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Mechanical thrombectomy for DVT
Mechanical Thrombectomy for DVT Kenneth D. Murphy, MD
Deep venous thrombosis is a common source of morbidity and mortality in the United States. Complications include pulmonary embolism and chronic post-thrombotic syndrome. Chronic postthrombotic syndrome is characterized by extremity pain, edema, venous claudication, skin changes, and skin ulceration. This syndrome is attributed to venous obstruction and valvular damage due to thrombus. The standard treatment of deep venous thrombosis consists of medical management with anticoagulation. Anticoagulation has proven efficacy in prevention of thrombus extension, pulmonary embolus, and re-thrombosis. The role of anticoagulation in post-thrombotic syndrome is unclear. Aggressive endovascular techniques for managing DVT have evolved as a result. Catheter-directed thrombolysis was the first such procedure with demonstrated efficacy, however its acceptance has been limited by perceived risks, time to lysis, and cost. As a result, alternative measures for managing DVT have evolved including mechanical thrombectomy. Mechanical thrombectomy for DVT has the potential to shorten the time for lysis, reduce the risk of thrombolytic agents, and potentially impact cost savings. © 2004 Elsevier Inc. All rights reserved.
echnological advances have promoted the evolution of percutaneous mechanical thrombectomy (PMT) as a potential alternative or adjunct to pharmacologic thrombolysis and/or surgical thrombectomy for management of acute thrombotic and thromboembolic arterial and venous occlusions. Clinical experience to date with PMT has demonstrated the effectiveness, safety, and limitations of the various devices, principally in the arena of dialysis access site management. Device improvements and clinical experience have facilitated evaluation of PMT thrombosis outside the dialysis bed, including the venous circulation. Deep venous thrombosis (DVT) is the major cause of morbidity and mortality in the United States. Approximately 20 million cases of lower-extremity and an estimated 200,000 to 600,000 cases of upper-extremity DVT occur annually in the United States.1 Complications include pulmonary embolism (PE), chronic postthrombotic syndrome (PTS) Phlegmasia Cerulea Dolens, Phlegmasia Alba Dolans, upperextremity venous insufficiency, and amputation. Pulmonary embolism is estimated to occur in 750,000 to 900,000 patients, with an annual mortality of 47,000 to 200,000 patients.1 PTS is the most common cause for long-term morbidity and disability.1 Extremity pain, swelling, chronic deep venous insufficiency, venous claudication, skin changes, and ulceration char-
T
From the Department of Radiology, Upstate Medical University, State University of New York, Syracuse, NY. Address reprint requests to Kenneth D. Murphy, Department of Radiology, Upstate Medical University, State University of New York, 750 E. Adams Street, Syracuse, NY 13210. © 2004 Elsevier Inc. All rights reserved. 1089-2516/04/0702-0006$30.00/0 doi:10.1053/j.tvir.2004.05.002
acterize this syndrome.2 It has been estimated that 400,000 to 500,000 Americans have or have had a postthrombotic venous ulcer.3 The syndrome is partially attributed to venous obstruction, as well as, clot organization at the valve level with resultant impairment of the valvular function.4,5 The incidence of PTS ranges from 35% to 70%,6-11 with differences because of variations in anticoagulation treatment regimens, underlying DVT clot age, use of compressive hosiery, and reporting standards. Despite recognition of risk factors and complications of venous thromboembolic (VTE) disease, preventive strategies and conventional treatment has been varied with widely discrepant results and outcomes. The variance of management strategies for VTE disease reflects the continued evolution of devices, drugs and treatment protocols for such complex patients. The intent of this review article is to present the evolving role of the mechanical thrombectomy device in managing patients with DVT, including the rationale, preclinical experience, clinical experience, limitations, and future.
PMT Rationale The conventional treatment of DVT has long been systemic anticoagulation with unfractionated heparin (UFH), followed by 3 to 6 months of warfarin. The goal of anticoagulation is to inhibit the thrombotic process and allow thrombus clearance by endogenous plasmin with minimal risk of bleeding. Recently, low-molecular weight heparins (LMWH), have demonstrated safety and efficacy for DVT prevention in high-risk patients and treatment of acute DVT.12-15 The conventional UFH/warfarin approach has largely been replaced with LMWH, as LMWH has several advantages including predictable pharmacokinetic properties, enhanced bioavailability, fixed weightbased dosing independent of partial-thromboplastin time, and independence from laboratory studies.16 Despite advances with heparin and heparin derivatives in managing DVT and VTE, the impact of such therapy on the development of PTS remains unknown and problematic. In a search for a more comprehensive DVT therapy algorithm that would include prevention of PTS, alternative treatment strategies have evolved, and continue to be investigated. With the advancement in endovascular management techniques, principally in the arterial tree, application in the venous circulation has grown significantly. Catheter-directed thrombolytic therapy for DVT has demonstrated feasibility and success in severe cases including phlegmasia, however, prospective, randomized trials defining the exact role of such an aggressive approach are lacking. Catheter-directed thrombolytic therapy is potentially attractive with respect to PTS, as it not only restores vein patency quickly but also has a potential to preserve valvular function and prevent PTS. In a multi-center venous registry, complete lysis was seen in 31% of patients with a 1-year patency of 79%.17 Although the 1-year patency rate is encouraging, the widespread acceptance of this
