Venous clot lysis and stenting

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1 IMAGING AND TREATING THE CLOT:WHAT S NEW? Venous clot lysis and stenting Suresh Vedantham 1 1 Interventional Radiology Section, Mallinckrodt Institute of Radiology, Washington University School of Medicine, St Louis, MO Venous thromboembolism (VTE) continues to represent a major source or mortality and morbidity. Although anticoagulation is the mainstay of therapy, adjunctive catheter-based interventions have shown substantial potential to improve clinically meaningful patient outcomes in patients with deep vein thrombosis (DVT), pulmonary embolism (PE), and the post-thrombotic syndrome (PTS). Catheter-directed thrombolysis (CDT) has been shown in a randomized trial to reduce the risk of PTS in patients with acute proximal DVT; data from a larger NIH trial is expected shortly. The use of CDT is being increasingly used for patients with submassive or massive pulmonary embolism. Preliminary studies suggest that endovascular stent placement and ablative therapies can improve quality-of-life in carefully selected patients with established PTS. In this article, we summarize the current status of thrombus removal and stent placement procedures for VTE and PTS, with the main purpose being to guide clinicians in individualizing treatment decisions for their challenging patients. Learning Objectives Summarize the indications for endovascular treatment for patients with acute deep vein thrombosis, acute pulmonary embolism, and established post-thrombotic syndrome Describe the results of a multicenter randomized trial that evaluated the use of catheter-directed thrombolysis as firstline therapy in patients with acute proximal DVT Venous thromboembolism (VTE), which includes deep vein thrombosis (DVT) and pulmonary embolism (PE), is a frequent condition that causes substantial morbidity and mortality. 1 Both DVT and PE, the two central manifestations of VTE, are associated with important early and late sequelae for patients. Early on, acute DVT causes pain, swelling, and activity limitation; acute PE is often fatal. Later, recurrent VTE episodes ultimately affect over one-third of VTE patients. 2 Patients are also vulnerable to the development of substantial disability and quality-of-life (QOL) impairment from development of the postthrombotic syndrome (PTS; after DVT) or cardiopulmonary dysfunction with reduced exercise tolerance (after PE). A subset of patients with VTE experience clinically severe presentations that put them at additional risk for early and late complications. In such patients, physicians have the ability to escalate the level of aggressiveness of therapy to mitigate these short-term and long-term VTE risks. The purpose of this article is to update the reader on the current status of evidence pertaining to the use of thrombolytic and interventional therapies for DVT, PE, and PTS. Acute DVT Anticoagulant therapy continues to represent the mainstay of treatment for acute DVT because it markedly reduces the risk of PE, thrombus extension, and VTE recurrence. 3 However, it is important to recognize that anticoagulation does not actively eliminate thrombus that has already formed and that after DVT, the venous system is vulnerable to the development of irreversible changes that may negatively impact patients recovery and long-term well-being. The thrombus often exhibits incomplete resolution which causes obstruction to blood flow, and the inflammatory response to thrombosis can contribute to permanent damage of the venous valves, leading to valvular incompetence. 4,5 Together, these factors result in chronic ambulatory venous hypertension and the clinical findings of PTS. 6 Prospective contemporary studies indicate that the PTS develops in 50% of patients who suffer a first episode of symptomatic, proximal, lower-extremity DVT. 7,8 Patients with PTS have diverse clinical phenotypes. For this reason, the diagnosis of PTS and the categorization of its severity are often aided by clinical scales that assess PTS symptoms and signs; examples of validated scales include the Villalta PTS Scale, the Venous Clinical Severity Scale, and the Clinical-Etiologic-Anatomic-Pathophysiologic Classification. That being said, PTS is a chronic condition that most typically causes daily limb pain/aching, fatigue, heaviness, and/or swelling. Many patients with PTS experience only mild interference with their daily activities. However, in approximately one-third of patients who develop PTS, severe manifestations including painful venous claudication, stasis dermatitis, subcutaneous fibrosis, and/or skin ulceration may develop. For these reasons, both the presence and severity of PTS have been identified as leading predictors of a DVT patient s health-related QOL 2 years after a DVT episode, and as sources of substantial direct and indirect costs to patients and society. 