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Abdominal aortic aneurysms in women
Abdominal aortic aneurysms in women Jean E. Starr, MD, FACS,a and Vivienne Halpern, MD, FACS,b Columbus, Ohio; and Phoenix, Ariz Abdominal aortic aneurysms have an incidence that is approximately four to six times higher in men than in women. However, the incidence in women also rises with older age, although starting later in life than in men. There are also sex differences in the risk of rupture and in outcomes after endovascular and open abdominal aortic aneurysm repair. Various explanations have been proposed. Women historically have been under-represented in clinical trials to evaluate the differences between the sexes. We present a review of current recommendations and recent literature to help identify some of these differences. (J Vasc Surg 2013;57:3S-10S.)
Abdominal aortic aneurysms (AAAs) are known to have an incidence that is approximately four to six times higher in men than in women. However, the incidence in women also rises with age, although starting later in life than in men. There are also sex differences in the risk of rupture and in outcomes after endovascular and open AAA repair. Here, we present a review of current recommendations and the literature to help identify some of these differences. PATHOPHYSIOLOGY OF SEX DIFFERENCES Some of the observed sex differences in AAA incidence may be related to the protective effects of estrogen against aneurysm development as well as the negative effects of testosterone on the aorta, as is supported by results in several animal models. McNulty et al1 demonstrated in 2004 that 17-b-estradiol slowed the development of angiotensin II-induced AAAs in apolipoprotein-deficient mice. Henriques et al2 similarly demonstrated that orchiectomy but not oophorectomy decreased aneurysm growth in the same model of AAA development. Ailawadi et al3 demonstrated that male rats developed larger AAAs than female rats in the elastase perfusion model of AAA. In addition, there was increased macrophage infiltration and levels of matrix metalloproteinase (MMP)-9, as evidenced by immunohistochemical staining and RNA expression in male vs female rats. More
From the Division of Vascular Diseases and Surgery, Department of Surgery, The Ohio State University College of Medicine and Wexner Medical Center, Columbusa; and the University of Arizona College of Medicine, Carl T. Hayden Phoenix VA Medical Center, Phoenix.b Author conflict of interest: none. Reprint requests: Jean E. Starr, MD, FACS, Associate Professor of Clinical Surgery, Division of Vascular Diseases and Surgery, Department of Surgery, The Ohio State University College of Medicine and Wexner Medical Center, 376 W 10th Ave, 701 Prior Hall, Columbus, OH 43210 (e-mail: [email protected]). The editors and reviewers of this article have no relevant financial relationships to disclose per the JVS policy that requires reviewers to decline review of any manuscript for which they may have a conflict of interest. 0741-5214/$36.00 Copyright Ó 2013 by the Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jvs.2012.08.125
interestingly, female rat aortas transplanted into male rats lost their resistance to aneurysm growth and were equivalent to control males. Female-to-female transplants retained the resistance to AAA development. Again, these differences were associated with differences in macrophage infiltration and MMP-9 levels. In addition, when 17-b-estradiol pellets were implanted in the necks of male rats, there was diminished growth of aneurysms, less elastin fragmentation, and diminished macrophage infiltration and MMP-9 levels.3 Further evidence was shown by Wu et al,4 who found that oophorectomized female rats had increased growth of AAAs in the elastase perfusion model compared with oophorectomized females and male rats who received 17-b-estradiol pellets. This was associated with increased levels of MMP-2 and MMP-9 expression.4 The role of testosterone in promoting aneurysm formation was further investigated by Henriques et al5 in 2008 in the angiotensin IIeinduced AAA model. They found that the aortic angiotensin II type A1 receptor was eight times more abundant in the abdominal aorta of male mice than in female mice. They demonstrated in orchiectomized males that the number of these receptors diminished but were restored by giving dihydrotestosterone (DHT) and that giving DHT increased the incidence of AAA formation in orchiectomized males as well as in females. To further this evidence, Cho et al6 demonstrated in 2009 that in orchiectomized male rats and oophorectomized female rats, the experimental male rats had a significantly decreased growth of aneurysm than did control males. There was no significant difference in the oophorectomized females compared with controls; however, the oophorectomized females who were given back estrogen, compared with those who were not, had a significant decrease in aortic growth. AAA growth increased in male rats that underwent orchiectomy and received testosterone pellets. Interestingly, when testosterone pellets were implanted in control male rats, there was a 30% increased incidence of rupture during the experiments compared with control male rats that were not given testosterone.6 The idea that estrogen may be protective is also supported in humans by the analysis by the 2008 Lederle et al7 data from the Women’s Health Initiative, which showed a lower incidence of AAA events (repairs and ruptures) in women taking hormone replacement therapy. 3S
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Interestingly, the evidence for testosterone causation in humans is not as clear. The only study to address this in humans was by Yeap et al8 in Australia. They found that lower free testosterone and higher luteinizing hormone levels were associated with increased AAA incidence in older men, which is contrary to the findings in the various animal models.8 All of these studies demonstrate that there is likely an aspect of hormonal regulation in the development of AAAs that could explain the sex differences, but the exact mechanisms are still unclear. Future studies are needed to further elucidate the exact nature the effect of sex hormones on AAA development. AAA SCREENING Current recommendations and prevalence. In February 2005, the United States Preventive Services Task Force (USPSTF) released its summary of recommendations for AAA screening.9 The summary of recommendations is listed in Table I, and the grade ranking and quality of evidence ratings are defined in Table II. The USPSTF recommended against routine screening in women because the prevalence of AAAs in women is very low and the number of deaths that could be prevented was small. It also suggested that the harm of routine screening outweighed the benefits due to the potential morbidity and mortality to women undergoing an increased number of surgeries for AAAs as well as psychologic harms incurred. The USPSTF noted that most AAA-related deaths occur in women aged >80 years and that screening would not be beneficial because of the increased concomitant risk factors at this age. Individualization of care, however, was still recommended. This issue of screening women for AAAs has not been readdressed since the USPSTF recommendations were released. The USPSTF recommendations were mostly based on a best-evidence systematic review.10 This document consisted of the review of only four population-based randomized, controlled trials of AAA screening, each with a different study design and with data collection mostly from men. The Multicentre Aneurysm Screening Study (MASS) dominated the pooled data over the other three studies due to the higher volume of patients enrolled. These trials were not conducted in the United States, so it is unclear how this may translate to United States populations. In addition, little specific information is available on racial and ethnic groups, age distributions, or women, except in isolated reports within the USPSTF recommendations. No physical harm from the ultrasound screenings was reported, and any psychologic or diminished general health perception did not last long. The question also arises regarding the accuracy of cause of death when information is obtained from death certificates. Personalized decision making regarding screening should take into account a patient’s individual risks as well as willingness to accept potential benefits and adverse effects. The United Kingdom Chichester study11 recruited 9342 women and 6433 men aged 65 to 80 years for AAA screening. AAA prevalence was six times lower in women
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than in men (1.3% vs 7.6%). The investigators recommended against screening for AAAs in women due to the low prevalence. Overall, 3052 women presented for screening because half were randomized to the control group of no screening. No reduction in AAA ruptures was found in the screened group at 5- and 10-year intervals; however, the denominator used for the screening group was all of those randomized to screening, including 1630 women who did not actually attend a screening. Also, at least partial data collection was from death certificates; therefore, cause-ofdeath determination may be inaccurate when based on official statistics and not on actual autopsy findings. The Stroke and Aneurysm Vascular Evaluation (SAVE) program (Medtronic Inc, Minneapolis, Minn) conducted a volunteer screening that was attended by 10,012 women and 7528 men. The results were evaluated by DeRubertis et al12 from New York Presbyterian Hospital. Although the AAA prevalence rate in women was confirmed to be lower (0.7% vs 3.9%), subgroups were identified that had elevated AAA rates. On the basis of these findings, screening for AAAs should be considered in women aged >65 years and women with a history or smoking or cardiovascular disease. Life Line Screening medical and lifestyle questionnaire and ultrasound imaging results from 2003 to 2008 were evaluated in 3.1 million patients.13 A scoring system to predict AAAs was created and was felt to identify AAAs more efficiently and include groups excluded from the USPSTF inclusion criteria for screening. This study estimated a national prevalence of 1.1 million AAAs (1.4% for those aged 50-84 years): 569,000 occurring in women, nonsmokers, and individuals aged <65 years. USPSTF criteria would identify only 29.5% of all AAAs due to the current selection criteria and does not identify AAAs in women, nonsmokers, and younger patients. The proposed scoring system would find 88.6% of AAAs in the group aged 50 to 84 years old. Although women represent only 20% of AAAs, they have demonstrated a three times higher rupture occurrence and a similar number of AAA deaths as men.14 This suggests that women are not being appropriately diagnosed or are not being offered AAA repair at a time when repair might be safer and effective at preventing rupture. Obviously, recognizing women at risk with improved and more efficacious screening methods would potentially help to decrease the morbidity and mortality from rupture and late identification. Risk factors and associations. Although one may not conclude that routine AAA screening should be instituted for all women according to prevalence alone, other considerations should be taken into account. Rupture rates are reportedly higher in women than in men. The United Kingdom Small Aneurysm Trial15 showed women had a threefold higher rupture rate than men, even after adjustment for age, initial AAA diameter, and body mass index or height. In addition, the mean diameter at rupture for women was 5.0 cm compared with an average diameter of 6.0 cm in men. This may be accounted for by differences in biomechanical properties of AAAs between men and
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Table I. United States Preventive Services Task Force (USPSTF) summary of recommendations for abdominal aortic aneurysm (AAA) screeninga USPSTF recommendation
Grade of recommendation
Quality of evidence
One-time screening for AAAs by ultrasound imaging in men aged 65 to 75 who have ever smoked No recommendation for or against screening for AAAs in men aged 65 to 75 who have never smoked No routine screening for AAAs in women
B
Fair
C
Fair
D
Fair
a
Available at http://www.uspreventiveservicestaskforce.org/uspstf05/aaascr/aaars.htm.
