P716) Page 16 Annual Clinical Update (216) r Patient 23121: Single barb separation on proximal component not associated with endoleak, migration, increase in size, or need for secondary intervention. s Patient 311214: Single barb separation on proximal component not associated with endoleak, migration, increase in size, or need for secondary intervention. t Patient 261212: Single barb separation on proximal component not associated with endoleak, increase in size, or secondary intervention caudal migration of the proximal component was noted at 24 months. u Patient 11126: Multiple (two) barb separation on proximal component not associated with endoleak, migration, increase in size, or need for secondary intervention. Continued Access Device integrity observations by the core lab were as follows: stent fracture (n=2, one at 36 months and one at 48 months), and barb separation (n=5, three at 36 months and two at 48 months). One patient required a secondary intervention. Patient 4154 had multiple barb separations reported from the proximal component (at 36-month follow-up) and underwent a secondary intervention for caudal migration of the proximal component and Type I endoleak at 825 days following the procedure, in the setting of insufficient device oversizing relative to the location of actual graft placement. No size increase, further endoleak, or further migration was reported. While not requiring reintervention, Patient 411511 (with multiple barb separations and multiple fractures of the distal bare stent of the distal device component at 36 months) also had migration of the distal component at 24 months not associated with endoleak or an increase in aneurysm size. Patient 41153 (with multiple barb separations from the proximal component at 48 months) also had migration of the proximal component at 48 months not associated with endoleak, increase in size, or need for secondary intervention. Patient 31153 (with multiple barb separations from the distal component at 48 months) also had cranial migration of the distal component at 24 months as well as a distal Type I endoleak at 6 months and an increase in aneurysm size at 36 and 6 months, in the setting of aneurysmal enlargement of aorta distal to the study device, which per core laboratory assessment, advanced over time to include aorta surrounding the distal device component, but without the need for secondary intervention. Post-approval Device integrity observations by the core lab are as follows thus far: barb separation (n=8, one at 1-month, one at 12-months, one at 24-months, four at 36-months, and one at 48-months). No patients underwent a secondary intervention due to device integrityrelated observations. While not requiring reintervention, Patient 57184 (with barb separation at 12 months) also had migration at 6 months and a Type IIa endoleak with no aneurysm growth. Patient 47184 (with barb separation at 36 months) also had migration reported at 12 months, though there were no other associated findings such as endoleak or aneurysm growth. Patient 46183 (with barb separation at 36 months) also
Zenith TX2 TAA Endovascular Graft (P716) Page 17 Annual Clinical Update (216) had a distal Type I endoleak identified at 3 days and 6 months, though there was no associated aneurysm growth or migration. Migration Migration (radiographic) was defined as core laboratory determination, with CEC confirmation, of antegrade or retrograde movement of the proximal or distal components of the endoprosthesis > 1 mm relative to anatomical landmarks identified on the first post-operative CT scan, with clinically significant migration defined as migration resulting in the need for secondary intervention. Pivotal Table 1 reports the percent of patients with migration (clinically significant and radiographic) based on date of first occurrence. The CEC confirmed migration in 12 patients during follow-up (one of which was considered clinically significant). Inadequate aortic neck anatomy and/or insufficient device oversizing relative to the location of actual graft placement was often identified as a potential contributing factor in the patients with migration. Table 1: Percent of Patients with CEC-confirmed Migration (Date of First Occurrence) 6-12- 24-36- 48- Item 3-day month month month month month Clinically significant migration (/112) (/112) (/19) (/9) (/88) 6- month 1.4% (1/71) a (/64) Radiographic 1.8% 4.4% 1.1% 4.2% 1.6% migration (/112) (/112) (2/19) (4/9) (1/88) (3/71) (1/64) a Patient 36126: Caudal migration of proximal end and cranial migration of distal end not associated with endoleak or increase in size (aneurysm size increase was previously noted at 24- and 36-month follow-ups, but no change from baseline size at 48-month follow-up, and size had decreased compared with 24-month follow-up) secondary intervention was performed (placement of proximal and distal main body extensions). Continued Access Migration was noted as follows: clinically significant migration (n=1, at 24 months), radiographic migration (n=4, one at 12 months, two at 24 months, and one at 48 months). Patient 4154 (with clinically significant caudal migration of the proximal edge of the proximal component at 24 months) had site reported proximal Type I endoleak requiring secondary intervention (placement of a proximal main body extension); there was no associated increase in size. Insufficient device oversizing relative to the location of actual graft placement may have been a contributing factor to migration.
Zenith TX2 TAA Endovascular Graft (P716) Page 18 Annual Clinical Update (216) Post-approval Migration has been noted as follows thus far: clinically significant migration (n=1, at 12 months), radiographic migration (n=13, seven at 6-months, two at 12-months, two at 24-months, one at 36-months, and one at 48-months). Patient 32183 (with clinically significant migration at 12 months) underwent a secondary intervention 91 days postprocedure for a site-reported distal Type I endoleak. None of the other patients with radiographic migration underwent associated reintervention. Secondary Interventions Pivotal Eleven (6.9%) endovascular treatment patients (1 aneurysm, 1 ulcer) and 6 (8.6%) open surgical control patients (4 aneurysm, 2 ulcer) underwent at least one reintervention subsequent to the initial aneurysm/ulcer repair procedure. The site-reported reasons for reintervention are provided in Table 11. There were no cases of conversion to open surgical repair in the endovascular treatment group.
