The post-thrombotic syndrome (PTS) develops in 25%-50% of patients with proximal lower extremity deep vein thrombosis (DVT) despite the use of standard anticoagulant therapy and elastic compression stockings. PTS is a major cause of quality of life impairment in DVT patients and often leads to limiting venous claudication, work disability, and venous ulcers. Endovascular thrombolytic procedures that eliminate venous thrombus, restore venous flow, and show strong potential to prevent PTS are now under study in multicenter randomized clinical trials. In addition, endovascular procedures can be used to treat valvular reflux and venous obstruction and thereby provide symptom improvement to patients with chronic established PTS.
Contemporary prospective studies suggest that despite the routine use of anticoagulant therapy, the post-thrombotic syndrome (PTS) develops in 25%-50% of patients who suffer a first episode of proximal deep vein thrombosis (DVT).1–3 PTS most commonly causes chronic, daily limb pain/aching, fatigue, heaviness, and/or swelling. In severely affected patients, limiting venous claudication, stasis dermatitis, subcutaneous fibrosis, and/or skin ulceration may develop. Studies have consistently shown that PTS clearly impairs DVT patients' quality of life (QOL).4,5 The recent Venous Thrombosis Outcomes (VETO) cohort study found the presence and severity of PTS to be leading predictors of patients' health-related QOL 2 years after a DVT episode.5,6 The direct medical costs of treating PTS and the indirect costs of the related work disability have been shown to result in substantial economic burden to health care systems.7
PTS: rationale for new approaches
The pathogenesis of PTS is complex and is only partly understood at a microscopic level. Studies have demonstrated that an initial inflammatory response to thrombosis strongly influences thrombus resolution, organization, and subsequent vein wall injury.8 At a macroscopic level, the continued presence of thrombus within the deep venous system during the initial weeks after an acute DVT leads to PTS by at least 2 pathways. First, even with anticoagulant therapy, incomplete clearance of thrombus is common, so residual thrombus that is present over the long run physically blocks venous blood flow (obstruction). Second, the inflammatory response to acute thrombosis directly damages the venous valves and alters the adjacent vein wall, leading to valvular reflux.9 Uninvolved distal deep veins and superficial collaterals may also dilate and exhibit valvular incompetence. When reflux and/or obstruction is present, ambulatory venous hypertension develops and ultimately leads to edema, tissue hypoxia and injury, progressive calf pump dysfunction, subcutaneous fibrosis, and skin ulceration.10–12 Recurrent ipsilateral DVT, large initial thrombus extent (specifically, “iliofemoral DVT,” which is defined as DVT involving the iliac vein and/or common femoral vein), and advancing age increase the risk of PTS, but other factors that predispose DVT patients to develop PTS are largely unknown.1,5,6,13 Available studies suggest that the daily use of graduated elastic compression stockings and/or an exercise program after a DVT episode can significantly reduce the frequency of PTS, and large multicenter trials are ongoing to substantiate these results.2,3,14
It has been hypothesized for many years that rapid thrombus elimination and restoration of unobstructed deep venous flow may prevent valvular reflux, venous obstruction, and PTS. Proof-of-concept support for this “open vein hypothesis” can be found in studies of DVT patients who were treated with anticoagulation alone. In a series of ultrasound studies, Meissner et al found that venous segments that developed valvular reflux had much longer endogenous clot clearance times than segments that did not.12 In a secondary analysis of data from a randomized trial evaluating the use of compression therapy, Prandoni et al found that 2-year PTS developed more frequently in proximal DVT patients who had residual venous thrombus or popliteal valvular reflux at the 6-month follow-up.11 In 2005, Hull et al performed a meta-analysis of 11 randomized DVT treatment trials and found a strong correlation between the amount of residual thrombus after a course of anticoagulant therapy and the subsequent incidence of recurrent VTE.15 Finally, a small randomized trial found that the use of contemporary surgical venous thrombectomy with anticoagulation resulted in better venous patency and reduced PTS than anticoagulation alone.16 Although this procedure is not likely to be widely adopted due to its invasiveness and dependence upon specialized surgical expertise, this study certainly adds to the evidence favoring aggressive clot removal for DVT.
