1. Suresh Vedantham, M.D. Professor of Radiology & Surgery Mallinckrodt Institute of Radiology Washington University in St. Louis Interventional Management of Deep Vein Thrombosis

2. DISCLOSURES Research support for NIH-funded ATTRACT Trial –National Heart Lung and Blood Institute (NIH) –BSN Medical –Covidien - Bacchus Vascular –MEDRAD Interventional – Possis - Bayer –Roche-Genentech Off-label: TPA for DVT; stents for iliac vein

3. “Acute DVT” Acute Phase of a Chronic Disease DVT causes severe leg pain and swelling With AC, time course for improvement varies Difficulty ambulating and returning to full activity impair QOL

4. Post-Thrombotic Syndrome  Common - chronic leg pain, fatigue, heaviness, swelling, skin changes  Less Common – venous ulcers PTS is frequent, lifelong, impairs QOL, has no consistently effective treatment Kahn SR et al. Ann Intern Med 2008. Kahn SR et al. J Thromb Haemost 2008.

5. PTS Incidence (AC + Compression) Clot Extent Matters Author/YearJournalN2-Year PTS Prandoni 1996Ann Intern Med35523% Brandjes 1997Lancet9623% Prandoni 2004Ann Intern Med9025% Partsch 2004Int J Angiol3746% Van Dongen 2005J Thromb Haemost24430% Kahn 2008Ann Intern Med38740% (60%) Enden 2012Lancet9956% Patients with iliofemoral DVT (common femoral and/or iliac vein) develop PTS 60% of the time

6. PTS - Mechanisms Acute inflammation => valvular reflux Residual clot => venous obstruction Long-term – propensity to inflammation => Ambulatory venous hypertension Shull KC et al. Arch Surg 1979. Markel A et al. J Vasc Surg 1992. Nicolaides AN et al. J Vasc Surg 1993. Meissner MH et al. J Vasc Surg 1998.

7. The Open Vein Hypothesis Does immediate clot removal speed symptom relief, save valves, preserve patency, and prevent PTS?

11. Ultrasound-Assisted Thrombolysis Ultrasound energy to speed lysis, reduce or eliminate use of drug Is it more efficient from operator’s perspective? Does it better remove valve-adherent clot? Fibrin without Ultrasound Fibrin With Ultrasound

12. Pharmacomechanical CDT Can Enable Single-Session Therapy Trellis-8 Catheter (Covidien) AngioJet Solent Proxi (MEDRAD)

13. Arguments for CDT: 1991-2011 AnatomicEmotional

14. Evidence-Based: Anticoagulation Recurrent ipsilateral DVT increases PTS risk –Prandoni P et al. Ann Intern Med 1996; 125:1-7. –Brandjes DPM et al. Lancet 1997; 349:759-762. –Prandoni P et al. Ann Intern Med 2004; 141:249-56. Non-therapeutic INR increases PTS risk –Van Dongen et al. J Throm Haemost 2005; 3:939-942. Long-term LMWH may reduce PTS risk –Hull RD et al. Am J Med 2006; 119:1062-1072.

15. Evidence-Based: Compression Single-center, open-label RCTs show that use of 30-40 mmHg graduated elastic compression stockings reduce 2-year PTS rate by about 50% –Assuming the garments are applied relatively early –Brandjes DPM et al. Lancet 1997; 349:759-762. –Prandoni P et al. Ann Intern Med 2004; 141:249-256. SOX – multicenter, double-blind, placebo RCT –Kahn SR et al. –Kahn SR et al. BMC Cardiovasc Dis 2007; 7:21.

16. Single-Center RCTs A 35-patient RCT found streptokinase to provide better 6-month patency (72% vs 12%, p < 0.01) and less valvular reflux (11% vs 41%, p = 0.042) –Elsharawy M et al. Eur J Vasc Endovasc Surg 2002. A 183-patient RCT found CDT-PCDT to reduce 6-month PTS (3.4% vs 27.2%, p < 0.001) and recurrent VTE (2.3% versus 14.8%, p = 0.003) –Sharifi M et al. Cathet Cardiovasc Interv 2010.

17. Consensus & Controversy Salvage vs. First-Line Therapy 2008 Guidelines – weak (2B) in favor of CDT/PCDT 2012 Chest Guidelines – weak (2C) against CDT BUT: Evidence-based? Multidisciplinary consensus?

