614 Trans-Atlantic Debate

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1 614 Trans-Atlantic Debate differences between men and women undergoing revascularization or amputation for lower extremity peripheral arterial disease. J Vasc Surg 2014;59(2):409e Sonesson B, Lanne T, Vernersson E, Hansen F. Sex difference in the mechanical properties of the abdominal aorta in human beings. J Vasc Surg 1994;20(6):959e Brown LC, Powell JT. Risk factors for aneurysm rupture in patients kept under ultrasound surveillance. UK Small Aneurysm Trial Participants. Ann Surg 1999;230(3):289e Grootenboer N, van Sambeek MR, Arends LR, Hendriks JM, Hunink MG, Bosch JL. Systematic review and meta-analysis of sex differences in outcome after intervention for abdominal aortic aneurysm. Br J Surg 2010;97(8):1169e Lo RC, Bensley RP, Hamdan AD, Wyers M, Adams JE, Schermerhorn ML, et al. Gender differences in abdominal aortic aneurysm presentation, repair, and mortality in the Vascular Study Group of New England. J Vasc Surg 2013;57(5): 1261e8. 23 Dillavou ED, Muluk SC, Makaroun MS. A decade of change in abdominal aortic aneurysm repair in the United States: have we improved outcomes equally between men and women? J Vasc Surg 2006;43(2):230e8. 24 Huber TS, Wang JG, Derrow AE, Dame DA, Ozaki CK, Zelenock GB, et al. Experience in the United States with intact abdominal aortic aneurysm repair. J Vasc Surg 2001;33(2): 304e Lederle FA, Larson JC, Margolis KL, Allison MA, Freiberg MS, Cochrane BB, et al. Abdominal aortic aneurysm events in the women s health initiative: cohort study. BMJ 2008;337:a Mehta M, Byrne WJ, Robinson H, Roddy SP, Paty PS, Kreienberg PB, et al. Women derive less benefit from elective endovascular aneurysm repair than men. J Vasc Surg 2012;55(4):906e Hultgren R, Vishnevskaya L, Wahlgren CM. Women with abdominal aortic aneurysms have more extensive aortic neck pathology. Ann Vasc Surg 2013;27(5):547e De Rango P, Lenti M, Cieri E, Simonte G, Cao P, Richards T, et al. Association between sex and perioperative mortality following endovascular repair for ruptured abdominal aortic aneurysms. J Vasc Surg 2013;57(6):1684e Moise MA, Woo EY, Velazquez OC, Fairman RM, Golden MA, Mitchell ME, et al. Barriers to endovascular aortic aneurysm repair: past experience and implications for future device development. Vasc Endovascular Surg 2006;40(3):197e Fernandez JD, Craig JM, Garrett Jr HE, Burgar SR, Bush AJ. Endovascular management of iliac rupture during endovascular aneurysm repair. J Vasc Surg 2009;50(6):1293e9. 31 Schanzer A, Greenberg RK, Hevelone N, Robinson WP, Eslami MH, Goldberg RJ, et al. Predictors of abdominal aortic aneurysm sac enlargement after endovascular repair. Circulation 2011;123(24):2848e Sweet MP, Fillinger MF, Morrison TM, Abel D. The influence of gender and aortic aneurysm size on eligibility for endovascular abdominal aortic aneurysm repair. J Vasc Surg 2011;54(4): 931e7. 33 Vavra AK, Kibbe MR. Women and peripheral arterial disease. Womens Health (Lond Engl) 2009;5(6):669e83. * Corresponding author. -address: mkibbe@nmh.org (Melina R. Kibbe) /$ e see front matter Ó 2014 European Society for Vascular Surgery. Published by Elsevier Ltd. All rights reserved. Part Two: Against the Motion. Evidence Does Not Support Reducing the Threshold Diameter to 5 cm for Elective Interventions in Women with Abdominal Aortic Aneurysms M.J. Bown a, J.T. Powell b,* a Leicester Cardiovascular Biomedical Research Unit, University of Leicester, Leicester, UK b Department of Surgery and Cancer, Imperial College London, St. Dunstan s Road, London W6 8RP, UK.and I will do no harm or injustice to [my patients] Hippocratic Oath The management of patients with asymptomatic abdominal aortic aneurysms (AAAs) is focused on the avoidance of rupture, which is associated with very high mortality. Therefore decision-making must balance the risk of rupture against the risk of prophylactic surgery. Therefore, in order to correctly manage patients, it is essential to quantify these risks. Randomised trial evidence has demonstrated that there is no benefit in repairing AAAs <5.5 cm in diameter, either by open or endovascular means. 1 Although these trials were conducted in men and women, as in most other randomised trials in cardiovascular disease, women were under-represented. However, from the trial with the highest proportion of women, women appeared to be at increased risk of aneurysm rupture. 