Techniques in Vascular and Interventional Radiology, Vol 7, No 2 (June), 2004: pp 79-85
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TABLE 1. Current Mechanical Thrombectomy Devices Wall Contact Devices Arrow Percutaneous Thrombectomy Device (PTD, Arrow International, Reading, PA) Solera (Bacchus Vascular, Santa Clara, CA) Cleaner (Rex Medical, Fort Worth, TX) MTI-Castaneda Brush (Microtherapeutics, San Clemente, CA) Fino (Bacchus Vascular, Santa Clara, CA) Cragg Brush (Microtherapeutics, San Clemente, CA) Prolumen (Datascope, Mahwah, NJ) Hydrodynamic Thrombectomy Fragmentation Devices Amplatz Thrombectomy Device (ATD/Helix, Microvena, White Bear Lake, MN) Rotarex catheter (Straub Medical, Wangs, Switzerland) Thrombex PMT (Edwards Lifesciences, Irvine CA) Rheolytic (Flow-Based) Thrembectomy AngioJet (Possis Medical, Minneapolis, MN) Oasis (Boston Scientific, Watertown, MA) Hydrolyzer (Cordis, Warren, NJ) Ultrasound Acrolysis probe (Angiosonics, Morrisville, NC) Resolution 360™ Therapeutic Wire (Omnisonics, Wilmington, MA) Combination Infusion Catheter/Isolated Oscillation Device Trellis Reserve (Bacchus Vascular, Santa Clara, CA)
procedure has been limited because of perceived risks, costs, and efficacy issues. Specific issues that have limited the acceptance of catheter-directed thrombolytic therapy include time to lysis, need for hospitalization and intensive care monitoring, risk of hemorrhage, cost of thrombolytic agents, and lack of prospective, randomized data. In this modern era where cost effectiveness and outcome results are important, alternative treatment strategies have developed with the intent to shorten treatment time, contain costs, and improve efficacy. The rationale for PMT is based on the potential that such a treatment strategy may result in a shorter time to restoration of vein patency, elimination of reduction in hospitalization cost, reduction in the risk of hemorrhage from thrombolytics, and overall cost savings because of elimination or reduction in thrombolytic drug.
Preclinical Experience Percutaneous mechanical thrombectomy is an evolving procedure for removal of thrombus from vessels and grafts. The FDA has approved several PMT devices with application principally limited to hemodialysis graft thrombosis. Based on these results, the devices have and continue to be evaluated for peripheral arterial and venous application.18 The PMT devices can be divided into wall contact devices and nonwall contact devices (Table 1). Wall contact devices include the Arrow-Trerotola percutaneous thrombectomy device (PTD) (Arrow International, Reading, PA), for which a large body of preclinical study has been performed to evaluate feasibility issues of PMT for DVT. The nonwall contact devices including the Amplatz thrombectomy device (ATD) (Microvena, White Bear Lake, MN), the Hydrolyzer (Cordis, Warren, NJ), the Angiojet (Possis Medical, Minneapolis, MN), and the Oasis thrombectomy catheter (Boston Scientific, Watertown, MA), which have all undergone preclinical animal evaluation. The concern with respect to PMT devices and their application to DVT is primarily of vessel wall injury and valvular injury. Because the goal of DVT therapy is thrombus removal and preservation of valvular flow, preclinical evaluation of PMT devices with respect to the potential for valvular injury is paramount. The PTD device has undergone the most extensive preclinical evaluation in animals, with special attention to the effect of PMT on vein wall and valvular function. McClennan and coworkers evaluated the effects of the PTD device on normal canine vein valves. In this animal model, they found the PTD device did not cause physiologically significant damage to valves 7 mm or larger in diameter.19 Trerotola demonstrated preclinical success in using the PTD device for treating DVT in the canine model. Thirteen dogs underwent PTD treatment for iliocaval subacute thrombosis using a modified PTD device with a prototype15 mm diameter basket. They demonstrated the modified PTD was effective in
Fig 1. (A) Symptomatic right lower-extremity iliofemoral DVT and caval filter thrombosis. (B) ATD via jugular approach. (C) Post ATD and iliac vein stent placement with patency restored.
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KENNETH D. MURPHY
Fig 2. (A) Left lower-extremity DVT treated with Angiojet. (B) Post-Angiojet vein patency with iliac artery compression at iliocaval junction. (C) Completion venogram after stent placement.
treating subacute (⬍7 days) venous thrombosis. Pulmonary emboli were documented, suggesting temporary filtration may be necessary as an adjunct to this approach.20 Preclinical evaluation of several other devices has also been evaluated in animal and in vitro models. The Angiojet,21,22 Oasis,23 Hydrolyzer,21 and ATD,24 have demonstrated feasibility and efficacy in clot removal from animal and in vitro flow models. MECHANICAL THROMBECTOMY FOR DVT
Clinical Experience Clinical experience to date using PMT for DVT has been limited to select case specific reports and small clinical series in peerreviewed literature. The literature is devoid of any prospective, randomized clinical trials, although some prospective trials with PTD and Fino (Bacchus Vascular, Santa Clara, CA) device,
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Fig 3. PTD for acute DVT.
