Stent-Graft Repair of Penetrating Atherosclerotic Ulcers in the Descending Thoracic Aorta: Mid-Term Results

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Stent-Graft Repair of Penetrating Atherosclerotic Ulcers in the Descending Thoracic Aorta: Mid-Term Results Philippe Demers, MD, MS, D. Craig Miller, MD, R. Scott Mitchell, MD, Stephen T. Kee, MD, Lynn Chagonjian, RN, and Michael D. Dake, MD Department of Thoracic and Cardiovascular Surgery and Division of Cardiovascular and Interventional Radiology, Stanford University School of Medicine, Stanford, California CARDIOVASCULAR Background. Localized aortic pathoanatomic abnormalities are good targets for endovascular stent-grafting but only short-term results have been reported. Our objective was to determine the effectiveness of endovascular stentgraft treatment of patients with descending thoracic atherosclerotic penetrating atherosclerotic ulcers (PAU) and to identify risk factors for treatment failure. Methods. Between 1993 and 2000 endovascular repair of PAU with first-generation (custom-fabricated) and second-generation (commercial) stent-grafts was performed in 26 patients (mean age, 70 years), 6 (23%) of whom had rupture. Fourteen patients (54%) were not candidates for open surgical repair. Follow-up was 100% complete (average, 51 months; maximum, 114 months). Outcome variables considered in the multivariable analysis included death and treatment failure (composite end-point comprising early death, endoleak, stent-graft mechanical fault, late aortic event, reintervention, and aortic-related or sudden death). Results. Three patients (12% 7% [ 70% confidence limits]) died within 30 days and 2 had an early type I endoleak. Primary success rate was 92%. Actuarial survival estimates at 1, 3, and 5 years were 85% 8%, 76% 8% and 70% 10% respectively and actuarial freedom from treatment failure was 81% 8%, 71% 9% and 65% 10%. Multivariable analyses identified previous cerebrovascular accident (hazard ratio [HR] 17.1, p 0.02) and female sex (HR 7.4, p 0.08) as independent risk factors for death. For treatment failure the predictors were increasing aortic diameter (HR 1.1 [per mm above the mean value], p 0.01) and female sex (HR 5.5, p 0.09). Conclusions. Endovascular stent-graft repair is effective but not curative treatment for selected, high surgical risk, elderly patients with a descending aortic PAU over the medium term. Assiduous serial follow-up imaging after stent-grafting is mandatory to detect late complications especially in those with a large aorta. (Ann Thorac Surg 2004;77:81 6) 2004 by The Society of Thoracic Surgeons Originally described by Shennan in 1934 [1] the natural history of atherosclerotic penetrating atherosclerotic ulcers (PAU) in the descending thoracic aorta was appreciated only in the 1980s, coinciding with advances in vascular imaging techniques [2]. Penetrating ulcers of the aortic wall are caused by rupture of an atherosclerotic plaque through the internal elastic lamina with subsequent hematoma formation between the media and the adventitia [3]. Unlike classic aortic dissection these localized lesions are usually located in the descending thoracic aorta, or type B according to the Stanford classification [4, 5], and can occasionally be associated with intramural hematoma (IMH). Reports discussing prognosis and treatment however did not distinguish between the two types of IMH, namely IMH caused by PAU and IMH without intimal disruption [6]. Recently Ganaha and associates [5] and Coady and coworkers [7] Accepted for publication April 1, 2003. Address reprint requests to Dr Miller, Department of Cardiothoracic Surgery, Falk Cardiovascular Research Center, Stanford University School of Medicine, Stanford, CA 94305-5247; e-mail: dcm@stanford.edu. recognized the more serious nature of PAU, with 40% to 50% of acutely symptomatic patients progressing to acute classic dissection or aortic rupture during initial hospital admission. The Yale group also documented late rupture as well as progressive aortic dilatation in patients with PAU treated medically [8]. Therefore early surgical graft replacement of the aorta is now advocated in symptomatic patients especially those with persistent pain, increasing pleural effusion, or with a large or expanding PAU [5, 7]. Endovascular stent-graft treatment of thoracic aortic