Suresh Vedantham, M.D.Suresh Vedantham, M.D.

Professor of Radiology & SurgeryProfessor of Radiology & Surgery

Mallinckrodt Institute of RadiologyMallinckrodt Institute of Radiology

Washington University in St. LouisWashington University in St. Louis

Interventional Management of Deep Vein Thrombosis

DISCLOSURESDISCLOSURES

Research support for NIH-funded ATTRACT TrialResearch support for NIH-funded ATTRACT Trial– National Heart Lung and Blood Institute (NIH)National Heart Lung and Blood Institute (NIH)– BSN MedicalBSN Medical– Covidien - Bacchus VascularCovidien - Bacchus Vascular– MEDRAD Interventional – Possis - BayerMEDRAD Interventional – Possis - Bayer– Roche-GenentechRoche-Genentech

Off-label: TPA for DVT; stents for iliac veinOff-label: TPA for DVT; stents for iliac vein

““Acute DVT” Acute DVT” Acute Acute PhasePhase of a Chronic Disease of a Chronic Disease

DVT causes severe DVT causes severe leg pain and swellingleg pain and swelling

With AC, time course With AC, time course for improvement variesfor improvement varies

Difficulty ambulating Difficulty ambulating and returning to full and returning to full activity impair QOLactivity impair QOL

Post-Thrombotic SyndromePost-Thrombotic Syndrome

Common - chronic leg pain, fatigue, Common - chronic leg pain, fatigue, heaviness, swelling, skin changesheaviness, swelling, skin changes

Less Common – venous ulcersLess Common – venous ulcers

PTS is frequent, lifelong, PTS is frequent, lifelong, impairs QOLimpairs QOL, , has no consistently effective treatmenthas no consistently effective treatment

Kahn SR et al. Ann Intern Med 2008.Kahn SR et al. Ann Intern Med 2008.

Kahn SR et al. J Thromb Haemost 2008.Kahn SR et al. J Thromb Haemost 2008.

PTS Incidence (AC + Compression)PTS Incidence (AC + Compression)Clot Extent MattersClot Extent Matters

Author/Year Journal N 2-Year PTS

Prandoni 1996 Ann Intern Med 355 23%

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 244 30%

Kahn 2008 Ann Intern Med 387 40% (60%)

Enden 2012 Lancet 99 56%

Patients with iliofemoral DVT (common femoral Patients with iliofemoral DVT (common femoral and/or iliac vein) develop PTS and/or iliac vein) develop PTS 60%60% of the time of the time

PTS - MechanismsPTS - Mechanisms

Acute inflammation => valvular Acute inflammation => valvular refluxrefluxResidual clot => venous Residual clot => venous obstructionobstructionLong-term – propensity to Long-term – propensity to inflammationinflammation

=> Ambulatory venous hypertension=> Ambulatory venous hypertension

Shull KC et al. Arch Surg 1979.Shull KC et al. Arch Surg 1979.Markel A et al. J Vasc Surg 1992.Markel A et al. J Vasc Surg 1992.Nicolaides AN et al. J Vasc Surg 1993.Nicolaides AN et al. J Vasc Surg 1993.Meissner MH et al. J Vasc Surg 1998.Meissner MH et al. J Vasc Surg 1998.

The Open Vein HypothesisThe Open Vein Hypothesis

Does Does immediate immediate clot removalclot removal speed speed

symptom relief, symptom relief, save valves, save valves,

preserve patency, preserve patency, and prevent PTS?and prevent PTS?

Ultrasound-Assisted ThrombolysisUltrasound-Assisted Thrombolysis

Ultrasound energy to Ultrasound energy to speed lysis, reduce or speed lysis, reduce or eliminate use of drugeliminate use of drug

Is it more efficient from Is it more efficient from operator’s perspective?operator’s perspective?

Does it better remove Does it better remove valve-adherent clot?valve-adherent clot?