9 Although anticoagulation probably does reduce the risk of PTS by preventing recurrent DVT, it is clearly not sufficient to protect many patients from this condition. Of published RCTs, none have been designed to directly compare different anticoagulant strategies for PTS prevention. In one randomized controlled trial (RCT) that compared the use of tinzaparin Conflict-of-interest disclosure: The author has received research funding from Covidien, Bayer Healthcare, Cook Inc, Volcano, and Therakos Inc; has received donation of a study drug from Genentech; and has received donation of stockings from BSN Medical. Off-label drug use: TPA for DVT thrombolysis Stents for venous use. 210 American Society of Hematology

2 monotherapy versus warfarin therapy for patients with DVT, a secondary analysis suggested a reduction in the risk of PTS in the tinzaparin group. 10 However, the PTS assessment in this study had substantial methodologic limitations. The anatomic extent of DVT is an important predictor of a patient s subsequent risk of developing PTS. Importantly, patients with iliofemoral DVT (defined as DVT involving the common femoral vein and/or iliac vein, with or without involvement of other veins as well), experience recurrent VTE twice as frequently as patients with less extensive proximal DVT, and have significantly more frequent and more severe PTS. 11,12 Elastic compression stockings (ECSs) have been carefully studied for their ability to prevent PTS. However, a large, placebo-controlled, double-blind, multicenter RCT (the SOX Trial) found no difference in the development of PTS over 2 years between symptomatic acute proximal DVT patients who used mmhg, knee-high ECSs versus sham stockings with minimal ankle pressure. 8 Hence, the prevention of PTS remains an important but elusive treatment objective that is often not met by traditional therapy. The use of systemic thrombolytic therapy to treat acute proximal DVT has been carefully assessed in randomized clinical trials. Although evidence of partial clot removal efficacy was demonstrated and two small, long-term follow-up studies with major methodological limitations did suggest a reduction in PTS, major bleeding was increased by 3-4 times over anticoagulation alone Therefore, systemic thrombolytic therapy is not recommended for the treatment of DVT. 3 CDT refers to the direct intrathrombus administration of a fibrinolytic drug via a catheter or device embedded within the thrombus using imaging guidance. 16 The theoretical advantages of intrathrombus infusion are several: (1) clot removal efficacy is enhanced by the ability to achieve a high intrathrombus drug concentration and avoid bypass of the drug around occluded venous segments; (2) the addition of mechanical thrombus disruption with some drug delivery methods may further enhance pharmacological dissolution of thrombus; (3) the improved efficacy may enable reduced thrombolytic drug dose, treatment time, hospital resource use, and bleeding complications; and (4) catheter access into the venous system may enable treatment of underlying venous anatomic abnormalities, which may help to reduce the risk of recurrent DVT. 17,18 It has long been known that CDT can enable rapid reduction of thrombus burden and restoration of venous patency. 17,18 However, any use of fibrinolytic drugs is associated with a small but real risk of bleeding complications. Because CDT is somewhat invasive, resource-intensive, and increases the risk of major bleeding, careful patient selection is paramount and should include consideration of the following factors 19 : (1) Projected risk of bleeding: all patients in whom CDT is being considered must undergo careful individualized assessment for factors that may increase the risk of bleeding, including ongoing or recent active bleeding; recent obstetrical delivery; recent ( 7-14 days, depending on the specific procedure) major surgery, trauma, or other invasive procedure; previous hemorrhagic stroke or the presence of other lesions that could bleed in critical areas, such as the central nervous system; and uncontrolled hypertension. A very low threshold should be applied to exclude patients if there are bleeding concerns. (2) Clinical severity of DVT: urgent thrombolysis is indicated to prevent life-, limb-, or organ-threatening complications of acute DVT in situations, such as phlegmasia cerulea dolens or progressive IVC thrombosis. Nonurgent thrombolysis may also be reasonable when there is an increase in clinical severity of DVT or severe physical limitation that is not relieved with anticoagulation alone. As summarized below, the limited