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1 7/23/2013 Which patients with acute lower extremity DVT should definitely, probably, and possibly be treated with catheter directed thrombolysis? Akhilesh K. Sista, M.D. Assistant Professor, Division of Interventional Radiology Weill Cornell Medical College No financial disclosures The decision is based on a risk-benefit analysis Vedantham S., Am. J. Hema- tol. 87:S113 S118,

2 7/23/2013 Phlegmasia Cerulea Dolens an illustrative case* 62 yo female with ovarian cancer and right pelvic lymph node mass. Developed DVT and placed on Lovenox and Warfarin Worsening symptoms and clot propagation Transferred from small facility to trauma center *Courtesy of Brooke Spencer, M.D. Phlegmasia continued Motor and sensory function were intact Arterial Doppler demonstrated triphasic waveforms Leg extremely painful No fevers, mild elevation of WBC, anemia 2

3 7/23/2013 Pharmacomechanical CDT Day 1 3

4 7/23/2013 Day 1 Day 2 Day 2 Day 3 Day 6 Day 10 4

5 7/23/2013 Rationale for treating phlegmasia Limb threatening venous hypertension Progression to gangrene and sepsis CDT or PCDT should be given to patients with IFDVT associated with limb-threatening circulatory compromise (ie, phlegmasia cerulea dolens) (Class I; Level of Evidence C). Progressive caval thrombosis rationale to treat Remove thrombus more rapidly than anticoagulation Avoid large PE Avoid extension/propagation into renal veins Avoid progression to phlegmasia 5

6 7/23/2013 The decision is based on a risk-benefit analysis Illustrative case 54 year old woman Status post trans-sphenoidal encephalocele repair, prophylactic filter placed 3 days prior to surgery 1 week after surgery presented with back pain, leg swelling, U/S showed LLE acute DVT from CFV to pop Was on anticoagulation for 2 weeks, but leg was getting clinically worse Initial meeting Left thigh 57 cm Left calf 43.5 cm In too much pain to move, lying in bed Left leg was tense, swollen, red, very tender Ordered CT venogram 6

7 7/23/2013 Initial Venography Post 40 h infusion femoral venography 7

8 7/23/2013 Post stent deployment pelvic venography Follow up Left calf went from 43.5 cm to 38 cm in circumference Left thigh went from 57 cm to 48 cm in circumference Rationale to treat DVTs progressing despite anticoagulation Symptom relief Avoid progression to the point of phlegmasia, caval thrombosis, large PE CDT or PCDT is reasonable for patients with IFDVT associated with rapid thrombus extension despite anticoagulation (Class IIa; Level of Evidence C) and/or symptomatic deterioration from the IFDVT despite anticoagulation (Class IIa; Level of Evidence B). 8

9 7/23/2013 The decision is based on a risk-benefit analysis The Post-Thrombotic Syndrome Iliofemoral DVTs confer the highest anatomic risk for developing the postthrombotic syndrome Kahn et al. Ann Intern Med. 2008;149:

10 7/23/2013 Conclusions Phlegmasia: acute limb threat necessitates aggressive and immediate thrombus removal Extensive caval thrombus: aggressive and urgent thrombus removal is warranted to avoid acute morbidity/mortality Clot propagation in spite of anticoagulation: should be strongly considered in low-risk patients to avoid acute consequences Iliofemoral thrombus: evidence points towards treating these patients since they have a significant likelihood of developing PTS Femoropoliteal thrombus: evidence points against treating these patients since they have a equivocal risk of developing PTS 10

11 Clinical Assessment of Thrombolysis Candidates Seth Klein, MD Assistant Professor Section of Vascular and Interventional Radiology Mallinckrodt Institute of Radiology Disclosures None Outline Pre-treatment evaluation - Contraindications - Patient choice issues - Additional work-up Peri-procedural preparation - Anticoagulation - Use of inferior vena cava filters

12 Pre-treatment Assessment Careful medical history and PE - Known VTE risk factors? - Prior VTE episodes/treatment - Preexisting and current limb symptoms - Recent PE symptoms SOB, chest pain, palpitations, hemoptysis, syncope etc Pre-treatment Assessment Identify co-morbidities (elev. bleeding risk) - Active ongoing bleeding - Intracranial disease - Recent trauma/surgery - Severe hepatic dysfunction - GI bleeding - Uncontrolled HTN Pre-treatment Assessment Identify co-morbidities - Pulmonary HTN - Cardiopulmonary disease - Renal failure - Active infection - *Cancer