Table II. United States Preventive Services Task Force (USPSTF) grade definitions and quality of evidencea Variable Grade of definitionsb A: Strongly recommended B: Recommended C: No recommendation D: Not recommended I: Insufficient evidence to make a recommendation Quality of evidence Good Fair Poor
Definition The USPSTF strongly recommends that clinicians provide [the service] to eligible patients. The USPSTF found good evidence that [the service] improves important health outcomes and concludes that benefits substantially outweigh harms. The USPSTF recommends that clinicians provide [the service] to eligible patients. The USPSTF found at least fair evidence that [the service] improves important health outcomes and concludes that benefits outweigh harms. The USPSTF makes no recommendation for or against routine provision of [the service]. The USPSTF found at least fair evidence that [the service] can improve health outcomes but concludes that the balance of benefits and harms is too close to justify a general recommendation. The USPSTF recommends against routinely providing [the service] to asymptomatic patients. The USPSTF found at least fair evidence that [the service] is ineffective or that harms outweigh benefits. The USPSTF concludes that the evidence is insufficient to recommend for or against routinely providing [the service]. Evidence that the [service] is effective is lacking, of poor quality, or conflicting and the balance of benefits and harms cannot be determined. Evidence includes consistent results from well-designed, well-conducted studies in representative populations that directly assess effects on health outcomes. Evidence is sufficient to determine effects on health outcomes, but the strength of the evidence is limited by the number, quality, or consistency of the individual studies, generalizability to routine practice, or indirect nature of the evidence on health outcomes. Evidence is insufficient to assess the effects on health outcomes because of limited number or power of studies, important flaws in their design or conduct, gaps in the chain of evidence, or lack of information on important health outcomes.
a
Available at http://www.uspreventiveservicestaskforce.org/uspstf/gradespre.htm#brec. Applies to recommendations voted on by the USPSTF before May 2007.
b
women. Vande Geest et al16 demonstrated a trend toward a decrease in tensile strength in AAA wall specimens in women compared with those taken from men, although this was not statistically significant. It has also been suggested that baseline normal aortic diameter may be smaller in women than in men. The Tromso Study17 monitored 4265 men and women with normally sized aortas for the development of AAAs during a 7-year period. The maximal aortic diameter at baseline was 19.4 mm in women vs 21.8 mm in men. Men were noted to have a statistically significant higher risk of developing AAAs during the follow-up period. The greater aortic size at baseline was implicated in the future development of AAAs; however, the question remains if smaller AAAs in women have the same significance as larger AAAs in men. The Aneurysm Detection and Management (ADAM) Veterans Affairs (VA) Cooperative Study18 noted
female gender was associated with a 0.14-cm reduction in aortic diameter. This difference was small but did reach statistical significance. Aortic diameters at all levels were measured in 389 computed tomography scans reviewed at Northwestern.19 Diameters were a function of age, sex (with men having larger aortas), and body surface area. This may again raise the concern of waiting to repair AAAs in women until they reach the same average size of AAAs in men. In addition, women present at an older age than men with similarly sized small AAAs.20 This translates into women undergoing repair at an older age, with possible increased risks. The same group from Kingston, Ontario, Canada, examined the risk of rupture in untreated AAAs with attention to sex differences.21 Women had a four times higher risk of rupture than men with AAAs of 5.0 to 5.9 cm (3.9% vs 0.8%). This would support an earlier intervention
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approach for women with AAAs smaller than that in men and re-emphasizes the importance of including women in AAA screening programs. Aside from pure size indications for repair, other risk factors have been shown to be associated with AAA development, especially in women, and therefore have potential implications for favoring screening. The Women’s Health Initiative Study Group enrolled 161,808 postmenopausal women from 1993 to 1998 and monitored them until the end of the study in 2005.7 A total of 184 AAA events were found and were strongly associated with age and smoking. Height, hypertension, cholesterol-lowering treatment, coronary artery disease, and peripheral arterial disease also had positive but weaker associations. Hormone replacement and diabetes (previously reported to have a positive association in men) had a negative association in women. Powel and Norman,22 in an editorial response to the Women’s Health Initiative findings, pointed out that smoking became popular for women 3 decades after men, and therefore, we may just now be realizing the effects in women. This would suggest that screening for AAAs may now be justified in women who have smoked and that public health initiatives should be aimed at smoking cessation in women. The authors also suggest that estrogens may decrease the risk of AAA formation by reducing AAA MMP expression. Another proposed association in women with AAAs is cerebral vascular disease. The ADAM VA study screened 122,272 male and 3450 female veterans and found an incidence of 4.3% in men and 1.0% in women.23 The association of AAAs with cerebral vascular disease had been suggested previously but was confirmed in the larger ADAM study. Lastly, advancing age has been suggested as a risk factor for AAA development as well as rupture. A French study24 examined women from mutiplex AAA families and found that affected female relatives were significantly older at diagnosis and surgery than men. It was suggested that men and women in families with more than two people affected with AAAs should both undergo routine screening, although the women became affected 10 years later than the men. This may raise concerns for routine AAA repair in a population of advanced age with an increasing number of comorbidities. Cost-effectiveness. MASS conducted a randomized trial of screening vs nonscreening for AAAs and a subsequent 10-year follow-up analysis in 67,770 men.25 The mortality benefit seen in the early portion of the study continued throughout this latter portion, with a relative 48% risk reduction for AAA-related deaths. Cost-effectiveness also became more favorable over time. Attendance at screenings should be encouraged, with subsequent clinical follow-up in those found to have AAAs. Attention to a low operative mortality and morbidity was also emphasized. Unfortunately, no cost-effectiveness data are available for women in this study because none were screened. The cost-effectiveness analyses for the USPSTF26 included four studies that addressed appropriate economic
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evaluation. None of these (including MASS) addressed any cost-effectiveness for AAA screening specifically in women. Wanhainen et al,27 however, found 18 suitable studies with female-specific data that were appropriate for use in the Markov cohort simulation model, which has been used to evaluate the cost-effectiveness of AAA screening in men. They found the incremental cost-effectiveness ratio for AAA screening in women was similar to that found in men. This may show that the lower AAA prevalence rate in women is balanced by a higher rupture rate and that exclusion of women from routine AAA screenings is not justified. Society recommendations. Overall, ultrasound screening has been shown to reduce AAA-related mortality. The Society for Vascular Surgery has also recommended ultrasound screening for women aged >65 years who have smoked or have a family history of AAAs.28 The level of recommendation was strong, with moderate quality of evidence. Although surveillance was recommended for most patients with an aneurysm of 4.0 to 5.4 cm, women with a slightly smaller aneurysm of 5.0 to 5.4 cm should be considered for earlier repair. Lastly, the SVS Executive Summary recognized the need for further research in several areas, including screening for AAAs in women and minorities. It would seem reasonable for now to include women in screening efforts until more data become available to help define the future role of AAA screening in this group. AAAs in women clearly behave differently, and more information on the natural history of AAAs in women is needed because a paucity of data exists. ENDOVASCULAR AAA REPAIR OUTCOME A less invasive approach to AAA repair may prove to be a better option for women, especially those of advanced age with significant comorbidities. Unfortunately, fewer women undergo endovascular AAA repair (EVAR) than men, ranging from 12% to 26% in recent series.29-32 Analysis of the American College of Surgeons National Surgical Quality Improvement Program (NSQIP) data set of 3662 EVARs revealed that 17.7% were women.33 Although this type of study does not always lend itself to the evaluation of underlying contributing factors, the authors suggested that future studies should address aneurysm anatomic details. In addition, this deserves investigation to elucidate the reasons why more women do not undergo EVAR and why more women are likely to present more physically debilitated and with ruptured AAAs. The NSQIP data only reflect 30-day outcome, and therefore, longitudinal studies would be of importance to determine late outcome from EVAR in women. AAA neck configuration is the most common anatomic feature that prohibits aortic endograft placement. Women have been found to have narrower and shorter necks, as well as narrower iliac arteries with a higher calcification score.2 A review of selection criteria for the Zenith AAA endovascular graft (Cook Inc, Bloomington, Ind) revealed that in patients who did not qualify for EVAR, the unsuitability was due to the proximal neck anatomy in 88%;