available evidence supports the use of CDT as first-line therapy (along with anticoagulation) for the purpose of PTS prevention, but larger studies are needed to reach confidence that this approach is suitable for large numbers of patients; (3) Anatomic extent of DVT: patients with acute iliofemoral DVT (symptom duration 14 days) are at much-increased risk for PTS and recurrent VTE and therefore appear to represent the most appropriate candidates for CDT. 19,20 Patients with DVT involving the axillosubclavian vein, especially if in the dominant arm, are also at significant risk of developing upper extremity PTS. 21 In contrast, patients with asymptomatic DVT or isolated calf vein or popliteal DVT should not undergo CDT since the benefits are not likely to outweigh the risks. In determining how to proceed, it is also important to consider the patient s life-expectancy, baseline ambulatory capacity, and comorbidities, and the patient should be made aware of the risks, benefits, and alternatives. With traditional drug infusion-only CDT, successful lysis of thrombus may be expected to occur after 1-3 days of thrombolytic therapy in 80%-90% of patients who present with symptom duration 14 days. 18 After thrombus removal is achieved, it is customary to manage any venous stenosis that is uncovered using endovascular stent placement (iliac vein) or balloon angioplasty (femoral vein), although few studies have directly addressed the utility of these adjuncts. In making decisions about stent placement, it is important to remember that these are permanent implants for which the long-term fate is unknown, and that it is unclear whether the presence of a stent should influence decisions on the optimal duration of anticoagulation and/or antiplatelet therapy. If the patient is being treated for symptomatic upper extremity DVT in the context of Paget Schroetter Syndrome ( effort thrombosis ), aggressive angioplasty and stent placement are not performed. Rather, surgical thoracic outlet decompression is performed to treat the underlying anatomic problem. In a multicenter RCT (the CAVENT Study) of patients with acute DVT involving the iliac and/or upper femoral venous system, CDT together with anticoagulant therapy and compression was associated with a 26% relative reduction in the risk of PTS over 2 years (41.1% vs 55.6%, p 0.04) compared with anticoagulant therapy and compression alone. 22 In this study, 3% of patients receiving CDT had a major bleed, including one who required surgery and another who received a blood transfusion, but there were no intracranial bleeds or deaths. Limitations of this study include its modest sample size (efficacy outcomes reported in 189 patients) and geographical limitation (4 treatment centers in Norway). To date, there are no randomized trials evaluating the use of CDT or related techniques for upper extremity DVT. In recent years, CDT has been refined to incorporate device technology aimed at enabling faster delivery and intrathrombus dispersion of the fibrinolytic drug. Ultrasound-assisted CDT involves the delivery of the fibrinolytic drug through a specialized catheter that also emits low-power ultrasound energy into the thrombus. However, a small randomized trial did not find an added benefit to use of the ultrasound catheter compared with a standard multisidehole catheter. 23 Pharmacomechanical CDT (PCDT) involves the use of catheter-mounted thrombectomy devices along with intrathrombus delivery of fibrinolytic drugs, although retrospective studies suggest that PCDT is associated with reductions in drug Hematology

3 dose and treatment time compared with infusion-only CDT, there are no completed multicenter RCTs evaluating PCDT. 24 The NIH-sponsored ATTRACT Trial, which has completed accrual, is expected to provide rigorous data on the benefit-to-risk ratio of PCDT. 25 In this study, patients with acute proximal DVT are randomized to receive PCDT together with anticoagulation and compression versus anticoagulation and compression alone, with PTS assessed over 2 years follow-up. The available studies of CDT and PCDT for the management of acute DVT suggest that periprocedural symptomatic PE occurs in 1%-2% of treated patients. 18,22 For this reason, the routine use of inferior vena cava filters in conjunction with CDT or PCDT is not recommended. 19,20 Acute PE Patients with acute PE should be carefully evaluated and grouped into three general categories: (a) low-risk or ordinary PE for which patient outcomes are good with anticoagulation alone; (b) high-risk or massive PE in which patients show signs of hemodynamic compromise; and (c) intermediate risk or submassive PE in which patients are hemodynamically stable but show evidence of right ventricular dysfunction and/or elevation of cardiac enzymes. 