among others, have been or are being attempted. The evolving investigation of PMT devices for DVT management is based on the limitations of catheter-directed thrombolytic therapy, technical advancements of the PMT devices, and growing arterial and hemodialysis PMT clinical experience. The greatest PMT for DVT experience has been with the ATD (Fig 1), the Angiojet (Fig 2), and PTD (Fig 3). In 1997, Uflacker first reported PMT for DVT in 1 patient with lower-extremity DVT and inferior vena cava thrombosis.25 In this report, the patient was treated with the ATD with partial success.25 In 1999 Gandini reported treating 8 patients with ilio-caval thrombosis using the ATD with a temporary IVC filter.26 Adjunct thrombolytics were not administered. Complete clot extraction was reported in 75% of patients.26 In 2001, Delomez reported a larger series of eighteen patients with DVT treated with the ATD using temporary IVC filtration, without adjunct thrombolytics.27 Successful recanalization was achieved in 83%, and the mean percentage of thrombus removed 66%. In mean follow-up of 29.6 months, there was only one limb with PTS.27 Transient arterial desaturation was observed in all patients immediately after PMT, despite negative pulmonary angiograms and temporary IVC filtration.27 These
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initial reports demonstrated the technical feasibility of PMT for DVT, however, the clot extraction rate and patency was still problematic. Based on these initial observations, the adjunct role of thrombolytics appeared beneficial, and subsequent reports in the literature reflected this observation. In 2001, Kasirajan described the effect of adjunct thrombolytics on PMT for DVT.28 He reported 17 patients with lowerand upper-extremity DVT treated initially with the Angiojet and catheter-directed thrombolytics as needed. Temporary filters were not utilized. After PMT alone, 24% had venographic evidence of greater than 90% thrombus removal, and 35% demonstrated 50% to 90% removal. Adjunctive thrombolytic therapy was utilized in 9 of 13 patients with less than 90% thrombus extraction by PMT alone. Four of 13 patients had contraindication to thrombolytics, therefore, were excluded. The overall clinical success of PMT with adjunct thrombolytics was 82%. DVT recurrence free survival was greatest in the ⬎90% clot extraction group. There were no procedure-related complications. Valvular reflux and PTS incidence was not reported. This small series is the first to demonstrate the potential benefit of combination PMT and thrombolysis therapy with respect to clinical improvement, clot extraction and recurrence free survival.28 In 2002, Vedantham reported the effect of adjunct PMT on catheter-directed thrombolysis for DVT. In a retrospective comparison of DVT management with catheter-directed thrombolysis versus combination therapy (PMT and thrombolysis), he described an approximate 40% reduction in time to lysis and a 60% reduction in lytic drug dose with adjunct PMT.29 Vendantham also reported minimal thrombus removal with PMT alone (26.0%), versus substantial thrombus removal with PMT and thrombolytics (62.0%).30 These limited series suggest stand alone PMT for DVT, despite reducing procedure time, is insufficient for adequate thrombus removal, and adjunct thrombolytics either pre- or post-PMT is likely necessary to achieve procedure success with current devices. As an alternative to separate, sequential PMT/ thrombolysis procedures for DVT, simultaneous administration of thrombolytics during PMT is an attractive concept with potential for reduced procedure time and enhanced thrombus removal. The mechanical effect on the molecule is important to consider as the drug-device techniques are potentially merged. Semba demonstrated the biostability of Alteplase in an in vitro model using the Angiojet.31 The simultaneous administration of thrombolytics during PMT, essentially true “combination therapy” has been reported with the Angiojet and Trellis devices, among others being investigated (Fig 4). Uppot reported a technique mixing the thrombolytic drug in the Angiojet saline infusion bag for direct administration during PMT.32 In this small series of 24 patients, complete or substantial thrombus removal was reported in 83.5%.32 Kasirajan reported success using the Trellis device, a novel infusion/PMT catheter device, in combination with thrombolytics in 20 patients.33 Such exciting combination strategies continue to be investigated, and further experience and follow-up is needed to assess the efficacy and impact on PTS.
Role of Retrievable Filters Utilization of a PMT for DVT management has the inherent risk of pulmonary embolism as a complication. The etiology of this complication includes clot displacement and/or particle embolization. With the recent FDA approval of “retrievable” or opKENNETH D. MURPHY
Fig 4. (A) Trellis infusion catheter system. (B) Bilateral massive iliofemoral DVT treated with bilateral Trellis devices in iliac veins. (C) Vein patency restored post-Trellis. (Color version of Fig 4a is available online.)
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TABLE 2. PMT for DVT-PE Incidence
Uflacker ( ) Kasirajan (28) Vedantham (29) Delomez (27) 25
Device
n
Filter
PE
ATD AJ AJ, ATD, PTD, Oasis ATD
3 17 10 18
n n n y
13
⁄ dyspnea NR 0% (clinical) 0% (PAgram) 100% desat
ATD ⫽ amplatz device; AJ ⫽ angioJet device; PTD ⫽ arrow percutaneous mechanical thrombectomy device; NR ⫽ not reported.
