NATIONAL INSTITUTE FOR HEALTH AND CARE EXCELLENCE GUIDANCE EXECUTIVE (GE)

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1 NATIONAL INSTITUTE FOR HEALTH AND CARE EXCELLENCE GUIDANCE EXECUTIVE (GE) Review of TA167; Endovascular stent-grafts for abdominal aortic aneurysms Final recommendation post consultation The guidance should be updated in an on-going clinical guideline. 1. Background This guidance was issued in February At the GE meeting of 18 August 2015 it was agreed that we would consult on the recommendations made in the GE proposal paper. A four week consultation has been conducted with consultees and commentators and the responses are presented below. 2. Proposal put to consultees and commentators The guidance should be updated in an on-going clinical guideline. 3. Rationale for selecting this proposal No new evidence has emerged that is expected to substantially change the recommendation in section 1.1. More experience with endovascular aortic stent grafts is now available which means that recommendations 1.2 and 1.3 could be further developed. More evidence has emerged that is relevant to recommendation 1.4. In order to develop up to date and consistent guidance, we propose that all recommendations are updated in the forthcoming clinical guideline on the diagnosis and management of abdominal aortic aneurysms. 4. Summary of consultee and commentator responses Page 1 of 13

2 Comments received in the course of consultations carried out by NICE are published in the interests of openness and transparency, and to promote understanding of how recommendations are developed. The comments are published as a record of the submissions that NICE has received, and are not endorsed by NICE, its officers or advisory committees. Respondent: Medtronic Response to proposal: Agree (with caveat) Medtronic support the proposal to supersede and update the TA167 recommendations into the forthcoming clinical guideline. However we wish it to be noted that we do have concerns that the removal of the mandated TA may impact patient access and politely request that audit measures or quality standards are concurrently developed to ensure patient access is not unduly impacted and objective measures are in place to monitor this access and unmet need. Medtronic look forward to offering input into the new guidelines and providing supporting clinical evidence related to Medtronic technologies where appropriate. Comment from Technology Appraisals Comment noted. NICE ensures that implementation issues are analysed and considered as an integral part of guideline development. NICE provides additional support for some guideline topics informed by priorities identified in the quality standards library and the selection of improvement areas within the quality standard development process. Respondent: Royal College of Surgeons Response to proposal: No comment We have passed this on to the Vascular Society. Comment from Technology Appraisals No action required Respondent: Royal College of Nursing Response to proposal: No comment Comment from Technology Appraisals No action required Page 2 of 13