20 In modern practice, aggressive strategies are frequently used for patients with massive PE and are considered for patients with submassive PE because these patients are at higher risk for short-term morbidity and long-term QOL impairment. In the largest RCT of systemic thrombolysis for submassive PE to date (the PEITHO Study), thrombolysis was shown to prevent hemodynamic decompensation at the price of an increased risk of major bleeding and intracranial bleeding. A mortality benefit was not demonstrated. It should be noted that this study enrolled patients at the more severe end of the submassive PE spectrum. 26 In 2014, three meta-analyses summarized the results of 16 randomized controlled trials that compared systemic thrombolysis with anticoagulation alone for the treatment of acute PE These trials suggest that systemic thrombolysis probably reduces mortality and prevents hemodynamic decompensation in patients with massive PE, but at the price of an increased risk of major and intracranial bleeding. Although the results of systematic meta-analyses differ on whether systemic thrombolysis reduces mortality in patients with submassive PE, it clearly increases major bleeding by about 3-fold and intracranial bleeding by about 5-fold. Hence, systemic thrombolysis is probably best used for patients with massive PE or those at the most severe end of the submassive PE spectrum. Interestingly, the double-blind, placebo-controlled, randomized TOPCOAT study found systemic thrombolysis recipients to be more likely to have normal RV function, exercise capacity, and perception of physical wellness (assessed using the SF-36 QOL measure) at 3 months compared with patients treated with anticoagulation alone. 30 The idea that thrombolysis may offer important clinical benefits, combined with the fear of bleeding with full-dose thrombolytic drug administration, has spurred interest in catheter-directed methods of thrombolytic therapy that reduce drug dose. 31 In a randomized controlled trial of 59 patients with submassive PE, the use of ultrasound-assisted CDT (using the EkoSonic Endovascular System) with 20 mg total dose rt-pa plus anticoagulation reduced the RV/LV diameter ratio from baseline to 24 hours to a greater extent than anticoagulation alone. 32 No patients undergoing ultrasoundassisted CDT died, suffered recurrent VTE, or developed major bleeding. A subsequent prospective, single-arm, multicenter study of ultrasound-assisted CDT in 150 patients with acute massive or submassive PE found similar hemodynamic effects, with a major bleeding rate of 10% (Piazza et al 33 ). Hence, data from larger randomized trials will be needed to determine whether ultrasoundassisted CDT or any catheter-based method should be routinely used for the management of submassive PE. At present, the use of catheter-directed therapy for acute PE may be considered for hemodynamically compromised patients or those with significant RV dysfunction when systemic thrombolysis has failed or as an alternative to systemic thrombolytic therapy, if local expertise is available. For patients with contraindications to thrombolysis, catheter-assisted embolectomy without thrombolysis may be used, but clinical efficacy is not established for any specific method at this time. Inferior vena cava (IVC) filters are used by some physicians to prevent recurrent PE in patients with massive PE. The use of retrievable IVC filters implanted for 3 months, in patients with less-severe PE (ie, patients with symptomatic PE and clinical features deemed to confer higher risk for poor outcome) who were able to receive anticoagulant therapy, was studied in the PREPIC-2 trial. In this multicenter RCT, IVC filters were not found to confer additional protection against death or recurrent PE. 34 Established PTS Many patients with PTS experience significant pain, activity limitation, and interference with life activities. Unfortunately, thrombosis care in 2015 tends to focus almost exclusively on the provision of anticoagulant therapy, so these patient-relevant symptoms and consequences tend to be underappreciated by many physicians who manage VTE. Even among physicians who are aware of and actively manage PTS, a broad range of approaches is used which may include lifestyle modifications (eg, periodic leg elevation, exercise, smoking cessation, weight loss), medical therapy (eg, anticoagulation, pentoxifylline, diuretics, venoactive medications), compressive strategies (eg, stockings, home edema pumps, wearable compression devices), and surgery (eg, debridement of ulcers, venous bypass procedures). 