diseases is a less invasive alternative to open surgical repair for selected, high surgical risk patients [9 11] and three reports have described the short-term results of endovascular treatment of PAU with stentgrafts [12 14]. Because such descending thoracic aortic focal lesions should be good anatomic targets for endovascular stent-grafts this approach is attractive, especially as many of these patients are quite elderly and have many comorbidities that make them poor surgical Doctors Mitchell and Dake disclose that they have a financial relationship with W. L. Gore. 2004 by The Society of Thoracic Surgeons 0003-4975/04/$30.00 Published by Elsevier Inc doi:10.1016/s0003-4975(03)00816-6

CARDIOVASCULAR 82 DEMERS ET AL Ann Thorac Surg STENT-GRAFTS FOR PENETRATING ULCERS 2004;77:81 6 Table 1. Preoperative Clinical Characteristics Characteristic Number Percent Age (years) 70 8 Sex Male 18 69% Female 8 31% Previous cardiac surgery 7 27% Hypertension 20 77% Smoking history 18 69% Coronary artery disease 8 31% Congestive heart failure 3 12% Previous cerebrovascular accident 4 16% Chronic obstructive pulmonary 13 50% disease Renal failure 3 12% New York Heart Association functional class I 13 50% II 10 38% III 3 12% IV 0 0% Not open surgical candidate 14 54% Rupture or contained aortic rupture 6 23% Stanford classification Type A 0 0% Type B 26 100% Presentation Acute ( 14 days of onset) 18 70% Chronic ( 14 days after onset) 8 30% Interval between onset and procedure (days) 17 17 candidates. We reviewed 26 patients with symptomatic descending thoracic aortic PAU treated with endovascular stent-grafts over 8 years to determine the mid-term results of this approach and to identify risk factors for treatment failure. Patients and Methods From March 1993 to December 2000, 26 consecutive patients underwent endovascular treatment of descending thoracic PAU with first-generation ( home brew, custom-fabricated, Dacron-covered self-expandable Z stents) or second-generation (Excluder, W.L. Gore, Flagstaff, AZ) stent-grafts on the Cardiovascular Surgical Service at Stanford University Medical Center under an investigational protocol approved by the Stanford University School of Medicine Institutional Review Board. The study population consisted of 18 men and 8 women with an average age of 70 8 years (range, 55 to 85). As shown in Table 1 most patients had several risk factors; in fact 14 patients (54%) were judged by a surgeon not to be reasonable operative candidates for conventional open surgical repair owing to a variety of cardiac, pulmonary, neurologic, or renal comorbidities. The interval between the onset of symptoms and the endovascular procedure was 17 17 days (range, 6 hours to 60 days). Indications for treatment were aortic rupture in 6 patients (23%), persistent or recurrent pain despite Fig 1. Aortogram before and after stent-graft placement showing (A) a large penetrating atherosclerotic ulceration in the descending thoracic aorta; and (B) complete exclusion of the penetrating ulcer after stent-graft placement. maximal medical therapy in 14 patients (54%), and progression of PAU or IMH size in 6 patients (23%). All patients underwent spiral computed tomographic angiography (CTA) scanning with three-dimensional reconstruction and calibrated aortography before stentgraft placement to determine the location, length, and diameter of the diseased aortic segment. The diagnosis of PAU pivoted on the presence of a deep ulcerated lesion in the aortic wall with or without associated hematoma and the absence of a demonstrable intimal flap or tear (Fig 1). Stent-graft dimensions were calculated from the CTA images (oversized by 10% to 15% compared with the landing zone diameters) and were at least 30 to 40 mm longer than the target lesions to ensure adequate wall contact and a tight circumferential seal. Location and size of intercostal arteries were assessed using CTA and angiographic images and stent-graft deployment was planned so as to minimize the number of intercostal arteries covered by the prosthesis, especially in cases of PAU located in the lower third of the descending thoracic aorta. First-generation stent-grafts (n 19) were customfabricated from modified Gianturco self-expandable Z stents (Cook, Bloomington, IN) covered with a woven polyester graft (MediTech Division, Boston Scientific