2 Recent evidence synthesis from the RESCAN project has confirmed the increased risk of rupture in women with small (<5.5 cm) AAA compared with men. 3 It is this finding that prompts the question of this debate: Should women be offered surgery at a lower AAA diameter threshold than men?. Answering this question requires knowledge of (i) the risk of AAA rupture at specific diameters; (ii) mortality after open and endovascular repair at specific aortic diameters; and (iii) the proportion of women anatomically suitable for endovascular repair and then must be set in the context of the proportion of women who are physiologically fit enough for any repair (Fig. 1).

2 European Journal of Vascular and Endovascular Surgery Volume 48 Issue 6 p. 611e619 December/ Figure 1. Simplistic model of clinical decision algorithm for women with small abdominal aoric aneurysms (AAAs). Data for operative mortality rates based on Mehta et al. and rupture/surveillance rates/times based on RESCAN data. 7,15 Note. OR ¼ open repair; EVAR ¼ endovascular aneurysm repair. EVIDENCE IS BASED ON EXTERNAL ANEURYSM DIAMETERS The majority of evidence about the size at which the repair of small AAAs (3.0e5.5 cm diameter in men and women) may be beneficial is based on the use of external diameter measurements, whether by ultrasonography or computerised tomography (CT). 1 The specification of how aneurysm diameter is measured is very important, but not always reported fully. 4 For the purposes of this debate, we define the reference diameter by anterioreposterior external diameters measured by ultrasonography. Equivalent CT diameters, which can be measured in other orientations, may be larger than the reference diameter, while internal diameters measured by ultrasonography will be smaller than the reference diameter by 0.3e0.5 cm. 5 Today, in some healthcare systems, it is becoming standard practice to use inner to inner or leading-edge to leading-edge measures for reporting AAA diameter: clinical decisions for patients based on such measurements should use intervention thresholds up to 0.5 cm smaller than external diameter thresholds. SEX-SPECIFIC RUPTURE RATES As the normal diameter of the aorta is smaller in women than in men, it might be anticipated that AAA rupture would occur at smaller aneurysm diameters in women. However, there is very little robust evidence regarding the diameter-specific rupture rates of small AAA in women. There are no large prospective studies of women with small AAAs with accurate ascertainment of cause of death. Brown et al. demonstrated a statistically nonsignificant fourfold higher risk of rupture for women with AAAs between 5.0 cm and 5.9 cm in diameter in a moderately sized prospective study. 6 The RESCAN data were gathered mainly from prospective observational studies, but similarly demonstrates that women with AAAs <5.5 cm in diameter have a fourfold higher rate of AAA rupture than men. 3 However, this is based on a small number of rupture events in both men (178 events in 13,728 patients) and women (49 events in 1,743 patients), 7 with 28 of the female ruptures occurring in 480 women from a single study. 8 In RESCAN, 7 women with AAAs between 5.0 cm and 5.5 cm in diameter had an annual risk of rupture of 2.97% (95% confidence interval [CI] 1.59e5.54). The same estimate for men was 0.64% (95% CI 0.43e0.95). These data suggest an increased rupture rate for women with AAAs of 5.0e5.5 cm in diameter but the limitations of these studies (owing to small numbers of events and hence lack of power) underline the need for actual evidence in this area. In addition, there is limited evidence that statins may reduce the risk of aneurysm

3 616 Trans-Atlantic Debate rupture but strong evidence that the prescribing of statins is lower in women than men. 9e12 SEX-SPECIFIC OPERATIVE MORTALITY RATES FOR ELECTIVE SURGERY Women undergoing elective aneurysm repair are older than men and most of the evidence suggests that they have worse operative and longer-term mortality rates than men after elective AAA repair. This is likely to be true for both open surgical repair and EVAR. For instance, for open repair, recent analyses of large-scale databases from the USA have shown that women (compared with men) have between a 1.3-fold to 2.0-fold increased 30-day mortality. 