Effect of type II endoleaks and antiplatelet therapy on abdominal aortic aneurysm shrinkage after endovascular repair

Effect of type II endoleaks and antiplatelet therapy on abdominal aortic aneurysm shrinkage after endovascular repair Atsushi Aoki, MD, a Takanori Suezawa, MD, a Kenji Sangawa, MD, b and Mamoru Tago, MD, a Kagawa and Matsuyama, Japan Objective: Endovascular repair of abdominal aortic aneurysm (EVAR) has been shown to be safe, and its use is increasing rapidly, but the long-term results of this procedure remain unclear. A decrease in the diameter of the aneurysm sac is considered to represent successful exclusion of the aneurysm from the circulation, but it has been reported that aneurysm shrinkage occurs in only about 60% of patients who have undergone EVAR. We analyzed several factors to determine whether they were related to aneurysm shrinkage after EVAR. Methods: From March 2007 to January 2010, EVAR was performed in 65 patients, 58 of whom underwent an enhanced computerized tomographic evaluation 6 months after the procedure. One patient was found to have a type Ia endoleak and was excluded from the study. In the remaining 57 patients, univariate and multiple regression analyses were used to determine whether there was a relationship between aneurysm shrinkage and various patient characteristics, aneurysm dimensions, and procedural outcomes. Aneurysm shrinkage was defined as a decrease in diameter of at least 4 mm. Results: On univariate analysis, a lack of aneurysm shrinkage by 7 days and 6 months after EVAR was significantly associated with hyperlipidemia, ongoing multiagent antiplatelet therapy with clopidogrel, ticlopidine, or cilostazol as well as aspirin, length of the proximal neck of the aneurysm, preprocedure maximum aneurysm diameter, and the presence of a type II endoleak. On multiple regression analysis, only multiagent antiplatelet therapy and type II endoleak were significantly related to a lack of aneurysm shrinkage 6 months after EVAR. Multiagent antiplatelet therapy and type II endoleak 6 months after EVAR were not significantly associated with each other. Conclusion: Patients with a persistent type II endoleak and patients undergoing multiagent antiplatelet therapy are at an increased risk of a lack of aneurysm shrinkage 6 months after EVAR. (J Vasc Surg 2011;54:947-51.) Randomized trials have shown that endovascular repair of abdominal aortic aneurysm (EVAR) yields favorable short-term results, with mortality rates significantly lower than those associated with surgical repair. 1,2 EVAR is now widely and increasingly used. The goal of an EVAR procedure is to prevent rupture by excluding the aneurysm from the circulation. A decrease in the size of the aneurysm sac is considered to represent successful exclusion of the aneurysm from the circulation. 3,4 However, aneurysm shrinkage has been reported to occur in only about 60% of patients who have undergone EVAR 5 ; therefore, the long-results of the procedure remain controversial. We investigated factors that might influence aneurysm shrinkage after EVAR. METHODS From March 2007 to January 2010, 65 patients with an atherosclerotic abdominal aortic aneurysm (AAA) From the Department of Cardiovascular Surgery, Kagawa Prefectural Central Hospital, Kagawa a ; and the Department of Cardiovascular Surgery, Matsuyama Shimin Hospital, Matsuyama. b Competition of interest: none. Reprint requests: Atsushi Aoki, MD, 5-4-16 Bancho Takamatsu, Kagawa 760-8557, Japan (e-mail: a-aoki@chp-kagawa.jp). 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 competition of interest. 