tional filters, consideration for utilization of such a device appears reasonable. In a preclinical canine study, Trerotola and co-workers described the development of segmental and subsegmental PE in dogs with iliocaval thrombosis treated with PMT utilizing the PTD device.20 Their conclusion was there likely is a role for temporary filtration during such a procedure.20 In a follow-up study, Trerotola compared DVT management in a canine model with the PTD device with and without a prototype nitinol temporary IVC filter.34 The pulmonary bed was evaluated with pulmonary angiography after PMT. Rare segmental and subsegmental PE were identified in the filter group, significantly less than the cohort without filters.34 Despite the temporary filtration, a mild increase in the pulmonary artery pressure, decrease in the pH and an increase in the pCO2 were observed postprocedure.34 There is limited analogous data with respect on the development of PE on human subjects undergoing PMT for DVT (Table 2). Uflacker reported 1 of 3 patients with DVT managed with ATD developed dysnea.25 Delomez reported a small series of patients with DVT treated with the ATD device using a temporary filter. Patients underwent post-PMT pulmonary arteriography and no pulmonary emboli were identified, however, oxygen desaturation was common.27 Vedantham described a small series of 10 patients who underwent DVT management with PMT using a variety of devices, and there were no clinical stigmata of PE.29 The preclinical animal studies suggest temporary filtration may be indicated utilizing the PTD device, however, the limited data and variable results in the human experience do not draw an evidence-based conclusion. The development of PE, whether it is a result of clot displacement or particulate embolization, appears to likely be device specific, and the role of temporary filtration is yet to be defined. Further investigation is needed to assess the role of retrievable filters in patients undergoing PMT for DVT.
Conclusion The role of PMT for management of DVT continues to evolve. The evolution reflects the changes in device technology and clinical experience. As with any new technique or device, patient and physician education is a necessary component for investigation and success. In the case of DVT, continued physician education is necessary to demonstrate the limitations of conventional systemic anticoagulation, and suggests the merits of a more aggressive endovascular approach using pharmacologic and mechanical thrombectomy devices to prevent the costly and disabling development of PTS. The potential for PMT in the area of DVT includes rapid thrombus removal, rapid restoration of vessel patency, reduction in PTS, and avoidance/reduction of lytic drug risk and cost. The limitations of PMT for DVT to date include incomplete thrombus removal,
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embolization risks, potential for vein/valve injury, and lack of experience and prospective data. Based on the experience to date, there is a call for improved devices, improved techniques, and more prospective data.
References 1. Markel A, Manzo RA, Bergelin RO, et al: Valvular reflux after deep vein thrombosis: Incidence and time of occurrence. J Vasc Surg 15:377-384, 1992 2. Strandness DE, Langlois YE, Cramer M, et al: Long-term sequelae of acute venous thrombosis. JAMA 250:1289-1292, 1983 3. Coon WW, Willis PV, Keller JB: Venous thromboembolism and other venous diseases in the Tecumseh Community Health Study. Circulation 48:839-846, 1973 4. Killewich LA, Bedford GR, Beach KW, et al: Spontaneous lysis of deep vein thrombi: Rate and outcome. J Vasc Surg 9:89-97, 1989 5. Shull KC, Nicolaides AN, Fernandez JF, et al: Significance of popliteal reflux in relation to ambulatory venous pressure and ulceration. Arch Surg 114:1304-1309, 1979 6. Johnson BF, Manzo RA, Bergelin RO, et al: The relationship between changes in the deep venous system and the development of the post-thrombotic syndrome after an acute episode of lower limb deep vein thrombosis: A one-to-six year follow-up. J Vasc Surg 21:307313, 1995 7. Milne AA, Stonebridge PA, Bradbury AW, et al: Venous function and clinical outcome following deep vein thrombosis. Br J Surg 81:847849, 1994 8. Meissner MH, Manzo RA, Bergeln RO, et al: Deep venous insufficiency: The relationship between lysis and subsequent reflux. J Vasc Surg 18:596-608, 1993 9. Killewich LA, Martin R, Cramer M, et al: An objective assessment of the physiologic changes in the post-thrombotic syndrome. Arch Surg 120:424-426, 1985 10. Monreal M, Martorell A, Callejas JM, et al: Venographic assessment of deep vein thrombosis and risk of developing post-thrombotic syndrome: A prospective study. J Intern Med 233:233-238, 1993 11. Labropoulos N, Giannoukas AD, Nicolaides AN, et al: New insights into the pathophysiologic condition of venous ulceration with colorflow duplex imaging: implications for treatment? J Vasc Surg 22:4550, 1995 12. Hirsh J, Levine MN: Low molecular weight heparin. Blood 79:1-17, 1992 13. Prandoni P, Lansing AW, Buller HR, et al: Comparison of subcutaneous lower molecular-weight heparin with intravenous standard heparin in proximal deep-vein thrombosis. Lancet 339:441-5, 1992 14. Hull RD, Raskob GE, Pineo GF, et al: Subcutaneous low-molecularweight heparin compared with continuous intravenous heparin in the treatment of proximal-vein thrombosis. N Engl J Med 326:975-82, 1992 15. Simonneau G, Charbonnier B, Decousus H, et al: Subcutaneous low-molecular-weight heparin compared with continuous intravenous unfractionated heparin in the treatment of proximal deep vein thrombosis. Arch Intern Med 53:1541-6, 1993 16. Dolovich LR, Ginsberg JS, Douketis JD, et al: A meta-analysis comparing low-molecular-weight heparins with unfractionated heparin in the treatment of venous thromboembolism. Arch Intern Med 160:181-8, 2000 17. Mewissen MW, Seabrook GR, Meissner MH, et al: Catheter-directed thrombolysis for lower extremity deep venous thrombosis: Report of a national multicenter registry. Radiology 211:39-49, 1999 18. Murphy, KD. Arterial applications of mechanical thrombectomy, in Darcy M, Vedanthan S, Kaufman JA (eds): Peripheral Vascular Interventions, 2nd ed. Fairfax, VA, SCVIR Publications, 2001, pp 339-352 19. McClennan G, Trerotola S, Davidson D, et al: The effects of a mechanical thrombolytic device on normal canine vein valves. J Vasc Interv Radiol 12:89-94, 2001 20. Trerotola SO, McLennan G, Davidson D, et al: Preclinical in vivo testing of the Arrow-Trerotola percutaneous thrombolytic device for venous thrombosis. J Vasc Interv Radiol 12:95-103, 2001 21. Hu¨ lsbeck SM, Grimm J, Leidt J, et al: In vitro effectiveness of mechanical thrombectomy devices for large vessel diameter and KENNETH D. MURPHY
22.
