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Suresh Vedantham, M.D. Professor of Radiology & Surgery Mallinckrodt Institute of Radiology

Suresh Vedantham, M.D. Professor of Radiology & Surgery Mallinckrodt Institute of Radiology Washington University in St. Louis. Interventional Management of Deep Vein Thrombosis. DISCLOSURES. Research support for NIH-funded ATTRACT Trial National Heart Lung and Blood Institute (NIH)

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Suresh Vedantham, M.D. Professor of Radiology & Surgery Mallinckrodt Institute of Radiology

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  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 ThrombHaemost 2008.

  5. PTS Incidence (AC + Compression)Clot Extent Matters • Patients with iliofemoral DVT (common femoral and/or iliac vein) develop PTS 60% of the time

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

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

  8. Fibrin without Ultrasound 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 With Ultrasound

  9. Pharmacomechanical CDTCan Enable Single-Session Therapy AngioJet Solent Proxi (MEDRAD) Trellis-8 Catheter (Covidien)

  10. Arguments for CDT: 1991-2011 Anatomic Emotional

  11. 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 ThromHaemost 2005; 3:939-942. • Long-term LMWH may reduce PTS risk • Hull RD et al. Am J Med 2006; 119:1062-1072.

  12. 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. BMC CardiovascDis 2007; 7:21.

  13. 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 VascEndovascSurg 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. CathetCardiovascInterv 2010.

  14. Consensus & ControversySalvage 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?

  15. Clinical Practice Guidelines AHA 2011 (IFDVT only) 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 • Class I – B FOR compression • Class I – IIaFOR 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) Jaff MR et al. Circulation 2011; 123:1788-1830. Kearon C et al. Chest 2012; 141(2) Suppl:e419s-494s.

  16. Evidence-Based – Infusion CDTCAVENT Study – NCT 00251771 • No intracranial bleeds; one major bleed needed surgery and one required blood transfusion • Enden T, et al. Lancet 2012; 379:31-38.

  17. 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

  18. DUTCH-CAVA StudyNCT 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)

  19. ATTRACT StudyNCT 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

  20. 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)

  21. 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

  22. 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

  23. 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?

  24. CLINICAL APPROACH1. 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 – 1st Line Lysis for PTS Prevention

  25. CLINICAL APPROACH2. 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

  26. CLINICAL APPROACH3. 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)

  27. CLINICAL APPROACH4. 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.

  28. CLINICAL APPROACH5. 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

  29. 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.

  30. PROCEDURAL TIPSA. 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

  31. PROCEDURAL TIPSB. 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

  32. PROCEDURAL TIPSC. 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!

  33. PROCEDURAL TIPSD. Use of RheolyticThrombectomy • AngioJetSolentProxi (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

  34. PROCEDURAL TIPSE. 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

  35. PROCEDURAL TIPSF. 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

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

  37. 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

  38. 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

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