Systemic thrombolytic therapy
Systemic DVT thrombolysis, which refers to venous thrombus dissolution using a fibrinolytic drug given via an intravenous line distant from the affected limb, has been evaluated in several randomized trials. In studies evaluating streptokinase, a first-generation fibrinolytic drug, > 50% clot lysis was observed more frequently in patients treated with streptokinase than in patients treated with heparin alone (62% vs 17%, P < .0001).17 Two follow-up studies subsequently observed that PTS developed less frequently in patients treated with streptokinase compared with heparin alone at long-term follow-up, but these studies were small and did not use validated outcome measures of PTS.18,19 In addition, bleeding complications were frequent (14% vs 4% in a pooled analysis) in the patients treated with streptokinase.17 For this reason, systemic streptokinase infusions are not used for DVT treatment in current practice.
Systemic infusion of recombinant tissue plasminogen activator (rt-PA), a drug with greater fibrin affinity than previous fibrinolytic agents, has also been studied for DVT therapy. An important observation was the finding that > 50% clot lysis occurred more frequently in patients with nonocclusive rather than occlusive thrombi (59% vs 14%, P < .005), raising the possibility that the modest clot removal efficacy observed may have been related to the systemic administration route, which afforded inadequate access of rt-PA to its target sites within thrombus.20
Patient selection: anatomical and clinical considerations
Given the clinical importance of PTS to the long-term health of the patient, and the invasiveness, risks, and costs of aggressive therapy, it is important for clinical decision making to be guided by rigorously performed randomized trials. However, because no adequately designed trial has been completed, clinical judgment must be applied in the use of these procedures in patients who are most likely to benefit and least likely to be harmed after assessing the factors discussed below.
Projected risk of bleeding
Patients in whom thrombolytic therapy is being considered must undergo careful evaluation for factors that may increase the risk of major bleeding complications, including (but not limited to) ongoing or recent active bleeding; recent major surgery, trauma, pregnancy, cardiopulmonary resuscitation, or other invasive procedure; thrombocytopenia or other bleeding diathesis; and the presence of bleeding-prone lesions in critical areas such as the central nervous system.21 Clinical studies of thrombolytic therapy in patients with pulmonary embolism (PE), a similar patient population, suggest that bleeding may be more common in patients > 65 years of age.22 Decisions as to whether to exclude patients from receiving thrombolytic therapy on the basis of these risk factors should be individualized based upon the clinical severity of DVT and the other factors noted below. In patients with a malignancy that is known to metastasize to the central nervous system, a magnetic resonance imaging examination may sometimes be worth obtaining before initiating thrombolysis.
Clinical severity of DVT
Patients should undergo careful clinical assessment to determine the primary intent of aggressive therapy, and should be divided into 3 general categories. First are patients for whom urgent endovascular thrombolysis is indicated to prevent life-, limb-, or organ-threatening complications of acute DVT. This would include situations in which limb perfusion is acutely compromised (eg, phlegmasia cerula dolens) or when extensive/progressive inferior vena cava (IVC) thrombosis despite anticoagulation may increase the risk of fatal PE or acute renal failure to unacceptably high levels. Second are patients for whom nonurgent second-line endovascular thrombolysis is reasonable due to a failure of initial anticoagulation to achieve early therapeutic objectives. Included are patients who have major anatomic DVT progression, a significant increase in clinical severity, and/or an inability to tolerate ongoing major DVT symptoms (ie, pain and swelling that are not relieved or that preclude physical activity) despite the use of initial anticoagulant therapy. In these situations, a low threshold should be applied to exclude patients if there are risk factors for bleeding. Third are patients with symptomatic DVT for whom nonurgent, first-line endovascular thrombolysis is being pursued as an adjunct to anticoagulant therapy with the primary purpose being to prevent late PTS. Overall, aggressive therapy for the first group should clearly be pursued even when the patient is clinically ill due to the absence of other good treatment options, whereas a low threshold for exclusion should be applied to the latter 2 groups when risk factors for complications exist because proof of a favorable risk-benefit ratio is lacking.