Fibrin without Ultrasound

Fibrin With Ultrasound

Pharmacomechanical CDTPharmacomechanical CDTCan Enable Single-Session TherapyCan Enable Single-Session Therapy

Trellis-8 Catheter (Covidien)

AngioJet Solent Proxi (MEDRAD)

Arguments for CDT: 1991-2011Arguments for CDT: 1991-2011

AnatomicAnatomic EmotionalEmotional

Evidence-Based: AnticoagulationEvidence-Based: Anticoagulation

Recurrent ipsilateral DVT increases PTS riskRecurrent ipsilateral DVT increases PTS risk– Prandoni P et al. Ann Intern Med 1996; 125:1-7.Prandoni P et al. Ann Intern Med 1996; 125:1-7.– Brandjes DPM et al. Lancet 1997; 349:759-762.Brandjes DPM et al. Lancet 1997; 349:759-762.– Prandoni P et al. Ann Intern Med 2004; 141:249-56.Prandoni P et al. Ann Intern Med 2004; 141:249-56.

Non-therapeutic INR increases PTS riskNon-therapeutic INR increases PTS risk– Van Dongen et al. J Throm Haemost 2005; 3:939-942.Van Dongen et al. J Throm Haemost 2005; 3:939-942.

Long-term LMWH may reduce PTS riskLong-term LMWH may reduce PTS risk– Hull RD et al. Am J Med 2006; 119:1062-1072Hull RD et al. Am J Med 2006; 119:1062-1072..

Evidence-Based: CompressionEvidence-Based: Compression

Single-center, open-label RCTs show that use of Single-center, open-label RCTs show that use of 30-40 mmHg graduated elastic compression 30-40 mmHg graduated elastic compression stockings reduce 2-year PTS rate by about 50%stockings reduce 2-year PTS rate by about 50%– Assuming the garments are applied relatively earlyAssuming the garments are applied relatively early– Brandjes DPM et al. Lancet 1997; 349:759-762.Brandjes DPM et al. Lancet 1997; 349:759-762.– Prandoni P et al. Ann Intern Med 2004; 141:249-256.Prandoni P et al. Ann Intern Med 2004; 141:249-256.

SOX – multicenter, double-blind, placebo RCTSOX – multicenter, double-blind, placebo RCT– Kahn SR et al. Kahn SR et al. BMC Cardiovasc Dis 2007; 7:21.

Single-Center RCTsSingle-Center RCTs

A 35-patient RCT found streptokinase to provide A 35-patient RCT found streptokinase to provide better better 6-month6-month patency (72% vs 12%, p < 0.01) patency (72% vs 12%, p < 0.01) and less valvular reflux (11% vs 41%, p = 0.042)and less valvular reflux (11% vs 41%, p = 0.042)– Elsharawy M et al. Eur J Vasc Endovasc Surg 2002.Elsharawy M et al. Eur J Vasc Endovasc Surg 2002.

A 183-patient RCT found CDT-PCDT to reduce A 183-patient RCT found CDT-PCDT to reduce 6-month6-month PTS (3.4% vs 27.2%, p < 0.001) and PTS (3.4% vs 27.2%, p < 0.001) and recurrent VTE (2.3% versus 14.8%, p = 0.003)recurrent VTE (2.3% versus 14.8%, p = 0.003)– Sharifi M et al. Cathet Cardiovasc Interv 2010.Sharifi M et al. Cathet Cardiovasc Interv 2010.

Consensus & ControversyConsensus & ControversySalvage vs. First-Line TherapySalvage vs. First-Line Therapy

2008 Guidelines – weak (2B) in favor of CDT/PCDT2008 Guidelines – weak (2B) in favor of CDT/PCDT

2012 Chest Guidelines – weak (2C) against CDT2012 Chest Guidelines – weak (2C) against CDT

BUT: Evidence-based? Multidisciplinary consensus?BUT: Evidence-based? Multidisciplinary consensus?

