Factors predicting long-term outcomes of percutaneous angioplasty and stenting of the superior mesenteric artery for chronic mesenteric ischemia
Abstract
Summary:Background: To analyse the long-term outcomes of percutaneous angioplasty and stenting of the superior mesenteric artery (SMA) in the treatment of chronic mesenteric ischemia (CMI), and to assess predictive factors for a better clinical outcome. Patients and methods: Retrospective analysis of 76 consecutive patients, treated percutaneously for CMI between January 1999 and January 2018 and followed up until the end of 2018. Patients’ pre-, peri- and post-interventional clinical and radiological data were gathered from the institutional electronic medical records. The Kaplan Meier method with log rank test or the Cox model were used to analyse overall survival; the cumulative incidence function with Pepe and Mori test or the Fine and Grey model were used to analyse relapse-free survival, considering death as a competing event. Results: Seventy-six consecutive patients with a mean age of 72 years were included in the study. Catheter-angiography revealed an ostial or non-ostial >90% stenosis in n=23 (29.7%) and n=53 (69.7%) of included patients, respectively. Immediate clinical success was achieved in n=68 (89.5%), and procedural complications were observed in n=13 (17.1%) patients. Long-term follow-up revealed relapse of symptoms in n=21 (28.8%) patients, and overall survival estimates are 81.8%, 57.0% and 28.2% after two, five and ten years of follow-up, respectively. A trend towards longer relapse-free survival was found in the circumferential stenosis group (78.2% at five years) compared with the non-circumferential stenosis group (55.5%) (P=0.063). Conclusions: Angioplasty and stenting of the SMA for CMI is relatively safe and effective despite a substantial number of patients experiencing clinical relapse over time. Patients with focal, circumferential stenosis might have longer relapse-free survival than patients with non-circumferential stenosis.
Introduction
Chronic mesenteric ischemia (CMI) is a rare clinical entity with symptoms including postprandial abdominal pain, weight loss and intermittent diarrhoea. CMI typically occurs in the elderly population, with a predilection for women, and is the result of inadequate blood flow to the intestines, most often caused by progressive, atherosclerotic disease of one or more mesenteric arteries [1]. Treatment of symptomatic CMI is mandatory to prevent acute mesenteric ischemia, which could potentially cause extensive bowel infarction and death. Today, catheter-directed angioplasty and stenting is considered in many centres to be the primary treatment option for CMI owing to the high technical success rate, low complication rate and acceptable short and medium-term clinical follow-up results [2, 3, 4, 5, 6, 7, 8, 9, 10]. In contrast to the percutaneous approach, surgical repair is associated with relatively high perioperative morbidity (15%–33%) and mortality (0%–17%) [11, 12, 13, 14]. Conversely, percutaneous angioplasty and stenting is associated with a high restenosis rate of up to 50% for the SMA and up to 80% of the coeliac trunk [2, 4, 15]. Occlusive disease of the superior mesenteric artery rather than the coeliac trunk seems to be associated with symptoms of CMI [16]. In addition, long-term outcomes [17, 18], as well as factors predictive for better or worse outcomes, are not well understood.
This retrospective study involved an assessment of the short and long-term clinical outcomes of a cohort of 76 patients treated with SMA angioplasty and stenting for symptomatic CMI, related to atherosclerotic stenosis, at a university centre for vascular disease. Factors predicting better clinical outcomes were also analysed.
Patients and methods
Study design
This is a retrospective review of a cohort of consecutive patients treated for symptomatic CMI related to atherosclerotic SMA-stenosis and drawn from the interventional radiology database at a university medical centre for vascular diseases between January 1999 and January 2018. Patients with thrombo-embolic occlusive disease of total atherosclerotic SMA-occlusions were excluded in this study analysis. The study was approved by the local Ethics Committee.
Clinical and radiological data analysis
Demographic data, including symptoms at presentation, comorbidities and preinterventional imaging, were collected from the institution’s electronic medical records and the Picture Archiving and Communication System (PACS, Agfa Gevaert, Mortsel, Belgium), respectively. Preinterventional imaging analysis, including the location of the stenosis, degree of stenosis and analysis of circumferential versus focal, non-circumferential aspect of the stenosis, was performed in collaboration consensus by two radiologists (with two and 20 years’ experience, respectively).