Anatomic extent of DVT
Patients with acute iliofemoral DVT, defined as DVT involving the iliac vein and/or common femoral vein with symptom duration of 14 days or less, are at significantly increased risk of both PTS and recurrent VTE.4–6,23 Therefore, patients with acute iliofemoral DVT who are at low projected risk of bleeding should be provided with a balanced discussion of the risks and possible benefits of elective first-line endovascular thrombolysis for the purpose of PTS prevention. Conversely, patients with asymptomatic DVT or isolated calf DVT should not undergo thrombolysis because the risks of developing severe PTS are low.24 For patients with femoropopliteal DVT that does not extend to the common femoral vein level, there is little published literature to support the added efficacy of thrombolytic therapy, and therefore it should probably be limited only to very symptomatic patients with low projected risk for bleeding. In patients with acute femoropopliteal DVT, the status of the deep (profunda) femoral vein is likely to be important in determining long-term outcome. Most patients with chronic femoropopliteal DVT should not receive thrombolytic therapy because the available data suggest that it is likely to be ineffective.25
Life expectancy, baseline ambulatory capacity, and comorbidities
Patients who are chronically unable to walk or who have very short life expectancy are less likely to benefit meaningfully from aggressive therapy to prevent PTS. In addition, some patients are likely to have difficulty in tolerating aggressive intervention; for example, patients with significant respiratory compromise who cannot lie prone and safely receive sedation for the procedure.
Patients' personal values and preferences
For aggressive therapies such as DVT thrombolysis, for which the benefits have not been conclusively established, it is important for the patient to receive a balanced discussion regarding the rationale, the intended benefits (and possible lack of benefits), the attendant risks and inconveniences, and treatment alternatives. Patients may arrive at different conclusions regarding their own amenability to aggressive therapy.
Endovascular treatment options
Role of imaging and imaging guidance
Patients undergoing aggressive therapy for DVT should have, at a minimum, an ultrasound, computed tomography (CT) scan, or venogram confirming the presence of DVT. Some physicians prefer to routinely obtain a pretreatment CT venogram with the purpose of clarifying thrombus extent, the presence of mass lesions, and the presence of intrinsic venous obstructive lesions (eg, iliac vein stenosis) before treatment. However, the downside of this practice is the additional contrast load that is delivered to the patient and the challenges of obtaining a diagnostic study that requires adequately timed opacification of the target veins in the setting of various degrees of venous occlusion. Other imaging such as CT scans of the pulmonary arteries or ventilation-perfusion scans are not routinely needed either before or after endovascular therapy.25 Ultrasound should be routinely used to obtain access to the target vein for treatment, and fluoroscopy is used throughout the endovascular procedures to guide catheter, guidewire, and device manipulations.
Catheter-directed intrathrombus thrombolytic infusions
In current practice, thrombolytic drugs are delivered into peripheral thrombi using catheter-based techniques to achieve a higher local intrathrombus drug concentration (enhancing efficacy) and thereby enable successful clot lysis with a reduced drug dose (enhancing safety). Catheter-directed intrathrombus thrombolysis (CDT), which refers to the infusion of a fibrinolytic drug directly into the venous thrombus via a multi-side-hole catheter embedded in the thrombus using imaging guidance, was the first endovascular thrombolytic method that was applied to DVT patients.26 With this technique, ultrasound guidance is used to obtain access into the deep venous system of the affected limb. A venogram is performed to define the extent of thrombus. A multi-side-hole catheter is embedded within the thrombus and attached to an infusion of a dilute solution of a thrombolytic drug. It should be noted that there continues to be great variability among operators in terms of specific parameters for drug dose, infusion duration, and type of delivery catheter. Although no drug is currently approved by the US Food and Drug Administration (FDA) for the indication of DVT treatment, drugs used in clinical practice include recombinant tissue plasminogen activator, reteplase, and tenecteplase. The infusion is typically continued for 6-24 hours, during which time the patient is carefully monitored for bleeding using clinical observation and laboratory testing (hematocrit, partial thromboplastin time, and fibrinogen values in some centers). Repeat venography is performed, the catheter is repositioned to span the remaining thrombus, and the infusion is continued. Clot maceration with an angioplasty balloon is also sometimes used to facilitate thrombolysis.
