Continuing Education Activity

The long-term patency and success of venous grafts in bypass surgery remains a challenge due to a variety of complications, such as the accelerated rates of atherosclerosis when 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:

• Describe the pathophysiology of vein graft stenosis.
• Outline the presentation of vein graft stenosis.
• Describe the treatment options for vein graft stenosis.
• Review the importance of improving care coordination among multidisciplinary team members to improve the outcomes for patients with vein graft stenosis.

Introduction

The long-term patency and success of vein grafts in bypass surgery remains a challenge due to their accelerated atherosclerotic rates when compared to their arterial counterparts. [1] Prevention of vein graft stenosis (VGS) is the cornerstone of management and includes tight control of blood pressure, blood sugars, lipid levels, body weight, and cessation of smoking. Nearly all patients with vein grafts should be treated with daily aspirin and a statin. [2][3][4][5][6]Further anticoagulation and antiplatelet therapy are determined by specific interventions performed and individualized patient factors. [7] The most common presentation of VGS following coronary artery bypass grafting (CABG) is angina. In the peripheral vascular system, VGS presents as rest pain, non-healing wounds, and claudication. If revascularization is necessary, endovascular therapy or surgical bypass should be offered to improve the arterial circulation of the obstructed native vessel. [8] To improve the primary or secondary patency, endovascular therapy of the vein graft itself may be attempted first. [9] An open approach is reserved for multivessel disease or those patients for whom endovascular methods are impossible. This article will discuss 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 three 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 occurring at the graft anastomoses such as the position of the graft, kinking of the graft, 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 a variety of mechanisms have been implicated. Perivascular myofibroblast remodeling, [11] platelet-derived growth factor smooth muscle proliferation, [12] decreased local nitric oxide release, decreased endothelial relaxation, [13] and intimal vein wall thickening are several of the mechanisms that have been implicated in short term venous graft stenosis and failure. [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 each year, the burden of the saphenous VGS on our healthcare system is of significant concern. Graft occlusion before hospital discharge has been reported to occur in approximately 10% of vein grafts. [10] During the first year after CABG, approximately 15% to 30% of grafts will occlude. After the first year post-CABG, the annual occlusion rate is about 2% and it rises to approximately 4% annually between postoperative years 6 and 10. [1]

An estimated 15% of individuals over the age of 70 will develop peripheral artery disease. [16] Of these, approximately 50% will become symptomatic. About 1% of those with symptoms will go on to develop critical limb ischemia potentially necessitating a PABG. [17] Rates of autogenous vein graft bypass failure remain high in the lower extremities with approximately 20% of grafts failing in the first year and as many as 50% failing by year five. [18][19]

Pathophysiology

The wall of a vein is traditionally divided into three 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 in the internal mammary artery. [1] 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 the time of harvest. 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% when compared to their "non-diseased" controls. [15]

Perioperative manipulations of veins before their insertion have been shown to produce significant tissue damage. Such implantation injury leads to endothelial dysfunction, endothelial cell injury, endothelial denudation, and smooth muscle cell injury. Each is an important factor in the initiation of intimal hyperplasia and VGS. Postoperative venous grafts, following exposure to the arterial environment, experience severe stretching, and increased tangential stress. These forces greatly 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 and is considered to result from both the migration of smooth muscle cells out of the media into the intima and 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 medial smooth muscle cell layer of the vein graft. During the initial perioperative period after saphenous vein grafting, early stenosis and occlusions occur in 5% to 8% of grafts due to intimal hyperplasia. Vein grafts with lower flows are associated with a greater intimal thickening. Similarly, low shear stress is also associated with 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 six months after implantation. Thus, it appears that these late occlusions of vein bypass grafts are due to the development of a rapidly progressive and structurally distinct form of atherosclerosis which has been termed "accelerated atherosclerosis" to distinguish it from "spontaneous atherosclerosis." [21] Accelerated atherosclerosis is morphologically different from spontaneous atherosclerosis in that its lesions appear to be 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 prime mediators of this type of atherosclerosis are likely to be the macrophage. Also, the endothelium overlying accelerated atherosclerotic lesions expresses the 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. Depending on the time frame of when the vein graft failed, patients may experience chest pain or 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 that 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 EKG is essential. Comparison with previous EKGs should be made and assessed for new bundle branch blocks, significant ST deviations, and possible T wave abnormalities. Laboratory evaluation should include cardiac troponin, creatine kinase-MB, and brain natriuretic peptide levels. A basic chest x-ray is unlikely to show any evidence of vein graft occlusion, but in the case of new-onset congestive heart failure due to ischemia, may demonstrate cardiomegaly and pulmonary congestion. [22] Pulmonary findings on chest x-ray may also include vascular redistribution, interstitial edema known as Kerley B lines, and alveolar edema. Lastly, an echocardiogram may be performed to assess for significant drops in ejection fraction, new wall motion abnormalities, or significant valvular regurgitation from malfunctioning papillary muscles. [24]

