Small Abdominal Aortic Aneurysms: Should We Wait?

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1 Small Abdominal Aortic Aneurysms: Should We Wait? George Galyfos, MD, PhD; Grigorios Voulalas, MD, PhD; Ioannis Stamatatos, MD, MSc; Stavros Kerasidis, MD, MSc; Ioannis Stefanidis, MD, MSc; Sotirios Giannakakis, MD, PhD; Georgios Kastrisios, MD; Georgios Geropapas, MD, MSc; Gerasimos Papacharalampous, MD; Chrisostomos Maltezos, MD, PhD From the Department of Vascular Surgery, KAT General Hospital, Athens, Greece. ABSTRACT: The proper management of small abdominal aortic aneurysms (AAAs), namely those under the threshold of 5.5 cm in diameter, has been under investigation for years. Risk of rupture for this group of AAAs is higher than the rest of the population, and specific factors have been associated with increased growth rate of small AAAs. This review aims to collect and present all available research data on the development and progress of small AAAs. Furthermore, the results of major randomized trials on proper treatment of such patients are discussed, and conclusions regarding interventional and conservative management are made. VASCULAR DISEASE MANAGEMENT 2015;12(8):E152-E159 Key words: abdominal aortic aneurysm, aneurysm repair, endovascular therapy, vascular therapy An abdominal aortic aneurysm (AAA) is defined as a dilatation of the aorta more than one and a half times its normal diameter at the level of the renal arteries. 1 Therefore, an aorta of more than 2 cm in diameter is considered an ectatic aorta that should be closely followed up using ultrasound imaging. 2 The latest guidelines recommend the repair of AAAs 5.5 cm in diameter or greater in asymptomatic patients. 3 Patients with symptomatic aneurysms and whose aneurysms increase in diameter by 0.5 cm or greater within 6 months should also undergo repair, regardless of aneurysm diameter. 3 However, there has been debate for years over the proper management (intervention or surveillance) of small AAAs, namely of sizes between 4 cm and 5.5 cm. This review will present all available data on the prognosis and management of small AAAs in order to produce useful conclusions. GROWTH RATE AND RISK FOR RUPTURE Several factors have been associated with small AAA growth rate and expansion. A large initial diameter and family history of aortic aneurysm have been identified as independent risk factors for more rapid growth of small AAAs.4 The growth rate of AAAs is significantly greater in women than in men as well, according to several studies. 5,6 This could have implications for the frequency of follow-up and timing of repair of AAA in women. Other factors have been reported to be associated with increased AAA expansion, including large Vascular Disease Management August

2 AAA thrombus size, high AAA wall stress, elevated plasma concentration of matrix metalloproteinase-9 and presence of carotid artery disease. 7,8 Collagen markers such as serum elastin peptides (SEP), plasminantiplasmin (PAP) complexes and interferon-gamma (IFN-gamma) have also been strongly associated with AAA development and growth. 9,10 However, there are factors negatively correlated with AAA growth such as diabetes mellitus and chronic limb ischemia.8 Progression of small AAA seems to be more than 60% lower in patients with diabetes. 11 Additionally, male sex, smaller aneurysms, and large body size seem to be linked with smaller risk for rupture. 12 This could help to identify subgroups of individuals at lower likelihood of AAA enlargement or rupture, for these patients early in the trial. However, mortality such as diabetic large men. 11 Regarding growth rate of small AAAs, Bown et al OPEN REPAIR VS SURVEILLANCE Regarding treatment, 2 major randomized trials have compared open repair of small AAAs with a noninterventional approach. In the 1990s, the UK Small Aneurysm Trial 17 evaluated 1,090 patients aged years, with asymptomatic abdominal aortic aneurysms 4.0 cm to 5.5 cm in diameter. The patients were randomized to undergo early elective open surgery (n=563) or ultrasonographic surveillance (n=527). Patients were followed-up for a mean of 4.6 years, and only if the diameter of aneurysms in the surveillance group exceeded 5.5 cm, surgical repair was recommended. The 30-day operative mortality in the early-surgery group was 5.8%, which led to a survival disadvantage did not differ significantly between groups at 2, 4, or even 6 years. Age, sex, or initial aneurysm size did not concluded in a recent meta-analysis that for each 0.5- modify the overall hazard ratio. Therefore, the authors cm increase in AAA diameter, growth rates increase concluded that ultrasonographic surveillance for small on average by 0.59 mm per year (95% confidence AAAs is safe, with early surgery not providing a longterm survival advantage. Finally, the same cohort of interval [CI], ) and rupture rates increase by a factor of 1.91 (95% CI, ).13 However, patients was followed for an average of 12 years by Powell et al found in a similar study that the pooled the collaborating authors, and they found that early mean growth rate was 2.32 (95% CI, ) mm/ elective surgery did not confer any survival benefit year although the heterogeneity between studies was in the fittest patients, although the least fit patients quite high.14 The authors concluded that a 3.5 cm showed a survival advantage with early open repair. 18 aneurysm would take a mean 6.2 years to reach the The second randomized trial was the ADAM trial limit of 5.5 cm, whereas a 4.5 cm aneurysm would take (Aneurysm Detection and Management Veterans Affairs Cooperative Study Group), evaluating more than only 2.3 years. Specifically for the diameter range 3.0 cm to 5.5 cm, rupture rates seem to range between 0 1,000 patients with small AAAs. 19 Patients included and 1.61 ruptures per 100 person years.15 However, in this study were years old, with AAAs ranging between 4 and 5.4 cm in diameter. They were even small AAAs have been associated with higher mortality compared to controls, independently from randomized either to open repair (n=569) or surveillance by ultrasonography or computed the presence of cardiovascular disease symptoms. 16 tomography Vascular Disease Management August