After the acute thrombus has been eliminated, the underlying veins are evaluated by venography, and any venous obstructive lesion identified is treated with balloon angioplasty and/or stent placement. Typically, stents are reserved for the iliac vein if possible, although extension into the common femoral vein is sometimes necessary. No stent has FDA approval for this specific indication at present. In discussing the procedure with patients beforehand, the fact that stents are permanent devices for which few long-term studies are available should be discussed. The risk of late stent occlusion, stenosis, or as-yet unknown complications should be mentioned.
Limitations of the original CDT technique include the long infusion times required to obtain complete lysis of extensive DVT (typically 1-3 days) and the health care resources used. In an early multicenter registry, major bleeds occurred in 11% of DVT patients treated with urokinase CDT infusions.25 In this registry, which included a fairly unselected patient population, intracranial bleeding was observed in 0.4% of patients. Symptomatic PE and fatal PE occurred in 1.3% and 0.2% of patients, respectively. In more recent experiences using infusions of rt-PA at low doses (0.5-1.0 mg/h), major bleeding has occurred in 2%-4% of patients.27 Reasons for this apparent difference may be improved patient selection, use of “subtherapeutic” unfractionated heparin dosing during thrombolysis, and the incorporation of routine ultrasound-guided venipuncture, which has largely eliminated the problem of local access site bleeding.
The subsequent evolution of CDT methods has been aimed at addressing the above limitations. One approach is the use of an ultrasound-emitting thrombolytic infusion catheter that speeds drug dispersion within the thrombus by loosening fibrin strands.28 Another approach is the use of percutaneous mechanical thrombectomy devices to macerate and/or aspirate thrombus that has been softened by the thrombolytic drug infusion (although these devices have not been effective as a stand-alone DVT treatment method, this method is now used frequently).29 This family of drug-device combination methods, known as pharmacomechanical catheter-directed thrombolysis or PCDT, has enhanced physicians' ability to efficiently remove large thrombus volumes in patients with DVT. In recent years, PCDT techniques30,31 have evolved to provide rapid drug dispersion, allowing “single session” or “on table” DVT treatment within a single 1- to 3-hour procedure. By obviating prolonged drug infusions, these methods may provide safer and more efficient therapy.
Retrievable IVC filters are sometimes used with the intent of preventing periprocedural PE in selected patients undergoing CDT and PCDT. In a large prospective registry of proximal DVT patients undergoing infusion CDT (without mechanical thrombectomy), symptomatic PE occurred in only 1.3%.25 Therefore, IVC filter placement is probably unnecessary in most patients undergoing traditional CDT. However, for patients being treated with single-session PCDT, which may involve more clot manipulation, there are sparse data to support or refute the use of filters, and limited evidence suggests that major PE can occur as a PCDT complication.32–34 Therefore, it may be reasonable to use a retrievable IVC filter when single-session PCDT is being used. When a filter is placed, it is imperative to periodically reassess the patient clinically after lysis is completed and to remove it as soon as the period of high PE risk subsides.