13 Similarly for endovascular repair, women have a 1.7- fold increase in 30-day mortality, with absolute risk increasing by up to 2.2%. These data are backed up by evidence from single-centre case series and meta-analyses of such series, which suggest that for open repair 30-day mortality rates in women are between 1.2-fold and 1.5- fold worse than in men, with an absolute risk increase of between 1.0% and 2.5%. 14,15 For endovascular repair, single-centre series suggest a 1.9e3.3-fold increased 30- day mortality risk in women. 13e16 Unpublished data from the EVAR 1 trial also showed that women had a 1.8- fold increase in 30-day mortality, although this narrowly failed to achieve statistical significance (p ¼.06). The perioperative risk assessment tool developed by Grant et al., 17 based upon a large series of AAA repairs from the UK, also shows twofold higher mortality for women undergoing both open and endovascular repair (C.N. McCollum, personal communication). The abovementioned data consider all patients undergoing AAA repair, both open and endovascular repair, irrespective of aneurysm size. Although some data indicate that patients with smaller AAAs have better perioperative outcomes and are more often suitable for EVAR, 18,19 therefore having lower short-term risk, this has not been demonstrated for women. Some indirect evidence exists from the four small aneurysm trials in which mortality according to categories of AAA diameter <5.5 cm is reported. In these studies the observed mortality rates for patients (men and women) with small AAAs do not appear to be significantly different from those observed in other studies of large AAAs. 1,14,20,21 SEX-SPECIFIC SUITABILITY FOR ELECTIVE ANEURYSM REPAIR Increasingly, there is reluctance to offer elective repair to patients considered to be at high risk of operative mortality. Both the physiological fitness and the aortic anatomy need to be considered. There is evidence to suggest that women are less likely to be anatomically suitable for endovascular aneurysm repair (EVAR) than men, independent of AAA size. 22 Case series demonstrate that the proportion of women who undergo EVAR is lower than men, 23,24 and while this is only a proxy for anatomical suitability, given the higher burden of cardiovascular and pulmonary disease in women, 25 it would be Figure 2. Best evidence available statistical simulation of short-/ medium-term outcomes (aneurysm-related mortality/rupture) in women with small (50 mm) AAAs based on best available evidence. Errors of estimates not shown and aneurysm-related postoperative events/mortality not included in endovascular aneurysm repair (EVAR) or open repair (OR) models owing to lack of data. expected that EVAR should be available to a higher proportion of women than men. Advances in endograft technology may enable EVAR to be used in a greater proportion of women than previously possible (and thus reduce overall short-term surgical mortality) 26 but there is no direct evidence of this effect at this point in time. Cardiovascular and pulmonary comorbidities are more prevalent in women than men with AAAs. 27e29 This is likely to influence both operative mortality and intervention rates. For elective surgery there is very limited evidence that nonintervention rates may be higher in women (partly owing to poor physiological fitness in women). 30 For emergency surgery, there is a strong bias against offering repair to women. 31 INTEGRATING THE EVIDENCE The balance of current evidence shows that women with small AAA are usually older than men with small AAAs and have an increase in both rupture risk and operative mortality risk after elective repair. A simulation of survival outcomes, based on the best available evidence at this time, suggests that for women with aneurysms of 5.0e5.5 cm in diameter (based on external aortic diameters) there is an early survival gain associated with surveillance rather than immediate repair (Fig. 2). Offering elective surgery to women with an AAAs between 5.0 cm and 5.5 cm in diameter might result in short-term harm. Therefore, there is no current evidence to support offering elective surgery to women with AAAs with external diameters of 5 cm. However, there is a clear need to integrate the available evidence into a better decision-making model. The modelling will be complex and include the physiological fitness of women with small AAAs, their anatomical suitability for EVAR, and nonintervention rates for both elective and emergency aneurysm repair.