0741-5214/$36.00 Copyright 2011 by the Society for Vascular Surgery. doi:10.1016/j.jvs.2011.03.269 underwent EVAR at our institutions. Fifty-eight of these patients had an enhanced computerized tomographic (CT) evaluation 6 months after the procedure. One patient was found to have a type Ia endoleak and was excluded from further investigation. The remaining 57 patients (49 men, 8 women; mean age, 76 years [range, 57-92 years]) were enrolled in the study. The variables that were analyzed with respect to their possible effect on aneurysm shrinkage included patient demographics and concomitant diseases, aneurysm characteristics, and the presence of a type II endoleak after EVAR (Table I). All the patients in the study who had hypertension or hyperlipidemia were receiving medical treatment for their condition. The 20 patients with coronary artery disease had previously undergone percutaneous coronary intervention or coronary artery bypass grafting. The 23 patients receiving antiplatelet therapy had a history of coronary artery disease (14 patients) or cerebral vessel attack (9 patients). Fourteen of the 23 were taking either clopidogrel bisulfate, ticlopidine hydrochloride, or cilostazol, as well as aspirin. Three patients were receiving warfarin potassium as anticoagulation therapy, two for chronic atrial fibrillation, and one because of a history of mitral valve replacement with a mechanical valve. We did not conduct analyses based on the type of anticoagulation therapy because of the small number of patients receiving this treatment. 947

948 Aoki et al JOURNAL OF VASCULAR SURGERY October 2011 Table I. Results of univariant analysis of factors possibly associated with aneurysm shrinkage at 6 months after EVAR in 57 patients Variable Results a P value Patient characteristics Age y 0.1 0.8x, r 0.012.449 Gender.388 F(n 8) 7.6 4.5 M(n 49) 5.7 6.0 Hypertension.347 Absent (n 13) 7.3 5.8 Present (n 44) 5.6 5.8 Hyperlipidemia.043 Absent (n 40) 7.0 6.2 Present (n 17) 3.6 4.2 Diabetes mellitus (type I or II).938 Absent (n 45) 5.9 5.7 Present (n 12) 6.1 6.5 Chronic obstructive pulmonary disease.623 Absent (n 52) 5.8 5.8 Present (n 5) 7.2 5.9 Smoking status.962 Nonsmoker (n 21) 6.2 6.4 Current smoker (n 36) 6.1 5.3 Coronary artery disease.470 Absent (n 37) 6.4 5.9 Present (n 20) 5.2 5.8 Antiplatelet therapy (including aspirin only).163 Not receiving (n 34) 7.3 5.9 Receiving (n 23) 4.7 5.5 Multiagent antiplatelet therapy b.003 Not receiving (n 43) 7.3 5.9 Receiving (n 14) 2.0 3.2 Type of endoprosthesis c.758 Zenith (n 31) 5.7 5.7 Powerlink (n 4) 2.8 2.6 Excluder (n 22) 6.9 6.3 Aneurysm characteristics Proximal neck length y 10.3-0.16x, r 0.281.034 Angle y 5.0 0.23x, r 0.084.533 Maximum diameter y 3.0 0.17x, r 0.314.017 Type II endoleak on EVAR completion angiogram.860 No (n 40) 6.2 6.1 Yes (n 17) 6.2 6.1 7 days after EVAR (enhanced CT).039 No (n 41) 7.0 6.3 Yes (n 16) 3.4 3.3 6 months after EVAR (enhanced CT).001 No (n 43) 7.5 5.9 Yes (n 14) 1.4 1.9 CT, Computerized tomographic scanning; EVAR, endovascular aneurysm repair. a Plus-minus values are mean SD millimeters of shrinkage. b Included both aspirin and either clopidogrel, ticlopidine, or cilostazol. c The manufacturers are Cook, Bloomington, Ind (Zenith); Endologix, Irvine, Calif (Powerlink); and W. L. Gore & Associates, Flagstaff, Ariz (Excluder). All patients underwent three assessments to detect type II endoleaks: completion angiography at the time of the EVAR procedure and enhanced CT scanning 7 days and 6 months afterward. To mitigate measurement error, aneurysm sac shrinkage was defined as a decrease of at least 4 mm in maximum sac diameter. 6 Nonpaired t testing, 2 testing, and regression analysis were used for univariate analysis of factors possibly associated with a lack of aneurysm shrinkage. Multiple regression analysis was used for multivariant assessments. A P value of less than.05 was considered to represent a significant correlation. All analyses were done with StatView 5 software (SAS Institute, Cary, NC). RESULTS During the study period, no AAA ruptures occurred, and no reinterventions to treat a type II endoleak were required. On admission, blood pressure values in patients with a history of hypertension were not significantly different from those in patients without such a