Corporation, Natick, MA) that had the crimp ironed flat. A long, large (22F to 24F) sheath-dilator-pusher rod delivery system (Cook, Bloomington, IN) was used for deployment and usually had to be advanced into the aortic arch. A second-generation commercially manufactured Gore Excluder stent-graft (W.L. Gore and Associates, Flagstaff, AZ) was used in 7 patients. This device is a self-expanding nitinol stent lined with expanded polytetrafluoroethylene (eptfe) graft material delivered using a coaxial over-the-wire technique with the sheath only advanced as far as the diaphragm. The size of the delivery system varied between 20F and 24F depending on the diameter of the device used. Deployment techniques have been previously described in detail [7 9]. General anesthesia was used in all patients. After surgical exposure of the artery used for

Ann Thorac Surg DEMERS ET AL 2004;77:81 6 STENT-GRAFTS FOR PENETRATING ULCERS Table 2. Operative Data Variable Number Percent Maximal aortic diameter (mm) 52 8 Length of diseased aortic segment (mm) 68 3 Proximal landing zone diameter (mm) 31 3 Distal landing zone diameter (mm) 31 3 Proximal landing zone Distal arch 1 4% Proximal third, descending aorta 13 50% Mid third, descending aorta 10 38% Distal third, descending aorta 2 8% Distal landing zone Proximal third, descending aorta 3 12% Mid third, descending aorta 11 42% Distal third, descending aorta 10 38% Supraceliac abdominal aorta 2 8% Type of stent-graft First generation 19 73% Second generation 7 27% Surgical access Femoral artery 14 54% Iliac artery 3 12% Infrarenal abdominal aorta 6 23% Old abdominal aortic graft 2 8% Aortic arch 1 4% Number of stent-grafts 1.2 0.5 More than 1 stent-graft used 4 15% Stent-graft length (mm) 123 7 Stent-graft diameter (mm) 33 3 Transposition of subclavian artery 1 4% Infrarenal aortic aneurysm repair 6 23% Concomitant cardiac surgery 1 4% Use of cardiopulmonary bypass 1 4% insertion and under fluoroscopic and transesophageal echocardiographic guidance the delivery system was advanced over a guidewire and positioned across the target lesion so as to cover the full extent of the PAU and any associated pseudoaneurysm and aneurysm (but not the entire length of any associated IMH) and the stentgraft was deployed. Currently whenever angiographic evidence of endoleak is present, additional procedures such as supplementary stent-graft placement, additional balloon dilatations or coil embolization are carried out. Preoperative anatomic characteristics of the diseased aortic segment as well as procedural data are listed in Table 2. The femoral artery was the most common site for insertion (14 patients, 54%). Four patients required deployment of more than one stent-graft. Simultaneous repair of an infrarenal aortic aneurysm using a retroperitoneal approach was performed in 6 patients (23%), where the new aortic graft was used as the access site for stent-graft insertion. One patient with unstable angina underwent simultaneous coronary artery bypass grafting on cardiopulmonary bypass with the stent-graft inserted through the aortic arch in an antegrade manner during hypothermic circulatory arrest. In another patient the proximal landing zone was judged too close to the left subclavian artery; a left common carotid left subclavian Fig 2. Computed tomography angiogram axial images from the same patient as in Figure 1, performed (A) 24 hours after the procedure showing complete exclusion of the penetrating atherosclerotic ulcer. (B and C) Three months and 3 years after the procedure there is continued absence of endoleak and progressive reduction in size of the associated intramural hematoma. bypass graft was performed before stent-graft deployment purposefully covering the left subclavian artery origin. The follow-up protocol included CTA imaging before hospital discharge, 3 and 6 months after stent-graft placement, and yearly thereafter (Fig 2). Follow-up status was obtained by contacting all surviving patients between June and August 2002 and was 100% complete; follow-up averaged 51 37 months (maximal follow-up, 114 months). Primary success was defined as complete exclusion of the PAU without additional intervention. Secondary success was defined as complete exclusion of the diseased aortic segment after any type of secondary intervention. Endoleaks were categorized according to the 2002 Reporting