4 European Journal of Vascular and Endovascular Surgery Volume 48 Issue 6 p. 611e619 December/ CONCLUSION It appears that any excess rupture risk in women (vs. men) with AAAs of 5.0e5.5 cm diameter is offset by an increase in operative mortality and therefore there is no convincing evidence or argument that women with 5-cm diameter aneurysms should be offered early elective repair. REFERENCES 1 Filardo G, Powell JT, Martinez MA, Ballard DJ. Surgery for small asymptomatic abdominal aortic aneurysms. Cochrane Database Syst Rev 2012;3:CD Brown LC, Powell JT. Risk factors for aneurysm rupture in patients kept under ultrasound surveillance. UK Small Aneurysm Trial Participants. Ann Surg 1999;230(3):289e96. 3 Sweeting MJ, Thompson SG, Brown LC, Powell JT. RESCAN Collaborators R. Meta-analysis of individual patient data to examine factors affecting growth and rupture of small abdominal aortic aneurysms. Br J Surg 2012;99(5):655e65. 4 Long A, Rouet L, Lindholt JS, Allaire E. Measuring the maximum diameter of native abdominal aortic aneurysms: review and critical analysis. Eur J Vasc Endovasc Surg 2012;43(5):515e24. 5 Hartshorne TC, McCollum CN, Earnshaw JJ, Morris J, Nasim A. Ultrasound measurement of aortic diameter in a national screening programme. Eur J Vasc Endovasc Surg 2011;42(2): 195e9. 6 Brown PM, Zelt DT, Sobolev B. The risk of rupture in untreated aneurysms: the impact of size, gender, and expansion rate. J Vasc Surg 2003;37(2):280e4. 7 Thompson S, Brown L, Sweeting M, Bown M, Kim L, Glover M, et al. Systematic review and meta-analysis of the growth and rupture rates of small abdominal aortic aneurysms: implications for surveillance intervals and their cost-effectiveness. Health Technol Assess 2013;17(41):1e Powell JT, Brown LC, Forbes JF, Fowkes FG, Greenhalgh RM, Ruckley CV, et al. Final 12-year follow-up of surgery versus surveillance in the UK Small Aneurysm Trial. Br J Surg 2007;94(6):702e8. 9 Cooper A, O Flynn N. Risk assessment and lipid modification for primary and secondary prevention of cardiovascular disease: summary of NICE guidance. BMJ 2008;336(7655):1246e8. 10 Majeed A, Moser K, Maxwell R. Age, sex and practice variations in the use of statins in general practice in England and Wales. J Public Health Med 2000;22(3):275e9. 11 Powell JT, Brown LC, Greenhalgh RM, Thompson SG. The rupture rate of large abdominal aortic aneurysms: is this modified by anatomical suitability for endovascular repair? Ann Surg 2008;247(1):173e9. 12 UK National Institute for Health and Clinical Excellence implementation report: statins for the prevention of cardiovascular events (web page). Available at: usingguidance/evaluationandreviewofniceimplementation evidenceernie/niceimplementationuptakecommissioned reports/nice_implementation_uptake commissioned_ reports.jsp?domedia¼1&mid¼919c0f1f-19b9-e0b5- D4FB02E142DE4F13 [accessed ]. 13 Egorova NN, Vouyouka AG, McKinsey JF, Faries PL, Kent KC, Moskowitz AJ, et al. Effect of gender on long-term survival after abdominal aortic aneurysm repair based on results from the Medicare national database. J Vasc Surg 2011;54(1):1e Grootenboer N, van Sambeek MR, Arends LR, Hendriks JM, Hunink MG, Bosch JL. Systematic review and meta-analysis of sex differences in outcome after intervention for abdominal aortic aneurysm. Br J Surg 2010;97(8):1169e Mehta M, Byrne WJ, Robinson H, Roddy SP, Paty PS, Kreienberg PB, et al. Women derive less benefit from elective endovascular aneurysm repair than men. J Vasc Surg 2012;55(4):906e Lo RC, Bensley RP, Hamdan AD, Wyers M, Adams JE, Schermerhorn ML, et al. Gender differences in abdominal aortic aneurysm presentation, repair, and mortality in the Vascular Study Group of New England. J Vasc Surg 2013;57(5): 1261e8. 