3 (CT; n=567). The follow-up period ranged between 3.5 and 8 years. The rate of death from any cause was not significantly different in the 2 groups (relative risk in the immediate-repair group as compared with the surveillance group: 1.21; 95% CI, ). Trends in survival did not favor immediate repair in any of the prespecified subgroups defined by age or diameter of aneurysm at entry. Although immediate open repair was followed in this study by a low total operative mortality of only 2.7%, the trial highlighted that survival is not improved by elective repair of small AAAs. Furthermore, a later analysis of results indicated that impotence was higher in the open repair group 1 year after randomization, although the same group showed 20±12 months (range, 0-41 months), the death rate was almost 4% in both groups, and the unadjusted hazard ratio for mortality in the early-evar group was 1.01 (95% CI, , P=.98). Aneurysm rupture and aneurysm-related death were also equivalent in both groups. Therefore, the investigators concluded that both approaches appear to be safe alternatives for patients with small AAAs, protecting the patient from rupture or aneurysm-related death for at least 3 years. 23 In the CAESAR (Comparison of surveillance vs Aortic Endografting for Small Aneurysm Repair) trial, 360 patients between 50 and 79 years of age, with an AAA of 4.1 cm to 5.4 cm, were randomly assigned (1:1 ratio) to receive immediate EVAR or surveillance by an improved perception of health in the first 2 years. 20 ultrasound and computed tomography. 24 Repair was also selected only after a defined threshold (diameter ENDOVASCULAR REPAIR VS SURVEILLANCE 5.5 cm, enlargement >1 cm /year, symptoms) was Endovascular repair of AAAs (EVAR) is a less invasive alternative to open surgical management. The ity. Mortality and rupture rates were low and no clear achieved. The main end point was all-cause mortal- short-term technical success rate of the endovascular advantage was shown between early or delayed EVAR approach ranges up to 95%. 21 Large randomized trials strategy. The investigators concluded that within 36 comparing EVAR with open repair have shown that months, 3 out of every 5 small aneurysms under surveillance might grow to require repair and 1 out of short-term morbidity and mortality rates are better after endovascular repair, although long-term survival every 6 might lose feasibility for EVAR. 24 Moreover, does not show any difference between the 2 methods. 22 patients with small AAA under surveillance had significant impaired functional health at 6 months after Two major randomized trials have been published in the last decade evaluating the potential role of EVAR assignment, although short-form 36 health-related in small AAA management. quality of life was similar between both groups after In the PIVOTAL (Positive Impact of Endovascular Options for treating Aneurysms Early) trial, 728 Although the results of previous trials did not show a a mean 31.8 months follow-up. 25 patients (13.3% women; mean age, 71±8 years) with difference between EVAR and surveillance, the results AAAs of 4 cm to 5 cm in diameter were randomly assigned to early EVAR (n=366 patients) or ultrasound data on patients with small AAAs from the multicenter of Zarins et al are opposing. 26 In this retrospective study, surveillance (n=362).23 After a mean follow-up of AneuRx trial treated endovascularly, were compared Vascular Disease Management August

