Effective treatment of abdominal aortic aneurysms. Short- and long-term outcome following endovascular aneurysm repair

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1 J CARDIOVASC SURG 2004;45: Short- and long-term outcome following endovascular aneurysm repair How does it compare to open surgery? C. K. ZARINS, M. A. HEIKKINEN, E. S. LEE, J. M. ALSAC, F. R. ARKO The primary objective of aneurysm repair is to prevent aneurysm rupture while avoiding aneurysm-related death. This manuscript reviews the primary and secondary outcome measures following endovascular aneurysm repair (EVAR) in relation to similar outcome measures for open surgical repair. Both EVAR and open repair are effective in preventing aneurysm rupture, although late ruptures can occur with either treatment method. The late risk of rupture following EVAR is less that 1% per year using current endovascular devices. Aneurysmrelated death rate appears to be lower following EVAR compared to open surgery, primarily due to a lower perioperative mortality rate. Actuarial 5-year survival after both endovascular and open aneurysm repair is approximately 70%. Perioperative outcome measures favor EVAR over open repair for patients with suitable anatomy with reduced morbidity and more rapid patient recovery. Short and long-term outcomes following endovascular repair compare favorably to open repair. However, prospective studies are needed to better define the long-term outcomes using comparable endpoints. KEY WORDS: Aortic aneurysms, abdominal, surgery - Stents - Vascular surgical procedures. Effective treatment of abdominal aortic aneurysms (AAAs) was first introduced a little more than 50 years ago with the first successful open surgical repair by Freeman in 1951, 1 followed closely by DuBost 1 month later. 2 This led to explosive growth of the field of vascular surgery with rapid development and evolution of surgical instrumentation and techniques, perfection of graft and suture materials as well as diagnostic and patient management strategies. For more than 3 decades, open surgical repair has served as the gold standard of aneurysm treatment 3 with well-docu- Address reprint requests to: C. K. Zarins, MD, Division of Vascular Surgery, Stanford University, SHS H3600, Stanford, CA , USA. zarins@stanford.edu Division of Vascular Surgery Stanford University, Medical Center Stanford, CA, USA mented short and long-term results. 4-6 Success of open surgical repair has been primarily determined by the operative mortality rate in relation to the risk of aneurysm rupture without operation. Despite well recognized late failures following open surgery, 4, 7 these failures have largely been ignored in considering the overall effectiveness of open surgical repair in comparison to endovascular repair. Rather, long-term survival has been used as the primary long term measure of success of open surgical repair. 6 The introduction and rapid acceptance of endovascular aneurysm repair (EVAR) during the past decade has revolutionized the treatment of aneurysms and introduced new outcome measures, over and above survival, for the evaluation of treatment effectiveness. Closely monitored and controlled clinical trials resulted in the first approval of endovascular devices in the US by the FDA in , 9 Ongoing surveillance of these patients along with improved imaging capabilities and worldwide interest in EVAR has resulted in much closer scrutiny of results than has previously been afforded to open surgical repair. Moreover, new and different endpoints have been utilized for following patients with EVAR than have been used in the past for open surgical repair, making direct comparison of results for the 2 procedures difficult. The purpose of this review is to evaluate the short- and longterm effectiveness of EVAR in comparison to the results of open surgery using comparable primary endpoints. Since there has been no uniformity in the endpoints Vol No. 4 THE JOURNAL OF CARDIOVASCULAR SURGERY 321

2 ZARINS SHORT- AND LONG-TERM OUTCOME FOLLOWING ENDOVASCULAR ANEURYSM REPAIR TABLE I. Primary and secondary endpoints in evaluating the success of treatment of abdominal aortic aneurysms. Primary endpoints-endovascular and open repair Prevention of aneurysm rupture Prevention of aneurysm related death Primary procedure mortality Secondary procedure mortality Rupture or device related mortality Surgical conversion (aortic reoperation after open surgery) Survival Secondary endpoints Endovascular Endoleak Aneurysm enlargement Migration Graft patency Graft infection Secondary procedure rate Technical success rate Open repair Anastomotic pseudoaneurysm rate Graft patency Aortoenteric fistula Graft infection New aneurysm formation used to report the results of open and endovascular repair we will begin by defining the endpoints we have used in this analysis. What is the purpose of treating aneurysms? The natural history of untreated aortic aneurysms is to enlarge and rupture with death as the inevitable consequence of rupture. 