Clinical Practice GuidelinesClinical Practice GuidelinesAHA 2011 (IFDVT only)AHA 2011 (IFDVT only)

Class I – B Class I – B FOR compressionFOR compression

Class I – IIa Class I – IIa FOR CDT/PCDTFOR CDT/PCDT– acute circulatory limb threat (acute circulatory limb threat (I – CI – C))– Symptom progression (Symptom progression (IIa - BIIa - B))– First-line therapy with AC (First-line therapy with AC (IIa -BIIa -B))– Rapid clot extension (Rapid clot extension (IIa - CIIa - C))

Class IIa – C Class IIa – C FOR post-lysis FOR post-lysis stents (iliac vein) or PTA (CFV)stents (iliac vein) or PTA (CFV)

ACCP 2012ACCP 2012

Grade 2B Grade 2B FOR compressionFOR compression

Grade 2C Grade 2C AGAINST use of CDTAGAINST use of CDT– no detail on clinical scenariono detail on clinical scenario

Not graded – PCDT & UATNot graded – PCDT & UAT

Not graded – PTA & stentsNot graded – PTA & stents

Jaff MR et al. Circulation 2011; 123:1788-1830.Jaff MR et al. Circulation 2011; 123:1788-1830.Kearon C et al. Chest 2012; 141(2) Suppl:e419s-494s.Kearon C et al. Chest 2012; 141(2) Suppl:e419s-494s.

Evidence-Based – Infusion CDTEvidence-Based – Infusion CDTCAVENT Study – NCT 00251771CAVENT Study – NCT 00251771

Study N CDT Arm Control P Value

Major Bleeds 209 3.2%* (did not affect outcome)

0% Not presented

PTS (Villalta) 189 41.1% 55.6% 0.047

VTE Over 2-Year F-U

189 11% (no CDT-related PE)

18% NS

No intracranial bleeds; one major bleed needed No intracranial bleeds; one major bleed needed surgery and one required blood transfusionsurgery and one required blood transfusion

Enden T, et al. Lancet 2012; 379:31-38.Enden T, et al. Lancet 2012; 379:31-38.

U.K. (NICE) Guidelines 2012U.K. (NICE) Guidelines 2012

Consider CDT for symptomatic IFDVT if:Consider CDT for symptomatic IFDVT if:– Symptom duration < 14 daysSymptom duration < 14 days– Good functional statusGood functional status– Life-expectancy of 1 year or moreLife-expectancy of 1 year or more– Low risk of bleedingLow risk of bleeding

Evidence graded “moderate” to “very low” qualityEvidence graded “moderate” to “very low” quality

Recommendation prioritized for implementation, Recommendation prioritized for implementation, considered to have high impact on outcomesconsidered to have high impact on outcomes

DUTCH-CAVA StudyDUTCH-CAVA StudyNCT 00970619 (Netherlands)NCT 00970619 (Netherlands)

180 patients with first-180 patients with first-episode iliofemoral DVTepisode iliofemoral DVT

Randomized to AC vs. Randomized to AC vs. AC + US-Assisted CDTAC + US-Assisted CDT

Primary Outcome – PTS Primary Outcome – PTS at 1 year (also – QOL, at 1 year (also – QOL, recurrent VTE, reflux)recurrent VTE, reflux)

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

STUDY ENROLLMENTPatient with proximal DVT meets eligibility

criteria and provides informed consent

PRE-RANDOMIZATION PROCEDURESInitiation of AC (LMWH or UFH) and completion

of baseline assessments

RANDOMIZATION (1:1 Ratio)

CONTROL ARM SUBJECTSComplete 5 days heparin therapy (LMWH

or UFH) and immediately bridge to warfarin (INR 2.0 – 3.0)

PCDT ARM SUBJECTSComplete 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 SUBJECTSLong-term (> 3 months) warfarin therapy and daily use of graduated elastic compression stockings (initiated 10 days

post-randomization)