Evaluation of the patient presenting with signs and symptoms of VGS following PABG includes both clinical and radiographic methodologies. Evaluation starts with a distal pulse assessment with the use of a handheld doppler. This can be augmented with extremity blood pressure measurements to determine an ankle-brachial index. A normal ratio is >0.9 to 1.1 and 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 with the use of non-invasive imaging modalities such as Doppler ultrasonography, computed tomography angiography, or magnetic resonance angiography. Invasive imaging with angiography and digital subtraction x-rays 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. Prevention of early (first 30 days after surgery) VGS is accomplished with good surgical technique and appropriate perioperative anticoagulation. Ensuring the correct position of the graft during surgery and avoidance of graft kinking or sharp turns are key. An adequately sized target vessel with sufficient runoff or distal perfusion must be chosen. Avoidance of complete vein graft skeletonization and decreased graft palpation during dissection may also serve a function in the avoidance of early graft failures. Prevention of short-term (30 days to 18 months) and late-term (greater than 18 months) VGS are centered around preventing and slowing the progression and development of intimal hyperplasia and atherosclerosis. There are a variety of factors that 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 cessation of smoking are recommended in all patients with peripheral or coronary artery disease. [25] The use of low dose aspirin in the postoperative period has been demonstrated to decrease the incidence of VGS and is recommended in all patients following both coronary and peripheral artery bypass procedures. [26][27]The DACAB trial demonstrated that the use of the P2Y12 receptor blocking agent, ticagrelor, in addition to aspirin, improved venous graft patency for those who have undergone CABG. [28] Conversely, the CASPAR trial demonstrated no significant decrease in VGS in patients following PABG with the addition of ticagrelor. [27] Therefore, with regards to 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. [29][30] 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.[4][31]

Another aspect of prevention is routine monitoring. With regards to peripheral vascular bypass, routine doppler ultrasonography examinations allow the early identification of VGS enabling endovascular reperfusion before complete graft failure. [32] Regular screening intervals are variable, but frequency declines as the time from surgery increases. Authors have proposed ultrasonographic examinations every three months for the first two years following surgery and every six to twelve months for subsequent years. [33][34]

When prevention fails and VGS worsens, there are several reperfusion options. These include endovascular reperfusion of the native vessel that was 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. [8] If this is not possible, endovascular reperfusion of the stenosed vein graft should be attempted. [35] Open surgery should be reserved for those who cannot be treated by less invasive strategies first. Patients who are poor surgical candidates may require medical management alone.

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 eight months of follow-up, the incidence of major adverse cardiovascular events (MACE) between the Symbiot and BMS groups were similar. [36] In the RRISC trial, it was reported that the sirolimus-eluting stent reduced late stent loss and increased the vessel revascularization rate when compared with BMS at 6-months of follow-up. [37] Several other smaller studies have shown, with some degree of variation, that DESs are preferred over BMSs with regards to the treatment of VGS as measured by in-stent restenosis. [38][39] However, despite these results, a recent meta-analysis comparing DESs with BMSs in VGS treatment failed to demonstrate a difference between the two groups at 42 months of follow-up when comparing all-cause mortality, MACE, cardiac death, myocardial infarction, and target lesion revascularization. [40] Therefore, the decision for the use of 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 the use of an embolic protection device in all feasible cases. [41]

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 for arterial stenosis with regards to overall mortality, length of event-free survival, and total vein graft disease at five years. [42][43]

The mortality rate of those undergoing redo-CABG compared to their index CABG operation have a perioperative mortality rate of 9.6% vs. 2.8%, respectively. Heart failure with reduced ejection fraction, insulin-dependent diabetes, redo surgery within one year of the index operation, and renal disease are all independent risk factors for increased mortality following redo-CABG. [44]

The prognosis of those diagnosed with critical limb ischemia, a common indication for PABG, is poor. At one year of follow-up, approximately 45% will be alive with both limbs, 30% will have been treated with an amputation, and 25% will have expired. At five years, approximately 60% of patients diagnosed with critical limb ischemia will be dead. [45] Prognosis is even worse for those with kidney disease, patients that continue to smoke, and those with diabetes. [46] Patency of vein grafts in the lower extremities continues to remain a challenge. Grafts monitored and treated for stenosis as identified on scheduled imaging maintained a patency rate of 82% to 93% at five years versus a patency rate of only 30% to 50% of those grafts that did not undergo regular interval screenings. [34]

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 two primary treatment options. Redo open surgery which is a major undertaking with a high degree of morbidity and mortality or 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 their 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 with the use of 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 will be 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 the healthcare team. Having received a bypass operation, patients are followed by an interprofessional team that includes physician assistants, nurse practitioners, nurses, residents, fellows, primary care providers, pharmacists, internists, and their 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 to meet with patients to continually monitor and ensure their recovery. [Level 4] [47]