5, 10, 11 The primary predictor of rupture is aneurysm diameter and the risk of rupture increases with increasing aneurysm size. 5 The risk of rupture of small aneurysms (<5.5 cm) can be low, provided there is close surveillance and early operative repair in the case of enlargement or the development of symptoms. However, despite such surveillance and prompt treatment, small aneurysms still rupture in approximately 1% of patients per year. 6, 12 Similarly, rupture can occur following treatment, be it endovascular 13 or open repair. 6, 14 Untreated aneurysms cm rupture at a rate of approximately 10% per year, with aneurysms larger than 6 cm having 10-25% or higher rupture rates. 10 Thus, since the primary and overriding purpose of treating aneurysms is to prevent their rupture and resultant patient death, the success of treatment efforts should be primarily measured in terms of their success in preventing aneurysm rupture and patient death. Some have assumed that the purpose of treating aneurysms is to prolong life. However, since the mere presence of an aneurysm does not shorten life, unless, of course, it ruptures or the patient dies as a result of the treatment itself, treatment of that aneurysm cannot be expected to prolong life. Rather, treatment of aneurysms is expected prevent premature death, thus leading to aneurysm specific death rates as a primary endpoint in evaluating the success of treatment. Since most patients with treated aneurysms die of causes unrelated to their aneurysm, overall survival, while useful as an endpoint, may not be very discriminating in evaluating different treatments for aneurysms. 6, 12 At times the purpose of treating aneurysms is described as the need to exclude them from the circulation. This leads to conclusions which identify endoleak as the major failure mode of endografting. 15 However, achieving the objective of eliminating endoleak does not necessarily ensure protection from rupture 13 or rupture related death, 16 suggesting that aneurysm exclusion and other indirect endpoints should be considered as secondary rather than primary endpoints of treatment. The primary and secondary endpoints in the treatment of AAAs are shown on Table I. Primary endpoints of treatment Prevention of rupture Prevention of aneurysm rupture is the primary purpose of both open and endovascular repair. Rupture may occur before, during the course of treatment or long after treatment is completed. Treatment related aneurysm ruptures, such as perforation of the aneurysm with an endovascular device, may de difficult to distinguish from rupture of a non-aneurysmal iliac artery or aortic neck or hemorrhage and death from other causes during the course of treatment. Thus, perioperative ruptures are reported inconsistently and may not be reported separately from perioperative mortality statistics. The most important measure in determining the success of aneurysm treatment in preventing rupture is the late (>30 days following treatment) aneurysm rupture rate. While success in preventing rupture is assumed with open surgical 322 THE JOURNAL OF CARDIOVASCULAR SURGERY August 2004

3 SHORT- AND LONG-TERM OUTCOME FOLLOWING ENDOVASCULAR ANEURYSM REPAIR ZARINS repair, this is not always the case. 6, 14 The endpoint of preventing rupture is suitable for both open and EVAR. Prevention of aneurysm related death Aneurysm related death for untreated aneurysms is directly related to the rupture rate. For treated aneurysms, aneurysm related death is the sum of 1) primary procedure mortality (death from any cause within 30 days of treatment or within the primary hospitalization, whichever is longer), 2) secondary procedure mortality (death from any cause within 30 days of secondary treatment or within the primary hospitalization for that treatment, whichever is longer) and 3) rupture or device related mortality (such as late aneurysm rupture and death with no treatment effort). In evaluating primary procedure mortality rates, it should be recognized that most published literature and most population based reports on operative mortality rates following open surgical repair refer to in-hospital mortality rates rather than the 30-day mortality rates most often used in evaluating EVAR. Avoidance of open surgical repair (surgical conversion) Avoidance of open abdominal surgery is a primary objective of EVAR and success in achieving this objective is a primary endpoint of analysis. This endpoint does not exist for open surgical repair. However, secondary intra-abdominal aortic procedures may be needed following open repair to treat hemorrhage, anastomotic pseudoaneurysms, graft occlusions, aortoenteric fistulae, graft infection and occasionally ruptures. 4, 7, 20 Such secondary aortic procedures may be considered to be surgical conversions of open abdominal repair and may be used for direct comparisons to EVAR. 20 Survival (all-cause mortality) Patient survival has long been used as a primary endpoint of aneurysm treatment and is equally applicable to open and endovascular repair. However, most patients with aneurysms are elderly and most have multiple comorbid conditions which are most likely to determine survival, provided the aneurysm has been treated. Thus, this endpoint may not be a sensitive measure for defining differences among treatment methods or endovascular devices. Secondary endpoints of treatment A number of secondary endpoints are useful in the evaluation of both endovascular and open aneurysm repair. 