Clinical studies of endovascular DVT thrombolysis
At present, there remains no published, adequately designed multicenter randomized controlled trial that has evaluated the ability of CDT or PCDT to improve important clinical outcomes such as PTS in patients with proximal DVT. The ability of CDT/PCDT to rapidly remove venous thrombus and prevent PTS in proximal DVT patients is supported by several comparative studies, each with significant methodological limitations. In 2000, Comerota et al analyzed data from 68 CDT-treated acute iliofemoral DVT patients from a multicenter prospective CDT registry and found that they had fewer PTS symptoms (71.40 ± 2.95 vs 55.80 ± 4.50, P = .006), better physical functioning (70.78 ± 3.62 vs 57.06 ± 5.56, P = .046), less stigma of chronic venous insufficiency (83.54 ± 3.07 vs 71.13 ± 4.72, P = .033), and less health distress (78.20 ± 3.20 vs 64.36 ± 4.87, P = .022) using Mathias scale scores at a mean follow-up of 16 months than 30 retrospectively “matched” patients who were treated with anticoagulation alone.35 However, this comparison was limited by marked age differences in the 2 cohorts. In 2001, AbuRahma et al described a prospective study in which 51 acute iliofemoral DVT patients were permitted to choose to receive adjunctive CDT (with urokinase or rt-PA) plus anticoagulation or anticoagulation alone. The patients treated with CDT had more frequent venous patency at 6 months (83% vs 24%, P < .0001) and absence of symptoms at 5 years (78% vs 30%, P = .0015).36 However, this study was limited by nonrandomized design, performance in a single center, and small sample size. In 2002, Elsharawy et al described a single-center Egyptian randomized trial comparing adjunctive CDT (with streptokinase) with anticoagulation alone in 35 patients with acute iliofemoral DVT. At 6 months, patients treated with CDT had a higher rate of normal venous function (72% vs 12%, P < .001) and less valvular reflux (11% vs 41%, P = .04).37 However, this study was limited by small sample size and performance in a single center, and did not evaluate clinically meaningful outcomes such as PTS and QOL. In 2009, Enden et al described the 6-month follow-up results from the first 100 patients randomized to either CDT plus anticoagulation or anticoagulation alone in the Norweigan multicenter CaVenT Trial.38 Venous patency was significantly superior in the CDT-treated patients (64% vs 36%, P < .05), but valvular reflux was no different (60% vs 66%, P = NS). In 2010, Sharifi et al described the results of a 183-patient single-center randomized controlled trial (the TORPEDO trial) in which CDT plus anticoagulation proved superior to anticoagulation alone at the 6-month follow-up in preventing PTS (3.4% vs 27.2%, P < .001) and recurrent VTE (2.3% vs 14.8%, P < .003).39 However, a validated measure of PTS was not used and the follow-up period was short.
The CaVenT trial noted above will assess patients for PTS over a 2-year follow-up.38 In addition, the Acute Venous Thrombosis: Thrombus Removal with Adjunctive Catheter-Directed Thrombolysis (ATTRACT) trial, a multicenter randomized trial sponsored by the National Heart Lung and Blood Institute (NHLBI) (www.clinicaltrials.gov, NCT00790335), is also ongoing in the United States. For this study, patients with symptomatic proximal DVT are being randomized at 50 sites to receive either PCDT plus standard DVT therapy (anticoagulant therapy plus elastic compression stockings) or standard DVT therapy alone. PTS is being assessed at follow-up visits every 6 months during the 2-year follow-up period. Secondary outcomes assessed include venous disease–specific and general QOL; resolution of acute DVT symptoms (pain and swelling); rates of major bleeding, symptomatic PE, recurrent VTE, and death; and cost-effectiveness.
Endovascular treatment of established PTS
Despite the high incidence and patient burden of PTS, evidence-based treatment options for established PTS are lacking. Currently, elastic compression stockings are the most frequently applied treatment, presumably because of their availability and safety; however, compression is inconvenient and uncomfortable for many patients, and the available evidence does not support its efficacy.24,40 The degree to which patients are compliant with therapy is limited and may vary widely by region. Venoactive medications such as aescin and rutosides are not available in the United States. Based upon very limited studies, mechanical-physiological compression devices and exercise may be effective in some PTS patients.41–43 However, no treatment has been shown to be consistently effective for the management of established PTS. Most commonly, affected patients are counseled to just accept PTS as a part of their daily lives.
