Rationale:

Anastomotic leakage (AL) is a severe complication of colon surgery, with an incidence of 2.7-11.9%. It is associated with long-term increased mortality, reduced quality of life, and high healthcare costs due to reoperations and prolonged hospitalization. Among colon cancer patients, 5-year survival rates are 70% for those with AL compared to 81% for those without. A retrospective case-control study identified a >50% stenosis of the Superior Mesenteric Artery (SMA) as a significant risk factor, increasing AL odds by six times (OR: 5.9, 95% CI: 2.7-12.6, p < .001).

Primary objective:

The ALPrES2MA study aims to evaluate whether preventive endovascular stenting of a >50% stenosed SMA origin reduces the risk of AL following colon surgery.

Secondary objectives:

Classification of severity of AL, incidence of delayed AL (>90 days), Mesenteric Artery Calcification Score (MACS), surgical complications, hospital (re)admissions, Quality of life (including health related quality of life), healthcare and societal costs, cost-effectiveness (expressed as incremental costs per quality-adjusted life year gained), and budget impact. Additionally, the added value of quantitative fluorescence angiography (qFA) in predicting AL during surgery, in hospitals with suitable equipment and experience, will be explored. This will enhance surgeons' capabilities in preventing AL.

Study design: Nationwide multicentre randomized controlled trail with a 1:1 fashion

Study population:

Patients, 40 years and over, in the participating hospitals in the Netherlands with a >50% SMA origin stenosis scheduled for elective colorectal resection with a primary anastomosis for malignant or benign colorectal pathology.

Intervention:

Intervention group will undergo preventive percutaneous transluminal angioplasty (PTA) and endovascular covered stenting of the SMA, within preferably two weeks prior to the colon resection. Control group will not undergo PTA and endovascular stenting of the >50% SMA stenosis prior to the colon resection. Both groups will be treated with a mono antiplatelet therapy, i.e., carbasalate calcium (Ascal ®), for stent patency and atherosclerotic risk reduction. Intervention group has an indication for lifelong mono antiplatelet therapy and control group for at least 12 months

Main study parameters/endpoints:

The primary endpoint is the incidence of a clinically relevant AL within 90 days post-surgery. Secondary endpoints include AL classification/severity, calcification scores of aortic and mesenteric vessels, stenting complications, stent patency, intra-operative qFA measurements, operative duration, all causes of post-operative complications within 90 days, all reinterventions; surgical (including endovascular) and non-surgical within 90 days, duration of primary postoperative hospital stay and readmission within 12 months, 12 month mortality, patient-reported outcomes on month 0-3-6-12, cost-effectiveness budget impact analysis and stent patency. The total follow-up duration will be a total of 12 months.

Background and Rationale:

Anastomotic leakage (AL) is one of the most severe complications following colon surgery. The pathogenesis of AL is multifactorial and includes patient-related, surgical, and perfusion-related factors. However, reliable preoperative identification of patients at high risk for AL remains challenging. Existing prediction models are heterogeneous and rarely incorporate mesenteric vascular disease as a risk factor.

A retrospective multicenter case-control study demonstrated that an asymptomatic >50% atherosclerotic stenosis at the origin of the superior mesenteric artery (SMA) is associated with a six-fold increased risk of AL following elective colon resection. Despite this association, current surgical and vascular guidelines do not address preventive treatment of asymptomatic SMA stenosis in patients undergoing colorectal surgery, and preventive endovascular revascularization is not standard practice.

Endovascular revascularization of the SMA using percutaneous transluminal angioplasty (PTA) and covered stent placement is a minimally invasive, low-risk procedure widely used in the treatment of chronic and acute mesenteric ischemia. The procedure has a low incidence of serious adverse events and is supported by international guidelines. Whether preventive SMA stenting can improve colon perfusion and reduce the risk of AL in asymptomatic patients undergoing colon surgery has not been prospectively evaluated.

The ALPrES²MA study (Anastomotic Leakage Prevention by Endovascular Stenting of the Superior Mesenteric Artery) is a multicenter randomized controlled trial designed to address this evidence gap.

Study Objectives The primary objective of this study is to determine whether preventive endovascular covered stenting of an asymptomatic 50% or more stenosis at the origin of the SMA reduces the incidence of clinically relevant anastomotic leakage within 90 days after elective colon resection with primary anastomosis.

Secondary objectives include comparison between intervention and control groups with respect to:

• Severity classification of AL (Grade A, B, or C)
• Incidence of delayed AL (>90 days, up to 12 months)
• Incidence of isolated, clinically non-significant AL
• Mesenteric Artery Calcification Score (MACS) on preoperative CT imaging
• Intraoperative microcirculatory perfusion assessed with quantitative fluorescence angiography (qFA), where available
• Postoperative complications classified by Clavien-Dindo
• Reinterventions (surgical and non-surgical)
• Hospital length of stay and readmissions
• All-cause mortality within 12 months
• Quality of life and health-related quality of life
• Healthcare consumption, productivity losses, cost-effectiveness, and budget impact

Secondary objectives specific to the intervention group include evaluation of stent-related adverse events, stent patency, access-site complications, and reinterventions related to SMA stenting.

Study Design

This is a multicenter, randomized controlled trial with a 1:1 allocation ratio. Eligible patients are randomized to either:

1. Preventive endovascular PTA with covered stent placement of the SMA prior to elective colon resection (intervention group), or
2. Elective colon resection without preventive SMA stenting (control group).

