Deep Venous Thrombosis: The Opportunity at Hand

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1 Vascular and Interventional Radiology Review Vedantham DVT: The Opportunity at Hand Vascular and Interventional Radiology Review Suresh Vedantham 1 Vedantham S FOCUS ON: Keywords: ATTRACT Trial, deep venous thrombosis, DVT, postthrombotic syndrome, thrombolysis DOI: /AJR Received June 19, 2009; accepted without revision June 24, The ATTRACT Trial is sponsored by the National Heart, Lung, and Blood Institute, grants U01HL and U01HL088018, with additional support provided by BSN Medical, Covidien, Genentech, and Medrad Interventional. The contents of this manuscript are solely the responsibility of the author, and do not necessarily reflect the official views of the NHLBI, NIH, or other contributors. 1 Departments of Radiology & Surgery, Mallinckrodt Institute of Radiology and Washington University School of Medicine, 510 S Kingshighway, Box 8131, St. Louis, MO Address correspondence to S. Vedantham (vedanthams@mir.wustl.edu). AJR 2009; 193: X/09/ American Roentgen Ray Society Deep Venous Thrombosis: The Opportunity at Hand OBJECTIVE. The use of imaging-guided treatments for deep venous thrombosis (DVT) is accelerating. Increased appreciation of the impact of postthrombotic syndrome on DVT patients quality of life and advances in thrombolytic methods have together sparked an unprecedented degree of interdisciplinary collaboration in developing contemporary DVT treatment guidelines and a pivotal clinical trial to establish the risk benefit ratio of interventional DVT therapy. CONCLUSION. Radiologists should improve their DVT education, support ongoing clinical trials, and collaborate with DVT-focused nonradiologists in their institutions. D eep venous thrombosis (DVT) and pulmonary embolism (PE) are estimated to occur in nearly 1 million persons per year in the United States alone [1]. Because PE is estimated to kill more than 100,000 persons per year, its prevention using anticoagulant therapy has been the mainstay of DVT treatment for nearly 50 years. However, it is now clear that even in anticoagulated DVT patients, postthrombotic syndrome (PTS) develops in 25 50% of patients and causes major late patient morbidity [2, 3]. Although robust proofof-concept evidence supports the idea that early thrombus removal can prevent PTS and preserve quality of life (QOL), the risk benefit profile of endovascular thrombolytic therapy for DVT has not been established in a multicenter randomized controlled trial. Fortunately, over the past few years, there has been a major change in the technology and environment for endovascular DVT interventions. The goals of this article are to increase the reader s knowledge in several areas: first, the physiologic basis underlying the potential efficacy of interventional DVT treatments; second, the status of PTS as a critical and recognized but unmet public health need; third, the current multidisciplinary consensus about when to use endovascular DVT thrombolysis; fourth, the launch of a pivotal randomized clinical trial funded by the National Institutes of Health (NIH) that will evaluate the ability of stateof-the-art catheter-directed thrombolytic meth- ods to improve patient outcomes (the Acute Venous Thrombosis: Thrombus Removal with Adjunctive Catheter-Directed Thrombolysis [ATTRACT] Trial); and, fifth, the ability of interventional radiologists to now seize this major opportunity to define a central position in the treatment of DVT by simultaneously pursuing the endovascular treatment of patients with established PTS. Acute DVT Is a Chronic Disease Acute DVT is now recognized as a chronic condition that causes significant consequences mainly recurrent venous thromboembolism (VTE) and PTS that may affect patients for more than 5 years after the initial diagnosis despite the use of optimal standard treatment [4]. Although anticoagulant therapy can reduce the rate of VTE recurrence, PTS often still develops. PTS commonly causes chronic limb fatigue or heaviness, swelling, pain, and paresthesias. In severely affected patients, venous claudication, stasis dermatitis, and skin ulcers may develop. It is important for radiologists to be aware that prospective studies have clearly established the significance of PTS to patients and society. Although most DVT patients experience gradual resumption of their baseline QOL within the first 4 months after a DVT episode, one third continue to experience QOL impairment that correlates closely with the development of PTS [5]. Because PTS symptoms are aggravated by standing or walking, patients are forced to alter their daily 922 AJR:193, October 2009