21 Secondary endpoints for endovascular repair include endoleak, aneurysm enlargement, device migration and component separation, device integrity, graft patency, secondary treatment procedure rate and procedural success rate (Table I). These endpoints are largely image-based findings and are important in evaluating failure modes of EVAR. They may help identify patients who are at increased risk of post-treatment aneurysm rupture allowing appropriate secondary treatments to be carried out in order to avoid aneurysm rupture. Secondary endpoints have long been used to evaluate open surgical repair including rates of anastomotic pseudoaneurysm and new aortoiliac aneurysm, graft patency, as well as aortoenteric fistula and graft infection rate. 6, 7 However, direct comparisons of secondary endpoints between open and EVAR have rarely been carried out. 20 Patient selection Patient selection is an important factor which influences both short- and long-term outcome after aneurysm treatment. For EVAR, anatomic morphologic considerations are of paramount importance in proper patient selection and may significantly influence both primary and secondary outcome measures. Angulated and tortuous aortic necks as well as short, wide or absent infrarenal aortic necks can preclude EVAR, as can small, tortuous or diseased iliac arteries. Advanced age or comorbid conditions rarely exclude patients from consideration of EVAR. Conversely, anatomic considerations usually do not limit successful open repair, whereas severe patient comorbidities may prohibit open surgical repair due to excessive perioperative risk. These differences complicate the direct comparison of open to EVAR. Although the FDA clinical trials were limited to good risk patients with concurrent surgical controls, primary endpoint comparison was based on a 1-year time frame. Subsequent follow-up included close monitoring of EVAR patients but surgical control patients did not receive the same degree of image analysis and followup scrutiny, thus making long-term comparison to EVAR difficult. Vol No. 4 THE JOURNAL OF CARDIOVASCULAR SURGERY 323

4 ZARINS SHORT- AND LONG-TERM OUTCOME FOLLOWING ENDOVASCULAR ANEURYSM REPAIR TABLE II. Aneurysm rupture rate after endovascular 1 and open 2 repair. Authors Publication Open/EVAR Number Mean (median) Perioperative Late rupture Total of patients follow-up rupture rate (%) rate (%) (%) Greenberg et al EVAR mo Abraham et al EVAR mo Dattilo et al EVAR mo Matsmura et al EVAR mo Moore et al EVAR mo Criado et al EVAR mo Zarins et al EVAR mo Dalainas et al EVAR mo Johnston Open mo n.a Hallett et al Open y n.a UK Small Aneurysm Trial Participants Open y n.a Biancari et al Open y n.a ) Includes anastomosis disruptions and pseduoaneurysm ruptures. 2) Includes pseudoaneurysm ruptures, aneurysm ruptures and dissections. Primary outcome measures Prevention of aneurysm rupture Both endovascular and open surgical repair are effective in preventing aneurysm rupture. However, the risk of rupture is not totally eliminated and late aneurysm ruptures have been reported following both endovascular and open repair 6, 8, 14, 16, 22 (Table II). 4-9, 14, The late rupture rate following EVAR ranges from 0% to 1.3% with a mean less than 1% per year. 8, 16 Ruptures have been reported using all endovascular devices and may be related to endovascular device failure 16, 25, 29 or failure of fixation or seal at the aortic neck or iliac arteries. 8, 9, 25-27, Ruptures have been found in patients with no endoleaks and decreasing aneurysm size as well as in patients with endoleaks and increasing aneurysm size. 13, 34 Harris et al. reported the incidence and risk factors for late rupture, conversion, and death after endovascular in patients in the Eurostar registry and found 14 patients (0.6%) who sustained aneurysm rupture. 35 The incidence of rupture peaked at 18 months and the annual cumulative rate of rupture approximated 1% (1.4% in the 1 st year and 0.6% in the 2 nd year). Among patients treated during the AneuRx clinical trial, 0.4% of patients died due to aneurysm rupture during a 6-year follow-up. 8 Kaplan-Meier analysis revealed freedom from early and late rupture in 97% of patients at 3-years follow-up. There was no late increase in risk of rupture and freedom from rupture was unchanged at 97% at 5 years with 286 patients at risk at this timepoint. The long-term risk of rupture following open repair is reported to vary from 0.4% to 7.6% (Table II). The figure 7.6% includes also thoracic aneurysm ruptures and dissections. In a prospective multicenter trial of long-term outcome after open AAA repair, risk of rupture was 1.5% with follow-up extending to 6 years. 14 There was an additional 1.5% risk of rupture of unassociated thoracic aneurysm in these patients. In a long-term outcome analysis of the UK Small Aneurysm Trial, 0.4% of patients died due to rupture after repair of AAA. 6 In a long-term study of 307 patients who underwent open AAA repair, the early and late rupture rate was 3% during the mean follow-up of 5.8 years. 