Continuing Education Activity

Bypass surgery with a greater saphenous vein graft or another alternative autologous venous graft is a well-established treatment of peripheral arterial disease (PAD) in the lower limbs. A wide spectrum of PAD with different underlying causalities, including chronic limb-threatening ischemia, intermittent claudication, peripheral limb aneurysms, and major arterial trauma, might be managed with bypass procedures. The long-term patency and success of venous grafts in bypass surgery remains a challenge due to various complications, such as the accelerated rates of atherosclerosis compared to their arterial counterparts. Treatment of vein graft stenoses ranges from primary prevention to revascularization. This activity will discuss vein graft stenosis etiology, diagnosis, prevention, and management, emphasizing the role of the multidisciplinary team in caring for patients.

Objectives:

• Identify the pathophysiology of vein graft stenosis.

• Assess the presentation of vein graft stenosis.

• Evaluate the treatment options for vein graft stenosis.

• Communicate the importance of improving care coordination among multidisciplinary team members to improve patient outcomes with vein graft stenosis.

Introduction

Bypass surgery with a greater saphenous vein graft or another alternative autologous venous graft is a well-established treatment of peripheral arterial disease in the lower limbs.[1] A wide spectrum of peripheral arterial disease with different underlying causalities, including chronic limb-threatening ischemia, intermittent claudication, peripheral limb aneurysms, and major arterial trauma, might be managed with bypass procedures. Bypass surgery has satisfactory outcomes, considering limb preservation and long-term graft patency rates. However, the possibility of vein graft failure due to stenoses significantly limits the durability of the procedure. Diagnosing stenoses through clinical and ultrasonographic surveillance, followed by treatment, avoids the grafts' complete occlusion.[1]

The long-term patency and success of vein grafts in bypass surgery remain challenging due to their accelerated atherosclerotic rates compared to their arterial counterparts.[2] Preventing vein graft stenosis (VGS) is the cornerstone of management and includes tight control of blood pressure, blood sugars, lipid levels, body weight, and smoking cessation. Nearly all patients with vein grafts should be treated with daily aspirin and statin.[3][4][5][6][7] Further anticoagulation and antiplatelet therapy are determined by specific interventions performed and individualized patient factors.[8] Angina is the most common presentation of VGS following coronary artery bypass grafting (CABG). VGS presents as rest pain, non-healing wounds, and claudication in the peripheral vascular system. If revascularization is necessary, endovascular therapy or surgical bypass should be offered to improve the arterial circulation of the obstructed native vessel.[9] Endovascular therapy of the vein graft itself may be attempted first to improve the primary or secondary patency.[10] An open approach is reserved for multivessel disease or patients for whom endovascular methods are impossible. This topic discusses VGS in the context of patients following CABG or peripheral artery bypass grafting (PABG) using the great saphenous vein as the most common venous conduit.

Etiology

Clinical graft patency of autogenous saphenous vein grafts in the arterial circulation can be divided into 3 temporal categories: early, defined as 0 to 30 days; short-term, defined as 30 days to 24 months; and long-term, defined as greater than 24 months. Early failures are ascribed most commonly to technical issues at the graft anastomoses, such as the graft's position, kinking, or poor distal runoff. These early graft failures account for as many as 10% of total vein graft failures.[10] The etiology of short-term failures is less well described, and various mechanisms have been implicated. Perivascular myofibroblast remodeling, platelet-derived growth factor smooth muscle proliferation, decreased local nitric oxide release, decreased endothelial relaxation, and intimal vein wall thickening are several mechanisms of short-term VGS and failure.[11][12][13][14] Late graft stenosis occurs via a mechanism similar to the formation of atherosclerosis, with plaque formation adjacent to areas of lipid deposition and intimal hyperplasia.[15]

Epidemiology

With over 300,000 patients undergoing CABG in the United States annually and saphenous vein graft serving as 1 of the alternative substitutes to bypass diseased coronary artery disease, therefore the burden of the saphenous VGS on the healthcare system is of significant concern. Graft occlusion before hospital discharge has been reported to occur in approximately 10% of vein grafts.[10] Approximately 15% to 30% of grafts occur during the first year after CABG. After the first year post-CABG, the annual occlusion rate is about 2%, rising to approximately 4% annually between postoperative years 6 and 10.[2] An estimated 15% of individuals over 70 develop peripheral artery disease.[16] Of these, approximately 50% become symptomatic. About 1% of those with symptoms develop critical limb ischemia, potentially necessitating a peripheral arterial bypass graft (PABG).[17] Autogenous vein graft bypass failure rates remain high in the lower extremities, with approximately 20% of grafts failing in the first year and 50% failing by year 5.[18][19]