2 DVT: The Opportunity at Hand activities to include periods of rest and recumbency. The severity of PTS has been shown to correlate with the severity of long-term QOL impairment, and the physical limitations of patients with PTS have been shown to match or exceed those of patients with other severe chronic medical conditions such as chronic obstructive pulmonary disease: Many PTS patients are disabled, unable to work, and unable to perform household duties [6 8]. Because PTS often causes venous ulcers, which are difficult to treat, and causes millions of workdays to be lost yearly, it is clearly responsible for a major economic burden to patients and society [9]. The microscopic cascade of events that occurs after DVT is poorly understood. However, the final macroscopic pathway that leads to PTS is the onset of ambulatory venous hypertension, which leads to chronic edema, tissue hypoxia and injury, progressive calf pump dysfunction, subcutaneous fibrosis, and skin ulceration [10, 11]. A large body of published research suggests that two key physiologic contributors to ambulatory venous hypertension are the development of valvular reflux and the presence of late venous obstruction due to incomplete clot clearance. Duplex ultrasound studies have shown that DVT leads to progressive venous valvular reflux in both thrombosed venous segments via direct inflammation-induced valvular damage that is usually irreversible; and via uninvolved venous segments that sometimes recover [12, 13]. Deep (femoro popliteal) venous reflux develops in more than 60% of DVT patients over 1-year follow-up, but it is important to understand that valvular reflux also develops in the superficial venous system, particularly if the greater saphenous vein was initially thrombosed [13]. Interestingly, veins that exhibit rapid endogenous clot clearance develop valvular reflux much less frequently ( times), supporting the use of early clot removal strategies [14]. The clinical importance of early thrombus resolution is strongly supported by available clinical studies. In a subgroup analysis from a single-center randomized trial evaluating elastic compression stockings for patients with proximal DVT, patients with residual thrombus on 6-month follow-up ultrasound were significantly more likely to develop PTS [15]. In a prospective study of 313 DVT patients, patients with residual thrombus on 6-month follow-up ultrasound were 2.4 times more likely to develop VTE recurrence [16]. In a meta-analysis of 11 randomized anticoagulation trials, the residual thrombus burden after initial DVT therapy correlated strongly with the risk of recurrent VTE [17]. Hence, early clot lysis correlates with better DVT outcomes. It is important for radiologists to understand the significance of the anatomic distribution of reflux and obstruction indeed, helping medical physicians incorporate this anatomic concept into their clinical thinking is likely to be a major contribution of radiology to the care of DVT patients. Duplex ultrasound studies have found that different venous segments exhibit different tendencies toward endogenous venous recanalization. With the femoropopliteal veins, recanalization is the rule and occurs in 50% of patients by 3 months and in more than 90% of patients by 1 year; however, unfortunately valvular reflux has already developed in 40% of patients as early as 1 month [12, 14]. In contrast, in patients with iliofemoral DVT, which is defined as DVT involving the iliac vein, common femoral vein, or both, complete venous recanalization rarely (< 5%) occurs with anticoagulation alone and PTS is clearly more frequent and severe in these patients [8, 18]. The Evolution of DVT Thrombolysis Methods Bleeding complications have always represented the Achilles heel of thrombolytic interventions; DVT has been no different. Although randomized controlled trials evaluating systemic streptokinase thrombolysis for DVT showed it to provide better clot removal efficacy and to reduce PTS, the threefold higher bleeding rate compared with anticoagulant therapy alone precluded its widespread adoption for DVT treatment [19]. In the 1990s, two changes in DVT treatment methods appeared very likely to markedly enhance procedural safety: first, the use of thrombolytic drugs with lower allergenicity and greater fibrin specificity; and, second, the development of endovascular catheter techniques with which to deliver the thrombolytic drug directly into the thrombus to reduce the needed dose. Catheter-Directed Intrathrombus Thrombolysis Catheter-directed intrathrombus thrombolysis refers to the original endovascular DVT thrombolytic technique in which a fibrinolytic drug is directly infused