4 Thus, both open and endovascular repair appear to have a low but persisting risk of rupture following treatment, suggesting that all patients with aneurysms should undergo long-term monitoring and follow-up surveillance. Prevention of aneurysm-related death Aneurysm-related death is a cumulative measure which includes primary and secondary procedure mortality as well as any aneurysm or graft related death. Primary perioperative mortality rates following endovascular and open aneurysm repair are shown in Table III. 6, 12, 14, 17-20, 25, 30, Mortality following endovascular repair ranges from 0-4% with a mean of 2% among nearly treated patients. 8, 9, 23, 26, 27, 36, 46, 47 Mortality following open surgical aneurysm repair range from 0% to 8% with a mean of 6% among nearly patients reported over the past 10 years (Table III). 324 THE JOURNAL OF CARDIOVASCULAR SURGERY August 2004

5 SHORT- AND LONG-TERM OUTCOME FOLLOWING ENDOVASCULAR ANEURYSM REPAIR ZARINS TABLE III. Primary procedure perioperative mortality rates: endovascular vs open surgical repair. Authors Publication Number Operative mortality year of patients SC/MC/POP* Open/EVAR (%) Arko et al SC EVAR 0.6 Dattilo et al SC EVAR 1.6 Alric et al SC EVAR 3.4 Ouriel et al SC EVAR 1.7 May MC EVAR 4.2 Zarins et al MC EVAR 1.8 Peppelenbosch et al MC EVAR 2.5 Lee et al MC EVAR 1.3 Endovascular repair (total) % Lloyd et al SC Open 2.4 Arko et al SC Open 3.7 Hertzer et al SC Open 1.2 Sasaki et al SC Open 1.0 Johnston et al MC Open 5.4 Dardik et al MC Open 3.5 UK Small Aneurysm Trial Participants MC Open 5.4 Lederle et al MC Open 2.4 Dimick et al MC Open 4.2 Lee et al MC Open 3.8 Katz et al POP Open 7.5 Lawrence et al POP Open 8.4 Pearce et al POP Open 5.7 Huber et al POP Open 4.2 Biancari et al POP Open 5.2 Open surgery (total) *) SC: single center study; MC: multi center study; POP: polulation based study. TABLE IV. Thirty day mortality rates in controlled clinical trials: endovascular vs open repair. Authors Publication No. of patients No. of patients 30-day mortality year Device EVAR Open repair EVAR repair vs open (%) p value Zarins et al AneuRx vs 0,3 NS Matsamura et al Excluder vs 0,3 NS Criado et al Talent vs 0,3 NS Moore et al EVT/Guidant vs 2.7 NS Greenberg et al Zenith vs 2.5 NS Single center reports generally have a lower mortality rate averaging 2% compared to multicenter reports which have an average mortality rate of 4%. 3, 6, 12, 14 Operative mortality rates in population-based studies average 7%. 17, 19, 45 If one considers only the most recent studies, reported in the past 2 years, among patients treated with EVAR, the mortality rate was 2% compared to an operative mortality of 4% among approximately patients treated with open surgery. 6, 12, 20, 38, 40, 43 Thirty-day mortality rates in studies comparing endovascular vs open repair Prospective, multicenter clinical trials of individual endovascular devices have been performed on good risk patients and have included open surgical control patients. These controlled clinical trials have found no significant difference in 30 day perioperative mortality rates between endovascular repair and open surgical repair (Table IV). 9, 22, 26, 27, 48 Perioperative mortality rates after endovascular repair varied Vol No. 4 THE JOURNAL OF CARDIOVASCULAR SURGERY 325

6 ZARINS SHORT- AND LONG-TERM OUTCOME FOLLOWING ENDOVASCULAR ANEURYSM REPAIR between 0.8% and 1.7% and after open repair varied from 0% to 2.7%. The lack of a difference in 30-day mortality between EVAR and open repair in prospective controlled trials appears to be due to a low perioperative mortality rate in both treatment groups and may be due to the inclusion of low risk patients in these clinical trials. In non-controlled reports comparing open to endovascular repair higher risk patients have been included and mortality rates for EVAR appear to be lower than for open repair. 20, 38 Arko et al. found a significantly lower 30-day mortality rate (0.6%) among 174 patients treated with EVAR compared to 243 concurrent patients treated with open repair (3.7%; p<0.05%). 21 Similarly, the 2001 National Inpatient Sample Database of patients revealed that the 30-day mortality following endovascular repair (1.3%) was significantly lower than following open surgery (3.8%), (p=0.0001). 38 It appears that endovascular patients are often older and have higher surgical risk, yet the perioperative mortality rates remains low. Thus, it seems that there is a reduced operative mortality rate for EVAR compared to open surgery, particulary for poor risk patients who may be at higher operative risk for open surgery. Secondary procedure mortality The secondary procedure rate following endovascular repair is relatively high, ranging from 10% to 30% during the first 2 years after EVAR but secondary procedure mortality rates are low. Secondary procedures most often are percutaneous angiographic procedures to treat endoleak or endovascular treatments through groin incisions. Such endovascular treatments comprise 90% of secondary procedures and have a very low mortality and morbidity. 20, 27, 49 Mortality rate following emergent surgical conversions for failed EVAR has been high, ranging from 18% to 25%. 23, 46, The secondary procedure rate to correct graft or aneurysm related complications after open surgical repair range from 8% to 13%. 