FOLLOW-UP VISITS – ALL SUBJECTSEarly (10 days & 30 days post-randomization)

Late (6, 12, 18, & 24 months post-randomization)

Endorsed by U.S. Surgeon GeneralEndorsed 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

ATTRACT Trial LeadershipATTRACT Trial Leadership

David Cohen, MD David Cohen, MD

Anthony Comerota, MDAnthony Comerota, MD

Samuel Goldhaber, MDSamuel Goldhaber, MD

Heather Gornik, MDHeather Gornik, MD

Jim Julian, PhDJim Julian, PhD

Michael Jaff, DOMichael Jaff, DO

Susan Kahn, MD, MScSusan Kahn, MD, MSc

Clive Kearon, MD, PhDClive Kearon, MD, PhD

Stephen Kee, MDStephen Kee, MD

Andrei Kindzelski, MD, PhDAndrei Kindzelski, MD, PhD

Lawrence Lewis, MDLawrence Lewis, MD

Elizabeth Mahoney, ScDElizabeth Mahoney, ScD

Timothy Murphy, MDTimothy Murphy, MD

Mahmood Razavi, MDMahmood Razavi, MD

Suresh Vedantham, MDSuresh Vedantham, MD

Ronald Warren, PhDRonald Warren, PhD

ATTRACT – Numerical RealitiesATTRACT – Numerical Realities

Through August 31, 2012 - Through August 31, 2012 - 337337 patients enrolled patients enrolled

1 million 1 million U.S. DVT cases during accrual periodU.S. DVT cases during accrual period

Only Only ONEONE paradigm-testing NIH ATTRACT Study paradigm-testing NIH ATTRACT Study

For the next 1-2 years, why not refer your patients For the next 1-2 years, why not refer your patients to a landmark NIH-sponsored multicenter RCT?to a landmark NIH-sponsored multicenter RCT?

CLINICAL APPROACHCLINICAL APPROACH1. Clinical Severity1. Clinical Severity

Group A – Urgent Lysis - Group A – Urgent Lysis - Save Life, Limb, OrganSave Life, Limb, Organ– Acute limb-threatening circulatory compromiseAcute limb-threatening circulatory compromise– Progressive IVC thrombosis => fatal PE or ARFProgressive IVC thrombosis => fatal PE or ARF

Group B – Group B – AC Failed to Meet Initial Tx GoalsAC Failed to Meet Initial Tx Goals– AnatomicAnatomic progression cephalad despite AC progression cephalad despite AC

– ClinicalClinical progression (pain & swelling) despite AC progression (pain & swelling) despite AC

Group C – Group C – 11stst Line Lysis for PTS Prevention Line Lysis for PTS Prevention

CLINICAL APPROACHCLINICAL APPROACH2. Anatomic Severity2. Anatomic Severity

Iliofemoral DVT Iliofemoral DVT is a high-risk is a high-risk condition that doubles the risk condition that doubles the risk of recurrent DVT and PTSof recurrent DVT and PTS– Douketis JD et al. Am J Med 2001.Douketis JD et al. Am J Med 2001.– Kahn SR et al. Ann Intern Med 2008.Kahn SR et al. Ann Intern Med 2008.– Enden T et al. Lancet 2012.Enden T et al. Lancet 2012.

PTS is infrequent with PTS is infrequent with isolated isolated calf DVTcalf DVT or or asymptomatic DVTasymptomatic DVT– Ginsberg JS et al. 2001Ginsberg JS et al. 2001

CLINICAL APPROACHCLINICAL APPROACH3. Expected Technical Success3. Expected Technical Success

AcuteAcute DVT (symptom duration DVT (symptom duration << 14 days 14 days) - ) - bestbest

Subacute-ChronicSubacute-Chronic DVT (symptoms > 14 days) DVT (symptoms > 14 days)– Femoropopliteal: will not achieve complete clot lysisFemoropopliteal: will not achieve complete clot lysis– Iliac: doable, but likely to require iliac vein stentsIliac: doable, but likely to require iliac vein stents