17 Grant SW, Hickey GL, Grayson AD, Mitchell DC, McCollum CN. National risk prediction model for elective abdominal aortic aneurysm repair. Br J Surg 2013;100(5):645e Tsilimparis N, Mitakidou D, Hanack U, Deussing A, Yousefi S, Ruckert RI. Effect of preoperative aneurysm diameter on longterm survival after endovascular aortic aneurysm repair. Vasc Endovascular Surg 2012;46(7):530e5. 19 Keefer A, Hislop S, Singh MJ, Gillespie D, Illig KA. The influence of aneurysm size on anatomic suitability for endovascular repair. J Vasc Surg 2010;52(4):873e7. 20 Lederle FA, Wilson SE, Johnson GR, Reinke DB, Littooy FN, Acher CW, et al. Immediate repair compared with surveillance of small abdominal aortic aneurysms. N Engl J Med 2002;346(19):1437e Brady AR, Fowkes FG, Greenhalgh RM, Powell JT, Ruckley CV, Thompson SG. Risk factors for postoperative death following elective surgical repair of abdominal aortic aneurysm: results from the UK Small Aneurysm Trial. On behalf of the UK Small Aneurysm Trial participants. Br J Surg 2000;87(6):742e9. 22 Sweet MP, Fillinger MF, Morrison TM, Abel D. The influence of gender and aortic aneurysm size on eligibility for endovascular abdominal aortic aneurysm repair. J Vasc Surg 2011;54(4): 931e7. 23 Hultgren R, Vishnevskaya L, Wahlgren CM. Women with abdominal aortic aneurysms have more extensive aortic neck pathology. Ann Vasc Surg 2013;27(5):547e May J, White GH, Yu W, Waugh R, Stephen M, Harris JP. Concurrent comparison of endoluminal repair vs. no treatment for small abdominal aortic aneurysms. Eur J Vasc Endovasc Surg 1997;13(5):472e6. 25 Hultgren R, Granath F, Swedenborg J. Different disease profiles for women and men with abdominal aortic aneurysms. Eur J Vasc Endovasc Surg 2007;33(5):556e Bendermacher BL, Grootenboer N, Cuypers PW, Teijink JA, Van Sambeek MR. Influence of gender on EVAR outcomes with new low-profile devices. J Cardiovasc Surg (Torino) 2013;54(5):589e Derubertis BG, Trocciola SM, Ryer EJ, Pieracci FM, McKinsey JF, Faries PL, et al. Abdominal aortic aneurysm in women: prevalence, risk factors, and implications for screening. J Vasc Surg 2007;46(4):630e5. 28 Rodin MB, Daviglus ML, Wong GC, Liu K, Garside DB, Greenland P, et al. Middle age cardiovascular risk factors and abdominal aortic aneurysm in older age. Hypertension 2003;42(1):61e8. 29 Singh K, Bonaa KH, Jacobsen BK, Bjork L, Solberg S. Prevalence of and risk factors for abdominal aortic aneurysms in a population-based study: the Tromso Study. Am J Epidemiol 2001;154(3):236e Karthikesalingam A, Nicoli TK, Holt PJ, Hinchliffe RJ, Pasha N, Loftus IM, et al. The fate of patients referred to a specialist vascular unit with large infra-renal abdominal aortic aneurysms

5 618 Trans-Atlantic Debate over a two-year period. Eur J Vasc Endovasc Surg 2011;42(3): 295e Karthikesalingam A, Holt PJ, Vidal-Diez A, Ozdemir BA, Poloniecki JD, Hinchliffe RJ, et al. Mortality from ruptured abdominal aortic aneurysms: clinical lessons from a comparison of outcomes in England and the USA. Lancet 2014;383(9921):963e9. * Corresponding author. -address: j.powell@imperial.ac.uk (J.T. Powell) /$ e see front matter Ó 2014 European Society for Vascular Surgery. Published by Elsevier Ltd. All rights reserved. EDITORS COMMENT Trans-Atlantic Debate: Does Evidence Support Reducing the Threshold Diameter to 5 cm for Elective Interventions in Women With Abdominal Aortic Aneurysms? A.R. Naylor, Editor-in-Chief, European Journal of Vascular and Endovascular Surgery * Vascular Research Group, Division of Cardiovascular Sciences, Clinical Sciences Building, Leicester