JOURNAL OF VASCULAR SURGERY Volume 54, Number 4 Aoki et al 949 Table II. Results of multiple regression analysis of factors possibly associated with aneurysm shrinkage at 6 months after EVAR in 57 patients Variable r Error t value P value Age 0.043 0.107 0.406.687 Gender 1.217 2.302 0.529.600 Hypertension 0.147 1.768 0.083.934 Hyperlipidemia 1.468 1.811 0.811.423 Diabetes mellitus 0.726 1.808 0.402.690 Chronic obstructive pulmonary disease 1.650 2.389 0.699.489 Smoking 0.668 1.574 0.425.674 Antiplatelet therapy (aspirin) 1.522 1.875 0.812.422 Multiagent antiplatelet therapy a 5.344 2.133 2.506.017 Aneurysm proximal neck length 0.033 0.089 0.365.717 Aneurysm angle 0.010 0.039 0.268.790 Aneurysm diameter 0.105 0.072 1.458.153 Type of endoprosthesis 2.038 1.261 1.616.114 Type II endoleak at EVAR 1.786 1.649 1.083.286 Type II endoleak 7 days after EVAR 1.171 1.914 0.612.544 Type II endoleak 6 months after EVAR 5.708 2.103 2.714.010 EVAR, Endovascular aneurysm repair. a Included both aspirin and either clopidogrel, ticlopidine, or cilostazol. history (mean SD, 125 15/73 10 mm Hg vs 118 8/69 8mmHg;P.22 for systolic and.24 for diastolic value). Table I shows the mean ( SD) millimeters of aneurysm shrinkage at 6 months according to the factors investigated, as well as the results of the univariate analysis. Among the 17 patients found to have a type II endoleak on completion angiography at the time of endovascular aneurysm repair (EVAR), 10 did not have an endoleak on enhanced computerized tomographic (CT) scanning 7 days after the procedure. In nine other patients, a type II endoleak was newly detected at 7 days. Therefore, at 7 days after EVAR, 16 patients (28% of all those in the study) had a type II endoleak. Six of these 16 patients did not have a type II endoleak 6 months after EVAR, but four other patients did; therefore, 14 patients (25%) had a type II endoleak 6 months after EVAR. The univariate analysis revealed that the following factors were significantly associated with a lack of aneurysm shrinkage 6 months after EVAR: hyperlipidemia, multiagent antiplatelet therapy, long aneurysm proximal neck, small preoperative maximum aneurysm diameter, and type II endoleak detected on enhanced CT scanning 7 days or 6 months after EVAR. On multiple regression analysis (Table II), only multiagent antiplatelet therapy and type II endoleak detected 6 months after EVAR were significantly related to a lack of aneurysm shrinkage at 6 months. There was no significant difference between patients receiving multiagent antiplatelet therapy and those not Fig. Aneurysm shrinkage at 7 days and 6 months after endovascular abdominal aortic aneurysm repair (EVAR) in patients with a type II endoleak who were receiving multiagent antiplatelet therapy (APT)(n 3), patients with a type II endoleak who were not receiving APT (n 11), patients without a type II endoleak who were receiving APT (n 11), and patients without a type II endoleak who were not receiving APT (n 32). Error bars represent mean SD. receiving this treatment in the frequency of type II endoleaks 6 months after EVAR (29% vs 30%). Also at 6 months after EVAR, 32 patients were neither undergoing multiagent antiplatelet therapy nor found to have a type II endoleak. In these patients, the amount of aneurysm sac shrinkage was significantly greater than it had been 7 days after EVAR (9.2 5.6 mm at 6 months vs 3.3 3.5 mm at 7 days; P.001; Fig). However, the aneurysm sac did not shrink in patients who had a type II endoleak detected 6 months after EVAR and were not receiving multiagent antiplatelet therapy or in patients with or without a type II endoleak who were undergoing multiagent antiplatelet therapy. DISCUSSION It has been reported that a reduction in aneurysm volume of more than 10% by 6 months after EVAR is predictive of good long-term results. 3 Moreover, a 75% reduction in the difference between the largest diameter of the aneurysm and the diameter of the stent graft body has been observed to be predictive of durable results after EVAR. 4 However, it has also been found that aneurysm shrinkage occurs in only 60% of patients who undergo EVAR and that the aneurysm diameter either does not change or increases in the remaining 40%. 