Acute-on-chronicAcute-on-chronic DVT – it may be worth lysing DVT – it may be worth lysing the acute component (e.g. for patent iliac vein)the acute component (e.g. for patent iliac vein)

CLINICAL APPROACHCLINICAL APPROACH4. Expected Risk of Bleeding4. Expected Risk of Bleeding

Lesions in critical locations (CNS, pericardium)Lesions in critical locations (CNS, pericardium)

Active bleeding, bleeding diathesis, low plateletsActive bleeding, bleeding diathesis, low platelets

Recent surgery/delivery/CPR/procedureRecent surgery/delivery/CPR/procedure

GI bleeds, severe liver disease, advanced ageGI bleeds, severe liver disease, advanced age

With careful patient selection, CDT appears to With careful patient selection, CDT appears to pose pose 2-4%2-4% risk of major bleed (ICH - rare) risk of major bleed (ICH - rare)

– Enden T et al. Lancet 2012.Enden T et al. Lancet 2012.

CLINICAL APPROACHCLINICAL APPROACH5. Co-Morbidities & Preferences5. Co-Morbidities & Preferences

Patients who are chronically non-ambulatory will Patients who are chronically non-ambulatory will experience little benefit from prevention of PTS.experience little benefit from prevention of PTS.

Patients with cardiopulmonary disease or acute Patients with cardiopulmonary disease or acute illness may not be able to tolerate procedureillness may not be able to tolerate procedure

Patients arrive at different conclusions regarding Patients arrive at different conclusions regarding their own suitability for an aggressive strategytheir own suitability for an aggressive strategy

Procedural TipsProcedural Tips

All procedural tips are provided by All procedural tips are provided by Dr. Vedantham alone. Some are Dr. Vedantham alone. Some are incorporated into the protocol for incorporated into the protocol for

the NIH-sponsored ATTRACT the NIH-sponsored ATTRACT Trial, which he leads.Trial, which he leads.

PROCEDURAL TIPSPROCEDURAL TIPSA. Venous AccessA. Venous Access

Routinely utilize US-guidance for accessRoutinely utilize US-guidance for access

Beware posteriorly crossing arteriesBeware posteriorly crossing arteries

IJ for chronic DVT, isolated iliac v. obstruction, IJ for chronic DVT, isolated iliac v. obstruction, or “limited-goal” treatment for high-risk patientsor “limited-goal” treatment for high-risk patients

““Good inflow” versus “poor inflow” situationsGood inflow” versus “poor inflow” situations

PROCEDURAL TIPSPROCEDURAL TIPSB. DOSING OF TPA (Off-Label)B. DOSING OF TPA (Off-Label)For infusion – For infusion – 0.01 mg/kg/hr 0.01 mg/kg/hr is reasonably safe is reasonably safe – but avoid prolonged (> 24-30 hours) infusions– but avoid prolonged (> 24-30 hours) infusions

For on-table use – maximum 25 mg in a sessionFor on-table use – maximum 25 mg in a session

Overall treatment – keep under 50 mg (35 mg)Overall treatment – keep under 50 mg (35 mg)

Mini-boluses of 1-5 mg during F-U proceduresMini-boluses of 1-5 mg during F-U procedures

PROCEDURAL TIPSPROCEDURAL TIPSC. Concomitant AnticoagulationC. Concomitant Anticoagulation

Can use either LMWH (bid dosing) or UFHCan use either LMWH (bid dosing) or UFH

UFH – ensure not supra-therapeuticUFH – ensure not supra-therapeutic– Know PTT and dose before startingKnow PTT and dose before starting– Puncture with patient fully anticoagulatedPuncture with patient fully anticoagulated– On-table: keep high-therapeutic (PTT 70-100)On-table: keep high-therapeutic (PTT 70-100)– Infusion: aim subtherapeutic (6-12 units/kg/hr)Infusion: aim subtherapeutic (6-12 units/kg/hr)

Individualize bleeding risk to dose properly!Individualize bleeding risk to dose properly!