Pathophysiology

The wall of a vein is traditionally divided into 3 anatomic layers: the intima, the media, and the adventitia. Veins are highly compliant over the range of venous pressures and are relatively non-compliant at arterial pressures. There are differences in the vasomotor function of the saphenous veins compared to the internal mammary arteries. Nitric oxide and prostacyclin-mediated relaxation responses of saphenous veins are much less, and the maximal contractile forces generated are much greater than the internal mammary artery.[2] Also, local angiotensin-converting enzyme activity, which converts angiotensin I to angiotensin II and degrades bradykinin (a potent mediator of nitric oxide release), is greater in the saphenous vein compared to the internal mammary artery. Saphenous veins demonstrate a spectrum of pre-existing pathological conditions ranging from significantly thickened walls to post-phlebitic changes and varicosities at harvest time. Between 2% and 5% of these veins are unusable, and up to 12% can be considered "diseased." These diseased veins have a patency rate of approximately 50% compared to their "non-diseased" controls.[15]

Perioperative manipulations of veins before their bypass anastomosis result in significant tissue damage. Such implantation injury leads to endothelial dysfunction, endothelial cell injury, endothelial denudation, and smooth muscle cell injury. Each is an essential factor in initiating neo-intimal hyperplasia and VGS. Following exposure to the arterial environment, postoperative venous grafts experience severe stretching and increased tangential stress. These forces significantly contribute to endothelial cell damage. Histological surveys of saphenous vein grafts have been derived from specimens obtained at autopsy or reoperation. Vein grafts obtained in the early postoperative period show focal loss of endothelial cells, particularly at the perianastomotic regions, with fibrin deposition on the intima.[20] Intimal hyperplasia is the universal response of a vein graft to insertion into the arterial circulation. It is considered to result from the migration of smooth muscle cells out of the media into the intima and the proliferation of these smooth muscle cells. Macroscopically, intimal hyperplastic lesions appear pale, smooth, firm, and homogenous; they are uniformly located between the endothelium and the vein graft's medial smooth muscle cell layer. Early stenosis and occlusions occur in 5% to 8% of grafts due to intimal hyperplasia during the initial perioperative period after saphenous vein grafting. Vein grafts with lower flows and higher rates of stasis are associated with greater intimal thickening. Similarly, low shear stress is also associated with the increased development of intimal hyperplasia in vein grafts.[11][15]

Histopathology

Vein grafts retrieved from patients with angiographic evidence of occlusive disease demonstrate histologic features of atherosclerosis. These lesions have been identified as early as 6 months after implantation. Thus, these late occlusions of vein bypass grafts appear due to the development of a rapidly progressive and structurally distinct form of atherosclerosis, termed "accelerated atherosclerosis," to distinguish it from non-iatrogenic "spontaneous atherosclerosis."[21] Accelerated atherosclerosis is morphologically different from spontaneous atherosclerosis because its lesions appear diffuse, more concentric, and have greater cellularity with varying degrees of lipid accumulation and mononuclear cell infiltration. The syndrome of accelerated atherosclerosis shares many of the pathophysiological features of intimal hyperplasia; however, the macrophage is likely to be the prime mediator of this type of atherosclerosis. Also, the endothelium overlying accelerated atherosclerotic lesions expresses class II antigens, which are not observed in spontaneous atherosclerosis.[15][21]

History and Physical

Patients presenting with VGS following CABG typically present with symptoms of angina. When the vein graft fails, patients may experience chest pain or a pressure-like sensation over their sternum with minimal to no exertion. Symptoms of ischemia may also include shortness of breath, palpitations, generalized weakness, diaphoresis, nausea, and epigastric discomfort.[22] Physical examination findings of the patient experiencing acute coronary syndrome include diaphoresis, pallor, elevated jugular venous pressure, pulmonary crackles, S3 or S4 cardiac heart tones, and bilateral lower extremity edema. Patients who develop VGS following PABG typically present with rest pain, claudication, and non-healing wounds. On physical examination, patients may demonstrate thinning of the skin, decreased leg temperature, hair loss, decreased or absent peripheral pulses, chronic non-healing wounds, subjective sensation loss, decreased motor function, and abnormal neuronal reflexes.[23]

Evaluation

During evaluation for possible cardiac ischemia from an occluded vein graft, a 12-lead electrocardiogram is essential. A comparison with previous electrocardiograms should be made for new bundle branch blocks, significant ST deviations, and possible T wave abnormalities. Laboratory evaluation should include cardiac troponin, creatine kinase-MB, and B-type natriuretic peptide levels. A baseline chest X-ray is unlikely to show evidence of vein graft occlusion. Still, in the case of new-onset congestive heart failure due to ischemia, it may demonstrate cardiomegaly and pulmonary congestion.[22] Pulmonary findings on chest X-ray may include vascular redistribution, interstitial edema known as Kerley B lines, and alveolar edema. Lastly, an echocardiogram may assess for significant drops in ejection fraction, new wall motion abnormalities, or valvular regurgitation from malfunctioning papillary muscles.[24]