4, 7, 20 The mortality rate following secondary operations to treat graft-related complications of open repair, such as false aneurysms, graft occlusions, graft infections or aortoenteric fistulae, range from 6% to 28%. 4, 7, 20, 54 Aneurysm related death Aneurysm-related death rates following EVAR range from 0.6% to 3.4% at follow-up periods ranging from 1 year to 3 years. Kaplan-Meier (KM) analysis of all patients treated during the course of the AneuRx clinical trial revealed an aneurysm-related death rate of 3% at 3 years. 8 The Eurostar registry of patients revealed an aneurysm-related death rate of 6% at 5 years by Kaplan-Meier analysis. 30 Although the Eurostar registry, which includes many devices no longer in use, suggests that there is an accelerating late adverse event rate following EVAR, 35 this has not been the case in the AneuRx trial where the aneurysmrelated death rate and rupture rate have remained unchanged at 3% at the 3, 4 and 5 year marks. 8 Aneurysm-related death has only recently been introduced as a measure to evaluate the long-term results of open aneurysm repair. 20 Calculation of aneurysm-related death rates from the published literature of long-term results following open surgery suggests that aneurysm-related death following open repair ranges between 4% and 6% at a mean follow-up of 5- years (Table V). 4, 6-8, 14, 20, 30, 32, 48, 54 In a single center 7 year retrospective analysis, 243 patients treated with open repair were compared to 174 patients treated with EVAR. The 30-day mortality following open surgery was 3.7% and following EVAR was 0.6 % (p<0.05). During the follow-up period, secondary procedures were performed in 21 open surgery patients with a 5% mortality rate and in 24 EVAR patients with 0% mortality rate (n.s.). Thus the aneurysm-related death rate following open surgery was 7-fold higher (4.1%) than following EVAR (0.6%), (p<0.05). 20 A definitive answer on the differences between aneurysm-related death for EVAR vs open repair will require results from prospective randomized clinical trials. Surgical conversion Early surgical conversion of patients to open repair has been reported in 0% to 5% of patients within 30 days of EVAR. 9, 16, 25, 26 The causes of early conversion have been access failure, arterial trauma, improper graft position, endoleak, acute rupture, or compromised limb flow. 9, 25 Early conversion rates have decreased as experience with EVAR has increased. In the EVT/Guidant bifurcated endograft clinical trial involving 574 patients, the intraoperative conversion rate decreased from 9.7% in the Phase II study to 5.2% in the Phase III study. 9 Late surgical conversion rates have been low, ranging between 1.5% and 4%. 9, 16, 25, 46, The most common reasons for late surgical conversion are 326 THE JOURNAL OF CARDIOVASCULAR SURGERY August 2004

7 SHORT- AND LONG-TERM OUTCOME FOLLOWING ENDOVASCULAR ANEURYSM REPAIR ZARINS TABLE V. Aneurysm-related death after endovascular and open repair. Authors Publication Mean or median Number of 30-day Late AAA Aneurysm related year EVAR/open follow-up of patients mortality mortality death rate Arko et al EVAR 12 mo Zarins et al EVAR 35 mo Ouriel et al EVAR 11 mo Greeeberg et al EVAR 12 mo Peppelenbosch et al EVAR 18 mo Crawford et al Open 4.5 y Johnston et al Open 5 y Hallett et al Open 5.8 y UK Small Aneurysm Trial Participants Open 8 y Arko et al Open 17 months Biancari et al Open 8 years Greenberg et al Open 12 mo endoleak, aneurysm enlargement, device migration or kinking, and rarely graft infection. 9, 55 In a retrospective review of 319 patients treated with EVAR from 1994 to 2002, Terramani et al. reported a 2.8% surgical conversion rate with device-specific conversion rates of 0.8% for AneuRx, 3.1% for Excluder, 3.1% for Ancure, and 10.7% for EVT tube grafts. 55 Tube grafts are rarely used in current practice because of the high late failure rate. 50, 56, 57 Moore reported the 5- year outcome of Guidant bifurcated endografts with a late conversion rate of 2.8%. 9 In a 6-year analysis, late surgical conversion rate for the AneuRx device was 3.2%. 8 The surgical conversion rate for the Excluder graft during the first 2 years following endografting is 1.3%. 26 Although persisting endoleaks are often indications for conversion, patients with type II endoleak have a low risk for rupture and usually do not require surgical conversion, unless there is significant aneurysm enlargement or evidence or poor graft fixation. Late surgical conversion following open repair Secondary abdominal aortic operations to treat late complications of open repair, such as anastomotic pseudoaneurysms, graft occlusions, graft infections and aortoenteric fistulae are analogous to surgical conversion following EVAR. The need for late surgical conversions following open repair have been reported to range from 2% to 8% 4, 7, 20 at a mean following time of 6 years. While secondary open surgical procedures (such as return to the OR for bleeding, bowel obstruction), occur with some frequency during the early postoperative period following open repair, these procedures are rarely separately reported. Such procedures could be counted as early surgical conversions, since they require second abdominal procedure within 30-days of the primary procedure of open repair. In a comparison of early and late surgical conversions among 417 patients undergoing primary elective treatment for infrarenal AAA, surgical conversions were performed in 9 of 243 patients (3.7%) treated with open repair and 2 of 174 patients (1.1%) treated with EVAR. This difference was not statistically significant (p=0.09) and suggests that the surgical conversion rates in the 2 procedures are similar for the 2 procedures. 