PROCEDURAL TIPSPROCEDURAL TIPSD. Use of Rheolytic ThrombectomyD. Use of Rheolytic Thrombectomy

AngioJet Solent Proxi (MEDRAD, AngioJet Solent Proxi (MEDRAD, Minneapolis, MN; Bayer)Minneapolis, MN; Bayer)

PowerPulse delivery – may use PowerPulse delivery – may use IVCF for selected patientsIVCF for selected patients– 5-10 mg in 50-100 ml5-10 mg in 50-100 ml– 30-minute dwell time 30-minute dwell time

Aspiration – guiding catheterAspiration – guiding catheter

Bradycardia – pt selection, pausesBradycardia – pt selection, pauses

Met-hemoglobinuria - awarenessMet-hemoglobinuria - awareness

PROCEDURAL TIPSPROCEDURAL TIPSE. Use of Isolated ThrombolysisE. Use of Isolated Thrombolysis

Trellis-8 Peripheral Infusion Trellis-8 Peripheral Infusion System (Covidien, Mansfield, MA)System (Covidien, Mansfield, MA)

4-8 mg per spin, 2 spins4-8 mg per spin, 2 spins

Dwell time, balloon maceration, no Dwell time, balloon maceration, no need to aspirate clot-TPAneed to aspirate clot-TPA

Single session most likely with Single session most likely with good popliteal inflowgood popliteal inflow

PROCEDURAL TIPSPROCEDURAL TIPSF. Use of Ultrasound-LysisF. Use of Ultrasound-Lysis

Concentrate TPA solutionConcentrate TPA solution

Does it add value for subacute clot? Does it add value for subacute clot?

If value is added, some may prefer If value is added, some may prefer return to quick-procedure CDT modelreturn to quick-procedure CDT model

EKOS Corporation, Bothell, WAEKOS Corporation, Bothell, WA

PROCEDURAL TIPSPROCEDURAL TIPSG. Use of Stents (Off-Label)G. Use of Stents (Off-Label)

Consent processConsent process

Comfort with use for iliac vein is Comfort with use for iliac vein is important (stenosis & thrombus)important (stenosis & thrombus)

Chronic – can extend into CFV-DFV-FV Chronic – can extend into CFV-DFV-FV

CONCLUSIONCONCLUSION

Evidence for DVT procedures Evidence for DVT procedures WILLWILL be demanded be demanded– When it is sensible to do so, and even when it is notWhen it is sensible to do so, and even when it is not

PCDT procedures performed in modern U.S. PCDT procedures performed in modern U.S. practice for DVT have not been validated in RCT practice for DVT have not been validated in RCT

Drug-only CDT is the only therapy that can be Drug-only CDT is the only therapy that can be defended as evidence-based, but the data and the defended as evidence-based, but the data and the treatment have limitations – treatment have limitations – support ATTRACTsupport ATTRACT

ACKNOWLEDGEMENTACKNOWLEDGEMENT

Dr. Vedantham’s academic work is supported by:Dr. Vedantham’s academic work is supported by:

NHLBI grants U01-HL088476 and U01-HL088118 for the NHLBI grants U01-HL088476 and U01-HL088118 for the ATTRACT TrialATTRACT Trial (National Principal Investigator) (National Principal Investigator)

NHLBI grant U01-HL112303 for the NHLBI grant U01-HL112303 for the Washington Washington University Translational Research Center in Thrombotic University Translational Research Center in Thrombotic and Hemostatic Disordersand Hemostatic Disorders (PI of Administrative Core) (PI of Administrative Core)

Talk content - sole responsibility of Dr. VedanthamTalk content - sole responsibility of Dr. Vedantham