Evaluation of the patient presenting with signs and symptoms of VGS following PABG includes clinical and radiographic methodologies. Evaluation starts with a distal pulse assessment using a handheld Doppler. This can be augmented with extremity blood pressure measurements to determine an ankle-brachial index. A normal ratio greater than 0.9 to 1.1 demonstrates that one’s peripheral vasculature is most likely patent. Claudication is typically denoted as those individuals obtaining a ratio of ankle systolic blood pressure to brachial systolic blood pressure of 0.4 to 0.9. Rest pain typically develops as this ratio falls to 0.2 to 0.4; non-healing wounds with ulceration and gangrene develop with ratios of 0 to 0.4. With abnormal findings, further evaluation is indicated. Vascular imaging may be completed using non-invasive imaging modalities such as Doppler ultrasonography, computed tomography, or magnetic resonance angiography. Invasive imaging and digital subtraction angiographies may also be used; however, this method requires direct cannulation of the artery and is associated with a higher degree of morbidity and mortality compared to less invasive imaging strategies.[23]

Treatment / Management

The key to the management of VGS is prevention. During the first 30 days after surgery, VGS is prevented with meticulous surgical technique and appropriate perioperative anticoagulation. Ensuring the correct graft position during surgery and avoiding graft kinking or sharp turns is key. An adequately sized target vessel with sufficient runoff or distal perfusion must be chosen. Avoiding unnecessary extra vein graft skeletonization and decreased graft palpation during dissection may prevent early graft failures. Prevention of short-term (30 days to 18 months) and long-term (greater than 18 months) VGS are centered around preventing and slowing the progression and development of intimal hyperplasia and atherosclerosis. Various factors have been implicated in the development of VGS, and they are thought to closely parallel the same risk factors for the development of arterial atherosclerosis. A healthy diet, control of blood glucose levels, regular exercise, maintenance of appropriate blood pressure, management of dyslipidemia, and smoking cessation are recommended in all patients with peripheral or coronary artery disease.[25] The use of low-dose aspirin in the postoperative period has decreased the incidence of VGS. It is recommended in all patients following coronary and peripheral artery bypass procedures.[26][27]

The Dual Ticagrelor Plus Aspirin Antiplatelet Strategy After Coronary Artery Bypass Grafting trial demonstrated the use of the P2Y12 receptor-blocking agent, ticagrelor, in addition to aspirin, improved venous graft patency with similar rates of major bleeding, for those who have undergone CABG.[28][29] Conversely, the clopidogrel and acetylsalicylic acid in bypass surgery for peripheral arterial disease trial demonstrated no significant decrease in VGS in patients following bypass surgery for peripheral arterial disease (PABG) with the addition of ticagrelor.[30][27] Therefore, regarding the prevention of VGS, patients should receive dual antiplatelet therapy following CABG but single antiplatelet therapy following PABG in the abscess of another clinical indication. Anticoagulation therapy has failed to demonstrate an ability to prevent VGS.[31][32] Statins and aggressive control of dyslipidemia have been repeatedly demonstrated to improve outcomes in patients following bypass surgery and have also been demonstrated to slow VGS.[5][33] Another aspect of prevention is routine, predetermined surveillance. Concerning peripheral vascular bypass, routine Doppler ultrasonography examinations allow the early identification of VGS, enabling endovascular reperfusion before complete graft failure.[34] Regular screening intervals are variable, but frequency declines as the time from surgery increases. Authors have proposed ultrasonographic examinations every 3 months for the first 2 years following surgery and every 6 to 12 months for subsequent years.[35][36]

When prevention fails, and VGS worsens, there are several reperfusion options.[1] These include endovascular reperfusion of the native vessel initially bypassed, endovascular reperfusion of the stenosed vein graft itself, or redo open surgery. If feasible, endovascular reperfusion of the native artery that was initially bypassed should be attempted first.[9] If this is not possible, endovascular reperfusion of the stenosed vein graft should be attempted next.[37] Open surgery should be reserved for those who cannot be treated by less invasive strategies first. Patients who are poor surgical candidates may be approached with medical management alone. Still, no randomized controlled trials compared endoluminal versus surgical intervention for stenosis in vein grafts following infrainguinal bypass. Currently, no high-certainty evidence supports using 1 type of intervention over another. High-quality studies must provide evidence on managing VGS following infrainguinal bypass.