Standards for Endovascular Aortic Aneurysm Repair [15]. Treatment failure was defined comprehensively as a composite end-point including (1) early death, (2) early or late endoleak, (3) stent-graft mechanical fault, (4) reintervention, or (5) aortic-related or sudden unexplained late death (without autopsy). Statistical Analysis Data are expressed as mean 1 SD. Important ratios or fractions are presented 70% confidence limits (70% CL). The Kaplan-Meier actuarial method was used to generate survival estimates, which are reported with 95% confidence limits. To identify independent risk factors for the two outcome variables, a multivariable forward stepwise Cox proportional hazard model was used after exploratory analysis of 28 preoperative and perioperative variables (Appendix). The p values for inclusion and retention of variables in the models were 0.15 and 0.10 respectively because of the small number of patients in this study. All statistical analyses were performed using SPSS (version 10.0; SPSS, Chicago, IL). Results Early Outcomes Satisfactory arterial access was achieved and the devices were deployed successfully in all patients. No surgical conversions were necessary. The primary success rate 83 CARDIOVASCULAR

CARDIOVASCULAR 84 DEMERS ET AL Ann Thorac Surg STENT-GRAFTS FOR PENETRATING ULCERS 2004;77:81 6 Table 3. Postoperative Morbidity and Mortality Number Percent Intensive care unit stay (days) 3 3 Postoperative stay (days) 7 5 Early endoleak Type I 2 8% Type II 0 0% Conversion to open repair 0 0% Paraplegia 0 0% Postoperative complications 5 19% Stroke 1 4% Pulmonary embolism 1 4% Wound infection 1 4% Ogilvie syndrome 1 4% Diverticulitis 1 4% Thirty-day mortality 3 12% was 92%. A type I endoleak was detected immediately in 2 patients (Table 3), one of whom underwent successful placement of a second stent-graft 90 days after the initial procedure, yielding a secondary success rate of 96%. There were 3 early deaths (12% 7%). The causes of early death were a retroperitoneal hemorrhage in 1, hemorrhagic cerebrovascular accident in 1, and sepsis with multiorgan failure in 1. Five patients (19% 8%) had postoperative complications (Table 3) including stroke with partial recovery in 1 patient, wound infection in 1, pulmonary embolism in 1, and abdominal complications in 2. No patient suffered paraplegia or paraparesis. Average intensive care unit stay was 3 3 days and total postoperative hospital stay was 7 5 days. Late Outcomes The actuarial survival estimates at 1, 3, and 5 years were 85% 8%, 76% 8% and 70% 10% respectively (Fig 3). Causes of late death were aortic rupture secondary to a late (untreated) type I endoleak in 1 patient, sudden, Fig 4. Kaplan-Meier actuarial estimates of freedom from treatment failure. unexplained death in 1, lung carcinoma in 1, and pneumonia in 2 patients. Actuarial freedom from the composite end-point treatment failure at 1, 3, and 5 years were 81% 8%, 71% 9%, and 65% 10% respectively (Fig 4). The 9 treatment failures included early death in 3 patients, early untreated type I endoleak in 1, secondary intervention for early type I endoleak in 1, late untreated type I endoleak with aortic rupture in 1 patient 7 years postoperatively, late stabilization wire fracture (Gore Excluder device) in 1, and late sudden unexplained deaths in 2. As shown in Table 4 the only significant independent determinants of early and late death were previous cerebrovascular accident and female sex. The independent determinants of treatment failure were increasing maximal aortic diameter and female sex (Table 5). Comment History, Definition, and Prevalence Aortic penetrating atherosclerotic ulcers were initially described in 1934 by Shennan [1]. The first report of successful operative repair of a PAU associated with rupture of the descending thoracic aorta was made by Shumacker in 1959 [16]. Thoracic aortic PAUs are areas of focal atheromatous plaque disruption, extending into the Table 4. Independent Risk Factors for Early and Late Deaths After Endovascular Repair of Penetrating Atherosclerotic Ulcers With Stent-Grafts According to Cox Proportional Hazards Model Variable Hazard Ratio 95% CL p Value Previous cerebrovascular 2.83 17.1 1.8 166 0.02 accident Female sex 2.00 7.4 0.8 72.5 0.08 Fig 3. Kaplan-Meier actuarial estimates of survival in all patients. CL confidence limits.