into the venous thrombus via a multi-side-hole catheter that is embedded within it using imaging guidance [20]. After the thrombus has been lysed by the drug, venography is performed to evaluate the underlying vein. Any stenosis identified is then treated with angioplasty or stenting during the same procedure. In a 473-patient prospective multicenter registry, the use of catheter-directed intrathrombus thrombolysis as an adjunct to anticoagulant therapy resulted in successful clot lysis in more than 80% of patients with acute proximal DVT [21]. Three studies have since compared the use of adjunctive catheter-directed intrathrombus thrombolysis and anticoagulant therapy versus anticoagulant therapy alone. The first study was a case-control study of 68 patients with acute iliofemoral DVT who underwent technically successful catheter-directed intrathrombus thrombolysis. In that study, Comerota et al. [22] found them to have fewer PTS symptoms and improved QOL at 16-month follow-up compared with a similar group of 30 patients who received anticoagulant therapy alone. AbuRahma et al. [23] found 5-year symptom resolution (78% vs 30%, p = ) to occur more frequently in DVT patients treated with catheter-directed intrathrombus thrombolysis. In a small randomized controlled trial, Elsharawy and Elzayat [24] found catheter-directed intrathrombus thrombolysis to yield a higher rate of normal venous function (72% vs 12%, respectively; p < 0.001) and less valvular reflux (11% vs 41%, p = 0.04) at 6 months than anticoagulant therapy alone. However, these studies had major design limitations that included reliance on surrogate outcome measures, single-center performance, small sample size, or nonrandomized design. In addition, in the 473-patient registry, catheter-directed intrathrombus thrombolysis had limitations in terms of safety (i.e., major bleeds in 11% of patients and intracranial bleeds in 0.4%) and health care resource utilization (i.e., 1- to 3-day ICU stays needed for patient monitoring during thrombolytic infusions that lasted an average of 48 hours). Hence, stand-alone catheter-directed intrathrombus thrombolysis was not a userfriendly treatment method and was perceived to have safety limitations that precluded its widespread use as first-line DVT therapy to prevent PTS. In recent years, advances in device technology have attempted to address these limitations of catheter-directed intrathrombus thrombolysis. Percutaneous Mechanical Thrombectomy Percutaneous mechanical thrombectomy (PMT) refers to the use of a percutaneous AJR:193, October

3 Vedantham catheter-based device that contributes to thrombus removal via fine thrombus fragmentation, maceration, aspiration, or a combination of these methods [25]. Unfortunately, currently available PMT devices cannot safely remove enough thrombus to be useful as a stand-alone treatment of most DVT patients, and this approach is largely relegated to clinical situations in which thrombolytic drugs cannot be used. Pharmacomechanical Catheter-Directed Thrombolysis Pharmacomechanical catheter-directed thrombolysis refers to thrombus dissolution via the combined use of catheter-directed intrathrombus thrombolysis and PMT [25]. Fibrinolytic drugs given via catheter-directed intrathrombus thrombolysis render thrombus more susceptible to mechanical fragmentation and removal (PMT) and also dissolve clot fragments that could otherwise embolize to the lungs. In addition, PMT devices macerate the thrombus, enhance dispersion of the fibrinolytic drug, and thereby accelerate thrombolysis. Some PMT devices also enable subsequent aspiration and removal of the fibrinolytic drug. Retrospective studies that compared first-generation pharmacomechanical catheter-directed thrombolysis methods with stand-alone catheter-directed intrathrombus thrombolysis observed that the use of pharmacomechanical catheter-directed thrombolysis reduced the needed thrombolytic drug dose and treatment time by 40 50% [26, 27]. In a study by Lin et al. [27], reductions in hospital costs ($47,742 vs $85,301, respectively; p < 0.01) and length of ICU stay (0.6 vs 2.4 days, p < 0.04) were also observed with the use of pharmacomechanical catheter-directed thrombolysis compared with catheter-directed intrathrombus thrombolysis. These findings support pharmacomechanical catheter-directed thrombolysis as being more efficient and possibly safer than stand-alone catheter-directed intrathrombus thrombolysis. For these reasons, most interventional physicians who treat DVT have modified their clinical practices to favor the routine use of pharmacomechanical catheterdirected thrombolysis in some form. Two pharmacomechanical catheter-directed