3 Respondent: Endologix Response to proposal: We agree with the proposal to update the guidance based on the availability of new information relevant to the treatment of ruptured infrarenal abdominal aortic aneurysms. We agree with the statement made in section 7 regarding endovascular stent grafts for un-ruptured infra-renal aneurysm: there is no data to suggest that different brands of endovascular stent grafts should be considered separately. Further in section 7, several new brands that have been CE Marked since TA167 was first issued are identified, including Anaconda, Endurant, Ovation, InCraft, and Aptus. Two brands are excluded, and we request that these be added: o AFX Endovascular AAA System, CE Marked in 2011 o We note that the LEOPARD randomized trial was included in the list of registered clinical trials (page 11). o Nellix EndoVascular Aneurysm Sealing System, CE Marked in o We note that the Nellix registered clinical studies (NCT and NCT ) are not shown in the list of registered clinical trials (page 11); we request these are added. o In addition, peer-review publications (excluding case reports) are available for reference: 1. Böckler D, Holden A, Thompson M, et al. Multicenter Nellix EndoVascular Aneurysm Sealing system experience in aneurysm sac sealing. J Vasc Surg 2015; 62: Brownrigg JRW, de Bruin JL, Rossi L, et al. Endovascular aneurysm sealing for infrarenal abdominal aortic aneurysms: 30-day outcomes of 105 patients in a single centre. Eur J Vasc Endovasc Surg 2015:50; Carpenter JP, Cuff RF, Böckler D, et al. Thirty-day results of the pivotal trial of the Nellix System for endovascular aneurysm sealing (EVAS). J Vasc Surg 2015;61:8S (abstract). Accepted for publication. 4. D Abate F, Harrison SA, Karthikesalingam A, et al. Sonographic appearance following endovascular aneurysm repair using the Nellix endovascular sealing system. J Endovasc Ther 2015;22(2): Commentary: Holden A and Reijnen MP. J Endovasc Ther 2015; 22: Ezite N, Savlovskis J, Gedins M, et al. Duplex ultrasound versus computed tomography for follow-up of complications after EVAR with Nellix endograft: first clinical experience. Acta Chir Lat 2013;13: Hill A. Nellix EVAS: Early Results From the Forward Registry and Beyond. J Vasc Surg 2015;62: Holden A. Endovascular sac sealing concept: will the Endologix Nellix device solve the deficiencies? J Comment from Technology Appraisals Comments noted. NICE acknowledges that the 2 brands highlighted by Endologix were omitted from the table of new brands that have become available since TA167 in the review proposal paper (AFX Endovascular AAA System and Nellix EndoVascular Aneurysm Sealing System). It should be noted that the AFX Endovascular AAA System is described on page 10 of the review proposal paper. NICE also acknowledges that the Nellix registered clinical studies (NCT and NCT ) were omitted from the list of registered clinical trials (page 11). Thank you for bringing these to our attention. NICE considers that, in the absence of additional further evidence for clinical or cost effectiveness, the additional products and registered trials noted by Endologix would not have changed the recommendations of the review proposal paper to update the guidance in an on-going clinical guideline. The processes of the technology appraisals programme do not allow for combining with assessments in the interventional procedures programme. Consideration of efficacy and safety in the interventional Page 3 of 13

4 Cardiovasc Surg 2015;56: Karthikesalingam A, Cobb RJ, Khoury A, et al. The morphological applicability of a novel endovascular aneurysm sealing (EVAS) system (Nellix) in patients with abdominal aortic aneurysms. Eur J Vasc Endovasc Surg 2013;46(4): Commentary: Tshomba Y and Chiesa R. Commentary: Eur J Vasc Endovasc Surg 2013;46(4): Karthikesalingham A, de Bruin JL, Patel SR, et al. Appearance of the Nellix Endovascular Aneurysm Sealing System on computed tomography: implications for postoperative imaging surveillance. J Endovasc Ther 2015;22(3): Commentary: Holden A, Reijnen MP. J Endovasc Ther 2015; 22: McWilliams RG, Fisher RK, England A, and Torella F. Observations on surveillance imaging after endovascular sealing of abdominal aortic aneurysms with the Nellix System. J Endovasc Ther 2015; 22: Commentary: Holden A and Reijnen MP. J Endovasc Ther 2015; 22: Savlovskis J, Krievins D, de Vries JP, et al. Aortic neck enlargement after endovascular aneurysm repair using balloon-expandable versus self-expanding endografts. J Vasc Surg 2015 (e-published). 12. van den Ham LH, Zeebregts CJ, de Vries JP, and Reijnen MM. Abdominal aortic aneurysm repair using Nellix EndoVascular Aneurysm Sealing. Surg Technol Int 2015;26: In Appendix 1, the fourth option is stated as A review of the guidance should be combined with a new technology appraisal that has recently been referred to NICE. The review will be conducted through the MTA process. This option was not selected. We believe the in process assessment for endovascular aneurysm sealing (IP1283) should be combined with TA167, because IP1283 currently only includes the CE Marked Nellix EndoVascular Aneurysm Sealing System. The Nellix EndoVascular Aneurysm Sealing (EVAS) System is among a class of CE Marked medical devices intended for the endovascular repair of abdominal aortic aneurysm (AAA). Its intended patient population and mode of action in providing an endovascular conduit to prevent aneurysm rupture in appropriately selected patients is consistent with other endovascular repair devices included or proposed for inclusion under TA167. Note that Endologix completed patient enrollment in the Nellix US Investigational Device Exemption (IDE) pivotal trial and in the Global Post-market Registry in Both studies are registered under (NCT and NCT , respectively). o The primary safety endpoint results from the Nellix IDE Study are reported in a procedures programme occurs before a Technology Appraisal Programme can address the clinical and cost effectiveness. NICE has considered the availability of the additional highlighted products (including the Nellix EVAS System), and as noted above, we consider the recommendations of the review proposal paper to update the guidance in an on-going clinical guideline should still stand. The appropriateness of including the Nellix EVAS System in the ongoing clinical guideline will be considered separately within that programme. Page 4 of 13