5 In this study, we observed a shrinkage in aneurysm sac diameter of more than 4 mm in 51% of patients who had undergone EVAR. Univariate analysis indicated that lack of aneurysm shrinkage was associated with aneurysms that had a long proximal neck or small preprocedure diameter, hyperlipidemia, and ongoing multiagent antiplatelet therapy but not antiplatelet therapy using aspirin only. Type II endoleaks detected by completion angiography at the time of EVAR had no relationship with aneurysm shrinkage, whereas type II endoleaks identified by enhanced CT scanning 7 days or 6 months after EVAR were correlated with a lack of shrink-

950 Aoki et al JOURNAL OF VASCULAR SURGERY October 2011 age. Multivariant analysis found that the presence of a type II endoleak 6 months after EVAR and multiagent antiplatelet therapy were each significantly related to a lack of aneurysm sac reduction. The presence of a type I or type III endoleak is a known risk factor for expansion and rupture of an aneurysm, and intervention is required if one of these high-pressure endoleaks is detected. 6-8 The importance of type II endoleaks, however, remains unknown. Some studies have found that type II endoleaks do not increase the risk of aneurysm rupture or conversion to open surgical repair, 9,10 whereas another investigation concluded that type II endoleaks are associated with a need for open surgery. 7 Currently, the consensus is that treatment of a type II endoleak should be considered when the aneurysm sac has expanded. 11 The variations in findings regarding the effect of type II endoleaks on the long-term results of EVAR may be at least partly due to the possible existence of several type II endoleak subgroups. Some type II endoleaks seal without intervention, 9,10,12-14 and those that disappear within 6 months after EVAR have been classified as transient, whereas those present for a longer period are designated persistent. Jones et al 14 reported that persistent type II endoleaks, but not transient type II endoleaks, represent a risk factor for aneurysm expansion and rupture. Arko et al 12 found that aneurysms in patients with a persistent type II endoleak did not shrink, whereas those in patients with a transient type II endoleak did. Hiatt and Rubin 15 divided type II endoleaks into simple and complex. In patients with a simple type II endoleak, only one artery is connected to the aneurysm; in those with a complex type II endoleak, two or more arteries feed and/or drain the aneurysm. Type II endoleaks also have differing hemodynamic characteristics. Bargellini et al 16 used contrast-enhanced ultrasonography to measure the interval between injection of the contrast medium and endoleak detection. Type II endoleaks were classified as either hyperdynamic (wash-in period, 100 s) or hypodynamic (wash-in period, 100 s). The researchers found that hypodynamic type II endoleaks, especially those with a washout time of more than 520 s, were associated with aneurysm expansion. Because these endoleaks had no drainage vessels, the pressure within the aneurysm sac was probably high. Dias et al 17 measured intrasac pressure in patients with endoleaks by using direct puncture. They then calculated a sac pressure index (SPI) as the ratio between the intrasac pressure and systemic pressure. The researchers found that in patients with a type II endoleak, the SPI ranged from 22% to 87%. Aneurysm shrinkage was associated with an SPI of 35% or less, whereas an SPI value of 74% to 78% was related to no reduction or expansion of the aneurysm. The mechanism by which type II endoleaks seal spontaneously is formation of thrombus in the aneurysm sac that results in occlusion of the feeding artery. However, the structure of thrombi and the pressure within them vary. 17,18 Vellabhaneni et al 18 assessed the relationship between the histologic features of a