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however, this was equally distributed between men and women.34 Inadequate neck length (15 mm) was the most common criterion within this group. Wolf et al31 also discovered that the mean diameters of the proximal neck, common iliac, and external iliac arteries were all smaller in women. In addition, the length of the proximal neck was shorter. One might conclude that a smaller proximal neck diameter might coincide with a smaller AAA diameter; however, at least two studies found that the AAA diameter between men and women undergoing EVAR was actually similar.29,31 Certainly, there are other factors that potentially contribute to women undergoing EVAR less frequently. As noted from screening studies, women who undergo EVAR tend to be older than men,29-31 and Becker et al32 reported that perioperative EVAR survivors were significantly younger, although this information was not stratified by sex. NSQIP data analysis33 also revealed that women had a higher incidence of five preoperative risk factors for morbidity and mortality, including emergency operation, functional dependence, recent weight loss, underweight status or morbid obesity, and severe chronic obstructive pulmonary disease. Women were confirmed to have a significantly higher rate of chronic obstructive pulmonary disease in the Wolf et al study.31 Assessment of actual EVAR procedures showed more procedures are aborted in women (16.7% vs 2.1%), but conversion to open repair was similar.35 Deployment success was also significantly higher in men than in women. Short-term outcome in those completing repair, however, was not significantly different, and there were similar early endoleak rates. There was a trend toward longer fluoroscopy times in women undergoing EVAR in the Mayo Clinic series.29 The Stanford group31 discovered a higher rate of intraoperative complications in women, mostly related to arterial access, with iliac avulsion and occlusion requiring more frequent arterial reconstruction. Despite this, they also determined that there was no difference between men and women in the rate of postoperative complications or death. During a 14-month mean follow-up, no genderrelated differences were noted in survival, endoleak rate, reintervention rate, or rate of change of AAA diameter or volume. Mathison et al35 also confirmed a lack of difference between men and women in perioperative mortality and major complication rates. The European Collaborators on Stent-Graft Techniques for AAA and Thoracic Aortic Aneurysm and Dissection Repair (EUROSTAR) data registry assessment of the early success rate of 1554 EVARs deemed female gender and age >70 years to be risk factors for primary endoleak.36 The Oschner Clinic group reviewed their experience with 101 men and 17 women undergoing EVAR37 and found a significantly longer length of procedure in women and a higher arterial dissection rate. Contrary to other reports, mortality and complication rates at 1 month were also higher in women. The NSQIP data set33 revealed that female gender was indeed an independent risk factor
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for length of stay, infection, wound complications, and postoperative transfusion. These data, however, do not assess intermediate-term or longer-term outcome. Data from the Nationwide Inpatient Sample (NIS)38 revealed that mortality was greater in women with intact AAAs undergoing EVAR and open repairs than in men. Few data exist to assess the long-term outcome of EVAR specifically in women. The Mayo Clinic series29 of 241 patients (12% women) found the postoperative outcomes at 2 years were similar between men and women, with a nonsignificant trend toward a higher rate of aortic neck dilatation in women. Men actually trended toward a lower limb patency rate. In contrast, a significantly higher graft limb occlusion rate occurred in women at 2 years in a Cleveland Clinic series.30 This was felt not to be related to iliac diameter but was potentially caused by intimal hyperplasia due to injury during deployment or to differences in thrombotic tendencies. They also discovered that although endoleak frequency and type were no different between men and women, sac shrinkage was more rapid at 2 years in women. ELECTIVE OPEN AAA REPAIR OUTCOME Similar to EVAR, sex differences seem to exist in patients undergoing elective open AAA repair. The Michigan inpatient database studied outcomes from 1980 to 1990 in 11,512 women and 29,846 men, aged $50 years, with a diagnosis of intact or ruptured AAA.39 Hospitalization for AAA was five times more common for men, and they were 1.8 times more likely to undergo surgery for intact AAAs than women. This and other differences prompted the authors to recommend a prospective study. There may also be a difference between the sexes in regard to demographics. The Canadian Society for Vascular Surgery Aneurysm Study Group examined the influence of gender on results of AAA repair.40 Women represented 19.7% of intact AAA repairs and were more likely to be older, have never smoked, have a positive family history of AAAs, and have a coexisting history of aortoiliac occlusive disease. Fewer women had electrocardiographic evidence of an old myocardial infarction or a history of femoral-popliteal aneurysms. The average AAA size in women was also smaller. These differences may help us identify and manage women with AAAs. Various studies have analyzed outcomes pertaining to the sexes. An NIS study reviewed 220,403 patient discharges and found women with an intact AAA had higher odds of inpatient death38; unfortunately, no explanation could be extracted from the data. A similar Centers for Medicare and Medicaid Services inpatient sample study sought to determine if outcomes have been equal between men and women.41 Although improvements have been made overall, increasing age, female sex, and open repair were predictors of elective and ruptured AAA repair mortality. Men were also more likely to be discharged to home. Speziale et al42 sought to identify factors that predicted postoperative renal failure. Female sex and a preoperative
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creatinine clearance of <40 mL/min were two predictive features. A Swedish single-center retrospective study found a higher standardized mortality ratio for women than for men, and thus, a shorter survival when compared with the age-matched general population.43 Similarly, another survival study discovered that the standardized mortality ratio was increased for both sexes after AAA repair compared with the general public, but the ratio was higher for women.44 This was felt to potentially be secondary to a higher aneurysm-related death in women. Long-term survival may also be worse in women than in men. Norman et al45 showed a worse 5-year survival in women than in men, but this was postulated to be due to greater cardiovascular morbidity in women. They acknowledged that women were also under-represented in statin trials, thereby resulting in this potentially protective drug being prescribed less frequently to women. There are studies, however, whose results have conflicted with those that showed worse outcome for women after elective AAA repair. One review of multiple population-based reports discovered there was indeed a discrepancy in results, with some studies showing similar perioperative mortality and others finding higher mortality for women undergoing elective AAA repair.46 In some studies, very low numbers of women were evaluated and treated. It was recommended that clinical research be pursued to determine sex-specific guidelines for the timing of AAA repair and why women undergo AAA repair less commonly. Starr et al47 found that the 5% perioperative death rate was similar for men and women. Men and women also possessed similar cardiac risks. RUPTURED OPEN AAA REPAIR OUTCOME Several reviews found women were less likely to undergo surgical treatment of ruptured AAAs.37,48-50 No unified explanation has been hypothesized. A review of the U.K. Lothian Surgical Audit database found women who were not operated on tended to be older, and older women (>60 years) were less likely to be offered repair or undergo repair.51 The diagnosis of ruptured AAAs in women may be delayed, leading to a late presentation for treatment and a more advanced, moribund state. Women’s overall health may also be inappropriately interpreted as worse than men, leading to repair being offered less frequently. However, gender was not found to influence perioperative mortality in men and women who had undergone surgery. The question still stands if a sex bias exists in selecting women for surgery. Women have been found to have worse outcomes after ruptured AAA repair. Total admissions for ruptured AAA repair for women are 40% that for men, but there has been an increase of 0.5% annually since 2005.45 Women tend to be underdiagnosed and undertreated, and this may account for the trend toward a worse prognosis for women with ruptured AAAs. The Centers for Medicare and Medicaid Services 10-year inpatient sample study showed the average ruptured AAA mortality rate was
higher in women (52.8% vs 44.2%).41 The rate of ruptured AAA repairs also decreased more in men than in women during the study period of 1994 to 2003. The NIS study, reviewed above for open AAA results, also examined the effect of gender on ruptured AAA outcomes from 2001 to 2004.38 Rupture was the indication for 17% of all aneurysm repairs and a higher percentage of women with AAAs presented with rupture than men. Unfortunately, this has not decreased over time. Women were less likely to undergo surgical repair of a ruptured AAA and also had higher inpatient mortality after repair. Again, due to the nature of this type of study, reasons for these differences could not be elicited. The Michigan inpatient database, previously reviewed for elective AAA repair, also found men were 1.4 times more likely than women to undergo open surgery for a ruptured AAA.39 Women had a 1.45 times greater chance than men of dying after surgery for a ruptured AAA. Another Canadian study of 3570 patients with ruptured AAAs, with 73% undergoing repair in Ontario, showed that men were significantly more likely to undergo repair than women (80% vs 58%).48 Women were significantly older than men, but the Charlson Comorbidity Index score was similar; therefore, the women were no sicker than the men. Men did receive care in higher-volume hospitals and in larger cities, implying a potential survival advantage. The Western Australia Health Services Research Database examined the results of ruptured AAAs in 648 men and 225 women; of whom, 37% of women and 63% of men underwent operation.49 Women were on average 6 years older than men when they presented with ruptured AAA. The overall mortality was 90% for women and 76% for men. Increased perioperative mortality in women was speculated to be related to advanced age.46 Despite the differences in immediate-term and shortterm mortality between men and women, long-term survival has been found to be comparable.40,51 Potential reasons for these differences have been given above. This supports the concept that intervening earlier and more frequently on women with ruptured AAAs may confer survival benefits in the short term and long term. CONCLUSIONS Although the actual underlying pathophysiologic mechanisms responsible for the difference in AAA prevalence in men vs women have not been determined, clearly, there are sex-specific risks that women possess. It is reasonable to recommend routine screening for women aged >65 years who have ever smoked or who have a family history of AAAs. Research shows that women undergo endovascular, open, and emergency AAA repair less frequently than men. Outcome results have varied, but some studies have shown that short-term and long-term results between men and women are similar, even though women present later and have a higher rupture rate. Certainly, focused sex-specific research is warranted to elucidate the reasons for differences between men and women and to attempt to provide the best medical care for everyone.