Preinterventional imaging
Diagnostic preinterventional imaging was performed using of catheter-directed angiography, magnetic resonance (MR) angiography and computed tomography (CT) angiography. Briefly, diagnostic catheter-directed angiography included anteroposterior and lateral flush aortography using a 4 or 5 French (F) pigtail catheter; the volume of nonionic iodised contrast medium ioprominde (Ultravist 240, Bayer AG, Berlin, Germany) was 30 ml and the injection rate 10 ml/second.
Three-dimensional MR angiography was performed on a 1.5 T MRI scanner using a six-element sensitivity encoding body coil. Imaging was performed in breath-hold using a coronal 3D centric reordered gradient echo acquisition (TR, 3.36 ms; TE, 1.23 ms; flip angle 25°; slice thickness 0.8 mm; field of view (FOV) 320×350 mm; matrix 336×384; parallel imaging factor 2). Data were reconstructed to an isotropic voxel size of 0.8×0.8×0.8 mm using zero-filling interpolation. Images were acquired during a first pass bolus of gadoterate meglumine at 2 ml/sec, using a standard dose of 0.2 mL/kg (0.1 mmol/kg) body weight.
CT angiography was performed on 4, 16 or 64-row scanners depending on the time period for which the patients were treated; two scan phases were performed: first without contrast medium, mainly to visualise the degree of calcified plaques, followed by an arterial phase using automated triggering in the abdominal aorta at 120 Hounsfield Units (HU). Axial and reconstructed coronal and sagittal images of the arterial phase were performed.
A circumferential stenosis of the SMA was defined as a stenotic plaque invading more than half of the circumference of the SMA vessel wall; whereas a focal stenosis was considered a focal plaque invading equal or less than half of the circumference of the SMA vessel wall.
SMA stenting technique
Patients gave informed consent before the start of the procedure. Under local anaesthesia, percutaneous access was made to the right common femoral or left brachial artery. Using a 5 French pigtail catheter, an anteroposterior and lateral flush aortography injection was performed using a non-ionic iodised contrast medium, or carbon dioxide (CO2) in the event of contraindications for an iodised contrast medium, in order to visualise and confirm the proximal high-grade stenosis of the SMA. Following the intra-arterial injection of 5,000 international units (IU) of heparin, cannulation of the stenosed SMA was carried out using different types of diagnostic 4 or 5 F catheters, including a Simmons 1, Cobra and vertebral catheter (Terumo Europe, Leuven, Belgium; Cook Medical, Bloomington, IN, USA). After exchange for a coronary 0.014 inch guide wire (Stabilizer, Cordis, Roden, the Netherlands) and a 6F guiding catheter (Viking, Guidant Vascular, Santa Clara, CA, USA) or guiding sheath (Flexor, Medical, Bloomington, IN, USA), the SMA stenosis was predilated with a 5 or 6 mm diameter and 20 mm long rapid exchange angioplasty balloon catheter. Finally, different types of vascular stents, including Hippocampus renal (Medtronic, Minneapolis, MN, USA), Tsunami peripheral (Terumo Europe, Leuven, Belgium), Corinthian and Genesis (Cordis, Roden, the Netherlands), Herculink and Acculink (Guidant Vascular, Santa Clara, CA, USA), Optimed Sinusstent (Optimed, Ettlingen, Germany), Express Vascular (Boston Scientific, Natick, MA, USA) and two types of coronary stents, namely Coroflex (B.Braun, Melsungen, Germany) and Rebel (Boston Scientific, Natick, MA, USA), were used at the discretion of the attending interventional radiologist. Self-expandable stents were used in case of long (>20 mm length) postostial SMA-stenosis. Postinterventional medical treatment included aspirin 80 mg lifelong and clopidogrel 75 mg for 1 month.
The type of stent used were mainly rapid-exchange 0.014 inch platform balloon-expandable stents dedicated for visceral artery stenting, including Herculink (…); in n=1 an 0.035 inch over-the-wire platform balloon-expanbable stent (Acculink) and in n=1 an 0.035 inch over-the-wire self-expanding stent (Sinusstent) were used related to the unavailability of large diameter (7 mm diameter) rapid-exchange 0.014 balloon-expandable stents at that time. In the remaining 2 patients a coronary stent, Coroflex (n=1) and Rebel (n=1) was used related to the small diameter (4 mm diameter) of the treated vessel segment.