Ann Thorac Surg DEMERS ET AL 2004;77:81 6 STENT-GRAFTS FOR PENETRATING ULCERS Table 5. Independent Risk Factors for Treatment Failure After Endovascular Repair of Penetrating Atherosclerotic Ulcers With Stent-Grafts According to Cox Proportional Hazards Model Variable Hazard Ratio 95% CL p Value Increasing aortic 0.13 1.1 1.0 1.3 0.01 diameter Female sex 1.71 5.5 0.8 39.0 0.09 CL confidence limits. internal elastic lamina and the aortic media. The prevalence of IMH with or without PAU in patients with acute aortic syndromes ranges from 5% to 15% [4 6]. In two recent series focusing on acutely symptomatic patients presenting with aortic IMH the proportion of patients with a PAU who had concomitant IMH was 50% to 60% [5, 7]. PAU Location, Epidemiology, and Natural History Penetrating ulcers are found almost exclusively in the descending thoracic aorta. Previous reports indicate that PAUs affect older patients more commonly than does classical aortic dissection [4]. The incidence of concomitant thoracic and abdominal aortic aneurysms is also higher, ranging between 38% and 42%. Accompanying medical problems including hypertension, chronic obstructive pulmonary disease, and coronary artery disease are also found in the majority of patients with PAU [4, 5] so that many are unattractive candidates for conventional open surgical procedures. In this series the mean age was 70 years and the prevalence of serious comorbidities was high. Quint and associates [17] reported a low incidence of life-threatening complications in patients with a PAU in an imaging registry series but many asymptomatic patients were included. More recently Coady and associates [7] and Genaha and coworkers [5] described the more malignant nature of acutely symptomatic patients with a PAU, with progression to aortic rupture or classical double-barreled dissection occurring in 40% to 50% of patients. Even after initial stabilization with medical therapy the Yale group observed progressive aortic enlargement and evolution to late dissection or rupture in some patients [8]. Because of these findings early surgical graft replacement of the descending thoracic aorta should be considered especially in patients with uncontrollable pain, increasing pleural effusion, or with a large or deep PAU [4, 5, 7, 18]. Results of Conventional Surgery and Endovascular Stent-Graft Repair The mortality rate associated with open conventional surgical graft replacement of the diseased aorta varies between 0% and 18% in patients with PAUs located in the descending thoracic aorta [5, 8, 19]. Morbidity can also be substantial after thoracotomy, especially in elderly patients with severe atherosclerosis and other major comorbidities. Endovascular stent-graft treatment of patients with thoracic aortic diseases was initiated in 1992 at Stanford University [9]. The application of this new technology was initially focused on the treatment of descending thoracic aneurysms with custom-made devices for highrisk surgical candidates. Initial results suggested that stent-graft treatment was an reasonable alternative to open surgical repair in patients who otherwise were inoperable. Subsequently endovascular stent-graft treatment of acute aortic dissection, traumatic aortic injuries, and PAU was reported [9 14]. Recently Kos and coworkers [14] reported short-term results in patients with a PAU treated with second generation stent-grafts. In their series of 10 elderly patients (mean age, 74 years) including 7 acutely symptomatic and 3 with aortic rupture, the perioperative mortality was 10% 10%. Early minor endoleak was observed in 4 of the surviving 9 patients (type I in 3) but the leak spontaneously thrombosed in 3 patients during the initial hospitalization, yielding a procedural success rate of 90%. During short-term follow-up (3 to 15 months, mean, 9) one additional late type II endoleak was observed. In this current series of 26 patients including 14 patients (54%) judged to be