Gender Disparities in Abdominal Aortic Aneurysm Treatment

Characterization of Human Aortic Anatomy Project A Critical Path Initiative Food and Drug Administration ELIGIBILITY FOR ENDOVASCULAR REPAIR OF SHORT NECK ABDOMINAL AORTIC ANEURYSMS Tina M. Morrison1, Clark A. Meyer1, Mark F. Fillinger2, Ron M. Fairman3, Marc H. Glickman4, Richard P. Cambria5, Mark A. Farber6, Thomas C. Naslund7, Peter S. Fail8, James R. Elmore9, Rodney A. White10; Carlo A. Dall Olmo11; David M. Williams12 1Center for Devices and Radiological Health, Food and Drug Administration, Silver Spring, MD; 2Dartmouth Hitchcock Medical Center, Lebanon, NH; 3University of Pennsylvania Medical Center, Philadelphia, PA; 4Sentara Norfolk General Hospital, Norfolk, VA; 5Massachusetts General Hospital, Boston, MA; 6University of North Carolina Medical Center, Chapel Hill, NC; 7Vanderbilt Medical Center, Nashville, TN; 8Cardiovascular Institute of the South, Houma, LA; 9Geisinger Medical Center, Danville, PA; 10Harbor UCLA Medical Center; Los Angeles, CA; 11Michigan Vascular Center, Flint, MI; 12University of Michigan Medical Center, Ann Arbor, MI

Background 200,000 people are diagnosed with an abdominal aortic aneurysms (AAA) annually. 25% women and 75% men CHAP studies to date indicate that, about 70% of AAA are infrarenal; 50% of women and 70% of men have suitable neck criteria for potentialtreatment with an endograft; The two main factors driving ineligibility are both infrarenal neck length and angulation; and Women are 8 times more likely to have an infrarenal neck length < 10 mm and angulation > 45o. 2 Stent Summit August 31, 2016

Objective To collect detailed, unadjusted 3D anatomic data from unbiased broad samples to better understand gender differences in anatomy for patients with short infrarenal neck lengths To understand ineligibility and identify gender disparities treatment options Medical Device Daily May 14, 2013 Women are less likely to be offered EVAR to correct an AAA, mainly because they have smaller arteries and the current endovascular devices are made to fit the male anatomy. -- Dr. Eva Rzucidlo, Dartmouth-Hitchcock Medical Center, Lebanon, NH 3 Stent Summit August 31, 2016

Methods We collected pre-operative CT scan data from eleven U.S. clinical centers that consecutivelysubmit their AAA cases to M2S, Inc. for 3D anatomical analysis. De-identified data were collected from time periods where all or nearly all cases were submitted, covering 7/96 to 11/12. Data were tested and found to be homogenous (p = NS). M2S Logo Cardiovascular Institute of the South, LA Dartmouth Hitchcock Medical Center, NH Geisinger Medical Center, PA Harbor UCLA Biomedical Research Center, CA Massachusetts General Hospital, MA Michigan Vascular Center, MI Sentara Norfolk General Hospital, VA University of North Carolina Medical Center, NC University of Michigan Medical Center, MI University of Pennsylvania Medical Center, PA Vanderbilt Medical Center, TN 4 Stent Summit August 31, 2016

Methods The CHAP database contains 14855 unique patients with a variety of untreated abdominal aortic pathologies. We filtered the database using anatomic criteria to isolate patients with short neck infrarenal aneurysms (snAAA): 1. Retained patients with AAA sac diameter 40 mm to eliminate non-aneurysm pathology. 9454 (65%) patients remaining 2. Retained patients with an infrarenal neck length < 10 mm based the shortest neck length criteria for endografts with 60o angulation. 3395 (36%) patients with AAA have short infrarenal neck 5 Stent Summit August 31, 2016

Methods 3. To further isolate the AAA to infrarenal snAAA, we retained patients with an infrarenal neck diameter 32 mm. 2837 (30%) patients remaining with short neck AAA 4. We retained the patients with snAAA that have moderate aortic tapering as defined by Infrarenal : Suprarenal diameter 1.1 Suprarenal : Infrarenal diameter 1.2 2343 (25%) patients remaining with short neck AAA In addition to the 25 standard anatomic parameters measured by M2S, Inc., we matched the most recent scan with the patient s year-of-birth and gender. 6 Stent Summit August 31, 2016

Methods The data were binned by gender and snAAA sac size in 5 mm increments for investigating ineligibility. Evaluated the anatomic data against the anatomic criteria for two commercially available endovascular grafts in the U.S. labeled for snAAA. Cook Trivascular Ovationb 2012 16-30 > 7 45c 8-20 14 Fenestrated 2012 19-31 4 45 c 7-21 23 Year of Release Neck diameter, mm Neck length, mm Infrarenal neck angulation, deg Iliac diameter, mm Smallest delivery system ODd Profile, Fr b Because the mid-line of the fill ring is 13 mm distal to the top of the graft, we also included a criteria that the diameter 15 mm below the renal artery 30 mm (for neck lengths < 15 mm) to ensure adequate sealing, which is a conservative estimate because we do not have the aortic diameter at 13 mm. c infrarenal and suprarenal, d outer diameter of sheath 7 Stent Summit August 31, 2016

Methods The non-parametric method Kolmogorov-Smirnov test was used to compare the distributions of each anatomic parameter between men and women. One way ANOVA model was used to compare the means of each anatomic parameter between men and women for the entire dataset and each of the binned categories of AAA size: anatomic variable = gender + error, where error is the random error following a normal distribution with mean of zero and a constant variance. 8 Stent Summit August 31, 2016

