Innovative DVT Therapy in 2016: Merely the End of the Beginning Suresh Vedantham, M.D. Professor of Radiology & Surgery Mallinckrodt Institute of Radiology Washington University in St. Louis

DISCLOSURES NIH-NHLBI: ATTRACT Study (U01-HL088476), Translational Research Center (U54-HL112321), C-TRACT Study Planning Grant (U34-HL123831) Research Support to Washington University BSN Medical, Volcano, Cook, Therakos Off-label: TPA for DVT; stents for iliac vein

Anticoagulation prevents fatal PE, recurrent VTE, and clot extension Traditional Approach Thrombosis is a “Field Condition” It’s the BIOLOGY Low Priority: By reducing recurrence, AC reduces risk of PTS HIGH PRIORITY Anticoagulation prevents fatal PE, recurrent VTE, and clot extension Compression reduces leg symptoms & prevents PTS

Health depends on “Open Vein” It’s the ANATOMY & PHYSIOLOGY Alternative Approach Health depends on “Open Vein” It’s the ANATOMY & PHYSIOLOGY AC therapy is necessary but not sufficient Clot extent and location matter – when large veins are obstructed or refluxing, patient will develop life-limiting symptoms and signs Compression is necessary but not sufficient

December 16, 2014 FULLY ENROLLED 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) FIGURE 1 – ATTRACT STUDY SCHEMA December 16, 2014 FULLY ENROLLED

Transforming Care Will Demand More

Trend: Precision Medicine Linkage with BIG DATA Genomic Biomarkers OUTCOMES of trials and patient care Imaging Biomarkers GOAL = TARGET Care to Potential for Benefit

TREND: Get More for Less $$$ Risky, Inconvenient, Unproven, COSTLY Endovenous Ablation for Saphenous Reflux Moving target – requirement for compression Gonadal Vein Embolization & Venous Stenting Reimbursement challenged due to lack of evidence CDT => risky, increases hospital costs by $58,000 Bashir R et al. JAMA 2014. If we don’t get actively engaged, others will decide

WE Must Re-Define Quality Venous Care 1. Avoidance of fatal PE and symptomatic PE 2. Avoidance of recurrent VTE (PE and DVT) 3. Avoidance of treatment-related bleeding 4. Avoidance of limb amputation (rare) 5. Avoidance of re-hospitalization (30 days) 6. Avoidance of Post-Thrombotic Syndrome 7. Avoidance of Venous Ulcer 8. Avoidance of CTPH and Post-PE Syndrome

PTS Must Be Required Study Outcome 2008: VETO Study shows that PTS is the leading determinant of a DVT patient’s 2-year HR-QOL Kahn SR et al. Ann Intern Med 2008. Kahn SR et al. J Thromb Haemost 2008. 2016: 4 New Oral Anticoagulants FDA approved Non-inferior to warfarin for preventing recurrent DVT More convenient and possibly safer than warfarin ZERO data on NOAC effect upon PTS prevention

We Must Simplify Early Referral NOACs have accelerated outpatient management ER discharge, no need for LMWH injection teaching Physician impetus can become a barrier to referral Technically possible to leverage EMR systems Need buy-in from ER physicians and health system Endovascular provider group must be willing to work closely with medical physicians on proper targeting Know ACCP guidelines, re-define patient flow

Credibility: Avoid Over-Treatment

Care Must Be Patient-Centered Better Communication resources to help convey balanced benefits and risks Better Care close monitoring of patients receiving PCDT excellent follow-up to ensure good AC therapy identify recurrences and PTS progression early Better Innovation Find ways to dissolve clot that don’t cause bleeds Explore non-invasive adjuncts (e.g. “venous rehab”)

Severe Iliac-Obstructive PTS PTS: chronic leg aching, fatigue, heaviness, swelling, (skin changes) Severe PTS: 5-10% of proximal DVT, major impact on daily life and QOL Thrombosis of iliac or CFV in 20-40% with proximal DVT => chronic phase Kahn SR et al. Ann Intern Med 2008. Kahn SR et al. J Thromb Haemost 2008. Kahn SR et al. Circulation 2014.

Clinical Observations & Feasibility

Patency & Symptom Relief

RANDOMIZATION (1:1 Ratio) FOLLOW-UP VISITS – ALL SUBJECTS C-TRACT STUDY STUDY ENROLLMENT Patient with SIO-PTS meets eligibility criteria, completes run-in period, and provides consent ALL PATIENTS Compression, DVT-appropriate AC, local preferences for “allowed” PTS treatments RANDOMIZATION (1:1 Ratio) CONTROL ARM SUBJECTS Continue conservative therapy with adjustments at 2-month and 4-month follow-up visits if non-improving ENDOVASCULAR ARM SUBJECTS Iliac vein stent placement Endovenous saphenous vein ablation Same conservative therapy as Control FOLLOW-UP VISITS – ALL SUBJECTS Scheduled: 2, 4, 6, 12, 18 months post-RAND Unscheduled: as needed for symptoms & recurrence OUTCOME ASSESSMENTS Primary: Change in VEINES-QOL from 0 to 6 months Secondary: Change VEINES-QOL, VCSS, Villalta Secondary: Ulcer healing, safety events, costs Multicenter, open-label, assessor-blind RCT (1:1) Endorsed: AVF, SIR, SVM, ACP, NATF

C-TRACT – Site Selection Best Chance for Study Success Strong medical, endovascular, and ulcer care expertise - PTS ATTRACT best-performing sites (accrual, data, responsiveness) Access to large volume of PTS patients (clinic and outreach) Endorsements: ACP, AVF, NATF, SIRF, SVM

New Era Collaboration Around DVT 2011 AHA Guidelines include far broader spectrum of DVT researchers and expertise Jaff M et al. Circulation 2011. Stronger collaborative track record: ACP, AVF, SIR, SVM Think globally, act locally

The End of the Beginning Tremendous opportunity to benefit public health will depend upon energy and practice-level collaboration