18. Clinical Practice Guidelines AHA 2011 (IFDVT only) Class I – B FOR compression Class I – IIa FOR CDT/PCDT –acute circulatory limb threat (I – C) –Symptom progression (IIa - B) –First-line therapy with AC (IIa -B) –Rapid clot extension (IIa - C) Class IIa – C FOR post-lysis stents (iliac vein) or PTA (CFV) ACCP 2012 Grade 2B FOR compression Grade 2C AGAINST use of CDT –no detail on clinical scenario Not graded – PCDT & UAT Not graded – PTA & stents Jaff MR et al. Circulation 2011; 123:1788-1830. Kearon C et al. Chest 2012; 141(2) Suppl:e419s-494s.

19. Evidence-Based – Infusion CDT CAVENT Study – NCT 00251771 StudyNCDT ArmControlP Value Major Bleeds2093.2%* (did not affect outcome) 0%Not presented PTS (Villalta)18941.1%55.6%0.047 VTE Over 2- Year F-U 18911% (no CDT- related PE) 18%NS No intracranial bleeds; one major bleed needed surgery and one required blood transfusion Enden T, et al. Lancet 2012; 379:31-38.

20. U.K. (NICE) Guidelines 2012 Consider CDT for symptomatic IFDVT if: –Symptom duration < 14 days –Good functional status –Life-expectancy of 1 year or more –Low risk of bleeding Evidence graded “moderate” to “very low” quality Recommendation prioritized for implementation, considered to have high impact on outcomes

21. DUTCH-CAVA Study NCT 00970619 (Netherlands) 180 patients with first- episode iliofemoral DVT Randomized to AC vs. AC + US-Assisted CDT Primary Outcome – PTS at 1 year (also – QOL, recurrent VTE, reflux)

22. ATTRACT Study NCT 00790335 (U.S.) Phase III, NIH-sponsored multicenter RCT evaluating if PCDT reduces 2-yr PTS in patients with proximal DVT June 28, 2009 Investigator Meeting: – –“The Surgeon General is passionate for the ATTRACT Trial to go forward” - RADM James Galloway, Asst U.S. Surg General August 14, 2012 – 330 patients enrolled

23. 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 2.0 – 3.0) PCDT ARM SUBJECTS Complete 5 days heparin therapy (LMWH or UFH) concurrent with performance of PCDT procedure, then bridge to warfarin (INR 2.0 – 3.0) 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)

24. Endorsed by U.S. Surgeon General Surgeon General’s Call to Action on DVT & PE highlights need for research on “strategies for dissolving or removing clots” “The Surgeon General is passionate for the ATTRACT Trial to go forward.” RADM James M. Galloway, Asst U.S. Surg General

26. ATTRACT Trial Leadership David Cohen, MD Anthony Comerota, MD Samuel Goldhaber, MD Heather Gornik, MD Jim Julian, PhD Michael Jaff, DO Susan Kahn, MD, MSc Clive Kearon, MD, PhD Stephen Kee, MD Andrei Kindzelski, MD, PhD Lawrence Lewis, MD Elizabeth Mahoney, ScD Timothy Murphy, MD Mahmood Razavi, MD Suresh Vedantham, MD Ronald Warren, PhD

27. ATTRACT – Numerical Realities Through August 31, 2012 - 337 patients enrolled 1 million U.S. DVT cases during accrual period Only ONE paradigm-testing NIH ATTRACT Study For the next 1-2 years, why not refer your patients to a landmark NIH-sponsored multicenter RCT?

28. CLINICAL APPROACH 1. Clinical Severity Group A – Urgent Lysis - Save Life, Limb, Organ –Acute limb-threatening circulatory compromise –Progressive IVC thrombosis => fatal PE or ARF Group B – AC Failed to Meet Initial Tx Goals –Anatomic progression cephalad despite AC –Clinical progression (pain & swelling) despite AC Group C – 1 st Line Lysis for PTS Prevention

29. CLINICAL APPROACH 2. Anatomic Severity Iliofemoral DVT is a high-risk condition that doubles the risk of recurrent DVT and PTS –Douketis JD et al. Am J Med 2001. –Kahn SR et al. Ann Intern Med 2008. –Enden T et al. Lancet 2012. PTS is infrequent with isolated calf DVT or asymptomatic DVT –Ginsberg JS et al. 2001