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AUTHOR CONTRIBUTIONS Conception and design: JS, VH Analysis and interpretation: JS, VH Data collection: JS, VH Writing the article: JS, VH Critical revision of the article: JS, VH Final approval of the article: JS, VH Statistical analysis: Not applicable Obtained funding: Not applicable Overall responsibility: JS, VH REFERENCES 1. McNulty BM, Tham DM, Cunha VD, da Cunha V, Ho JJ, Wilson DW, et al. 17-b-estradiol attenuates development of angiotensin II-induced abdominal aortic aneurysms in apolipoprotein Edeficient mice. Atheroscler Thromb Vasc Biol 2003;23:1627-32. 2. Henriques TA, Huang J, D’Souza SS, Daugherty A, Cassis LA. Orchidectomy, but not ovariectomy, regulates angiotensin II-induced vascular diseases in apolipoprotein E-deficient mice. Endocrinology 2004;145:3866-72. 3. Ailawadi G, Eliason JL, Roelofs KJ, Sinha I, Hannawa KK, Kaldjian EP, et al. Gender differences in experimental aortic aneurysm formation. Atheroscl Thromb Vasc Biol 2004;24:2116-22. 4. Wu XF, Zhang J, Paskauskas S, Xin SJ, Duan ZQ. The role of estrogen in the formation of experimental abdominal aortic aneurysms. Am J Surg 2009;197:49-54. 5. Henriques T, Zuang X, Yiannikouris FB, Daugherty A, Cassis LA. Androgen increases ATIa1 receptor expression in abdominal aortas to promote Angiotensin II-induced AAAs in apolipoprotein E deficient mice. Atheroscler Thromb Vasc Biol 2008;28:1251-6. 6. Cho BS, Woodrum DT, Roelofs KJ, Stanley JC, Henke PK, Upchurch GR Jr. Differential regulation of aortic growth in male and female rodents is associated with AAA development. J Surg Res 2009;155:330-8. 7. Lederle FA, Larson JC, Margolis KL, Allison MA, Freiberg MS, Cochrane BB, et al; Women’s Health Initiative Cohort Study. Abdominal aortic aneurysm events in the women’s health initiative: cohort study. BMJ 2008;337:a1724. 8. Yeap BB, Hyde Z, Norman PE, Chubb SA, Golledge J. Association of total testosterone, sex hormone-binding globulin, calculated free testosterone and luteinizing hormone with prevalence of abdominal aortic aneurysms in older men. J Clin Endocrinal Metab 2010;95:1123-30. 9. U.S. Preventive Services Task Force. Screening for abdominal aortic aneurysm recommendation statement. Ann Intern Med 2005;142: 198-202. 10. Fleming C, Whitlock EP, Beil TL, Lederle FA. Screening for abdominal aortic aneurysm: a best-evidence systematic review for the U.S. Preventive Services Task Force. Ann Intern Med 2005;142: 203-11. 11. Scott RA, Bridgewater SG, Ashton HA. Randomized clinical trial of screening for abdominal aortic aneurysm in women. Br J Surg 2002;89: 283-5. 12. 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;46:630-5. 13. Kent KC, Zwolak RM, Egorova NN, Riles TS, Manganaro A, Moskowitz AJ, et al. Analysis of risk factors for abdominal aortic aneurysm in a cohort of more than 3 million individuals. J Vasc Surg 2010;52:539-48. 14. Vouyouka AG, Kent KC. Arterial vascular disease in women. J Vasc Surg 2007;46:1295-302. 15. Brown L, Powell JT; U.K. Small Aneurysm Trial Participants. Risk factors for aneurysm rupture in patients kept under ultrasound surveillance. Ann Surg 1999;230:289-97. 16. Vande Geest JP, Dillavou ED, Di Martino ES, Oberdier M, Bohra A, Makaroun MS, et al. Gender-related differences in the tensile strength of abdominal aortic aneurysm. Ann N Y Acad Sci 2006;1085:400-2.
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17. Solberg S, Forsdahl SH, Singh K, Jacobsen BK. Diameter of the infrarenal aorta as a risk factor for abdominal aortic aneurysm: the Tromso study, 1994-2001. Eur J Vasc Endovasc Surg 2010;39: 280-4. 18. Lederle FA, Johnson GR, Wilson SE, Gordon IL, Chute EP, Littooy FN, et al. Relationship of age, gender, race, and body size to infrarenal aortic diameter. The Aneurysm Detection and Management (ADAM) Veterans Affairs Cooperative Study Investigators. J Vasc Surg 1997;26:595-601. 19. Pearce WH, Slaughter MS, LeMaire S, Salyapongse AN, Feinglass J, McCarthy WJ, et al. Aortic diameter as a function of age, gender, and body surface area. Surgery 1993;114:691-7. 20. Brown PM, Sobolev B, Zelt DT. Selective management of abdominal aortic aneurysms smaller than 5.0 cm in a prospective sizing program with gender specific analysis. J Vasc Surg 2003;38:762-5. 21. 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;37:280-4. 22. Powell JT, Norman PE. Abdominal aortic aneurysm events in postmenopausal women [editorial]. Br Med J 2008;337:a1894. 23. Lederle FA, Johnson GR, Wilson SE. Aneurysm Detection and Management Veterans Affairs Cooperative Study. Abdominal aortic aneurysm in women. J Vasc Surg 2001;34:122-6. 24. Le Hello C, Koskas F, Cluzel P, Tazi Z, Gallos C, Piette JC, et al. Association Universitaire pour la Recherche en Chirurgie. French women from multiplex abdominal aortic aneurysm families should be screened. Ann Surg 2005;242:739-44. 25. Thompson SG, Ashton HA, Gao L, Scott RA. Screening men for abdominal aortic aneurysm: 10 year mortality and cost effectiveness results from the randomized Multicentre Aneurysm Screening Study. Br Med J 2009;338:b2185. 26. Meenan RT, Fleming C, Whitlock EP, Beil TL, Smith P. Costeffectiveness analyses of population-based screening for abdominal aortic aneurysm: evidence synthesis. AHRQ Publication No. 05-0569-C, February 2005. Available at: http://www.uspreventiveservicestaskforce. org/uspstf05/aaascr/aaacost.htm. 27. Wanhainen A, Lundkvist J, Bergqvist D, Björck M. Cost-effectiveness of screening women for abdominal aortic aneurysm. J Vasc Surg 2006;43:908-14; discussion 914. 28. Chaikof EL, Brewster DC, Dalman RL, Makaroun MS, Illig KA, Sicard GA, et al. SVS practice guidelines for the care of patients with an abdominal aortic aneurysm: executive summary. J Vasc Surg 2009;50: 880-96. 29. Sampaio SM, Panneton JM, Mozes GI, Andrews JC, Noel AA, Karla M, et al. Endovascular abdominal aortic aneurysm repair: does gender matter? Ann Vasc Surg 2004;18:653-60. 30. Ouriel K, Greenberg RK, Clair DG, O’hara PJ, Srivastava SD, Lyden SP, et al. Endovascular aneurysm repair: gender-specific results. J Vasc Surg 2003;38:93-8. 31. Wolf YG, Arko FR, Hill BB, Olcott C 4th, Harris EJ Jr, Fogarty TJ, et al. Gender differences in endovascular abdominal aortic aneurysm repair with the AneuRx stent graft. J Vasc Surg 2002;35:882-6. 32. Becker GJ, Kovacs M, Mathison MN, Katzen BT, Benenati JF, Zemel G, et al. Risk stratification and outcomes of transluminal endografting for abdominal aortic aneurysm: 7-year experience and long-term follow-up. J Vasc Interv Radiol 2001;12:1033-46. 33. Abedi NN, Davenport DL, Xenos E, Sorial E, Minion DJ, Endean ED. Gender and 30-day outcome in patients undergoing endovascular aneurysm repair (EVAR): an analysis using the ACS NSQIP dataset. J Vasc Surg 2009;50:486-91. 34. Simons P, van Overhagen H, Nawijn A, Bruijninckx B, Knippenberg B. Endovascular aneurysm repair with a bifurcated endovascular graft at a primary referral center: influence of experience, age, gender, and aneurysm size on suitability. J Vasc Surg 2003;38:758-61. 35. Mathison M, Becker GJ, Katzen BT, Benenati JF, Zemel G, Powell A, et al. The influence of female gender on the outcome of endovascular abdominal aortic aneurysm repair. J Vasc Interv Radiol 2001;12: 1047-51. 36. Buth J, Laheij RJ. Early complications and endoleaks after endovascular abdominal aortic aneurysm repair: report of a multicenter study. J Vasc Surg 2000;31:134-46.