13 Pre-treatment Assessment Medications - Influence on coagulation? - Platelet function? Allergies? - Contrast dye Patient choice issues Life expectancy Baseline ambulatory capacity Co-morbidities Patient s personal values and preferences Contraindications Any patient with - Hemorrhagic disorder - Anatomical lesion that is prone to bleeding - Absolute contraindication to anticoagulant therapy

14 Additional Imaging VTE symptoms are nonspecific - CT chest to confirm PE, Echo Anatomical extent of DVT - Duplex u/s, CT Malignancies that metastasize to CNS - Brain imaging (MRI, CT) Labs Hct Plt INR, PTT Cr hcg - women of childbearing age Fibrinogen baseline preprocedure

15 Peri-procedural anticoagulation Before and after CDT/PCDT, patients should receive therapeutic-level anticoagulation - w/ similar dosing, monitoring, and duration - Kearon C, Akl E, Comerota A, Prandoni P, et al. ACCP Guidelines (9 th ED) Chest 2012; 141;e419S-e494S During CDT Infusion Have evolved toward use of reduceddose UFH over therapeutic-level UFH - Supported by indirect clinical evidence from arterial lysis trials - The STILE trial. Ann Surg 1994;220(3): Ouriel K, Veith FJ, Sasahara AA; (TOPAS) Investigators. N Engl J Med 1998;338(16): During CDT Infusion Relatively low rate of major bleeding observed, in which reduced-dose UFH used in addition to rt-pa CDT for proximal DVT - Enden T, Haig Y, Klow NE, Slagsvold CE, et al. (the CaVenT study). Lancet 2012;379(9810):31-8

16 During CDT Infusion Use of sub-therapeutic UFH during DVT thrombolysis is supported by current guidelines of the AHA and SIR During CDT Infusion Optimal dosing? - May differ among thrombolytic drugs - No specific studies CDT vs. Single-session PCDT Optimal degree of anticoagulant effect may differ substantially w/ singlesession PCDT - Manipulations tend to be more robust - Greater endothelial damage? - Potential for thrombus migration and PE may be slightly higher

17 Single-session PCDT Generally use full-therapeutic UFH - Including follow-up sessions after infusion CDT - Low inflow situations? LMWH and Antiplatelet tx Have not been directly studied during or after DVT thrombolysis We (and others) have used LMWH as a substitute for UFH during PCDT Peri-procedural IVC Filter The incidence of clinical PE during infusion CDT does not appear to exceed that observed in patients who receive anticoagulant therapy alone - Mewissen MW, Seabrook GR, Meissner MH, et al. (report of a multicenter registry). Radiology 1999;211:39-49

18 Peri-procedural IVC Filter Do not advocate IVC filters for most patients undergoing infusion CDT - Risks of migration - Late recurrent DVT - Cost - Decousus H, Leizorovicz A, Parent F, et al. (PREPIC study) N Engl J Med 1998;338(7): Peri-procedural IVC Filter However, for patients treated with single-session PCDT methods - Limited evidence suggests that major PE can occur - Bush RL, Lin PH, Bates JT, et al. J Vasc Surg 2004;40(5): Sharifi M, Bay C, Skrocki L, et al. (the FILTER-PEVI trial). Cardiovasc Intervent Radiol 2012;35(6): Peri-procedural IVC Filter May be reasonable to use retrievable IVC filter prior to single-session PCDT Lower threshold if - Iliocaval thrombus present - Pulmonary HTN - Other cardiopulmonary co-morbidity

19 Interventional Treatment of Proximal DVT Mahmood Razavi, MD Director Center for Clinical Trials St Joseph Vascular Institute Faculty Disclosure Scientific/strategic advisory boards for: Abbott Vascular; Altura; 480 BioMedical; Bard Peripheral Vascular; Boston Scientific; Cordis Corp.; Covidien/ev3; Mercator; Perfint; Trivascular; Veneti; Stockholder: Altura; Arsenal Medical; Atheromed; Curaseal; Endologix/Nellix; Mercator; Neuravi; Trivascular; Veneti Grant/financial support: National Institute of Health; Cordis; WL Gore; Basic Principle Access in an antegrade fashion Popliteal/ brachial/basilic veins Should have inflow if using PMTD only Infusion of lytics needed otherwise Establish outflow Recanalization & stenting if necessary

20 Venous Access Popliteal or high tibial vein access Avoid pop artery or its branches Color flow imaging helpful to identify collateral veins as well Careful positioning of micropuncture needle tip under US Use of a robust wire may become necessary Popliteal vein puncture using ultrasound and micropuncture set