5 manuscript accepted for publication in the Journal of Vascular Surgery see Appendix A at the end of this paper. o Presented results from the Nellix Global Registry are summarized in comparison to the published results from the ENGAGE and GREAT Registries (see Appendix). Note that the 1-year results of the Registry are intended for publication (manuscript in preparation). To illustrate the appropriateness for inclusion of the Nellix System in TA167 and the ongoing guideline, please see a comparative summary of the Indications for Use for the Nellix EVAS System and two other devices for which post-market registry data are available (Medtronic Endurant, ENGAGE Registry; Gore Excluder, GREAT Registry) below: Anatomical Dimension Nellix Indication Endurant Indication Excluder Indication Access vessel diameter Compatible with 17Fr outer profile Compatible with 18 to 20Fr outer profile Compatible with 18Fr introducer (inner profile) Infrarenal neck diameter 18 to 32mm 19 to 32mm 19 to 32mm Infrarenal neck length and angulation to the aneurysm sac 10mm with 60 (without significant calcium or thrombus) 10mm with 60 (without significant calcium or thrombus) 15mm with 75 (without significant calcium or thrombus) Suprarenal neck angulation (10mm neck length) 60 (15mm neck length) Common iliac artery diameter 9 to 35mm (lumen diameter) 8 to 25mm (vessel diameter) 15mm with 60 (without significant calcium or thrombus) to 25mm (vessel diameter) The Nellix EVAS System received marketing authorization in Europe in February 2013 based upon the 1-year results of a multicenter single arm clinical study with continuing post-market follow-up. Since that time, more than 3,000 patients have received the Nellix device in Europe and abroad. Likewise, all EVAR devices have received European marketing authorization based upon an initial single arm clinical study of Page 5 of 13

6 similar design and size with continuing follow-up. It is therefore appropriate to include the Nellix System in TA167 and the on-going guidance for endovascular repair of abdominal aortic aneurysm. Paper signed off by: Elisabeth George, 10 December 2015 Contributors to this paper: Technical Lead: Project Manager: Chris Chesters Andrew Kenyon Page 6 of 13

7 % Pts with Reintervention Appendix A additional evidence from Endologix In a published assessment, it has been reported that post-evar secondary intervention rates increase with time and with more hostile neck anatomy as encountered in clinical practice: 1 Secondary Intervention Rates Over Time: Favorable and Hostile Neck Anatomy 25 Favorable Anatomy Hostile Anatomy 20 20% 15 15% 12% % 5% 7% 6% 9% 8% 10% 10% 2.8% 0 1Mo 1Yr 2Yrs 3Yrs 4Yrs 5Yrs Among published 5-year reports of the European EVAR randomized trials and large observational studies of relatively unselected patients, secondary intervention rates of 13% to 26% are reported. This fairly consistent profile suggests that post-evar secondary intervention remains a considerable concern. 1 Stather PW, Sayers RD, Cheah A, et al. Outcomes in endovascular aneurysm repair in patients with hostile neck anatomy. Eur J Vasc Endovasc Surg 2012;44: Page 7 of 13