23.
24.
25.
26.
27.
low-pressure fluid dynamic applications. J Vasc Interv Radiol 13: 831-839, 2002 Sharafuddin MJA, Hicks ME, Jenson ML, et al: Rheolytic thrombectomy with use of the AngioJet–F105 catheter: Preclinical evaluation of safety. J Vasc Interv Radiol 8:939-945, 1997 Tacke J, Vorwerk D, Bu¨ cker A: Experimental treatment of early chronic iliac vein thrombosis with a modified hydrodynamic thrombectomy catheter: Preliminary animal experience. J Vasc Interv Radiol 10:57-63, 1999 Gu X, Sharafuddin MJA, Titus JL, et al: Acute and delayed outcomes of mechanical thrombectomy with use of the steerable amplatz thrombectomy device in a model of subacute inferior vena cava thrombosis. J Vasc Interv Radiol 8:947-956, 1997 Uflacker R: Mechanical thrombectomy in acute and subacute thrombosis with use of the amplatz device: Arterial and venous applications. J Vasc Interv Radiol 8:923-932, 1997 Gandini R, Maspes F, Sodani G, et al: Percutaneous ilio-caval thrombectomy with the Amplatz device: Preliminary results. Eur Radiol 9:951-958, 1999 Delomez M, Beregi JP, Willoteaux S, et al: Mechanical thrombectomy in patients with deep venous thrombosis. Cardiovasc Intervent Radiol 24:42-48, 2001
MECHANICAL THROMBECTOMY FOR DVT
28. Kasirajan K, Gray B, Ouriel K: Percutaneous AngioJet thrombectomy in the management of extensive deep venous thrombosis. J Vasc Interv Radiol 12:179-185, 2001 29. Vedantham S, Parti N, Vesely TM, et al: Lower extremity venous thrombolysis with adjunctive mechanical thrombectomy. J Vasc Interv Radiol 13(S):S54, 2002 30. Vendantham S, Vesely TM, Parti N, et al: Lower extremity venous thrombolysis with adjunctive mechanical thrombectomy. J Vasc Interv Radiol 13:1001-1008, 2002 31. Semba C, Week S, Razavi MK, et al: Alteplase stability and bioactivity after thrombolysis-facilitated rheolytic or high-speed maceration thrombectomy. J Vasc Interv Radiol 13(S):S76, 2002 32. Uppot RN, Garcia MJ, Roe C, et al: Management of deep venous thrombosis using the Angiojet rheolytic thrombectomy system. J Vasc Interv Radiol 13:S116, 2003 33. Kasirajan K, McNamara TO, Vina RF, et al: Use of a mechanical thrombectomy infusion catheter with emboli protection for lower extremity deep venous thrombosis. J Vasc Interv Radiol 13:S116, 2002 34. Trerotola SO, McLennan G, Eclavea AC, et al: Mechanical thrombolysis of venous thrombosis in an animal model with use of temporary caval filtration. J Vasc Interv Radiol 12:1075-1085, 2001
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Deep venous thrombosis is a common source of morbidity and mortality in the United States. Complications include pulmonary embolism and chronic post-thrombotic syndrome. Chronic postthrombotic syndrome is characterized by extremity pain, edema, venous claudication, skin changes, and skin ulceration. This syndrome is attributed to venous obstruction and valvular damage due to thrombus. The standard treatment of deep venous thrombosis consists of medical management with anticoagulation. Anticoagulation has proven efficacy in prevention of thrombus extension, pulmonary embolus, and re-thrombosis. The role of anticoagulation in post-thrombotic syndrome is unclear. Aggressive endovascular techniques for managing DVT have evolved as a result. Catheter-directed thrombolysis was the first such procedure with demonstrated efficacy, however its acceptance has been limited by perceived risks, time to lysis, and cost. As a result, alternative measures for managing DVT have evolved including mechanical thrombectomy. Mechanical thrombectomy for DVT has the potential to shorten the time for lysis, reduce the risk of thrombolytic agents, and potentially impact cost savings. © 2004 Elsevier Inc. All rights reserved.