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37. Nordness PJ, Carter G, Tonnessen B, Charles Sternbergh W 3rd, Money SR. The effect of gender on early and intermediate results of endovascular aneurysm repair. Ann Vasc Surg 2003;17:615-21. 38. McPhee JT, Hill JS, Eslami MH. The impact of gender on presentation, therapy, and mortality of abdominal aortic aneurysm in the United States, 2001-2004. J Vasc Surg 2007;45:891-9. 39. Katz DJ, Stanley JC, Zelenock GB. Gender differences in abdominal aortic aneurysm prevalence, treatment, and outcome. J Vasc Surg 1997;25:561-8. 40. Johnston KW. Influence of sex on the results of abdominal aortic aneurysm repair. Canadian Society for Vascular Surgery Aneurysm Study Group. J Vasc Surg 1994;20:914-23; discussion 923-6. 41. 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;43:230-8; discussion 238. 42. Speziale F, Ruggiero M, Sbarigia E, Marino M, Menna D. Factors influencing outcome after open surgical repair of juxtarenal abdominal aortic aneurysms. Vascular 2010;18:141-6. 43. Stenbaek J, Granath F, Swedenborg J. Outcome after abdominal aortic aneurysm repair. Difference between men and women. Eur J Vasc Endovasc Surg 2004;28:47-51. 44. Hultgren R, Granath F, Swedenborg J. Different disease profiles for women and men with abdominal aortic aneurysms. Eur J Vasc Endovasc Surg 2007;33:556-60.
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45. Norman PE, Powell JT. Abdominal aortic aneurysm: the prognosis in women is worse than in men. Circulation 2007;115:2865-9. 46. Harthun NL, Cheanvechai V, Graham LM, Freischlag JA, Gahtan V. Prevalence of abdominal aortic aneurysm and repair outcomes on the basis of patient sex: should the timing of intervention be the same? J Thorac Cardiovasc Surg 2004;127:325-8. 47. Starr JE, Hertzer NR, Mascha EJ, O’Hara PJ, Krajewski LP, Sullivan TM, et al. Influence of gender on cardiac risk and survival in patients with infrarenal aortic aneurysms. J Vasc Surg 1996;23:870-80. 48. Dueck AD, Johnston KW, Alter D, Laupacis A, Kucey DS. Predictors of repair and effect of gender on treatment of ruptured abdominal aortic aneurysm. J Vasc Surg 2004;39:784-7. 49. Semmens JB, Norman PE, Lawrence-Brown MMD, Holman CDA. Influence of gender on outcome from ruptured abdominal aortic aneurysm. Br J Surg 2000;87:191-4. 50. Filipovic M, Seagroatt V, Goldacre MJ. Differences between women and men in surgical treatment and case fatality rates for ruptured aortic abdominal aneurysm in England. Br J Surg 2007;94:1096-9. 51. Evans SM, Adam DJ, Bradbury AW. The influence of gender on outcome after ruptured abdominal aortic aneurysm. J Vasc Surg 2000;32:258-62.
Submitted Mar 23, 2012; accepted Aug 25, 2012.
Abdominal aortic aneurysms (AAAs) are known to have an incidence that is approximately four to six times higher in men than in women. However, the incidence in women also rises with age, although starting later in life than in men. There are also sex differences in the risk of rupture and in outcomes after endovascular and open AAA repair. Here, we present a review of current recommendations and the literature to help identify some of these differences. PATHOPHYSIOLOGY OF SEX DIFFERENCES Some of the observed sex differences in AAA incidence may be related to the protective effects of estrogen against aneurysm development as well as the negative effects of testosterone on the aorta, as is supported by results in several animal models. McNulty et al1 demonstrated in 2004 that 17-b-estradiol slowed the development of angiotensin II-induced AAAs in apolipoprotein-deficient mice. Henriques et al2 similarly demonstrated that orchiectomy but not oophorectomy decreased aneurysm growth in the same model of AAA development. Ailawadi et al3 demonstrated that male rats developed larger AAAs than female rats in the elastase perfusion model of AAA. In addition, there was increased macrophage infiltration and levels of matrix metalloproteinase (MMP)-9, as evidenced by immunohistochemical staining and RNA expression in male vs female rats. More
From the Division of Vascular Diseases and Surgery, Department of Surgery, The Ohio State University College of Medicine and Wexner Medical Center, Columbusa; and the University of Arizona College of Medicine, Carl T. Hayden Phoenix VA Medical Center, Phoenix.b Author conflict of interest: none. Reprint requests: Jean E. Starr, MD, FACS, Associate Professor of Clinical Surgery, Division of Vascular Diseases and Surgery, Department of Surgery, The Ohio State University College of Medicine and Wexner Medical Center, 376 W 10th Ave, 701 Prior Hall, Columbus, OH 43210 (e-mail: [email protected]). The editors and reviewers of this article have no relevant financial relationships to disclose per the JVS policy that requires reviewers to decline review of any manuscript for which they may have a conflict of interest. 0741-5214/$36.00 Copyright Ó 2013 by the Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jvs.2012.08.125
interestingly, female rat aortas transplanted into male rats lost their resistance to aneurysm growth and were equivalent to control males. Female-to-female transplants retained the resistance to AAA development. Again, these differences were associated with differences in macrophage infiltration and MMP-9 levels. In addition, when 17-b-estradiol pellets were implanted in the necks of male rats, there was diminished growth of aneurysms, less elastin fragmentation, and diminished macrophage infiltration and MMP-9 levels.3 Further evidence was shown by Wu et al,4 who found that oophorectomized female rats had increased growth of AAAs in the elastase perfusion model compared with oophorectomized females and male rats who received 17-b-estradiol pellets. This was associated with increased levels of MMP-2 and MMP-9 expression.4 The role of testosterone in promoting aneurysm formation was further investigated by Henriques et al5 in 2008 in the angiotensin IIeinduced AAA model. They found that the aortic angiotensin II type A1 receptor was eight times more abundant in the abdominal aorta of male mice than in female mice. They demonstrated in orchiectomized males that the number of these receptors diminished but were restored by giving dihydrotestosterone (DHT) and that giving DHT increased the incidence of AAA formation in orchiectomized males as well as in females. To further this evidence, Cho et al6 demonstrated in 2009 that in orchiectomized male rats and oophorectomized female rats, the experimental male rats had a significantly decreased growth of aneurysm than did control males. There was no significant difference in the oophorectomized females compared with controls; however, the oophorectomized females who were given back estrogen, compared with those who were not, had a significant decrease in aortic growth. AAA growth increased in male rats that underwent orchiectomy and received testosterone pellets. Interestingly, when testosterone pellets were implanted in control male rats, there was a 30% increased incidence of rupture during the experiments compared with control male rats that were not given testosterone.6 The idea that estrogen may be protective is also supported in humans by the analysis by the 2008 Lederle et al7 data from the Women’s Health Initiative, which showed a lower incidence of AAA events (repairs and ruptures) in women taking hormone replacement therapy. 3S
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Interestingly, the evidence for testosterone causation in humans is not as clear. The only study to address this in humans was by Yeap et al8 in Australia. They found that lower free testosterone and higher luteinizing hormone levels were associated with increased AAA incidence in older men, which is contrary to the findings in the various animal models.8 All of these studies demonstrate that there is likely an aspect of hormonal regulation in the development of AAAs that could explain the sex differences, but the exact mechanisms are still unclear. Future studies are needed to further elucidate the exact nature the effect of sex hormones on AAA development. AAA SCREENING Current recommendations and prevalence. In February 2005, the United States Preventive Services Task Force (USPSTF) released its summary of recommendations for AAA screening.9 The summary of recommendations is listed in Table I, and the grade ranking and quality of evidence ratings are defined in Table II. The USPSTF recommended against routine screening in women because the prevalence of AAAs in women is very low and the number of deaths that could be prevented was small. It also suggested that the harm of routine screening outweighed the benefits due to the potential morbidity and mortality to women undergoing an increased number of surgeries for AAAs as well as psychologic harms incurred. The USPSTF noted that most AAA-related deaths occur in women aged >80 years and that screening would not be beneficial because of the increased concomitant risk factors at this age. Individualization of care, however, was still recommended. This issue of screening women for AAAs has not been readdressed since the USPSTF recommendations were released. The USPSTF recommendations were mostly based on a best-evidence systematic review.10 This document consisted of the review of only four population-based randomized, controlled trials of AAA screening, each with a different study design and with data collection mostly from men. The Multicentre Aneurysm Screening Study (MASS) dominated the pooled data over the other three studies due to the higher volume of patients enrolled. These trials were not conducted in the United States, so it is unclear how this may translate to United States populations. In addition, little specific information is available on racial and ethnic groups, age distributions, or women, except in isolated reports within the USPSTF recommendations. No physical harm from the ultrasound screenings was reported, and any psychologic or diminished general health perception did not last long. The question also arises regarding the accuracy of cause of death when information is obtained from death certificates. Personalized decision making regarding screening should take into account a patient’s individual risks as well as willingness to accept potential benefits and adverse effects. The United Kingdom Chichester study11 recruited 9342 women and 6433 men aged 65 to 80 years for AAA screening. AAA prevalence was six times lower in women