thrombus and the transmission of pressure through it by studying thrombi removed during open abdominal aortic aneurysm (AAA) repair. They found that pressure transmission was inversely correlated with the matrix density of a thrombus. Thus, when the matrix density was 97%, the pressure transmission was 6%, but when the matrix density was 52%, the pressure transmission was 100%. In our study, the aneurysm sac did not shrink in patients undergoing multiagent antiplatelet therapy. This finding suggests that the thrombus in the aneurysm sac in these patients did not become hard because of the disruption of coagulation mechanisms caused by the treatment. Enhanced CT scanning is widely used to detect endoleaks, and the sensitivity and specificity of this method have been reported to be as high as 92% and 90%, respectively. 15 Enhanced CT scanning cannot, however, identify all endoleaks. Bargellini et al 16 reported that of 18 endoleaks detected by using contrast-enhanced ultrasonography, enhanced CT scanning found only 10. Expansion of an aneurysm sac in the absence of an endoleak on enhanced CT scanning is termed endotension. Endotension may actually represent a small endoleak that is undetectable by enhanced CT scanning. Thrombus formation in an aneurysm sac depends on the relationship between coagulation and fibrinolysis. Antiplatelet therapy suppresses blood coagulation and thrombus formation in the sac and may also prevent thrombus organization. These actions may have been responsible for the significant correlation between multiagent antiplatelet therapy and a lack of aneurysm sac shrinkage after EVAR in the patients in our study. With respect to the possible effects of anticoagulation therapy after EVAR, Biebl et al 19 observed that long-term treatment with warfarin was safe and that spontaneous endoleak resolution could occur in patients undergoing such therapy. In contrast, Bobadilla et al 20 found that warfarin therapy increased the risk of development of endoleaks, especially type II endoleaks. We could not evaluate the effect of anticoagulation therapy on aneurysm sac shrinkage in our series because of the small number of patients who were receiving this treatment, and this clearly represents a limitation of our study. Embolization by means of transarterial 21 or direct 22 puncture has been advocated for treating type II endoleaks when aneurysm expansion has occurred. Open surgery is currently the only available treatment for expansion of the aneurysm sac caused by endotension. However, discontinuing all antiplatelet therapy except aspirin, if possible because lack of aneurysm shrinkage was not associated with aspirin-only therapy in this study, or administering an agent that enhances coagulation or suppresses fibrinolysis might accelerate thrombosis in the aneurysm sac and thereby avoid an endotension-related increase in aneurysm size. The authors thank Renée J. Robillard, MA, ELS, for editorial assistance.

JOURNAL OF VASCULAR SURGERY Volume 54, Number 4 Aoki et al 951 AUTHOR CONTRIBUTIONS Conception and design: AA Analysis and interpretation: AA Data collection: TS, KS Writing the article: AA Critical revision of the article: AA Final approval of the article: MT Statistical analysis: AA Obtained funding: Not applicable Overall responsibility: AA REFERENCES 1. Greenhalgh RM, Brown LC, Kwong GP, Powell JT, Thompson SG, et al; EVAR trial participants. Comparison of endovascular aneurysm repair with open repair in patients with abdominal aortic aneurysm (EVAR trial 1), 30-day operative mortality results: randomised controlled trial. Lancet 2004;364:843-8. 2. Prinssen M, Verhoeven EL, Buth J, Cuypers PW, van Sambeek MR, Balm R, et al; Dutch Randomized Endovascular Aneurysm (DREAM) Trial Group. A randomized trial comparing conventional and endovascular repair of abdominal aortic aneurysms. N Engl J Med 2004;351: 1607-18. 3. Lee JT, Aziz IN, Lee JT, Haukoos JS, Donayre CE, Walot I, et al. 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