echnological advances have promoted the evolution of percutaneous mechanical thrombectomy (PMT) as a potential alternative or adjunct to pharmacologic thrombolysis and/or surgical thrombectomy for management of acute thrombotic and thromboembolic arterial and venous occlusions. Clinical experience to date with PMT has demonstrated the effectiveness, safety, and limitations of the various devices, principally in the arena of dialysis access site management. Device improvements and clinical experience have facilitated evaluation of PMT thrombosis outside the dialysis bed, including the venous circulation. Deep venous thrombosis (DVT) is the major cause of morbidity and mortality in the United States. Approximately 20 million cases of lower-extremity and an estimated 200,000 to 600,000 cases of upper-extremity DVT occur annually in the United States.1 Complications include pulmonary embolism (PE), chronic postthrombotic syndrome (PTS) Phlegmasia Cerulea Dolens, Phlegmasia Alba Dolans, upperextremity venous insufficiency, and amputation. Pulmonary embolism is estimated to occur in 750,000 to 900,000 patients, with an annual mortality of 47,000 to 200,000 patients.1 PTS is the most common cause for long-term morbidity and disability.1 Extremity pain, swelling, chronic deep venous insufficiency, venous claudication, skin changes, and ulceration char-
T
From the Department of Radiology, Upstate Medical University, State University of New York, Syracuse, NY. Address reprint requests to Kenneth D. Murphy, Department of Radiology, Upstate Medical University, State University of New York, 750 E. Adams Street, Syracuse, NY 13210. © 2004 Elsevier Inc. All rights reserved. 1089-2516/04/0702-0006$30.00/0 doi:10.1053/j.tvir.2004.05.002
acterize this syndrome.2 It has been estimated that 400,000 to 500,000 Americans have or have had a postthrombotic venous ulcer.3 The syndrome is partially attributed to venous obstruction, as well as, clot organization at the valve level with resultant impairment of the valvular function.4,5 The incidence of PTS ranges from 35% to 70%,6-11 with differences because of variations in anticoagulation treatment regimens, underlying DVT clot age, use of compressive hosiery, and reporting standards. Despite recognition of risk factors and complications of venous thromboembolic (VTE) disease, preventive strategies and conventional treatment has been varied with widely discrepant results and outcomes. The variance of management strategies for VTE disease reflects the continued evolution of devices, drugs and treatment protocols for such complex patients. The intent of this review article is to present the evolving role of the mechanical thrombectomy device in managing patients with DVT, including the rationale, preclinical experience, clinical experience, limitations, and future.
PMT Rationale The conventional treatment of DVT has long been systemic anticoagulation with unfractionated heparin (UFH), followed by 3 to 6 months of warfarin. The goal of anticoagulation is to inhibit the thrombotic process and allow thrombus clearance by endogenous plasmin with minimal risk of bleeding. Recently, low-molecular weight heparins (LMWH), have demonstrated safety and efficacy for DVT prevention in high-risk patients and treatment of acute DVT.12-15 The conventional UFH/warfarin approach has largely been replaced with LMWH, as LMWH has several advantages including predictable pharmacokinetic properties, enhanced bioavailability, fixed weightbased dosing independent of partial-thromboplastin time, and independence from laboratory studies.16 Despite advances with heparin and heparin derivatives in managing DVT and VTE, the impact of such therapy on the development of PTS remains unknown and problematic. In a search for a more comprehensive DVT therapy algorithm that would include prevention of PTS, alternative treatment strategies have evolved, and continue to be investigated. With the advancement in endovascular management techniques, principally in the arterial tree, application in the venous circulation has grown significantly. Catheter-directed thrombolytic therapy for DVT has demonstrated feasibility and success in severe cases including phlegmasia, however, prospective, randomized trials defining the exact role of such an aggressive approach are lacking. Catheter-directed thrombolytic therapy is potentially attractive with respect to PTS, as it not only restores vein patency quickly but also has a potential to preserve valvular function and prevent PTS. In a multi-center venous registry, complete lysis was seen in 31% of patients with a 1-year patency of 79%.17 Although the 1-year patency rate is encouraging, the widespread acceptance of this
Techniques in Vascular and Interventional Radiology, Vol 7, No 2 (June), 2004: pp 79-85
79
TABLE 1. Current Mechanical Thrombectomy Devices Wall Contact Devices Arrow Percutaneous Thrombectomy Device (PTD, Arrow International, Reading, PA) Solera (Bacchus Vascular, Santa Clara, CA) Cleaner (Rex Medical, Fort Worth, TX) MTI-Castaneda Brush (Microtherapeutics, San Clemente, CA) Fino (Bacchus Vascular, Santa Clara, CA) Cragg Brush (Microtherapeutics, San Clemente, CA) Prolumen (Datascope, Mahwah, NJ) Hydrodynamic Thrombectomy Fragmentation Devices Amplatz Thrombectomy Device (ATD/Helix, Microvena, White Bear Lake, MN) Rotarex catheter (Straub Medical, Wangs, Switzerland) Thrombex PMT (Edwards Lifesciences, Irvine CA) Rheolytic (Flow-Based) Thrembectomy AngioJet (Possis Medical, Minneapolis, MN) Oasis (Boston Scientific, Watertown, MA) Hydrolyzer (Cordis, Warren, NJ) Ultrasound Acrolysis probe (Angiosonics, Morrisville, NC) Resolution 360™ Therapeutic Wire (Omnisonics, Wilmington, MA) Combination Infusion Catheter/Isolated Oscillation Device Trellis Reserve (Bacchus Vascular, Santa Clara, CA)
procedure has been limited because of perceived risks, costs, and efficacy issues. Specific issues that have limited the acceptance of catheter-directed thrombolytic therapy include time to lysis, need for hospitalization and intensive care monitoring, risk of hemorrhage, cost of thrombolytic agents, and lack of prospective, randomized data. In this modern era where cost effectiveness and outcome results are important, alternative treatment strategies have developed with the intent to shorten treatment time, contain costs, and improve efficacy. The rationale for PMT is based on the potential that such a treatment strategy may result in a shorter time to restoration of vein patency, elimination of reduction in hospitalization cost, reduction in the risk of hemorrhage from thrombolytics, and overall cost savings because of elimination or reduction in thrombolytic drug.