35 However, because few treatment strategies for established PTS have been subjected to rigorous clinical study, there is a lack of evidence-based management options. For any PTS patient, it is first important to confirm the diagnosis of PTS (as opposed to other conditions which may cause lower extremity symptoms) and to consider whether the clinical severity of the disease merits an aggressive treatment approach. Fundamental elements of the clinical approach include a directed medical history and physical exam, venous Duplex ultrasound to evaluate for signs of iliofemoral venous obstruction or saphenous venous valvular reflux, and careful verification that key elements of low-risk conservative therapy have been used (eg, anticoagulation appropriate for the DVT history, compression, and professional wound care for venous ulcers). Although the pathogenesis of PTS is complex and some venous changes are irreversible, 2 physiological elements are often amenable to endovascular correction: (1) iliac vein obstruction is amenable to stent placement (at present, this requires off-label device use), which can enhance outflow and thereby reduce venous 212 American Society of Hematology

4 pressures; and (2) saphenous vein reflux is amenable to endovenous thermal (radiofrequency or laser) ablation, which eliminates an additional pathway for downward transmittal of venous pressures. These treatments can be delivered to most patients in outpatient procedure centers with the use of conscious sedation, without interruption of ongoing anticoagulation. Because stents may be associated with recurrent thrombosis or other as yet unknown long-term risks, their implantation should be targeted to those patients in most need of benefit, and only after conveying the risks and uncertainties to the patient. Intractable pain, massive edema, progression of skin changes, or venous ulcer formation are the most common scenarios in which stents can be used. In preliminary studies, stent placement in chronically occluded iliac veins of patients with PTS was associated with ulcer healing and symptom improvement. While RCTs are still needed, the largest series found that patients (n 464) with moderate-tosevere PTS who received stents have marked reduction in pain, reduction in swelling, ulcer healing, and improvement in QOL. 36 Patients who either have a patent iliac vein or who continue to experience lifestyle-limiting PTS symptoms after stent placement should undergo repeat Duplex ultrasound to evaluate for saphenous vein reflux. If present, endovenous thermal ablation (EVTA) can be used to eliminate the refluxing superficial vein. 37 EVTA involves the delivery of thermal energy to the vein wall with a specialized catheter, resulting in irreversible fibrosis and resorption of the vein. This procedure tends to be durable in patients with primary valvular insufficiency, but has not been robustly studied in patients with PTS. Two retrospective studies that evaluated treatment strategies combining iliac vein stent placement with EVTA reported favorable outcomes in terms of relief of pain, relief of swelling, and ulcer healing. 38,39 Of note, the above studies are relatively small, lack control groups, and have a number of methodological limitations that confer a high potential for bias. It is hoped that rigorous prospective studies of PTS treatment by multidisciplinary investigator groups will be performed in the near future. Conclusion Endovascular therapy holds great promise to improve treatment outcomes in severely affected patients with acute DVT, acute PE, and established PTS. The use of CDT as up-front adjunctive therapy for patients with acute proximal DVT is now supported by one multicenter RCT, and the results of a larger NIH trial will be available in Studies evaluating endovascular therapy strategies for acute submassive PE and established PTS will be welcomed during the upcoming years. Correspondence Suresh Vedantham, Professor of Radiology & Surgery, Mallinckrodt Institute of Radiology, Washington University School of Medicine, 510 S. Kingshighway, Box 8131, St Louis, MO 63110; Phone: ; Fax: ; vedanthams@mir.wustl.edu. References 1. Huang W, Goldberg RJ, Anderson FA, Kiefe CI, Spence FA. Secular trends in occurrence of acute venous thromboembolism: Worcester VTE Study ( ). Am J Med. 2014;127(9): :e5. 2. Prandoni P, Noventa F, Ghirarduzzi A, et al. The risk of recurrent venous thromboembolism after discontinuing anticoagulation in patients with acute proximal deep vein thrombosis or pulmonary embolism: a prospective cohort study in 1,626 patients. Haematologica. 2007;92(2): Kearon C, Akl EA, Comerota AJ, et al. Antithrombotic therapy for VTE disease: antithrombotic therapy and prevention of thrombosis, 9th Ed: American college of chest physicians evidence-based clinical practice guidelines. Chest. 2012;141(2 suppl):e419s-494s. 4. 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