8 It is important to recognize that EVAR stent graft devices typically leave the aneurysm sac intact and therefore remain prone to type II endoleak from collateral vessels. In their long-term follow-up of EVAR patients, researchers in France determined that the presence of type II endoleak doubled the reintervention rate and led to sac expansion in 40% of patients as illustrated below. 2 Although endovascular intervention is routinely performed for type II endoleak with sac expansion, it does not appear to alter the rate of sac growth, and the majority of patients display persistent/recurrent endoleak. 3 This clinical problem of secondary interventions due to endoleaks of all kinds also translates to a significant economic problem for the healthcare system. 4 In a 5-year follow-up of post-placement costs, Noll and colleagues identified nearly a 5-fold increase in costs to the healthcare system when an endoleak is present post-evar. To address the continued unmet clinical need, the Nellix EVAS System was designed to seal the aneurysm sac from all forms of endoleak. When placed properly, the Polymer-filled Endobags consume the blood lumen space from the 2 El Batti S, Cochennec, F, Roudot-Thoraval F, Becquemin JP. Type II Endoleaks after endovascular repair of abdominal aortic aneurysm are not always a benign condition. J Vasc Surg 2013;57: Aziz A, Menias CO, Sanchez LA, et. al. Outcomes of percutaneous endovascular intervention for Type II endoleak with aneurysm expansion. J Vasc Surg 2012;55: Noll RE, Tonnessen BH, Mannava K, et al. Long-term postplacement cost after endovascular aneurysm repair. J Vasc Surg 2007;46:9-15. Page 8 of 13

9 infrarenal segment to the distal common iliac arteries, thereby minimizing the potential for failure modes leading to endoleak, including migration or lateral movement. CE Mark approval for the Nellix EVAS System was granted in February Following site selection, qualification, and ethics committee approvals, the EVAS Global Post-market Registry was initiated, enrolling 300 unselected (i.e., referred commonly to as real world ) patients at 18 sites in Europe and New Zealand. The 300-patient enrollment chart and top-level site enrollment information by country is shown below. Germany (5 sites): N=43 Latvia (1 site): N=10 Luxembourg (1 site): N=9 Netherlands (5 sites): N=90 New Zealand (1 site): N=38 Norway (1 site): N=5 UK (2 sites): N=98 Sweden (2 sites): N=7 After enrollment, patients are to be followed per the institutional standard of care at 30 days, 6 months, 1 year, and annually thereafter through 5 years. A Core Lab evaluates CT scans for evidence of endoleak of any type, stent fracture, migration, occlusion, or other device integrity issue. Adverse events are adjudicated by an independent assessor for analysis. Procedural outcomes and follow-up results to one year were presented at the 2015 Charing Cross (London, UK) meeting by Principal Investigator Matt Thompson, MD (St. George s Institute, London, UK). A broad array of aneurysm anatomies were treated, including those generally within the approved indications for use (Cohort 1, 64%), and those outside of the indications for use: Cohort 2 (short neck or highly angulated anatomies, 13%), Cohort 3 (juxtarenal/pararenal aneurysms, 12%), and Cohort 4 (failed EVAR repair; ruptured AAA repair; paraanastamotic aneurysm repair, 8.3%). For benchmarking purposes, the characteristics of patients enrolled with challenging anatomies in the Nellix EVAS Registry are compared to those in published post- Page 9 of 13