Royal Infirmary, Leicester LE27LX, UK T.L. Forbes, Associate Editor, Journal of Vascular Surgery Division of Vascular Surgery, London Health Sciences Centre & Western University, 800 Commissioners Road East, Room E2-119, London, ON N6A 5W9, Canada The evidence for reducing the diameter threshold for elective intervention in asymptomatic women with abdominal aortic aneurysms (AAAs) to 5.0 cm is that (i) women have significantly narrower aortas (compared with men), so that the diameter of an AAA requiring intervention should be smaller; (ii) comorbidities (risks) increase with age, meaning it is better to intervene at an earlier age (size) in order to reduce operative mortality; (iii) if rupture occurs, women face higher mortality rates than men; and (iv) data from randomised and nonrandomised studies suggest that women rupture their AAAs at slightly smaller diameters than men (5.0 cm). Advocates for reducing the diameter threshold to 5 cm concede that women incur higher perioperative mortality rates (compared with men), but that mortality rates after elective open repair (OR) or endovascular aneurysm repair (EVAR) are several magnitudes lower than the mortality associated with the treatment of ruptured AAA. Advocates for leaving diameter thresholds unchanged argue that while some of the points (raised above) have evidential support, there are important confounding issues: (i) women were under-represented in the trials, which were never powered to perform subgroup analyses regarding sex; (ii) data suggesting that women may be rupturing at slightly smaller aortic diameters are statistically weak (small number of events in a small number of patients) and might represent a type II statistical error; (iii) even if women did rupture at slightly smaller aortic diameters, any potential benefit through early intervention would be negated by the twofold excess mortality rate following elective EVAR or OR. So which side wins? One (undiscussed) issue remains the historical selection of 5.5 cm as the diameter threshold for intervening in the first place. The choice of 5.5 cm was not based upon science, but upon the equipoise of those surgeons who were prepared to randomise patients with AAAs of 5 cm, 5.5 cm, or 6.0 cm in diameter. At the time, the consensus was 5.5 cm, but this one size fits all measurement was never designed to deliver optimal diameter thresholds for men as opposed to women. Moreover, because some European and US guidelines now tacitly support consideration for elective interventions in women with 5.0e5.5-cm diameter AAAs, the vox populi interpretation is likely to be that this is reasonable. However, there are important caveats for those surgeons/ interventionists who advocate elective interventions in women with 5.0-cm AAAs. First, they need to be very clear about which diameter measurement method they are using. Those measuring inner-to-inner AAA diameter using ultrasound will document diameters 4e5 mm less than if the outer-to-outer measurement method is used. However, if computed tomography is used to measure an outer-to-outer diameter, this will then be 4e5 mm greater than the corresponding ultrasound measurement (and up to 1 cm greater than any inner-to-inner ultrasound-derived measurement). Second (and at the very least), there should be no talk of time bombs during the consent process, and women with 5-cm AAAs under consideration for surgery need to be informed about the underlying controversy. Put simply, there should be no rush towards performing EVAR/OR in women with 5-cm AAAs. Like it or not, they do face a higher morbidity/mortality (than men) and it is incumbent on the