When percutaneous coronary intervention (PCI) is completed, the decision for the use of a bare-metal stent (BMS) or a drug-eluting stent (DES) must be made. The Symbiot trial compared the Symbiot DES with a BMS. At 8 months of follow-up, the incidence of major adverse cardiovascular events between the Symbiot and BMS groups was similar.[38] In the Reduction of Restenosis in Saphenous Vein Grafts with Cypher Sirolimus-Eluting Stents trial, it was reported that the sirolimus-eluting stent reduced late stent loss and increased the vessel patency rate compared with BMS at 6-months of follow-up.[39][40] Several other smaller studies have shown, with some degree of variation, that DESs are preferred over BMSs concerning the treatment of VGS as measured by in-stent restenosis.[41][42] However, despite these results, a recent meta-analysis comparing DESs with BMSs in VGS treatment failed to demonstrate a difference between the 2 groups at 42 months of follow-up when comparing all-cause mortality, major adverse cardiovascular event, cardiac death, myocardial infarction, and target lesion revascularization.[43] Therefore, the decision to use a DES vs. a BMS is dictated by individualized patient factors, physician comfort, and facility availability. Regardless of the stent type used, care must be taken to avoid distal embolization of plaque fragmentation during endovascular intervention, necessitating an embolic protection device in all feasible cases.[44]

Differential Diagnosis

Differential following CABG with a vein graft:

• Myocardial ischemia of a native artery
• Cardiac arrhythmia
• Pulmonary embolism
• Aortic dissection
• Musculoskeletal pain 

Differential following PABG with a vein graft:

• Critical limb ischemia of a native artery
• Arterial aneurysm
• Arterial dissection
• Thromboembolism
• Neurological pain
• Musculoskeletal pain

Prognosis

Revascularization for stenosed vein grafts is less effective than arterial stenosis concerning overall mortality, length of event-free survival, and total vein graft disease at 5 years.[45][46] Compared to their index CABG operation, those undergoing redo-CABG procedure have a perioperative mortality rate of 9.6% vs. 2.8%, respectively. Heart failure with reduced ejection fraction, insulin-dependent diabetes, redo surgery within 1 year of the index operation, and renal disease are all independent risk factors for increased mortality following redo-CABG.[47] The prognosis of those diagnosed with critical limb ischemia, a common indication for PABG, is poor. At 1 year of follow-up, approximately 45% survive with both limbs, 30% have been treated with an amputation, and 25% have expired. At 5 years, approximately 60% of patients diagnosed with critical limb ischemia die.[48] The prognosis is even worse for those with kidney disease, patients who continue to smoke, and those with diabetes.[49] The patency of vein grafts in the lower extremities remains challenging. Grafts monitored and treated for stenosis as identified on scheduled imaging maintained a patency rate of 82% to 93% at 5 years versus a patency rate of only 30% to 50% of those grafts that did not undergo regular interval screenings.[36]

Complications

Complications following great saphenous CABG include bleeding, immediate graft failure, delayed graft failure, infection, heart failure, myocardial infarction, distal thromboembolism, pericarditis, renal failure, shock, and death. Complications following great saphenous PABG include compartment syndrome, distal thromboembolism, critical limb ischemia, electrolyte abnormalities, arterial aneurysm, arterial dissection, bleeding, infection, renal failure, and death.

Deterrence and Patient Education

The best management of VGS is prevention. Maintaining a healthy weight, taking your medications as prescribed, exercising, and cessation of tobacco use is key to avoiding another procedure or surgical operation. When VGS of the coronary vessels is diagnosed, there are 2 primary treatment options: redo open surgery, which is a significant undertaking with a high degree of morbidity and mortality, and PCI. PCI uses a catheter-based system through an artery in your arm or leg to place a stent in the coronary vessels and increase blood flow. Careful precautions are taken to prevent distal embolization of plaques during PCI stenting. VGS of the peripheral arterial system is similar. Endovascular reperfusion methods are preferred, such as using a stent or balloon to open an occluded vessel and restore blood flow. If endovascular techniques fail or are impossible, an open surgical approach may be required. Unfortunately, some patients are not candidates for endovascular or open approaches, and these patients are treated with medications alone that thin the blood to restore blood flow.

Enhancing Healthcare Team Outcomes

Best patient outcomes are achieved through the combined efforts of an interprofessional healthcare team. After receiving a bypass operation, this interprofessional team follows patients, including physician assistants, nurse practitioners, nurses, residents, fellows, primary care providers, pharmacists, internists, and surgeons. Before discharge, patients typically receive some form of rehabilitation necessitating the assistance of physical and occupational therapists. Once discharged, at-home nurses may continue meeting with patients to monitor and ensure their recovery.[50] The vascular surgeon is the primary "driver" in these cases, but the patient's primary care clinician can also be instrumental in post-procedural monitoring. Nurses in all clinics help coordinate patient care and follow-up and serve as liaisons between the various specialists. Pharmacists review medication regimens to ensure appropriate dosing and no drug interactions and counsel the patient about their drugs. Open communication between all team members and accurate record-keeping enable the interprofessional paradigm to guide optimal patient outcomes.