10 market registry studies (Endurant ENGAGE and Excluder GREAT Registries). 5,6 These are reasonable comparators because the Nellix, Endurant, and Excluder intended uses are all for the endovascular repair of AAA, and the indicated patient populations and mode of action to prevent aneurysm rupture are similar. This comparison suggests the Nellix Registry has a higher prevalence of patient anatomies treated that are outside of the approved IFU than the comparator Registries. The increasing anatomical challenge among Cohorts 1 to 3 in the Nellix Registry is further reflected in the baseline aneurysm characteristics, summarized below. Key procedural characteristics among Cohorts 1 to 3 are shown below. The overall data suggest predictable and favorable fluoroscopy and procedure times. As would be expected, the more complex repairs in Cohort 3 required more time. One 5 Stokmans RA, Teijink JA, Forbes TL, et al. Early results from the ENGAGE registry: real-world performance of the Endurant Stent Graft for endovascular AAA repair in 1262 patients. Eur J Vasc Endovasc Surg 2012;44: Verhoeven ELG, Katsargyris A, Bachoo P, et al. Real-world performance of the new C3 Gore Excluder stent graft: 1-year results from the European C3 module of the global registry for endovascular aortic treatment (GREAT). Eur J Vasc Endovasc Surg 2014;48: Cohort 4 is not included due to the severe departure in device use in treating ruptures and failed EVAR/surgical implants. Page 10 of 13

11 procedural conversion to open repair occurred in Cohort 3 (catheter retraction issue), resulting in a procedural technical success rate of 99.7%. This success rate is similar to that in ENGAGE (98.6%) and GREAT (99%). The incidence of protocol-defined major adverse events (MAEs) within 30 days and in follow-up >30 days to 1 year are show below. Three perioperative deaths were related to co-morbidities in this elderly patient population and were determined by the independent assessor to be not device-related. By way of comparison, the ENGAGE 30-day MAE rate is reported similarly as 3.9%. GREAT does not report events using a similar categorization. Despite the prevalence of high-risk enrolled patients, Nellix Registry patient follow-up to 1 year identifies Kaplan-Meier estimated freedom from all-cause mortality of 96%. This compares favorably with the corresponding results from the GREAT Registry (96%) and the ENGAGE Registry (92%). The Nellix freedom from aneurysm-related mortality at 1 year is 99%, similar to the comparator reported results (ENGAGE, 98.8%). Page 11 of 13

12 Core Lab assessment of 30-day CT scans identified no stent fracture or occlusion. Two patients (0.7%) were identified with type IA endoleak, both of which were attributed to procedural malplacement. No type II endoleak was observed. This total endoleak profile among a broad array of patient anatomies treated compares favorably with the rate for the reporting comparator (ENGAGE, 12% [1.5% type I or III, 11% type 2). The incidence of type I or III endoleak, occlusion, or implant compression/kinking/twisting at 30 days in the Nellix Registry and each comparator are shown in the table below, confirming the relative acceptability of the Nellix results. Core Lab Finding at 30 Days Nellix Registry [(n (%)] Comparison 1 (ENGAGE) Comparison 2 (GREAT) Occlusion/Stenosis 0 2.0%/1.4% 1.3% Endoleak Type I or III 2 (0.7%) 1.5% 1.0% Stent Graft Compression/Kinking/Twisting 0 1.7% 0.5% TOTAL 0.7% 3.2% 2.8% Endoleak: type 1=attachment point; 3=junctional separation or fabric hole/tear. Core Lab assessment at 1 year identified two Nellix patients (0.7%) with type IA endoleak, both of which were attributed to procedural malplacement in off-label anatomies. No type II endoleak was observed. A comparison to the outcomes among multiple devices (Cook Zenith, Medtronic Endurant, Lombard Aorfix, Gore Excluder, Cordis Incraft, and Trivascular Ovation) in selected patients enrolled in either US IDE or CE studies demonstrates a positive profile consistent with the 1- month outcomes: As illustrated below, the Nellix Registry 1-year freedom from secondary intervention for occlusion and endoleak is 99% and 96%, respectively. The overall freedom from any endovascular or surgical secondary intervention is 93%, consistent with the ENGAGE and GREAT Registry reported overall freedom from secondary intervention at 1 year (95%). It is noted that differing definitions for secondary intervention is used in the comparator reports. Page 12 of 13

13 These results in the Nellix EVAS System Registry are consistent with the comparator results, with low rates of endoleak and reintervention observed despite treating a broad range of patient anatomies. Page 13 of 13