thrombolysis techniques have drawn significant interest because they appear to enable DVT treatment to be completed in a single procedure session, obviating continuous thrombolytic infusions and ICU monitoring in many or most patients. Powerpulse refers to the use of the AngioJet Rheolytic Thrombectomy System (Possis Medical) to provide single-session pharmacomechanical catheter-directed thrombolysis of DVT [28, 29] by forcefully pulse-spraying a thrombolytic drug into the venous thrombus to thereby achieve better drug dispersion and faster treatment. Isolated thrombolysis refers to the use of the Trellis Peripheral Infusion System (Bacchus Vascular) to deliver and disperse small bolus doses of a thrombolytic drug into the venous thrombus. Two catheter-mounted balloons are inflated to effectively isolate the clot-containing treatment zone, and a dispersion wire oscillates within the catheter to disperse the drug within the thrombus. For both of these methods, early published reports suggest that perhaps 75% of patients may be successfully treated with single-session therapy [28 31]. Also exciting is the recent incorporation of state-of-the-art ultrasound technology into catheter-based clot removal devices. A drug delivery catheter (EkoSonic Endovascular System, EKOS Corporation) that emits lowpower ultrasound energy during the infusion to loosen fibrin strands and thereby enhance fibrinolytic drug dispersion has shown potential to speed thrombolytic therapy with minimal additional mechanical perturbation of the vein [32]. A catheter that utilizes cavitational ultrasound to remove thrombus has also undergone preliminary evaluation for its clot removal ability. A Changing Environment for DVT Interventions It is important to understand that no published data to date exist that attest to the clinical outcomes that can be obtained with the use of these new devices. It is not known whether they truly enhance procedural safety or PTS prevention or whether the additional mechanical manipulation or energy deposition causes beneficial or adverse effects on the vein. However, if ultimately shown to enable successful PTS prevention via a single, safe, minimally invasive procedure, these methods could certainly revolutionize the treatment of DVT. However, skeptics have cited methodologic limitations of the existing studies and the uncertainty surrounding the rate of bleeding complications that may be expected when using the newest catheter-directed intrathrombus thrombolysis methods. Before 2008, these differences were embodied in conflicting recommendations of the American College of Chest Physicians (ACCP) 2004 consensus guidelines (against the use of catheter-directed intrathrombus thrombolysis for primary PTS prevention) and a 2006 position statement of the Society of Interventional Radiology (SIR) (in favor of catheter-directed intrathrombus thrombolysis for selected patients with acute iliofemoral DVT) [33, 34]. At the level of clinical practice, the conflicting recommendations have resulted in wide variability in catheter-directed intrathrombus thrombolysis utilization thresholds. In 2008, the National Heart, Lung, and Blood Institute (NHLBI) decided to fund the ATTRACT Trial. This phase III, openlabel, assessor-blinded, multicenter randomized controlled trial will evaluate the ability of pharmacomechanical catheter-directed thrombolysis to prevent PTS in 692 patients with symptomatic acute proximal DVT who will be randomized to either pharmacomechanical catheter-directed thrombolysis and standard DVT therapy or standard DVT therapy alone in U.S. clinical centers. The ATTRACT Trial, for which subject enrollment will start in late 2009, will address the following questions: Does the routine first-line use of pharmacomechanical catheter-directed thrombolysis in patients with symptomatic proximal DVT actually prevent PTS at 24 months follow-up? Does pharmaco mechanical catheter-directed thrombolysis bet ter preserve QOL? Is pharmacomechanical catheter-directed thrombolysis safe enough? Is pharmacomechanical catheter-directed thrombolysis cost-effective? Moreover, the rates of major bleeding, transfusion, intracranial bleeding, symptomatic PE, recurrent VTE, and death will be evaluated. If pharmacomechanical catheter-directed thrombolysis is found to prevent PTS, a formal cost-effectiveness analysis will be conducted to estimate the number of quality-adjusted life-years gained with the use of pharmacomechanical catheter-directed thrombolysis. Do successful clot removal and the absence of valvular reflux predict lower PTS risk? The ATTRACT Trial is fairly unique in being a high-profile NIH-funded DVT treatment trial being led by an interventional radiology investigator, so it is hoped that its conduct will be strongly supported by practicing radiologists. In particular, radiologists who manage vascular ultrasound laboratories where DVT is routinely diagnosed should strongly encourage local physicians to consider their patients with acute symptomatic proximal DVT for enrollment in the ATTRACT Trial. The impact 924 AJR:193, October 2009