Preclinical Experience Percutaneous mechanical thrombectomy is an evolving procedure for removal of thrombus from vessels and grafts. The FDA has approved several PMT devices with application principally limited to hemodialysis graft thrombosis. Based on these results, the devices have and continue to be evaluated for peripheral arterial and venous application.18 The PMT devices can be divided into wall contact devices and nonwall contact devices (Table 1). Wall contact devices include the Arrow-Trerotola percutaneous thrombectomy device (PTD) (Arrow International, Reading, PA), for which a large body of preclinical study has been performed to evaluate feasibility issues of PMT for DVT. The nonwall contact devices including the Amplatz thrombectomy device (ATD) (Microvena, White Bear Lake, MN), the Hydrolyzer (Cordis, Warren, NJ), the Angiojet (Possis Medical, Minneapolis, MN), and the Oasis thrombectomy catheter (Boston Scientific, Watertown, MA), which have all undergone preclinical animal evaluation. The concern with respect to PMT devices and their application to DVT is primarily of vessel wall injury and valvular injury. Because the goal of DVT therapy is thrombus removal and preservation of valvular flow, preclinical evaluation of PMT devices with respect to the potential for valvular injury is paramount. The PTD device has undergone the most extensive preclinical evaluation in animals, with special attention to the effect of PMT on vein wall and valvular function. McClennan and coworkers evaluated the effects of the PTD device on normal canine vein valves. In this animal model, they found the PTD device did not cause physiologically significant damage to valves 7 mm or larger in diameter.19 Trerotola demonstrated preclinical success in using the PTD device for treating DVT in the canine model. Thirteen dogs underwent PTD treatment for iliocaval subacute thrombosis using a modified PTD device with a prototype15 mm diameter basket. They demonstrated the modified PTD was effective in
Fig 1. (A) Symptomatic right lower-extremity iliofemoral DVT and caval filter thrombosis. (B) ATD via jugular approach. (C) Post ATD and iliac vein stent placement with patency restored.
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KENNETH D. MURPHY
Fig 2. (A) Left lower-extremity DVT treated with Angiojet. (B) Post-Angiojet vein patency with iliac artery compression at iliocaval junction. (C) Completion venogram after stent placement.
treating subacute (⬍7 days) venous thrombosis. Pulmonary emboli were documented, suggesting temporary filtration may be necessary as an adjunct to this approach.20 Preclinical evaluation of several other devices has also been evaluated in animal and in vitro models. The Angiojet,21,22 Oasis,23 Hydrolyzer,21 and ATD,24 have demonstrated feasibility and efficacy in clot removal from animal and in vitro flow models. MECHANICAL THROMBECTOMY FOR DVT
Clinical Experience Clinical experience to date using PMT for DVT has been limited to select case specific reports and small clinical series in peerreviewed literature. The literature is devoid of any prospective, randomized clinical trials, although some prospective trials with PTD and Fino (Bacchus Vascular, Santa Clara, CA) device,
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Fig 3. PTD for acute DVT.
among others, have been or are being attempted. The evolving investigation of PMT devices for DVT management is based on the limitations of catheter-directed thrombolytic therapy, technical advancements of the PMT devices, and growing arterial and hemodialysis PMT clinical experience. The greatest PMT for DVT experience has been with the ATD (Fig 1), the Angiojet (Fig 2), and PTD (Fig 3). In 1997, Uflacker first reported PMT for DVT in 1 patient with lower-extremity DVT and inferior vena cava thrombosis.25 In this report, the patient was treated with the ATD with partial success.25 In 1999 Gandini reported treating 8 patients with ilio-caval thrombosis using the ATD with a temporary IVC filter.26 Adjunct thrombolytics were not administered. Complete clot extraction was reported in 75% of patients.26 In 2001, Delomez reported a larger series of eighteen patients with DVT treated with the ATD using temporary IVC filtration, without adjunct thrombolytics.27 Successful recanalization was achieved in 83%, and the mean percentage of thrombus removed 66%. In mean follow-up of 29.6 months, there was only one limb with PTS.27 Transient arterial desaturation was observed in all patients immediately after PMT, despite negative pulmonary angiograms and temporary IVC filtration.27 These
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initial reports demonstrated the technical feasibility of PMT for DVT, however, the clot extraction rate and patency was still problematic. Based on these initial observations, the adjunct role of thrombolytics appeared beneficial, and subsequent reports in the literature reflected this observation. In 2001, Kasirajan described the effect of adjunct thrombolytics on PMT for DVT.28 He reported 17 patients with lowerand upper-extremity DVT treated initially with the Angiojet and catheter-directed thrombolytics as needed. Temporary filters were not utilized. After PMT alone, 24% had venographic evidence of greater than 90% thrombus removal, and 35% demonstrated 50% to 90% removal. Adjunctive thrombolytic therapy was utilized in 9 of 13 patients with less than 90% thrombus extraction by PMT alone. Four of 13 patients had contraindication to thrombolytics, therefore, were excluded. The overall clinical success of PMT with adjunct thrombolytics was 82%. DVT recurrence free survival was greatest in the ⬎90% clot extraction group. There were no procedure-related complications. Valvular reflux and PTS incidence was not reported. This small series is the first to demonstrate the potential benefit of combination PMT and thrombolysis therapy with respect to clinical improvement, clot extraction and recurrence free survival.28 In 2002, Vedantham