20 Survival Life expectancy of patients with aortic aneurysms is reduced compared to an age-matched population of persons without aneurysms, primarily due to associated cardiac disease. 14 Actuarial 5-year survival following endovascular repair is 64-75% and is no different from patients treated with open surgical repair, 64-77%. 6, 9, 12, 30 The most common reason for early death after endovascular and open repair has been cardiac failure (30%). 39, 58 Secondary outcomes measures Periprocedural measures Technical success in deployment of endovascular devices is high, ranging from 96% to 100%. 8, 9, 23, Vol No. 4 THE JOURNAL OF CARDIOVASCULAR SURGERY 327

8 ZARINS SHORT- AND LONG-TERM OUTCOME FOLLOWING ENDOVASCULAR ANEURYSM REPAIR TABLE VI. Secondary outcome measures after endovascular aneurysm repair with FDA approved devices. 6 months 1 year 2 years Endoleak Medronic AneuRx 13.7% 13.9% 16.7% (135/987) (132/951) (129/772) Gore Excluder 20% 17% 20% (36/177) (27/156) (24/119) Cook Zenith n.a. 8.2% 7.1% (21/256) (12/169) Enlargment definition 6 months 1 year 2 years Aneurysm enlargement Medronic AneuRx >5 mm 5.8% 7.0% 8.3% (41/710) (48/689) (46/551) Gore Excluder 5 mm 3% 7% 14% (5/182) (13/181) (21/146) Cook Zenith >5 mm n.a. 1.1% n.a. (3/268) Migration definition 6 months 1 year 2 years Migration Medronic AneuRx >5 mm 1.1% 2.2% 5.3% (10/920) (20/904) (39/732) Gore Excluder >10 mm 3.0% 2.3% 1.4% (5/171) (4/175) (4/144) Cook Zenith >5 mm n.a. 2.3% n.a. (6/261) 25-27, 46, 47 Periprocedural outcome measures such as blood loss and transfusion requirements, ICU length of stay, recovery time, time to ambulation and length of hospital stay have consistently come out in favor of EVAR compared to open surgery. 9, 26, 27, 58 This is consistent with the fact that EVAR requires small groin incisions and no aortic cross-clamping while open repair requires direct exposure of the aorta and aortic cross clamping. Short term recovery following EVAR is significantly faster for EVAR, with few patients requiring posthospital care, in comparison to open repair where many patients require skilled nursing and rehabilitation care following hospital discharge. 21, 38 Within 6-12 months, there is no significant difference in patient recovery between EVAR and open repair. 21 In a study of perioperative outcomes of patients treated with EVAR compared to patients treated with open repair, the mean and median hospital length of stay was 5 days shorter after EVAR compared to open repair and the rate of discharge to an institutional facility vs home was almost 2/3 less after EVAR than open repair (p=0.0001). 38 EVAR-related secondary outcome measures Secondary outcome measures of endoleak, aneurysm enlargement and device migration/component separation are shown on Table VI. Endoleaks are radiographic or ultrasound evidences of blood flow in the aneurysm sac and are commonly seen following EVAR. At 1 month, endoleak rates range from 7% to 22%. 8, 24, 25, 59 Endoleak rates at 1-2 years following EVAR range from 7% to 20% (Table VII) 6-9, 12, 14, 16, 23, 26, 60 and persist in 10-15% of patients at 5-year following treatment. 8, 9, 30 Endoleaks are a strong predictor of aneurysm enlargement, 61 however, the significance of endoleak in relation to clinical outcome, particularly with respect to the primary endpoints of aneurysm rupture and aneurysm related death is less clear. Independent Core Laboratory evaluation of endoleaks in the AneuRx clinical trial revealed that the presence of an endoleak following stent graft repair was not a significant predictor of primary or secondary outcome measures. 61 On the other hand, specific endoleak types, such as proximal type I endoleaks and type III endo- 328 THE JOURNAL OF CARDIOVASCULAR SURGERY August 2004

9 SHORT- AND LONG-TERM OUTCOME FOLLOWING ENDOVASCULAR ANEURYSM REPAIR ZARINS TABLE VII. Survival following endovascular and open aortic aneurysm repair: 5 year Kaplan-Meier estimates. Authors Publication Number of 1-year 2-year 3-year 4-year 5-year year Device patients survival survival survival survival survival Endovascular repair Zarins et al AneuRx N.A. Matsamura et al Excluder Moore et al EVT/guidant Vallabhaneni et al Several devices a b 76 b Greenberg et al Zenith Lifeline Unpublished 5 devices Total Open surgical repair Johnston et al Koskas et al d89 d Biancari et al c87 c Lederle et al UK Small Aneurysm Trial Participants Moore et al Total a ) Data from Eurostar registry. Devices: AneuRx, EVT/Ancure, Excluder, Stentor, Talent, Vanguard, Zenith and Other. b ) Five-year survival from Eurostar report by Peppelenbosch et al. (2004). c ) Thirty-day mortality (4.5% for elective operations) added included to the survival figures in this study. d ) Thirty-daymortality (4.8% for elective operations) added to the survival figures in this study. leaks are strongly associated with poor outcome and aneurysm rupture. 