4 DVT: The Opportunity at Hand A of the ATTRACT Trial, with any outcome but especially if the results are positive, on interventional radiology s credibility as a scientifically rigorous discipline could be tremendous. In the meantime, a highly individualized approach to determining which DVT patients should receive pharmacomechanical catheterdirected thrombolysis is recommended [35]. Proximal DVT is not a monolithic condition. Rather, the anatomic extent of venous thrombosis, the clinical severity of initial DVT manifestations, the expected risk of suffering a bleeding complication, comorbidities, and the patient s baseline activity level, ambulatory capacity, and life expectancy vary considerably among individual patients and are major considerations in determining whether to pursue aggressive therapy. The use of urgent endovascular DVT thrombolysis to prevent life-threatening, limb-threatening, or organ-threatening complications of acute DVT is no longer controversial. Thrombolytic therapy can enable limb salvage in patients with acute limb threat due to phlegmasia cerulea dolens and is also indicated to prevent PE or visceral organ compromise in patients with iliocaval venous thrombosis that is extensive or rapidly progressive despite initial anticoagulant therapy. Although thresholds for use differ greatly among physicians, catheter-directed intrathrombus thrombolysis may also be reasonably used for proximal DVT patients who meet three conditions: First, they are failing to meet therapeutic benchmarks (e.g., relief of presenting DVT symptoms) during initial DVT therapy; second, after careful evaluation, they are believed to be at low risk for bleeding during thrombolysis; and, third, after a balanced discussion, aggressive therapy is consistent with the patient s preference. The use of endovascular DVT therapy as first-line DVT treatment for the primary purpose of PTS prevention is a promising treatment strategy, but the benefits of this approach have not yet been evaluated in a high-quality randomized controlled trial against the associated risks, costs, and inconveniences. In 2008, clinical practice guidelines from the ACCP and the SIR finally came to a consensus, suggesting the use of pharmacomechanical catheter-directed thrombolysis for carefully selected patients with extensive acute proximal DVT (i.e., acute iliofemoral DVT), good functional status, low risk of bleeding, and life expectancy of 1 year [36]. In contrast, it is clear that patients with elevated bleeding risk, CNS lesions, chronic DVT limited to the femoropopliteal veins (catheterdirected intrathrombus thrombolysis tends to be ineffective), isolated calf DVT, or asymptomatic DVT (they rarely develop PTS) should not receive pharmacomechanical catheter-directed thrombolysis [22, 36, 37]. Treatment of Established PTS It is logical to hypothesize that the treatment of reflux and obstruction may improve symptoms in patients with established PTS. Although methodologically rigorous studies have not yet addressed this issue with particular attention to PTS, available data and consistent anecdotal experiences attest to the ability of novel endovascular therapies to help patients with established PTS. I present my preferred general clinical approach to patients with established PTS here. First the patient s medical history is obtained and a physical examination is performed to determine whether the character or severity of the clinical PTS manifestations merit a more aggressive approach to therapy. If so, a detailed duplex ultrasound examination is performed to determine whether reversible anatomic or Fig year-old man with history of right lower extremity deep venous thrombosis (DVT) 1 year earlier who presented complaining of chronic, worsening right lower extremity pain, swelling, and venous claudication. Initial duplex ultrasound (not shown) depicted chronic thrombosis of right common femoral vein, femoral vein, and popliteal vein. A, Transjugular venogram shows complete occlusion of right common femoral vein. Stump of occluded femoral vein is identified. Deep (profunda) femoral vein (containing catheter) is of good caliber. B, Venogram obtained after two Wallstents (10 and 12 mm; Boston Scientific) were deployed extending from right external iliac vein into deep femoral vein shows excellent anatomic result with good inflow from robust deep femoral vein. Although stenting across inguinal ligament is generally contraindicated in arterial system, placement of longitudinally flexible self-expandable stents in venous system is safe and is often the only available option to expect alleviation of limiting symptoms of PTS. C, Poststenting venogram shows patency of right external and common iliac veins. Patient experienced dramatic clinical improvement, with elimination of claudication and aching and reduction in swelling. B C AJR:193, October