21 Popliteal vein using Site-Rite Without compression With compression v A A Beware of variations in PV anatomy and relations Without compression With compression 38 yo female with factor V Leiden & 2 weeks post partum

22 After O.N. infusion of 0.5 mg/hr TNK

23 Basic Principle Angioplasty alone is largely ineffective in non-dialysis venous stenoses/occlusions Stents have had a good outcome in central venous obstruction Exception: tumor invasion of the vein Stents do not have a good outcome in peripheral veins Below SFJ and peripheral to BCV Technique + side-holes in the sheath Place infusion catheter through the length of the clotted segments Start thrombolysis( + coaxial system) mg/hr t-pa mg/hr TNK U rpa K U UK Technique Bolus/lacing Probably accelerates lysis Heparin Sub-therapeutic vs full dose Mechanical thrombectomy Not effective as stand alone technique Useful in de-bulking clot (pre or post lysis)

24 Technique Volume of lytics cc/hr Infusion catheter selection not critical Volume of lytics < 25 cc/hr (CHF, renal failure, etc.) Type of infusion catheter important Technique Step-down unit (ICU not necessary)? Fibrinogen level If < 100, give FFP or temporarily stop thrombolysis Routine lab parameters (CBC, PTT, etc) Repeat venography the following day Lytic Assisted & PMT Devices Trellis Angiojet DVX/ AVX Xpeedior EKOS Lysus system Hydrolyzer Oasis Trerotola Device Helix/X-Sizer/Brush Resolution 360 wire Akonya Eliminator Aspirex/Rotarex Thrombex PMT ProLumen Rinspirator

25 tpa dosing for Trellis procedure 1 mg per 3 cm clot segment Min. starting dose 4 mg Divide the dose equally if more than 1 treatment zones is planned (ie >24 cm)

26 Angiojet Power-pulse Protocol Dilute tpa dose in ml NS Put Drive unit in PowerPulse mode Start tpa infusion by activating PP from the cephelad extent of clot by withdrawing catheter at ~1cm every 3 sec Allow a dwell time of 30 min Advance DVX through clot with Drive unit in aspiration mode Complete Lysis No stenosis Stenosis FV/pop Iliac Done? PTA PTA/stent Partial lysis at f/u venography Fem-pop clear diseased or clotted iliac Residual clot FV Mech. Thromb. PTA/stent iliacs Continue lysis

27 7/22/2013 DVT Thrombolysis Outcomes: Known and Unknown Suresh Vedantham, M.D. Professor of Radiology & Surgery Mallinckrodt Institute of Radiology Washington University in St. Louis Research Support from NIH Grant Awards ATTRACT Study: U01-HL088476, U01-HL Wash U Thrombosis Research Center: U54-HL Dr. Vedantham is solely responsible for talk content Supplemental Support for ATTRACT Study Bayer, BSN Medical, Covidien, Genentech-Roche Off-label: lytic drugs for DVT, venous stents Post-Thrombotic Syndrome (PTS) causes chronic leg pain, fatigue, swelling, skin changes, and ulcers PTS is common, lifelong, impairs QOL, has no effective treatments Kahn SR et al. Ann Intern Med Kahn SR et al. J Thromb Haemost Venous ulcers often recur and are difficult and expensive to treat 1

28 7/22/2013 Author/Year Journal N 2-Year PTS Prandoni 1996 Ann Intern Med % Brandjes 1997 Lancet 96 23% Prandoni 2004 Ann Intern Med 90 25% Partsch 2004 Int J Angiol 37 46% Van Dongen 2005 J Thromb Haemost % Kahn 2008 Ann Intern Med % (60%) Enden 2012 Lancet 99 56% (Kahn 2013) Presented at ASH % PTS rate iliofemoral DVT (CFV/iliac) - 60% Recurrent VTE more common with IFDVT 2