Follow-up
Patients’ clinical follow-up was performed by review of the electronic medical records, including all types of follow-up imaging, up to the most recent hospital visit and phone calls with the patient’s general practitioner.
Definitions and statistical analysis
Technical success was defined as a residual stenosis <30% as measured on completion of the profile view angiography. Pressure measurements above and below the stenosis were not systematically performed. A technical failure was defined as inability to cross or dilate the stenotic lesion or a residual stenosis >30%. Perioperative complication was defined as an unintended event related to the endovascular procedure and was categorised according to the Society of Interventional Radiology (SIR) classification of procedural complications [19].
Short-term clinical success was defined as a cessation of the clinical symptoms of CMI which prompted the intervention. Long-term clinical success was defined as an absence or significant reduction of the symptoms of CMI up to the end of the follow-up period.
Statistical analysis included estimating symptom relapse rates using the Cumulative Incidence Function (CIF). The Pepe and Mori test was used to assess group differences. The Fine and Grey model was used to assess predictor effects. The Kaplan-Meier method was used for estimating overall survival. The log-rank test was used to compare groups on survival curves. Lastly, the Cox model was used to analyse the effect of stent diameter on survival. Analyses were performed using SAS software (version 9.4 of the SAS System for Windows, Cary, NY, USA).
Results
Patient demographics
The patient cohort comprised 76 patients (39 female) with a mean age of 72 years (standard deviation: 11.1 years; range 35–96 years). Patients’ medical comorbidities are summarised in electronic supplementary material (ESM) 1. Fifty of the 76 patients (66%) presented with three or more of the analysed comorbidities. Clinical symptoms at presentation included: postprandial pain (n=51; 67%), weight loss of more than 5 kg over 2 months (n=43; 56.6%), nausea (n=7; 9.2%), vomiting (n=8; 10.5%) and diarrhoea (n=23; 30.3%).
Preinterventional imaging
Non-invasive imaging prior to the intervention included duplex ultrasound (n=5; 6.6%), CT angiography (n=53; 69.7%), MR angiography (n=13; 17.1%). The type of non-invasive preinterventional imaging changed over time as summarised in ESM 2. Procedural angiography revealed ostial SMA-stenosis (n=23; 30.2%) or non-ostial SMA-stenosis (n=53; 69.7%). Fifty CT angiographic studies and four MR angiographic studies included sufficient imaging data for further stenosis characterisation into circumferential and focal stenosis. Circumferential stenosis was identified in 29 patients (53.7%) (Figure 1); in the remaining 25 patients (46.3%), the stenotic plaque was considered as focal and, non-circumferential (Figure 2).
Technical and immediate clinical outcome
Vascular access was obtained through the right common femoral artery (n=66; 86.8%) or left brachial artery (n=10; 13.1%). In one patient (1.3%) cannulation of the high-grade stenosis failed resulting in an intention-to-treat immediate technical success rate of 98.7%. The types of stents used were mainly rapid-exchange 0.014 inch platform balloon-expandable stents dedicated for visceral artery stenting, including Herculink (n=8), Tsunami (n=30), Express Vascular (n=8), Corynthian/Genesis (n=6), Hippocampus (n=8); in n=1 an 0.035 inch over-the-wire platform balloon-expandable stent (Acculink) and in n=1 an 0.035 inch over-the-wire self-expanding stent (Sinusstent) were used related to the unavailability of large diameter (7 mm diameter) rapid-exchange 0.014 balloon-expandable stents at that time. In the remaining 2 patients a coronary stent, Coroflex (n=1) and Rebel (n=1) was used related to the small diameter (4 mm diameter) of the treated vessel segment. In 54 patients (71%) one stent was inserted; eight patients (10.5%) received two stents; two patients (2.6%) received three stents; and one patient (1.3%) received 5 stents. The average diameter and length of the stents used was 5.7 mm (4–7 mm) and 17.6 mm (12–40 mm), respectively. After angioplasty and stent placement, the residual stenosis was <30% in all patients.