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than in men (1.3% vs 7.6%). The investigators recommended against screening for AAAs in women due to the low prevalence. Overall, 3052 women presented for screening because half were randomized to the control group of no screening. No reduction in AAA ruptures was found in the screened group at 5- and 10-year intervals; however, the denominator used for the screening group was all of those randomized to screening, including 1630 women who did not actually attend a screening. Also, at least partial data collection was from death certificates; therefore, cause-ofdeath determination may be inaccurate when based on official statistics and not on actual autopsy findings. The Stroke and Aneurysm Vascular Evaluation (SAVE) program (Medtronic Inc, Minneapolis, Minn) conducted a volunteer screening that was attended by 10,012 women and 7528 men. The results were evaluated by DeRubertis et al12 from New York Presbyterian Hospital. Although the AAA prevalence rate in women was confirmed to be lower (0.7% vs 3.9%), subgroups were identified that had elevated AAA rates. On the basis of these findings, screening for AAAs should be considered in women aged >65 years and women with a history or smoking or cardiovascular disease. Life Line Screening medical and lifestyle questionnaire and ultrasound imaging results from 2003 to 2008 were evaluated in 3.1 million patients.13 A scoring system to predict AAAs was created and was felt to identify AAAs more efficiently and include groups excluded from the USPSTF inclusion criteria for screening. This study estimated a national prevalence of 1.1 million AAAs (1.4% for those aged 50-84 years): 569,000 occurring in women, nonsmokers, and individuals aged <65 years. USPSTF criteria would identify only 29.5% of all AAAs due to the current selection criteria and does not identify AAAs in women, nonsmokers, and younger patients. The proposed scoring system would find 88.6% of AAAs in the group aged 50 to 84 years old. Although women represent only 20% of AAAs, they have demonstrated a three times higher rupture occurrence and a similar number of AAA deaths as men.14 This suggests that women are not being appropriately diagnosed or are not being offered AAA repair at a time when repair might be safer and effective at preventing rupture. Obviously, recognizing women at risk with improved and more efficacious screening methods would potentially help to decrease the morbidity and mortality from rupture and late identification. Risk factors and associations. Although one may not conclude that routine AAA screening should be instituted for all women according to prevalence alone, other considerations should be taken into account. Rupture rates are reportedly higher in women than in men. The United Kingdom Small Aneurysm Trial15 showed women had a threefold higher rupture rate than men, even after adjustment for age, initial AAA diameter, and body mass index or height. In addition, the mean diameter at rupture for women was 5.0 cm compared with an average diameter of 6.0 cm in men. This may be accounted for by differences in biomechanical properties of AAAs between men and
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Table I. United States Preventive Services Task Force (USPSTF) summary of recommendations for abdominal aortic aneurysm (AAA) screeninga USPSTF recommendation
Grade of recommendation
Quality of evidence
One-time screening for AAAs by ultrasound imaging in men aged 65 to 75 who have ever smoked No recommendation for or against screening for AAAs in men aged 65 to 75 who have never smoked No routine screening for AAAs in women
B
Fair
C
Fair
D
Fair
a
Available at http://www.uspreventiveservicestaskforce.org/uspstf05/aaascr/aaars.htm.
Table II. United States Preventive Services Task Force (USPSTF) grade definitions and quality of evidencea Variable Grade of definitionsb A: Strongly recommended B: Recommended C: No recommendation D: Not recommended I: Insufficient evidence to make a recommendation Quality of evidence Good Fair Poor
Definition The USPSTF strongly recommends that clinicians provide [the service] to eligible patients. The USPSTF found good evidence that [the service] improves important health outcomes and concludes that benefits substantially outweigh harms. The USPSTF recommends that clinicians provide [the service] to eligible patients. The USPSTF found at least fair evidence that [the service] improves important health outcomes and concludes that benefits outweigh harms. The USPSTF makes no recommendation for or against routine provision of [the service]. The USPSTF found at least fair evidence that [the service] can improve health outcomes but concludes that the balance of benefits and harms is too close to justify a general recommendation. The USPSTF recommends against routinely providing [the service] to asymptomatic patients. The USPSTF found at least fair evidence that [the service] is ineffective or that harms outweigh benefits. The USPSTF concludes that the evidence is insufficient to recommend for or against routinely providing [the service]. Evidence that the [service] is effective is lacking, of poor quality, or conflicting and the balance of benefits and harms cannot be determined. Evidence includes consistent results from well-designed, well-conducted studies in representative populations that directly assess effects on health outcomes. Evidence is sufficient to determine effects on health outcomes, but the strength of the evidence is limited by the number, quality, or consistency of the individual studies, generalizability to routine practice, or indirect nature of the evidence on health outcomes. Evidence is insufficient to assess the effects on health outcomes because of limited number or power of studies, important flaws in their design or conduct, gaps in the chain of evidence, or lack of information on important health outcomes.
a
Available at http://www.uspreventiveservicestaskforce.org/uspstf/gradespre.htm#brec. Applies to recommendations voted on by the USPSTF before May 2007.
b
women. Vande Geest et al16 demonstrated a trend toward a decrease in tensile strength in AAA wall specimens in women compared with those taken from men, although this was not statistically significant. It has also been suggested that baseline normal aortic diameter may be smaller in women than in men. The Tromso Study17 monitored 4265 men and women with normally sized aortas for the development of AAAs during a 7-year period. The maximal aortic diameter at baseline was 19.4 mm in women vs 21.8 mm in men. Men were noted to have a statistically significant higher risk of developing AAAs during the follow-up period. The greater aortic size at baseline was implicated in the future development of AAAs; however, the question remains if smaller AAAs in women have the same significance as larger AAAs in men. The Aneurysm Detection and Management (ADAM) Veterans Affairs (VA) Cooperative Study18 noted
female gender was associated with a 0.14-cm reduction in aortic diameter. This difference was small but did reach statistical significance. Aortic diameters at all levels were measured in 389 computed tomography scans reviewed at Northwestern.19 Diameters were a function of age, sex (with men having larger aortas), and body surface area. This may again raise the concern of waiting to repair AAAs in women until they reach the same average size of AAAs in men. In addition, women present at an older age than men with similarly sized small AAAs.20 This translates into women undergoing repair at an older age, with possible increased risks. The same group from Kingston, Ontario, Canada, examined the risk of rupture in untreated AAAs with attention to sex differences.21 Women had a four times higher risk of rupture than men with AAAs of 5.0 to 5.9 cm (3.9% vs 0.8%). This would support an earlier intervention
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approach for women with AAAs smaller than that in men and re-emphasizes the importance of including women in AAA screening programs. Aside from pure size indications for repair, other risk factors have been shown to be associated with AAA development, especially in women, and therefore have potential implications for favoring screening. The Women’s Health Initiative Study Group enrolled 161,808 postmenopausal women from 1993 to 1998 and monitored them until the end of the study in 2005.7 A total of 184 AAA events were found and were strongly associated with age and smoking. Height, hypertension, cholesterol-lowering treatment, coronary artery disease, and peripheral arterial disease also had positive but weaker associations. Hormone replacement and diabetes (previously reported to have a positive association in men) had a negative association in women. Powel and Norman,22 in an editorial response to the Women’s Health Initiative findings, pointed out that smoking became popular for women 3 decades after men, and therefore, we may just now be realizing the effects in women. This would suggest that screening for AAAs may now be justified in women who have smoked and that public health initiatives should be aimed at smoking cessation in women. The authors also suggest that estrogens may decrease the risk of AAA formation by reducing AAA MMP expression. Another proposed association in women with AAAs is cerebral vascular disease. The ADAM VA study screened 122,272 male and 3450 female veterans and found an incidence of 4.3% in men and 1.0% in women.23 The association of AAAs with cerebral vascular disease had been suggested previously but was confirmed in the larger ADAM study. Lastly, advancing age has been suggested as a risk factor for AAA development as well as rupture. A French study24 examined women from mutiplex AAA families and found that affected female relatives were significantly older at diagnosis and surgery than men. It was suggested that men and women in families with more than two people affected with AAAs should both undergo routine screening, although the women became affected 10 years later than the men. This may raise concerns for routine AAA repair in a population of advanced age with an increasing number of comorbidities. Cost-effectiveness. MASS conducted a randomized trial of screening vs nonscreening for AAAs and a subsequent 10-year follow-up analysis in 67,770 men.25 The mortality benefit seen in the early portion of the study continued throughout this latter portion, with a relative 48% risk reduction for AAA-related deaths. Cost-effectiveness also became more favorable over time. Attendance at screenings should be encouraged, with subsequent clinical follow-up in those found to have AAAs. Attention to a low operative mortality and morbidity was also emphasized. Unfortunately, no cost-effectiveness data are available for women in this study because none were screened. The cost-effectiveness analyses for the USPSTF26 included four studies that addressed appropriate economic