30. CLINICAL APPROACH 3. Expected Technical Success Acute DVT (symptom duration < 14 days) - best Subacute-Chronic DVT (symptoms > 14 days) –Femoropopliteal: will not achieve complete clot lysis –Iliac: doable, but likely to require iliac vein stents Acute-on-chronic DVT – it may be worth lysing the acute component (e.g. for patent iliac vein)

31. CLINICAL APPROACH 4. Expected Risk of Bleeding Lesions in critical locations (CNS, pericardium) Active bleeding, bleeding diathesis, low platelets Recent surgery/delivery/CPR/procedure GI bleeds, severe liver disease, advanced age With careful patient selection, CDT appears to pose 2-4% risk of major bleed (ICH - rare) –Enden T et al. Lancet 2012.

32. CLINICAL APPROACH 5. Co-Morbidities & Preferences Patients who are chronically non-ambulatory will experience little benefit from prevention of PTS. Patients with cardiopulmonary disease or acute illness may not be able to tolerate procedure Patients arrive at different conclusions regarding their own suitability for an aggressive strategy

33. Procedural Tips All procedural tips are provided by Dr. Vedantham alone. Some are incorporated into the protocol for the NIH-sponsored ATTRACT Trial, which he leads.

34. PROCEDURAL TIPS A. Venous Access Routinely utilize US-guidance for access Beware posteriorly crossing arteries IJ for chronic DVT, isolated iliac v. obstruction, or “limited-goal” treatment for high-risk patients “Good inflow” versus “poor inflow” situations

35. PROCEDURAL TIPS B. DOSING OF TPA (Off-Label) For infusion – 0.01 mg/kg/hr is reasonably safe – but avoid prolonged (> 24-30 hours) infusions For on-table use – maximum 25 mg in a session Overall treatment – keep under 50 mg (35 mg) Mini-boluses of 1-5 mg during F-U procedures

36. PROCEDURAL TIPS C. Concomitant Anticoagulation Can use either LMWH (bid dosing) or UFH UFH – ensure not supra-therapeutic –Know PTT and dose before starting –Puncture with patient fully anticoagulated –On-table: keep high-therapeutic (PTT 70-100) –Infusion: aim subtherapeutic (6-12 units/kg/hr) Individualize bleeding risk to dose properly!

37. PROCEDURAL TIPS D. Use of Rheolytic Thrombectomy AngioJet Solent Proxi (MEDRAD, Minneapolis, MN; Bayer) PowerPulse delivery – may use IVCF for selected patients –5-10 mg in 50-100 ml –30-minute dwell time Aspiration – guiding catheter Bradycardia – pt selection, pauses Met-hemoglobinuria - awareness

38. PROCEDURAL TIPS E. Use of Isolated Thrombolysis Trellis-8 Peripheral Infusion System (Covidien, Mansfield, MA) 4-8 mg per spin, 2 spins Dwell time, balloon maceration, no need to aspirate clot-TPA Single session most likely with good popliteal inflow

39. PROCEDURAL TIPS F. Use of Ultrasound-Lysis Concentrate TPA solution Does it add value for subacute clot? If value is added, some may prefer return to quick-procedure CDT model EKOS Corporation, Bothell, WA

40. PROCEDURAL TIPS G. Use of Stents (Off-Label) Consent process Comfort with use for iliac vein is important (stenosis & thrombus) Chronic – can extend into CFV-DFV-FV

41. CONCLUSION Evidence for DVT procedures WILL be demanded –When it is sensible to do so, and even when it is not PCDT procedures performed in modern U.S. practice for DVT have not been validated in RCT Drug-only CDT is the only therapy that can be defended as evidence-based, but the data and the treatment have limitations – support ATTRACT

42. ACKNOWLEDGEMENT Dr. Vedantham’s academic work is supported by: NHLBI grants U01-HL088476 and U01-HL088118 for the ATTRACT Trial (National Principal Investigator) NHLBI grant U01-HL112303 for the Washington University Translational Research Center in Thrombotic and Hemostatic Disorders (PI of Administrative Core) Talk content - sole responsibility of Dr. Vedantham