In addition to the stenting of the SMA, a balloon angioplasty of the coeliac trunk (n=1), stenting of the common or external iliac artery (n=3) and stenting of a renal artery (n=1) was performed in the same session.
In total, 13 patients (17.1%) experienced procedural or immediate postprocedural complications related to the procedure, with major complications in three patients (4%), as summarised in ESM 3. In three cases a pseudo-aneurysm at the access site was managed using an ultrasound-guided thrombin injection; prolonged bleeding at the access site was resolved with 24 hours of external compression. Periprocedural stent dislodgement into the abdominal aorta was managed with retrieval of the stent into the right external iliac artery and postdilatation of the stent in the external iliac artery. The other minor complications, including contrast-induced nephropathy, post-procedural hypotension and retroperitoneal haematoma, were resolved using conservative measures. The major complications included femoral artery thrombosis with non-viable leg ischemia related to the insertion of a closure device (Angioseal, Terumo Europe, Leuven, Belgium) and thrombosis of an aortofemoral bypass graft, both requiring immediate open surgical intervention. Finally, a dissection of the proximal common femoral artery was managed through placement of a stent.
Immediate clinical success was achieved in 68 out of 76 patients (89.5%); in the remaining eight patients, including one patient where there was a failure to cannulate the stenosis, symptom relief was insufficient; 30-day mortality was 2.6%: one patient died due to myocardial infarction 23 days after the index procedure, while another patient died from intestinal ischemia 22 days after the stent procedure. In the latter patient, a Herculink stent 6 mm/18 mm was inserted, and patient’s risk factors included dilated cardiomyopathy, peripheral vascular disease and renal insufficiency. Follow-up imaging was not available for either of these two patients.
Long-term outcome
In ten patients (13.2%), a reintervention was performed to manage an in-stent-occlusion (n=2), an in-stent >90% restenosis (n=3) or an in-stent >70% restenosis (n=5) after a mean time of 26.5 months. Reinterventions included re-stenting (n=7) and open surgical bypass (n=3), resulting in cessation of symptoms in seven of the ten patients. Two patients underwent a third endovascular intervention to treat a recurrent in-stent restenosis.
The mean clinical follow-up period was 45.5 months; three patients were lost to follow-up. 21 patients (28.8%) presented with relapse of symptoms during follow-up. Average time to symptomatic relapse was 14.9 months. Cumulative Incidence Function estimates a relapse-free number of patients of 78.9%, 72.3% and 70.3% after two, five and ten years of follow-up, respectively (Figure 3). Ten out of 21 patients with persistent or recurrent symptoms of chronic mesenteric ischemia were re-treated as described supra; the remaining 11 patients did not receive additional interventional or surgical treatment: repeat imaging did not demonstrate SMA-stenosis (n=8), occlusion of the SMA distal tot the stented segment without potential for surgical revascularization (n=1), severe comorbid disease, including stroke, and early death (n=2).
At the end of the follow-up period, 45 patients (59.2%) had died, with a median overall survival of 79 months. Cause of death was determined in 35 patients and is summarised in ESM 4. Another 2 patients died related to intestinal ischemia; however, no imaging nor autopsy was available to determine if the SMA-stents were patent or not in these cases. Kaplan-Meier estimates for overall survival were 81.8%, 57.0% and 28.2% at two, five and ten years of follow-up, respectively (Figure 4). Demographic and angiographic factors potentially predicting risk for early or late restenosis are summarized in ESM 5.
Patient freedom from symptom relapse was compared in the group of patients with a circumferential stenosis of the SMA versus patients with a focal, non-circumferential stenosis, and showed a trend towards longer relapse-free survival in the circumferential stenosis group (78.2% versus 55.5% at five years); however, the difference was not statistically significant (P=0.063) (Figure 5); survival analysis between both groups was unable to demonstrate any statistically significant difference (P=0.64) (Figure 6). Other factors also showed no difference in relapse-free survival, including patients presenting with an ostial versus non-ostial stenosis (P=0.35) and patients treated with smaller or larger stent diameters (P=0.33).