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evaluation. None of these (including MASS) addressed any cost-effectiveness for AAA screening specifically in women. Wanhainen et al,27 however, found 18 suitable studies with female-specific data that were appropriate for use in the Markov cohort simulation model, which has been used to evaluate the cost-effectiveness of AAA screening in men. They found the incremental cost-effectiveness ratio for AAA screening in women was similar to that found in men. This may show that the lower AAA prevalence rate in women is balanced by a higher rupture rate and that exclusion of women from routine AAA screenings is not justified. Society recommendations. Overall, ultrasound screening has been shown to reduce AAA-related mortality. The Society for Vascular Surgery has also recommended ultrasound screening for women aged >65 years who have smoked or have a family history of AAAs.28 The level of recommendation was strong, with moderate quality of evidence. Although surveillance was recommended for most patients with an aneurysm of 4.0 to 5.4 cm, women with a slightly smaller aneurysm of 5.0 to 5.4 cm should be considered for earlier repair. Lastly, the SVS Executive Summary recognized the need for further research in several areas, including screening for AAAs in women and minorities. It would seem reasonable for now to include women in screening efforts until more data become available to help define the future role of AAA screening in this group. AAAs in women clearly behave differently, and more information on the natural history of AAAs in women is needed because a paucity of data exists. ENDOVASCULAR AAA REPAIR OUTCOME A less invasive approach to AAA repair may prove to be a better option for women, especially those of advanced age with significant comorbidities. Unfortunately, fewer women undergo endovascular AAA repair (EVAR) than men, ranging from 12% to 26% in recent series.29-32 Analysis of the American College of Surgeons National Surgical Quality Improvement Program (NSQIP) data set of 3662 EVARs revealed that 17.7% were women.33 Although this type of study does not always lend itself to the evaluation of underlying contributing factors, the authors suggested that future studies should address aneurysm anatomic details. In addition, this deserves investigation to elucidate the reasons why more women do not undergo EVAR and why more women are likely to present more physically debilitated and with ruptured AAAs. The NSQIP data only reflect 30-day outcome, and therefore, longitudinal studies would be of importance to determine late outcome from EVAR in women. AAA neck configuration is the most common anatomic feature that prohibits aortic endograft placement. Women have been found to have narrower and shorter necks, as well as narrower iliac arteries with a higher calcification score.2 A review of selection criteria for the Zenith AAA endovascular graft (Cook Inc, Bloomington, Ind) revealed that in patients who did not qualify for EVAR, the unsuitability was due to the proximal neck anatomy in 88%;
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however, this was equally distributed between men and women.34 Inadequate neck length (15 mm) was the most common criterion within this group. Wolf et al31 also discovered that the mean diameters of the proximal neck, common iliac, and external iliac arteries were all smaller in women. In addition, the length of the proximal neck was shorter. One might conclude that a smaller proximal neck diameter might coincide with a smaller AAA diameter; however, at least two studies found that the AAA diameter between men and women undergoing EVAR was actually similar.29,31 Certainly, there are other factors that potentially contribute to women undergoing EVAR less frequently. As noted from screening studies, women who undergo EVAR tend to be older than men,29-31 and Becker et al32 reported that perioperative EVAR survivors were significantly younger, although this information was not stratified by sex. NSQIP data analysis33 also revealed that women had a higher incidence of five preoperative risk factors for morbidity and mortality, including emergency operation, functional dependence, recent weight loss, underweight status or morbid obesity, and severe chronic obstructive pulmonary disease. Women were confirmed to have a significantly higher rate of chronic obstructive pulmonary disease in the Wolf et al study.31 Assessment of actual EVAR procedures showed more procedures are aborted in women (16.7% vs 2.1%), but conversion to open repair was similar.35 Deployment success was also significantly higher in men than in women. Short-term outcome in those completing repair, however, was not significantly different, and there were similar early endoleak rates. There was a trend toward longer fluoroscopy times in women undergoing EVAR in the Mayo Clinic series.29 The Stanford group31 discovered a higher rate of intraoperative complications in women, mostly related to arterial access, with iliac avulsion and occlusion requiring more frequent arterial reconstruction. Despite this, they also determined that there was no difference between men and women in the rate of postoperative complications or death. During a 14-month mean follow-up, no genderrelated differences were noted in survival, endoleak rate, reintervention rate, or rate of change of AAA diameter or volume. Mathison et al35 also confirmed a lack of difference between men and women in perioperative mortality and major complication rates. The European Collaborators on Stent-Graft Techniques for AAA and Thoracic Aortic Aneurysm and Dissection Repair (EUROSTAR) data registry assessment of the early success rate of 1554 EVARs deemed female gender and age >70 years to be risk factors for primary endoleak.36 The Oschner Clinic group reviewed their experience with 101 men and 17 women undergoing EVAR37 and found a significantly longer length of procedure in women and a higher arterial dissection rate. Contrary to other reports, mortality and complication rates at 1 month were also higher in women. The NSQIP data set33 revealed that female gender was indeed an independent risk factor
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for length of stay, infection, wound complications, and postoperative transfusion. These data, however, do not assess intermediate-term or longer-term outcome. Data from the Nationwide Inpatient Sample (NIS)38 revealed that mortality was greater in women with intact AAAs undergoing EVAR and open repairs than in men. Few data exist to assess the long-term outcome of EVAR specifically in women. The Mayo Clinic series29 of 241 patients (12% women) found the postoperative outcomes at 2 years were similar between men and women, with a nonsignificant trend toward a higher rate of aortic neck dilatation in women. Men actually trended toward a lower limb patency rate. In contrast, a significantly higher graft limb occlusion rate occurred in women at 2 years in a Cleveland Clinic series.30 This was felt not to be related to iliac diameter but was potentially caused by intimal hyperplasia due to injury during deployment or to differences in thrombotic tendencies. They also discovered that although endoleak frequency and type were no different between men and women, sac shrinkage was more rapid at 2 years in women. ELECTIVE OPEN AAA REPAIR OUTCOME Similar to EVAR, sex differences seem to exist in patients undergoing elective open AAA repair. The Michigan inpatient database studied outcomes from 1980 to 1990 in 11,512 women and 29,846 men, aged $50 years, with a diagnosis of intact or ruptured AAA.39 Hospitalization for AAA was five times more common for men, and they were 1.8 times more likely to undergo surgery for intact AAAs than women. This and other differences prompted the authors to recommend a prospective study. There may also be a difference between the sexes in regard to demographics. The Canadian Society for Vascular Surgery Aneurysm Study Group examined the influence of gender on results of AAA repair.40 Women represented 19.7% of intact AAA repairs and were more likely to be older, have never smoked, have a positive family history of AAAs, and have a coexisting history of aortoiliac occlusive disease. Fewer women had electrocardiographic evidence of an old myocardial infarction or a history of femoral-popliteal aneurysms. The average AAA size in women was also smaller. These differences may help us identify and manage women with AAAs. Various studies have analyzed outcomes pertaining to the sexes. An NIS study reviewed 220,403 patient discharges and found women with an intact AAA had higher odds of inpatient death38; unfortunately, no explanation could be extracted from the data. A similar Centers for Medicare and Medicaid Services inpatient sample study sought to determine if outcomes have been equal between men and women.41 Although improvements have been made overall, increasing age, female sex, and open repair were predictors of elective and ruptured AAA repair mortality. Men were also more likely to be discharged to home. Speziale et al42 sought to identify factors that predicted postoperative renal failure. Female sex and a preoperative