4 with the surveillance group from the UK Small trial. Inclusion criteria were the age limit (60 years to 76 years) and the size of the aneurysm (4 cm to 5.5 cm). The authors concluded that EVAR of small AAAs significantly reduces the risk of fatal aneurysm rupture and aneurysm-related death and improves overall patient survival compared to an ultrasound surveillance strategy with selective open surgical repair. In this study, ruptures occurred in 1.6% of EVAR patients and 5.1% of patients under surveillance, although this difference was not significant. Fatal aneurysm rupture rate, adjusted for follow-up time, was 4 times higher in patients under surveillance (0.8/100 patient years) than in patients treated endovascularly (0.2/100 patient years, P<.001). Elective operative mortality rate SAT; HR 1.21, 95% CI 0.95 to 1.54, mean follow-up was significantly lower in the EVAR group (1.9% vs 5.9%, P<.01). Finally, all-cause mortality rate was significantly higher in the surveillance group (8.3/100 vs 1.01, 95% CI, 0.49 to 2.07, mean follow-up 20 months 6.4/100 patient years, P=.02). However, one should for PIVOTAL). When analyzing the 2 trials evaluating open repair (with a maximum follow-up of 7 to underline that this was a retrospective analysis, without a primary randomized designation of study. 8 years), the authors found no statistically significant In order to produce better conclusions from future difference in survival between immediate open repair studies, reports of EVAR should stratify their outcomes and surveillance (propensity score-adjusted HR 0.99; according to the diameter of the aneurysm. Large 95% CI, 0.83 to 1.18), and that this lack of treatment aneurysms need a more rigorous post-evar surveillance schedule than do smaller aneurysms. In a large ticipant age (P=.61). The meta-analysis of mortality at effect did not vary by AAA diameter (P=.39) or par- retrospective study enrolling more than 4,000 patients 1 year for the endovascular trials likewise showed no treated with EVAR from the EUROSTAR database, significant association, compared to surveillance (risk the authors found that small AAAs show lower rupture rates, better follow-up results at 4 years and less ratio at 1 year 1.15, 95% CI, 0.60 to 2.17). aneurysm-related death compared to patients with FUTURE RECOMMENDATIONS AAAs larger than 5.5 cm in diameter (P<.0001).27 Data so far indicate that a more conservative management would be more appropriate for patients with In another large prospective study by Zarins et al, 923 patients undergoing EVAR were stratified into dif- small AAAs. Surveillance intervals of several years are ferent groups according to AAA size. 28 The authors concluded that patients with small AAAs (<5.0 cm) are more favorable candidates for EVAR and have the best long-term outcomes, with 99% freedom from AAA death at 5 years. Finally, a pooled analysis of all four major randomized trials (UKSAT, ADAM, CAESAR and PIVOTAL) was published recently in order to shed light on proper management of small AAAs.29 A total of 3,314 patients were analyzed. Although early survival rates favored the surveillance group (due to 30-day operative mortality with surgery), there was no significant differences in long-term survival (adjusted hazard ratio 0.88, 95% CI, 0.75 to 1.02, mean follow-up 10 years for UK- 4.9 years for ADAM; HR 0.76, 95% CI, 0.30 to 1.93, median follow-up 32.4 months for CAESAR; HR Vascular Disease Management August

5 clinically acceptable for men with AAAs in the range of 3.0 cm to 4.0 cm, and AAAs <3 cm do not require a repeat scan for 5 years. 30 According to Thompson et al, intervals of around 1 year are suitable for AAAs of 4.0 cm to 4.9 cm, whereas intervals of 6 months would be acceptable for AAAs of 5.0 cm to 5.4 cm. 31 Research results so far show that lengthening surveillance intervals for the smallest aneurysms seems to be cost effective as well. Concerning the surveillance method, ultrasound imaging is quite reliable for follow-up, with 3D ultrasound reconstruction demonstrating lately acceptable reproducibility and good agreement with CT scanning. 32 Regarding the optimal medical treatment during with small AAAs. 39 Smoking cessation should be sug- the surveillance period, several drug categories have gested for such patients, although antihypertensive and been associated with reduction of AAA growth rate. Lipid-lowering drug treatment as well as initial AAA role of medical treatment on small AAA growth and progress were evaluated. 38 Quality of evidence from the collected trials was quite unclear and did not lead to solid conclusions, mainly due to the small size of the different trials. The meta-analysis included only two trials with antibiotics, showing that mainly roxithromycin has a small but significant protective role. More studies referred to the role of beta-blockers, especially propranolol. This agent showed low tolerance in the majority of the trials, although its positive effect was limited. Therefore, the initiation of such agents during surveillance period is still controversial. Furthermore, diabetes and smoking have been strongly associated other cardioprotective medication does not seem to affect small AAAs significantly. 39 Low-dose aspirin has diameter appear to be independently associated with been associated with lower expansion rates and less lower AAA growth rates. 33,34 Therefore, medical treatment with statins seems to offer some benefit. Moso- In conclusion, the consensus in the literature is that need for later repair in AAAs sized above 3.5 cm. 40 rin et al have also found that statins slightly decrease small AAAs should be followed up rather than operated immediately, until recommended indication for the AAA growth rate and significantly improve freedom from aneurysm repair and rupture. 35 Moreover, repair is set. Surveillance programs should consider statins appear to be associated with attenuation of AAA regulating specific risk factors such as smoking, as appropriate. Results so far regarding the protective role growth, irrespective of other known factors influencing aneurysm growth. 36 Shouten et al showed that of medical regimes against small AAAs progression statin users had a 1.16 mm/year lower AAA growth and rupture are still controversial. However, data so far rate compared to non-users (95% CI mm/ could help define certain subgroups of patients that year). 36 However, in the largest cohort to date evaluating the effect of statins on small AAAs (n=652), no indicated candidates for surgical repair sooner. n could be under tighter surveillance and thus recognize association between statins or LDL levels with AAA expansion was found. 37 Editor s note: Disclosure: The authors have completed In a large Cochrane database research involving more and returned the ICMJE Form for Disclosure of Potential than 1,500 patients, randomized trials studying the Conflicts of Interest. The authors report no financial relation- Vascular Disease Management August