Discussion
Recent, high-volume studies show that the technical success rate of catheter-directed percutaneous angioplasty and stenting for symptomatic SMA stenosis is very high, ranging between 90% and 100%, as summarised in ESM 6. Additionally, SMA angioplasty and stenting is considered to be a safe procedure with a complication rate mostly below 15%. The total complication rate in the presented study was 17%; major complications (SIR classification C-F) were observed in three patients (4%) and consisted in access-related complications, successfully managed with open or endovascular repair. These high success rates associated with a low rate of serious procedural complications have resulted in the endovascular approach to manage symptomatic SMA-stenoses being the first-choice treatment in many institutions, with surgical repair as a back-up in the event of endovascular failure [13, 14, 20]. The major drawback of the endovascular approach is the relatively high recurrence rate of in-stent restenosis, ranging between 30% and 45%; in addition, further progression of the atherosclerotic disease over the whole visceral vascular bed might even increase these numbers. In the presented study, 13% of patients underwent a redo endovascular or surgical procedure to manage in-stent occlusive disease. Although redo procedures with or without stenting can be performed, resulting in a primary-assisted patency rate of more than 90% [18], late death related to intestinal ischemia was 8.6% in this study. In order to lower the recurrence rate of intestinal ischemia related to in-stent restenosis, potential alternatives to bare metal stenting (BMS) have been proposed, including covered stents [21] or drug-eluting stents (DES) [22]. In a retrospective, comparative study by Oderich et al. [21] a significantly superior patency rate at 3 years of follow-up in favor of covered stents (92%±4% for covered stents versus 50%±5% for BMS) was demonstrated and Girault et al. [23] very recently found 76%, 95% and 95% primary, primary-assisted and secondary patency rates at 2 years of follow-up for covered stents in SMA occlusive disease. In addition, a multicenter, randomized trial of covered versus bare metal stents for chronic mesenteric ischemia is underway [24]. However, no difference was found in a prospective, comparative study of BMS versus DES in patients with renal artery stenosis [25]; the techniques of renal artery and mesenteric artery stenting, including the types of wires, angioplasty balloon and stents used, are very similar. However, in renal artery stenting, smaller stent-diameter is associated with a higher risk of restenosis id covered stents are used [26], but not when drug-eluting stents are inserted [27]. No similar data are available for SMA-stenting.
Long-term estimated survival after SMA-angioplasty and stenting was 82%, 57% and 28% after 2, 5 and 10 years of follow-up respectively, which is in line with the survival data of other centres, as summarized in ESM 7.
This study demonstrated a trend towards longer time to symptom relapse in patients with circumferential SMA-stenosis compared to patients with a focal, non-circumferential stenosis (P=0.063). These findings may be in line with in vitro findings described by Ladisa et al. [28]. In a time-dependent 3D computational fluid dynamics model, these researchers found that higher cell density gradients and neointimal hyperplasia developed in regions with non-uniform shear stress. Differences in the shape of the stenosis might alter the distribution of stress along the vessel wall, which could influence the long-term stability of the stenosis, depending on its configuration [29]. However, these hypotheses need to be confirmed by prospective data.
Limitations
Finally, this study has some limitations, including its retrospective nature covering a long time interval (1999–2018), the use of various different types of stents, including over-the-wire 0.035 and rapid-exchange 0.014 inch technology, with various lengths and diameters. In addition, concommitant occlusion of the celiac trunk and inferior mesenteric artery were not assessed in this study. Patency or occlusion of these visceral arteries might influence durability of symptoms relief and patency of the SMA-stent. Lastly, follow-up in this study was based only on clinical assessment, with no routine follow-up imaging of visceral arteries and finally, the cause of death in 10 patients was unknown, potentially increasing the total number of deaths related to restenosis or thrombotic occlusion of the SMA-stent.
Conclusions
This retrospective study, focusing on the long-term outcome of angioplasty and stenting of symptomatic SMA stenosis in a substantial number of patients over a long time period, demonstrates high efficacy accompanied by a low complication rate. Recurrent symptoms related either to in-stent restenosis or to further progression of the atherosclerotic disease remain the major drawback, with an incidence of 30% at a mean follow-up of 45 months. Angioplasty and stenting of circumferential stenosis might be associated with better outcomes compared to patients with focal, non-circumferential stenosis.
Electronic supplementary material
The electronic supplementary material (ESM) is available with the online version of the article at https://doi.org/10.1024/0301-1526/a000964
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