Zenith TX2 TAA Endovascular Graft (P716) Page 19 Annual Clinical Update (216) Table 11: Site-reported Reasons for Secondary Interventions Endovascular 31-366- 731-196- Reason (per site) -3 365 73 195 146 days days days days days 1461-1825 days -3 days 31-365 days Open Surgical 731-195 days 366-73 days 196-146 days Aneurysm rupture Component separation 2 a,b 1 o n/a n/a n/a n/a n/a n/a Symptoms 1 b 1 j 1 k Occlusion Device stenosis n/a n/a n/a n/a n/a n/a Device kink n/a n/a n/a n/a n/a n/a Device migration 1 p n/a n/a n/a n/a n/a n/a Infection Endoleak Proximal Type I Distal Type I Type IIa Type IIb Type III Type IV Unknown 3 1 d 1 e 1 f 2 c 2 c 1 b 1 b 1 i 1 i 1 o 1 o 1461-1825 days n/a n/a n/a n/a n/a n/a Other 3 g 1 h 3 j,l 2 k,m 1 n n/a not applicable. a Patient 361212: Aneurysm patient treated with placement of an additional proximal component for decreasing component overlap from device alignment with greater curve. b Patient 41121: Aneurysm patient with symptoms from Type III endoleak due to component separation treated with placement of additional main body components; retrospective review of procedural imaging suggests length of overlap achieved between components at time of initial deployment was less than minimum recommended amount. c Patient 261211: One aneurysm patient had two interventions for a distal Type I endoleak bare stent placement and stent placement/coil embolization/distal extension placement. d Patient 41216: Aneurysm patient treated with proximal main body extension placement. e Patient 41218: Aneurysm patient treated with molding balloon angioplasty and distal extension placement. f Patient 25121: Aneurysm patient underwent angiogram to rule out endoleak; no endoleak was detected and the endovascular graft was intact. g Includes one ulcer patient with iliac artery occlusion, treated with femoral-femoral bypass (6121); one aneurysm patient with size increase treated with distal extension placement in overlap and distal end of graft (9123); and one aneurysm patient who developed a pseudoaneurysm at follow-up, treated with proximal extension placement (15124). h Patient 9123: One aneurysm patient with size increase, treated with placement of additional endovascular graft components, who also underwent secondary intervention for increase at 31-365 days, as discussed in note g. i Patient 41214: Aneurysm patient treated with distal main body extension placement. j Patient 11141: One ulcer patient with multiple reasons (symptoms and other [continued bleeding]), treated with re-exploration and hemostatic sealing agents. k Patient 33142: Aneurysm patient who developed symptoms due to tracheal stoma bleeding was treated with sternotomy and patch repair. l Includes one aneurysm patient with intrapleural hematoma, treated with exploratory thoracotomy and evacuation (9139); one ulcer patient with bleeding and tamponade, treated with intercostal vessel ligation (14131).
Zenith TX2 TAA Endovascular Graft (P716) Page 2 Annual Clinical Update (216) m Patient 15131: One aneurysm patient who developed an aortoesophageal fistula at follow-up, treated with custom endograft placement. n Patient 9142: Aneurysm patient developed juxtarenal AAA and upstream thoracoabdominal aortic aneurysm and was treated with endograft placement extending from the prior proximal repair. o Patient 41218: Aneurysm patient with Type III endoleak in setting of aortic elongation, treated with placement of an additional proximal component to bridge the gap between the initial proximal component and a distal main body extension that had been placed in a previous secondary intervention at -3 days, as discussed in note e. p Patient 36126: Aneurysm patient who experienced caudal migration of proximal end and cranial migration of distal end, not associated with endoleak or increase in size (aneurysm size increase was noted at 24- and 36-month follow-ups, but no change from baseline size at 6-month follow-up, and size had decreased compared with 24-month follow-up) was treated with placement of proximal and distal main body extensions. Continued Access Two patients required a secondary intervention. Patient 4154 underwent placement of a proximal extension 825 days postprocedure to treat a site reported proximal Type I endoleak. Patient 32151 underwent placement of a proximal extension 385 days post-procedure to extend proximal coverage of the thoracic device during unrelated endovascular AAA repair. Post-approval There have been five secondary interventions reported thus far. Patient 32183 underwent distal extension placement for a site-reported distal Type I endoleak at 91 days post-procedure. Patient 491812 underwent proximal extension placement for site-reported proximal Type I endoleak at 119 days post-procedure. Patient 47188 underwent proximal extension placement for site-reported proximal Type I endoleak at 287 days post-procedure. Patient 41186R had a proximal extension placed for the site-reported reasons of unknown endoleak and enlarging aneurysm at 832 days post-procedure. Patient 4182R had a stent placed due to device kink at 1,421 days post-procedure.