5 Vedantham physiologic conditions that may be contributing to the patient s clinical PTS manifestations are present. Specifically, information about the presence of three important factors is sought: chronic iliac vein or IVC obstruction, superficial venous reflux, and superimposed acute DVT. First, chronic iliac vein or IVC obstruction causes major elevations of ambulatory venous pressure and often leads to disabling venous claudication, but can usually be reversed using endovascular stent recanalization [38]. The relative disadvantages of intervention are the procedure is moderately challenging and has a technical failure rate of, perhaps, 10 30% depending on the length of the venous obstruction and the skill, experience, and determination of the endovascular physician; the long-term fate of venous stents is unknown and there is no device that is currently Food and Drug Administration approved for the iliac veins or the inferior vena cava (IVC); and if there is poor inflow into the common femoral vein due to previous femoropopliteal DVT, long-term patency may be limited. On the other hand, the procedure has a very low likelihood of harming the patient and, when successful, tends to produce dramatic clinical improvement (Fig. 1). Second, saphenous vein reflux can be an important contributor to clinical PTS sequelae and is reversible using endovenous thermal (radiofrequency or laser) ablation. These procedures are performed in minutes in an outpatient fashion using local anesthesia alone or in conjunction with conscious sedation [38, 39]. The procedures have a high (> 95%) rate of technical success and usually produce improvement in PTS symptoms, ulcer healing, or both. Potential disadvantages are the risk of triggering a recurrent DVT episode (anticoagulants may be used during the periprocedural period) and the lack of published efficacy data in this clinical setting. Finally, when a patient presents with a very recent (< 2 3 weeks), pronounced symptom exacerbation, the possibility of superimposed acute thrombosis must be considered. In carefully selected patients with acute thrombus and a low bleeding risk, catheter-directed thrombolytic therapy can be used to eliminate the acute thrombus and return the patient to his or her baseline symptom level. Unfortunately, chronic femoropopliteal venous obstruction and deep valvular reflux are not particularly amenable to nonsurgical treatments [21]. Hence, some PTS patients evaluated for potential treatment will simply not be candidates for endovascular therapy. In addition, many PTS patients will have both reversible and irreversible components; for this reason, patients undergoing endovascular PTS treatment must be counseled that the intervention is expected to palliate symptoms but that it is unlikely to completely eliminate the symptoms. Fortunately, most patients with moderate-to-severe PTS do have at least one of the reversible factors noted above. Established PTS has no consistently effective medical treatments, and most affected patients are generally told that they will just need to adjust their lives to this condition. Therefore, given the major QOL impairment they have been suffering (often for many years) and the general sense they have received that PTS is not treatable, the results of interventional radiologic treatment of PTS can be tremendously satisfying to the patient and physician. Conclusion On September 15, 2008, the U.S. Surgeon General [40] issued a national Call to Action on DVT and PE. In this Call to Action, the impact of DVT, PE, and PTS on public health was highlighted, and the need for new research and multidisciplinary partnerships to address these challenges was emphasized. Specifically, in the Call to Action document, the potential for interventional radiologic clot removal treatments to improve patient outcomes by preventing PTS is listed as an important research priority [40]. Hence, there can be no question that, at present, DVT and its long-term consequences are a public health problem of the first order. 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