reported the effect of adjunct PMT on catheter-directed thrombolysis for DVT. In a retrospective comparison of DVT management with catheter-directed thrombolysis versus combination therapy (PMT and thrombolysis), he described an approximate 40% reduction in time to lysis and a 60% reduction in lytic drug dose with adjunct PMT.29 Vendantham also reported minimal thrombus removal with PMT alone (26.0%), versus substantial thrombus removal with PMT and thrombolytics (62.0%).30 These limited series suggest stand alone PMT for DVT, despite reducing procedure time, is insufficient for adequate thrombus removal, and adjunct thrombolytics either pre- or post-PMT is likely necessary to achieve procedure success with current devices. As an alternative to separate, sequential PMT/ thrombolysis procedures for DVT, simultaneous administration of thrombolytics during PMT is an attractive concept with potential for reduced procedure time and enhanced thrombus removal. The mechanical effect on the molecule is important to consider as the drug-device techniques are potentially merged. Semba demonstrated the biostability of Alteplase in an in vitro model using the Angiojet.31 The simultaneous administration of thrombolytics during PMT, essentially true “combination therapy” has been reported with the Angiojet and Trellis devices, among others being investigated (Fig 4). Uppot reported a technique mixing the thrombolytic drug in the Angiojet saline infusion bag for direct administration during PMT.32 In this small series of 24 patients, complete or substantial thrombus removal was reported in 83.5%.32 Kasirajan reported success using the Trellis device, a novel infusion/PMT catheter device, in combination with thrombolytics in 20 patients.33 Such exciting combination strategies continue to be investigated, and further experience and follow-up is needed to assess the efficacy and impact on PTS.
Role of Retrievable Filters Utilization of a PMT for DVT management has the inherent risk of pulmonary embolism as a complication. The etiology of this complication includes clot displacement and/or particle embolization. With the recent FDA approval of “retrievable” or opKENNETH D. MURPHY
Fig 4. (A) Trellis infusion catheter system. (B) Bilateral massive iliofemoral DVT treated with bilateral Trellis devices in iliac veins. (C) Vein patency restored post-Trellis. (Color version of Fig 4a is available online.)
MECHANICAL THROMBECTOMY FOR DVT
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TABLE 2. PMT for DVT-PE Incidence
Uflacker ( ) Kasirajan (28) Vedantham (29) Delomez (27) 25
Device
n
Filter
PE
ATD AJ AJ, ATD, PTD, Oasis ATD
3 17 10 18
n n n y
13
⁄ dyspnea NR 0% (clinical) 0% (PAgram) 100% desat
ATD ⫽ amplatz device; AJ ⫽ angioJet device; PTD ⫽ arrow percutaneous mechanical thrombectomy device; NR ⫽ not reported.
tional filters, consideration for utilization of such a device appears reasonable. In a preclinical canine study, Trerotola and co-workers described the development of segmental and subsegmental PE in dogs with iliocaval thrombosis treated with PMT utilizing the PTD device.20 Their conclusion was there likely is a role for temporary filtration during such a procedure.20 In a follow-up study, Trerotola compared DVT management in a canine model with the PTD device with and without a prototype nitinol temporary IVC filter.34 The pulmonary bed was evaluated with pulmonary angiography after PMT. Rare segmental and subsegmental PE were identified in the filter group, significantly less than the cohort without filters.34 Despite the temporary filtration, a mild increase in the pulmonary artery pressure, decrease in the pH and an increase in the pCO2 were observed postprocedure.34 There is limited analogous data with respect on the development of PE on human subjects undergoing PMT for DVT (Table 2). Uflacker reported 1 of 3 patients with DVT managed with ATD developed dysnea.25 Delomez reported a small series of patients with DVT treated with the ATD device using a temporary filter. Patients underwent post-PMT pulmonary arteriography and no pulmonary emboli were identified, however, oxygen desaturation was common.27 Vedantham described a small series of 10 patients who underwent DVT management with PMT using a variety of devices, and there were no clinical stigmata of PE.29 The preclinical animal studies suggest temporary filtration may be indicated utilizing the PTD device, however, the limited data and variable results in the human experience do not draw an evidence-based conclusion. The development of PE, whether it is a result of clot displacement or particulate embolization, appears to likely be device specific, and the role of temporary filtration is yet to be defined. Further investigation is needed to assess the role of retrievable filters in patients undergoing PMT for DVT.
Conclusion The role of PMT for management of DVT continues to evolve. The evolution reflects the changes in device technology and clinical experience. As with any new technique or device, patient and physician education is a necessary component for investigation and success. In the case of DVT, continued physician education is necessary to demonstrate the limitations of conventional systemic anticoagulation, and suggests the merits of a more aggressive endovascular approach using pharmacologic and mechanical thrombectomy devices to prevent the costly and disabling development of PTS. The potential for PMT in the area of DVT includes rapid thrombus removal, rapid restoration of vessel patency, reduction in PTS, and avoidance/reduction of lytic drug risk and cost. The limitations of PMT for DVT to date include incomplete thrombus removal,
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embolization risks, potential for vein/valve injury, and lack of experience and prospective data. Based on the experience to date, there is a call for improved devices, improved techniques, and more prospective data.
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