Results The anatomic criteria were analyzed in 2343 patients with untreated short neck infrarenal AAA (25% of infrarenal AAA). 1631 (70%) men and 712 (30%) women The ages (mean standard deviation and range) are: Men: 75 9 [49 92] years Women: 78 8 [53 93] years p < 0.0001. 9 Stent Summit August 31, 2016

Results Aortic anatomy for the 11-center snAAA patient cohort (percentiles) by gender M-W Women (n = 712, 30%) 10 25 50 67 73 78 Men (n = 1631,70%) 10 25 50 63 69 76 Difference 10 50 Percentile 75 83 90 87 75 82 90 86 90 Age -4 -2 -1 AAA Sac diameter 2 2 7 44 49 53 59 66 46 51 55 62 73 2 18 22 3 20 33 5 22 44 7 25 56 9 3 20 17 4 6 24 34 8 26 46 9 29 59 Infrarenal neck length Infrarenal neck diameter Infrarenal angle 1 2 -5 1 2 0 1 28 69 22 25 -10 -10 8 20 13 21 22 23 34 25 48 29 7 22 11 23 19 25 28 27 38 29 Suprarenal angle Suprarenal diameter (min) -1 2 -3 2 -10 0 Aortic diameter 15 mm below the renal arteries Diameter at aortic bifurcation Centerline path from renal arteries to aortic bifurcation 21 12 103 25 14 113 29 16 124 35 20 135 40 24 148 23 14 105 26 16 115 30 20 126 35 24 139 41 31 152 2 2 2 1 4 2 1 7 4 9 6 4 32 14 10 6 5 41 18 11 7 5 53 25 12 8 6 64 31 15 9 7 75 38 10 7 5 33 14 12 8 6 43 19 14 9 7 53 24 16 10 8 67 32 19 11 9 81 39 Common iliac diameter (ave) Femoral diameter (ave) Femoral diameter (min) Common iliac length Iliac Tortuosity 1 1 1 1 0 3 2 2 0 -1 4 2 2 6 1 10

Results While the suprarenal neck angulation is moderate, it is higher for women. The difference is more dramatic for the infrarenal neck angulation, a 10o difference. M-W Women (n = 712, 30%) 10 25 50 8 13 22 22 33 44 Men (n = 1631,70%) 10 25 50 7 11 19 17 25 34 Difference 50 -3 -10 Percentile 75 34 56 90 48 69 75 28 46 90 38 59 10 -1 -5 90 -10 -10 Suprarenal angle Infrarenal angle 11

Results The diameter at the aortic bifurcation is smaller for women. The length of the centerline path from the renal arteries to the aortic bifurcation was not noticeably different, as one would expect. M-W Women (n = 712, 30%) 10 25 50 12 14 16 103 113 124 135 148 105 115 126 139 152 Men (n = 1631,70%) 10 25 50 14 16 20 Difference 50 4 2 Percentile 75 20 90 24 75 24 90 31 10 2 2 90 7 4 Diameter at aortic bifurcation Centerline path from renal arteries to aortic bifurcation 14 18 25 31 38 14 19 24 32 39 0 -1 1 Iliac Tortuosity Index 12

Percent of patients eligible for on-label treatment with commercially available endografts 80% neck criteria only 70% Men, Cook Fenestrated Percent Eligible 60% 50% Women, Cook Fenestrated 40% 30% Men, Trivascular Ovation 20% 10% Women, Trivascular Ovation 0% [40-45) [45-50) [50-55) [55-60) [60-65) [65-70) [70-75) 75 snAAA Sac Diameter Ranges 13

35% of Men and 60% of Women with snAAA are ineligible for EVAR in the treatment range. 100% 90% 80% Percent Ineligible Women 70% 60% 50% Men 40% 30% 20% 10% 0% [40-45) [45-50) [50-55) [55-60) [60-65) [65-70) [70-75) 75 snAAA sac diameter 14

Reasons for Ineligibility Cook Fenestrated A majority of ineligibility is due to the angulation criteria of the infrarenal and suprarenal neck. Men Women Stent Summit August 31, 2016 15

Reasons for Ineligibility Trivascular Ovation A majority of ineligibility is due to the infrarenal neck length, and a combination of infrarenal neck angulation and length. Men Women Stent Summit August 31, 2016 16

Limitations We have excluded patients with an infrarenal neck length of 10-14 mm. This enabled us to focus on the critical anatomic issues, but lowered the denominator of patients with potential eligibility for devices that can treat an infrarenal neck < 15 mm. We solely examined ineligibility based on anatomic criteria of the instruction for use this does not necessarily reflect clinical practice or confer medical eligibility for the procedure. 17 Stent Summit August 31, 2016

Conclusions From a representative sample of the AAA population, we learned that 1/3 of patients have a short infrarenal neck. We further characterized the anatomy of those patients Clinically meaningful gender differences were noted in the angulation of the infrarenal and suprarenal neck, along with the diameter at the aortic bifurcation. Treating AAA below the standard threshold diameter would have a minor impact on eligibility. 18 Stent Summit August 31, 2016

Conclusions We compared the anatomic data of snAAA to the IFU criteria of commercially available endografts. For Cook Fenestrated, both suprarenal and infrarenal neck angulation are the driving factors for ineligibility. For Trivascular Ovation, it is a combination of infrarenal neck angulation and length that are the driving factors for ineligibility. At least 30% of Men and 60% of Women with snAAA are not eligible for EVAR with the current commercially available endografts at the current treatment threshold of 55 mm Ineligibility increases with larger size AAA 19 Stent Summit August 31, 2016

Acknowledgements M2S Logo http://www.sentara.com/SiteCollectionImages/Sentara/Layout/logo_banner.gif Contact: tina.morrison@fda.hhs.gov 20