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creatinine clearance of <40 mL/min were two predictive features. A Swedish single-center retrospective study found a higher standardized mortality ratio for women than for men, and thus, a shorter survival when compared with the age-matched general population.43 Similarly, another survival study discovered that the standardized mortality ratio was increased for both sexes after AAA repair compared with the general public, but the ratio was higher for women.44 This was felt to potentially be secondary to a higher aneurysm-related death in women. Long-term survival may also be worse in women than in men. Norman et al45 showed a worse 5-year survival in women than in men, but this was postulated to be due to greater cardiovascular morbidity in women. They acknowledged that women were also under-represented in statin trials, thereby resulting in this potentially protective drug being prescribed less frequently to women. There are studies, however, whose results have conflicted with those that showed worse outcome for women after elective AAA repair. One review of multiple population-based reports discovered there was indeed a discrepancy in results, with some studies showing similar perioperative mortality and others finding higher mortality for women undergoing elective AAA repair.46 In some studies, very low numbers of women were evaluated and treated. It was recommended that clinical research be pursued to determine sex-specific guidelines for the timing of AAA repair and why women undergo AAA repair less commonly. Starr et al47 found that the 5% perioperative death rate was similar for men and women. Men and women also possessed similar cardiac risks. RUPTURED OPEN AAA REPAIR OUTCOME Several reviews found women were less likely to undergo surgical treatment of ruptured AAAs.37,48-50 No unified explanation has been hypothesized. A review of the U.K. Lothian Surgical Audit database found women who were not operated on tended to be older, and older women (>60 years) were less likely to be offered repair or undergo repair.51 The diagnosis of ruptured AAAs in women may be delayed, leading to a late presentation for treatment and a more advanced, moribund state. Women’s overall health may also be inappropriately interpreted as worse than men, leading to repair being offered less frequently. However, gender was not found to influence perioperative mortality in men and women who had undergone surgery. The question still stands if a sex bias exists in selecting women for surgery. Women have been found to have worse outcomes after ruptured AAA repair. Total admissions for ruptured AAA repair for women are 40% that for men, but there has been an increase of 0.5% annually since 2005.45 Women tend to be underdiagnosed and undertreated, and this may account for the trend toward a worse prognosis for women with ruptured AAAs. The Centers for Medicare and Medicaid Services 10-year inpatient sample study showed the average ruptured AAA mortality rate was
higher in women (52.8% vs 44.2%).41 The rate of ruptured AAA repairs also decreased more in men than in women during the study period of 1994 to 2003. The NIS study, reviewed above for open AAA results, also examined the effect of gender on ruptured AAA outcomes from 2001 to 2004.38 Rupture was the indication for 17% of all aneurysm repairs and a higher percentage of women with AAAs presented with rupture than men. Unfortunately, this has not decreased over time. Women were less likely to undergo surgical repair of a ruptured AAA and also had higher inpatient mortality after repair. Again, due to the nature of this type of study, reasons for these differences could not be elicited. The Michigan inpatient database, previously reviewed for elective AAA repair, also found men were 1.4 times more likely than women to undergo open surgery for a ruptured AAA.39 Women had a 1.45 times greater chance than men of dying after surgery for a ruptured AAA. Another Canadian study of 3570 patients with ruptured AAAs, with 73% undergoing repair in Ontario, showed that men were significantly more likely to undergo repair than women (80% vs 58%).48 Women were significantly older than men, but the Charlson Comorbidity Index score was similar; therefore, the women were no sicker than the men. Men did receive care in higher-volume hospitals and in larger cities, implying a potential survival advantage. The Western Australia Health Services Research Database examined the results of ruptured AAAs in 648 men and 225 women; of whom, 37% of women and 63% of men underwent operation.49 Women were on average 6 years older than men when they presented with ruptured AAA. The overall mortality was 90% for women and 76% for men. Increased perioperative mortality in women was speculated to be related to advanced age.46 Despite the differences in immediate-term and shortterm mortality between men and women, long-term survival has been found to be comparable.40,51 Potential reasons for these differences have been given above. This supports the concept that intervening earlier and more frequently on women with ruptured AAAs may confer survival benefits in the short term and long term. CONCLUSIONS Although the actual underlying pathophysiologic mechanisms responsible for the difference in AAA prevalence in men vs women have not been determined, clearly, there are sex-specific risks that women possess. It is reasonable to recommend routine screening for women aged >65 years who have ever smoked or who have a family history of AAAs. Research shows that women undergo endovascular, open, and emergency AAA repair less frequently than men. Outcome results have varied, but some studies have shown that short-term and long-term results between men and women are similar, even though women present later and have a higher rupture rate. Certainly, focused sex-specific research is warranted to elucidate the reasons for differences between men and women and to attempt to provide the best medical care for everyone.
JOURNAL OF VASCULAR SURGERY Volume 57, Number 4S
AUTHOR CONTRIBUTIONS Conception and design: JS, VH Analysis and interpretation: JS, VH Data collection: JS, VH Writing the article: JS, VH Critical revision of the article: JS, VH Final approval of the article: JS, VH Statistical analysis: Not applicable Obtained funding: Not applicable Overall responsibility: JS, VH REFERENCES 1. McNulty BM, Tham DM, Cunha VD, da Cunha V, Ho JJ, Wilson DW, et al. 17-b-estradiol attenuates development of angiotensin II-induced abdominal aortic aneurysms in apolipoprotein Edeficient mice. Atheroscler Thromb Vasc Biol 2003;23:1627-32. 2. Henriques TA, Huang J, D’Souza SS, Daugherty A, Cassis LA. Orchidectomy, but not ovariectomy, regulates angiotensin II-induced vascular diseases in apolipoprotein E-deficient mice. Endocrinology 2004;145:3866-72. 3. Ailawadi G, Eliason JL, Roelofs KJ, Sinha I, Hannawa KK, Kaldjian EP, et al. Gender differences in experimental aortic aneurysm formation. Atheroscl Thromb Vasc Biol 2004;24:2116-22. 4. Wu XF, Zhang J, Paskauskas S, Xin SJ, Duan ZQ. The role of estrogen in the formation of experimental abdominal aortic aneurysms. Am J Surg 2009;197:49-54. 5. Henriques T, Zuang X, Yiannikouris FB, Daugherty A, Cassis LA. Androgen increases ATIa1 receptor expression in abdominal aortas to promote Angiotensin II-induced AAAs in apolipoprotein E deficient mice. Atheroscler Thromb Vasc Biol 2008;28:1251-6. 6. Cho BS, Woodrum DT, Roelofs KJ, Stanley JC, Henke PK, Upchurch GR Jr. Differential regulation of aortic growth in male and female rodents is associated with AAA development. J Surg Res 2009;155:330-8. 7. Lederle FA, Larson JC, Margolis KL, Allison MA, Freiberg MS, Cochrane BB, et al; Women’s Health Initiative Cohort Study. Abdominal aortic aneurysm events in the women’s health initiative: cohort study. BMJ 2008;337:a1724. 8. Yeap BB, Hyde Z, Norman PE, Chubb SA, Golledge J. Association of total testosterone, sex hormone-binding globulin, calculated free testosterone and luteinizing hormone with prevalence of abdominal aortic aneurysms in older men. J Clin Endocrinal Metab 2010;95:1123-30. 9. U.S. Preventive Services Task Force. Screening for abdominal aortic aneurysm recommendation statement. Ann Intern Med 2005;142: 198-202. 10. Fleming C, Whitlock EP, Beil TL, Lederle FA. Screening for abdominal aortic aneurysm: a best-evidence systematic review for the U.S. Preventive Services Task Force. Ann Intern Med 2005;142: 203-11. 11. Scott RA, Bridgewater SG, Ashton HA. Randomized clinical trial of screening for abdominal aortic aneurysm in women. Br J Surg 2002;89: 283-5. 12. 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;46:630-5. 13. Kent KC, Zwolak RM, Egorova NN, Riles TS, Manganaro A, Moskowitz AJ, et al. Analysis of risk factors for abdominal aortic aneurysm in a cohort of more than 3 million individuals. J Vasc Surg 2010;52:539-48. 14. Vouyouka AG, Kent KC. Arterial vascular disease in women. J Vasc Surg 2007;46:1295-302. 15. Brown L, Powell JT; U.K. Small Aneurysm Trial Participants. Risk factors for aneurysm rupture in patients kept under ultrasound surveillance. Ann Surg 1999;230:289-97. 16. Vande Geest JP, Dillavou ED, Di Martino ES, Oberdier M, Bohra A, Makaroun MS, et al. Gender-related differences in the tensile strength of abdominal aortic aneurysm. Ann N Y Acad Sci 2006;1085:400-2.
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45. Norman PE, Powell JT. Abdominal aortic aneurysm: the prognosis in women is worse than in men. Circulation 2007;115:2865-9. 46. Harthun NL, Cheanvechai V, Graham LM, Freischlag JA, Gahtan V. Prevalence of abdominal aortic aneurysm and repair outcomes on the basis of patient sex: should the timing of intervention be the same? J Thorac Cardiovasc Surg 2004;127:325-8. 47. Starr JE, Hertzer NR, Mascha EJ, O’Hara PJ, Krajewski LP, Sullivan TM, et al. Influence of gender on cardiac risk and survival in patients with infrarenal aortic aneurysms. J Vasc Surg 1996;23:870-80. 48. Dueck AD, Johnston KW, Alter D, Laupacis A, Kucey DS. Predictors of repair and effect of gender on treatment of ruptured abdominal aortic aneurysm. J Vasc Surg 2004;39:784-7. 49. Semmens JB, Norman PE, Lawrence-Brown MMD, Holman CDA. Influence of gender on outcome from ruptured abdominal aortic aneurysm. Br J Surg 2000;87:191-4. 50. Filipovic M, Seagroatt V, Goldacre MJ. Differences between women and men in surgical treatment and case fatality rates for ruptured aortic abdominal aneurysm in England. Br J Surg 2007;94:1096-9. 51. Evans SM, Adam DJ, Bradbury AW. The influence of gender on outcome after ruptured abdominal aortic aneurysm. J Vasc Surg 2000;32:258-62.
Submitted Mar 23, 2012; accepted Aug 25, 2012.