Randomization is stratified by participating center to ensure balanced distribution of center-specific factors, including the use of intraoperative fluorescence angiography. This is a non-blinded study.

Study Population The study population consists of patients aged 40 years or older who are scheduled for elective colon resection with primary anastomosis for malignant or benign colorectal disease and who have an asymptomatic 50% or more atherosclerotic stenosis at the origin of the SMA.

Key exclusion criteria include symptomatic mesenteric ischemia, significant celiac artery stenosis (50% or more), prior mesenteric revascularization, simultaneous major additional abdominal resections, creation of diverting stomas, contraindications to antiplatelet therapy, pregnancy, or known intolerance to study medications or devices.

Assessment of SMA Stenosis All patients undergo routine preoperative abdominal CT imaging as part of standard surgical planning. CT scans are centrally reviewed by an independent Corelab consisting of trained radiologists and vascular surgeons to assess the degree of SMA stenosis and vascular calcification. If image quality is insufficient or stenosis severity is uncertain, an additional CT angiography with slice thickness <1 mm is performed in accordance with international guidelines.

Interventions Patients randomized to the intervention group undergo preventive PTA and placement of a covered balloon-expandable stent (GORE® VIABAHN® Balloon Expandable Endoprosthesis) at the origin of the SMA, preferably within two weeks prior to colon surgery. The procedure is performed by experienced vascular specialists in designated regional centers using standard endovascular techniques.

Patients in both study groups receive mono antiplatelet therapy with carbasalate calcium (100 mg daily). In the intervention group, antiplatelet therapy is prescribed lifelong to support stent patency; in the control group, therapy is prescribed for at least 12 months for secondary prevention of atherosclerotic disease.

Elective colon resection is performed according to standard local and national guidelines at the patient's primary surgical center.

Intraoperative Fluorescence Angiography:

In participating centers where fluorescence angiography with indocyanine green (ICG) is part of standard care, intraoperative assessment of anastomotic perfusion is performed in both study groups. Quantitative fluorescence angiography (qFA) parameters, including time-to-peak and normalized peak slope, are analyzed centrally for exploratory evaluation of microperfusion and its association with AL.

Follow-up and Data Collection Patients are followed for a total of 12 months after colon surgery. The primary endpoint is assessed within the first 90 days. Secondary clinical outcomes, stent patency, mortality, and reinterventions are assessed throughout the 12-month follow-up.

Patient-reported outcomes are collected preoperatively and at multiple postoperative time points using validated questionnaires, including WHO-QoL-BREF, EQ-5D-5L, iMTA Medical Consumption Questionnaire, and iMTA Productivity Cost Questionnaire. Data are collected electronically, on paper, or via structured interviews without requiring additional hospital visits.

Outcome Measures The primary outcome is the incidence of clinically relevant anastomotic leakage (Grade B or C) within 90 days postoperatively. AL is defined according to established international criteria.

Secondary outcomes include AL severity, delayed AL, postoperative complications, hospital utilization, mortality, quality of life, health economic outcomes, and SMA stent patency.

Sample Size and Statistical Analysis:

Based on an expected reduction in AL incidence from 14% to 5%, a total sample size of 360 patients (180 per group) provides 80% power with a two-sided alpha of 0.05, accounting for a 10% dropout rate. An interim analysis is conducted for sample size re-estimation and futility assessment without formal hypothesis testing.

Primary analysis compares AL incidence between groups using chi-square or Fisher's exact tests and logistic regression. Secondary outcomes are analyzed using appropriate parametric or non-parametric methods, generalized estimating equations for repeated measures, and multivariable models to adjust for predefined confounders.

Health Economic Evaluation A cost-effectiveness analysis is performed from a societal perspective over a 12-month time horizon, expressing results as incremental cost per quality-adjusted life year gained. A budget impact analysis evaluates nationwide implementation scenarios over a five-year period from societal, governmental, and insurer perspectives.

Ethical Considerations All interventions used in this study are established, CE-marked devices or approved medicinal products used within their authorized indications. The potential benefits of reducing AL-related morbidity and mortality are weighed against the low procedural risks associated with preventive SMA stenting. Written informed consent is obtained from all participants prior to enrollment.

Inclusion Criteria:

• Age >40 years.
• Patient scheduled for elective colon resection above the recto-sigmoid junction with a primary anastomosis (side-to-side, side-to-end, or end-to-end).
• Presence of an asymptomatic >50% atherosclerotic origin stenosis of the superior mesenteric artery (SMA)

Exclusion Criteria:

• All patients with symptomatic chronic or acute mesenteric ischemia (i.e., mesenteric artery stenosis in combination with symptoms as postprandial abdominal pain, fear of eating, altered eating patterns, weight loss, diarrhoea, nausea, or exercise-induced abdominal pain).
• Presence of a >50% stenosis of the celiac artery, regardless of the underlying pathology (i.e., intra-articular atherosclerosis, intra articular thrombus or external compression by the median accurate ligament).
• Simultaneous performed during the colon resection: a substantial abdominal organ resection, or T4b/T4c colon tumour resection, or a second colon anastomosis or a diverting stoma
• History of mesenteric revascularization, including endovascular stenting, thrombectomy, or bypass surgery involving any of the mesenteric arteries
• Patients with a history of heparin induced thrombocytopenia-type 2 due to contraindication for VBX Stent Graft.
• Patients with a contra-indication for mono antiplatelet therapy with Ascal due to comorbidities, allergy or intolerance.
• Pregnancy