Historical studies support the concept that there may be anatomic and physiologic factors that are amenable to reversal in patients with PTS. Whereas gradual venous recanalization with flow restoration is the norm for the femoral and popliteal segments, complete recanalization of a thrombosed iliac vein occurs rarely with anticoagulation alone. Venous obstruction above the entry of the deep (profunda) femoral vein, the dominant collateral vein when the femoral vein is occluded, causes particularly significant pressure elevations that can lead to severe claudication and disability.8 In addition, although it is known that proximal DVT frequently leads to deep valvular reflux, it is also true that valvular reflux develops in major superficial veins such as the great saphenous vein, especially if it was thrombosed at the time of the DVT.44
In recent years, 2 image-guided endovascular techniques have become more frequently used in the treatment of lower extremity venous disorders. Venous stent placement has been used to treat venous obstruction in patients with acute iliofemoral DVT (after catheter-directed thrombolysis)26 and endovenous thermal (radiofrequency or laser) ablation has been used to treat patients with symptomatic primary valvular insufficiency (saphenous vein reflux).45 In recent years, these techniques have been applied to patients with established PTS in some centers with advanced venous expertise.46,47
Typically, a careful medical history is obtained and a physical examination is performed. Patients with a history and/or physical findings indicative of PTS and symptoms deemed severe enough to warrant intervention are evaluated by the interventional radiology physician with Duplex ultrasound. In this initial clinical-imaging examination, particular attention is paid to determining whether iliac vein obstruction should be suspected, based upon the presence of: (1) pain or swelling of the entire limb (thigh and calf) as a feature of the initial DVT episode, the daily PTS symptoms, or the physical examination; (2) dominance of venous claudication as a daily symptom; (3) a history of imaging-proven thrombosis of the common femoral vein (CFV) and/or iliac vein; and (4) a CFV that is incompletely compressible or that exhibits poor Doppler phasicity compared with the contralateral CFV. Patients with suspected iliac vein obstruction are subsequently evaluated with catheter venography. When an iliac vein obstruction is identified, it is treated with stent placement. The patient is reevaluated in the clinic in 1 month. If residual symptoms are present and the stents are likely to be patent, assessment of the great and small saphenous veins for valvular reflux is performed. If present and felt to be causing major ongoing symptoms of importance to the patient's QOL, endovenous thermal ablation of these veins is performed. It should be noted that this application of endovenous thermal ablation is relatively new and that high-quality outcome studies of this approach are currently lacking. It is also likely that patients with concomitant femoropopliteal obstruction and/or deep valvular reflux may be less likely to exhibit improvement with such an approach.
Each of the above procedures is usually performed on an outpatient basis. Patients are instructed to continue their compression therapy and, when applicable, their wound care for venous ulcers, and are seen in follow-up 1-3 months later.
We and others have observed a high rate of success in recanalizing the obstructed iliac vein and in alleviating pain and swelling using this approach.46,47 Periprocedural complications have been minor, and the more feared complications of symptomatic PE, stent migration, or stent fracture have been absent or rare. It is worth noting that the procedures can be technically challenging and time consuming, with failure rates of 2%-20% depending upon the extent of 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 FDA-approved for use in this clinical scenario. When there is poor inflow into the common femoral vein due to chronic thrombosis of its tributary veins, stent patency may be limited. In such situations, surgical therapies may be worth considering. Some specialized surgeons use thrombevenectomy of the common femoral vein and its tributaries to improve inflow into a stented iliac vein. Alternately, surgical venous bypass may be performed, with placement of an arteriovenous fistula for several months to assist the early patency of the bypass. These procedures have a low likelihood of harming the patient in the short term, and when successful tend to produce dramatic clinical improvement.
Acute DVT should be viewed as a chronic disease by treating physicians, because the associated long-term patient disability is quite substantial. Catheter-based endovascular therapies offer the potential to preserve life and limb (for severely affected patients), prevent PTS, and improve QOL in patients with proximal DVT. Multicenter randomized clinical trials are ongoing to determine which patients should be treated in this manner. Selected patients with established PTS may also now have a reasonable chance of experiencing symptom alleviation with the use of endovascular therapies. Hematologists and other thrombosis physicians should be aware of these options and consult their endovascular colleagues for patients in need of salvage therapy.
Conflict-of-interest disclosure: The author has received research funding from Covidien, MEDRAD Interventional, BSN Medical, and Genentech. Off-label drug use: TPA for DVT stents for venous obstruction.
Suresh Vedantham, MD, Professor of Radiology & Surgery, Mallinckrodt Institute of Radiology, 510 S Kings Highway, Box 8131, St Louis, MO 63110; Phone: (314) 362-2900; Fax: (314) 362-2276; e-Mail: email@example.com.