6 ships or conflicts of interest regarding the content herein. Manuscript received March 27, 2015; manuscript accepted May 4, Address for correspondence: George Galyfos, MD, PhD, KAT General Hospital, Department of Vascular Surgery, Nikis 2, Kifisia , Greece. hotmail.com REFERENCES 1. Basnyat PS1, Aiono S, Warsi AA, Magee TR, Galland RB, Lewis MH. Natural history of the ectatic aorta. Cardiovasc Surg. 2003;11(4): Devaraj S, Dodds SR. Ultrasound surveillance of ectatic abdominal aortas. Ann R Coll Surg Engl. 2008;90(6): Rooke TW, Hirsch AT, Misra S et al; American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines; Society for Cardiovascular Angiography and Interventions; Society of Interventional Radiology; Society for Vascular Medicine; Society for Vascular Surgery ACCF/AHA focused update of the guideline for the management of patients with peripheral artery disease (updating the 2005 guideline): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines: developed in collaboration with the Society for Cardiovascular Angiography and Interventions, Society of Interventional Radiology, Society for Vascular Medicine, and Society for Vascular Surgery. J Vasc Surg. 2011;54(5):e32-e Akai A, Watanabe Y, Hoshina K, et al. Family history of aortic aneurysm is an independent risk factor for more rapid growth of small abdominal aortic aneurysms in Japan. J Vasc Surg. 2015;61(2): Mofidi R, Goldie VJ, Kelman J, Dawson AR, Murie JA, Chalmers RT. Influence of sex on expansion rate of abdominal aortic aneurysms. Br J Surg. 2007;94(3): Solberg S, Singh K, Wilsgaard T, Jacobsen BK. Increased growth rate of abdominal aortic aneurysms in women. The Tromsø study. Eur J Vasc Endovasc Surg. 2005;29(2): Speelman L, Hellenthal FA, Pulinx B, et al. The influence of wall stress on AAA growth and biomarkers. Eur J Vasc Endovasc Surg. 2010;39(4): Hendy K, Gunnarson R, Golledge J. Growth rates of small abdominal aortic aneurysms assessed by computerised tomography--a systematic literature review. Atherosclerosis. 2014;235(1): Lindholt JS, Heickendorff L, Vammen S, Fasting H, Henneberg EW. Five-year results of elastin and collagen markers as predictive tools in the management of small abdominal aortic aneurysms. Eur J Vasc Endovasc Surg. 2001;21(3): Urbonavicius S1, Urbonaviciene G, Honoré B, Henneberg EW, Vorum H, Lindholt JS. Potential circulating biomarkers for abdominal aortic aneurysm expansion and rupture--a systematic review. Eur J Vasc Endovasc Surg. 2008;36(3): De Rango P, Cao P, Cieri E, et al. Comparison of surveillance vs. Aortic Endografting for Small Aneurysm Repair (CAESAR) investigators group. Effects of diabetes on small aortic aneurysms under surveillance according to a subgroup analysis from a randomized trial. J Vasc Surg. 2012;56(6): Lo RC, Lu B, Fokkema MT, et al; Vascular Study Group of New England. Relative importance of aneurysm diameter and body size for predicting abdominal aortic aneurysm rupture in men and women. J Vasc Surg. 2014;59(5): RESCAN Collaborators; Bown MJ, Sweeting MJ, Brown LC, Powell JT, Thompson SG. Surveillance intervals for small abdominal aortic aneurysms: a meta-analysis. JAMA. 2013;309(8): Powell JT, Sweeting MJ, Brown LC, Gotensparre SM, Fowkes FG, Thompson SG. Systematic review and meta-analysis of growth rates of small abdominal aortic aneurysms. Br J Surg. 2011;98(5): Powell JT, Gotensparre SM, Sweeting MJ, Brown LC, Fowkes FG, Thompson SG. Rupture rates of small abdominal aortic aneurysms: a systematic review of the literature. Eur J Vasc Endovasc Surg. 2011;41(1): Sohrabi S, Wheatcroft S, Barth JH, et al. Cardiovascular risk in patients with small and medium abdominal aortic aneurysms, and no history of cardiovascular disease. Br J Surg. 2014;101(10): Vascular Disease Management August

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