29 7/22/2013 Study N CDT Arm Control P Value Major Bleeds %* (did not affect outcome) 0% Not presented PTS (Villalta) % 55.6% VTE Over 2- Year F-U % (no CDTrelated PE) 18% NS Pro: no ICH; one surgery and one transfusion Con: small sample, Norway, no devices Enden T et al. Lancet CDT is often reasonable for acute IFDVT Vedantham S et al. J Vasc Interv Radiol (SIR) Kearon C et al. Chest Suppl (ACCP 8 th ) Jaff M et al. Circulation (AHA) Meissner MH et al. J Vasc Surg (SVS-AVF) Recommend AC alone over CDT Kearon C et al. Chest Suppl (ACCP 9 th ) Treatment AC Alone CDT + AC Major Bleeds (all) 1.5% Unknown Major Bleeds (culled) 0% 3-5% Basis Over 100,000 patients 90 patients in one RCT Delivery Uniform Heterogeneous Level of Confidence Exceedingly HIGH Exceedingly LOW Evolution New drugs trial-proven to enable reliable AC Value of added devices or US totally unproven Cost Low outpatient High: $30,000 $50,000 3

30 Cumulative incidence Villalta PTS 7/22/2013 Compression SOX Trial Courtesy of S. Kahn (previously known, but now we know better) Active ECS Placebo ECS HR adj (95% CI) 52.1% 52.2% 0.96 ( ) p=0.69 Clinical trials suggest safer than LMWH-warfarin PRO: once-daily oral dosing, rapid onset, no need for INRs or dietary modifications, few interactions CON: lack of antidote, missed doses => rapid loss of effect, cannot use with severe renal dysfunction SUGGEST: do not use within 24 hours of lysis; engage medical physician to assist with transitions STUDY ENROLLMENT Patient with proximal DVT meets eligibility criteria and provides informed consent PRE-RANDOMIZATION PROCEDURES Initiation of AC (LMWH or UFH) and completion of baseline assessments RANDOMIZATION (1:1 Ratio) CONTROL ARM SUBJECTS Complete 5 days heparin therapy (LMWH or UFH) and immediately bridge to warfarin (INR ) PCDT ARM SUBJECTS Complete 5 days heparin therapy (LMWH or UFH) concurrent with performance of PCDT procedure, then bridge to warfarin (INR ) LONG-TERM TREATMENT - ALL SUBJECTS Long-term (> 3 months) warfarin therapy and daily use of graduated elastic compression stockings (initiated 10 days post-randomization) FOLLOW-UP VISITS ALL SUBJECTS Early (10 days & 30 days post-randomization) Late (6, 12, 18, & 24 months post-randomization) 4

31 7/22/ PTS Symptoms scored 0-3: leg heaviness, pain, pins and needles, cramping, itching 6 PTS Clinical Signs scored 0-3: pretibial edema, skin induration, hyperpigmentation, venous ectasia, redness, pain during calf compression PTS = Score > 5 or presence of ulcer in index leg Testing for 1/3 reduction in PTS at 2 years Does PCDT Reduce PTS Severity? Villalta, VCSS, CEAP Does PCDT Lead to Better Quality of Life? SF-36, VEINES-QOL/Sym Does PCDT Speed Symptom Relief? Likert pain scale, leg circumference Is PCDT Safe and Cost-Effective? Bleeds, VTE, death, $/QALY Operational Separation of PI from Data Management Co-Interventions: AC, Compression, Filters Equal Surveillance via Electronic Schedule Central Randomization with Stratification Allocation Concealment & Explicit Blinding Precautions 5

32 7/22/2013 Leadership National Institutes of Health National Heart Lung & Blood Inst Diverse Steering Committee Community Support SIR and SIR Foundation American College of Phlebology American Venous Forum Venous Disease Coalition The ATTRACT Study: Credible and Rigorous Multi-Specialty Site Teams Endovascular physicians Medical physicians Emergency physicians Vascular ultrasound lab Core Institutions Washington University McMaster University Mass General - VasCore St. Luke s Hospital - MAHI The Surgeon General is passionate for the ATTRACT Trial to go forward RADM James M. Galloway, Assistant U.S. Surgeon General ATTRACT Accrual: 70% of Total July 17, 2013: 486 Patients 6

33 7/22/2013 Receive and pay for a risky therapy to prevent a nonlethal condition (if it does), OR Choose the Study: - Receive treatment under optimized conditions: treatment methods endorsed by national DVT experts & NIH (study - by Surgeon General) - Receive FREE stockings, TPA, stockings, US exam - Be closely monitored by DVT experts who will communicate with you, actively assist with care Preventing PTS by achieving an open, thrombus-free vein is considered an integral element of DVT care NIH & industry make robust investments in venous endovascular innovation ATTRACT Vision for the Future Providers know which patients are best suited for clot removal and triage them appropriately Groundwork for more pivotal DVT trials is laid by proven clinical research consortium Patients benefit from evidence-based care delivered by expert multidisciplinary teams 7