35 Such endoleaks originate from device attachment sites in the aortic neck and iliac arteries, or at modular junctions allowing direct communication of pulsatile aortic flow into the aneurysm sac. Attachment site (type I or III) endoleaks have been reported in 7-16% of patients at 1 year and may occur with all current devices. 8, 9, 26, 27, 29 Type I and III endoleaks should be promptly treated by either endovascular technique or open surgical repair if endovascular repair is unsuccessful and the patient s overall health status permits. Although there is a clear relationship between type II endoleak and aneurysm enlargement, 31, 62 no clear causal relationship between the presence of persistent type II endoleak and aneurysm rupture has been established. 35, 63 While isolated case reports have documented aneurysm rupture in patients with type II endoleaks following endovascular repair, 35, 64 they may be associated with unrecognized type I endoleaks. 65 Type II endoleaks are seen in 10-20% of patients following EVAR. Although many of these resolve with time without any interventions, many persists. 31 Intrasac Doppler velocities have been found to predict whether a type II endoleak will spontaneously seal or how it reacts to endovascular treatment. 66 To date, there is no prospective study comparing the watchful waiting of type II endoleaks versus aggressive management. While some propose aggressive treatment of type II endoleaks, 67, 68 others suggest watchful waiting of type II endoleaks. 63 Long-term prospective studies are needed to clarify the importance of type II endoleaks. Aneurysm enlargement Numerous investigators have reported on size changes following EVAR, with or without endoleaks. 62, However, the true significance of aneurysm enlargement with respect to the primary endpoints of aneurysm repair remains undefined. Indeed, aneurysm ruptures have been reported in patients with decreasing, 62 increasing 31 and stable aneurysm sizes following endovascular repair 62 suggesting that factors other than aneurysm size changes may be the primary determinants of aneurysm rupture. An analysis of 46 patients with aneurysm enlargement of 5 mm or more following EVAR revealed no increased risk of aneurysm rupture or decrease in patient survival during a 3-year observation period. 62 Vol No. 4 THE JOURNAL OF CARDIOVASCULAR SURGERY 329

10 ZARINS SHORT- AND LONG-TERM OUTCOME FOLLOWING ENDOVASCULAR ANEURYSM REPAIR Aneurysm enlargement rates reported from US clinical trials of FDA approved devices are shown on Table VI. At 3 years, enlargement of 5 mm or more have been seen in approximately 12% of patients treated with EVAR. 8, 30 However, enlargement in and of itself without evidence of type I endoleak or evidence of insecure fixation has not been shown to be a predictor of rupture. 62 Aneurysm size rather that enlargement of >5 mm appears to be a more reliable indication of potential rupture. Nonetheless, patients with evidence of enlargement with persisting endoleak are often treated with surgical conversion. 26 Aneurysm enlargement may occur in the absence of endoleak. Such enlargement has been noted in 1-5% of patients following EVAR 9, 16, 26, 75 and has been attributed to endotension. 76 The significance of such enlargement is unclear and it is unknown whether patients with such enlargement are of risk for aneurysm rupture. Surgical conversion may be indicated for large diameter aneurysms with progressive enlargement under these circumstances. Migration Continuous downward displacement forces are exerted on aortic devices by the pulsatile nature of blood flow with cumulative effects over time. Thus, it is not surprising that migration has been noted with all current endovascular devices and configurations, including those with modular design, unibody design, infrarenal fixation, suprarenal fixation, hook and barb fixation, longitudinal columnar support and flexible designs. 8, 9, 26, 27, 30, 75 Migration has also been noted with prosthetic aortic grafts placed at open surgery if there is fracture or failure of the anastomostic suture. The risk of migration increases with time and can result in loss of device fixation and seal proximally, distally, or at modular junctions resulting in aneurysm rupture. The reported incidence of endograft migration varies widely and comparison is complicated by different definitions of endograft migration and differing follow-up periods. Migration has been noted with all FDA-approved endovascular devices with similar migration rates of 2% at 1 year. 8, 24, 26 Longer follow-up, to 5 years, has been reported from the prospective, multicenter AneuRx clinical trial with the finding of stent graft migration in 94 of patients (8.4%) with a mean time following implantation of 30±11 months (range 0.5 to 61 months). Kaplan-Meier estimates for freedom from migration was 99% at 1 year (migration on 9 of patients at risk), 93% at 2 years was (32 migrations in 852 patients at risk) and 81% at 3 years was (35 migrations in 427 patients at risk). 