unacceptable candidates for conventional thoracotomy the procedural primary success rate was 92% and perioperative mortality was 12% 7%. No case of paraplegia or paraparesis was observed after endovascular treatment of these localized lesions. Survival estimates at 1 and 5 years were 85% and 70%, which is similar to that reported after conventional surgical repair [8]. The only independent determinants of death were previous cerebrovascular accident and female sex. Freedom from the composite end-point treatment failure at 1 and 5 years was 81% and 65% respectively, which compares favorably with the overall Stanford series [9]. Both larger maximal aortic diameter and female sex were identified as significant independent predictors of treatment failure. These risk factors reflect the importance of careful patient selection based on anatomic criteria and clinical factors. The six late treatment failures underscore the well-known importance of strict, serial clinical and radiologic imaging follow-up of these patients to detect late problems after endovascular stent-graft repair. Limitations One weakness of this study is its retrospective, observational nature, which included an 8-year interval characterized by major changes in imaging and stent-graft technologies. Also owing to our evolving experience with this new technology, patient selection criteria, and techniques changed over time. We now believe that endovascular stent-graft treatment should be offered to elderly patients at high surgical risk for conventional surgical repair. Ideal anatomic targets are localized lesions with normal-sized, minimally angulated, cylindrical proximal and distal landing zones of adequate length. Adequate vascular access in terms of arterial size and lack of excessive tortuosity and occlusive disease is also critical for a safe and successful stent-graft deployment. Another weakness of this study is related to the absence of systematic, serial imaging follow-up in all patients. At least one late imaging study was performed in only 85% 85 CARDIOVASCULAR

CARDIOVASCULAR 86 DEMERS ET AL Ann Thorac Surg STENT-GRAFTS FOR PENETRATING ULCERS 2004;77:81 6 of the survivors, reflecting the fact that many of these patients were referred from long geographic distances and could not return to Stanford for more assiduous imaging follow-up. Conclusions These mid-term results suggest that endovascular stentgraft repair is effective and is associated with low perioperative morbidity and mortality rates in selected high surgical risk, elderly patients with a PAU located in the descending thoracic aorta. Such localized pathology is an ideal anatomic target for a stent-graft. Because the use of stent-grafts is associated with endoleaks and other unique problems, it cannot be considered curative as in the sense of open surgical graft replacement of the aorta. Thus strict, serial radiologic imaging follow-up is mandatory to detect late complications. 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Appendix Preoperative, Anatomic, and Operative Variables Examined as Potential Independent Risk Factors in the Multivariable Analyses Demographic Age (years) Sex Comorbidity Hypertension Tobacco use Previous cerebrovascular accident Coronary artery disease Previous myocardial infarction Unstable angina Congestive heart failure Chronic pulmonary obstructive disease Renal failure Preoperative Status New York Heart Association functional class Emergency surgery Not an open surgical candidate Anatomic Characteristics Maximal aortic diameter (mm) Intramural hematoma length (mm) Proximal landing zone location Proximal landing zone diameter (mm) Distal landing zone location Distal landing zone diameter (mm) Operative Variables Insertion site Number of stent-grafts Stent-graft diameter (mm) Stent-graft total length (mm) Transposition of the left subclavian artery Simultaneous abdominal aortic aneurysm repair Use of cardiopulmonary bypass Experience Operative year