8 The cause of stent graft migration was investigated with univariate and multivariate analysis of all relevant factors including aneurysm size, neck length and diameter, iliac diameter and device sizing parameters. The only significant predictors of stent graft migration were proximal fixation length (p=0.005) and the distance from the renal artery to the top of the stent graft (p=0.001). In addition, the clinical site at which the procedure was done was a highly significant predictor of migration risk (p<0.001). 77 The migration rate varied from 0% to 30% among the 13 clinical sites, and these findings suggest that migration was related to the precision of the device deployment rather than a characteristic of device itself. Deployment of the device far below the renal arteries or in the proximal part of the aneurysm sac was associated with high risk of migration. For each millimeter increase in the distance between the renal arteries and the top of the stent graft the hazard of device migration increased by 5.8%. 72 Improvements in intraoperative imagining and improved precision in deployment techniques since completion of the clinical trial in 1999 have significantly reduced the risk of migration. Graft patency rates of current endovascular devices used to treat aneurysms are high, ranging from 96% to 98%. 8, 75, 78 Early design devices without structural support to prevent compression have had high graft limb thrombosis rates of 11-13%. 75, 79 Graft limb occlusion rates following open surgical aneurysm repair have been reported to range from 2-5% over time periods extending to 15 years. 4, 7 Conclusions Both open and endovascular repair of AAAs are highly effective in achieving the primary objective of aneurysm repair, namely prevention of aneurysm rupture. However, the potential for rupture is not entirely eliminated with either technique and thus patients with aortic aneurysms require long-term monitoring and surveillance regardless of treatment method. When considering the 2 primary treatment options for patients with aortic aneurysms, both short- and long-term results need to be considered. This requires long-term outcome analysis over and above survival 330 THE JOURNAL OF CARDIOVASCULAR SURGERY August 2004

11 SHORT- AND LONG-TERM OUTCOME FOLLOWING ENDOVASCULAR ANEURYSM REPAIR ZARINS as the primary endpoint for comparison of the 2 treatment strategies. The primary endpoints for evaluating endovascular and open treatments methods for aneurysms are effectiveness in: a) preventing aneurysm rupture, b) preventing aneurysm-related death, c) avoiding surgical conversion (EVAR) or secondary aortic or graft-related surgery (open repair) and d) enhancing overall survival. Secondary endpoints include treatment related morbidity, complications secondary treatments and costs. Short-term results of EVAR are significantly better than for open surgery with reduction in blood loss, shorter hospital stay, more rapid recovery and earlier return to function. Perioperative mortality rates for young, good-risk patients are similar for open and EVAR. However, many patients with aortic aneurysms are elderly and have multiple co-morbidities with increased surgical risk. When broad populations of aneurysm patients are considered, perioperative mortality rates for EVAR appears to be significantly lower than for EVAR. Thus, short-term results favor EVAR over open repair for selected patients who have suitable anatomy. Unfortunately many patients with aortic aneurysms do not have suitable morphology and thus are not candidates for EVAR. The primary measure for long-term effectiveness in treating aortic aneurysms is aneurysm related death rate which includes both short-term mortality related to the primary treatment and late mortality related to secondary treatments, aneurysm rupture or graft complications. Aneurysm-related death rate appears to be significantly lower for EVAR, primarily as a result of a lower initial perioperative mortality rate. While it is possible that late deaths due to complications of EVAR may overcome this early advantage, there is no evidence that this point in time to support this notion. Prospective randomized trials comparing these 2 procedures will be required to resolve this issue. Surgical conversions following EVAR and secondary abdominal operations to treat aneurysm or graft complications following open repair may occur with similar frequency, but data is sparse in this regard. Mortality following such procedures is significantly higher than following primary procedures to treat aneurysms. Long-term survival of patients who have undergone treatment for AAAs is similar, regardless of method of treatment. This is consistent with the advanced age of patients with aneurysms and the fact that most die of causes unrelated to their aneurysm. The need for secondary treatments and the unresolved and ongoing issues of endoleak, aneurysm enlargement and endograft migration following EVAR must be taken into consideration when evaluating EVAR. Some of these issues may be device dependent and some may be related to the early learning curve of EVAR. 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