Venous Thromboembolism: BIG CLOTS - AC Forum

Suresh Vedantham, M.D.

Professor of Radiology & Surgery

Mallinckrodt Institute of Radiology

Washington University in St. Louis

Venous Thromboembolism:

BIG CLOTS

DISCLOSURES

NHLBI grants: U01-HL088476 (ATTRACT Trial),

U54-HL112321 (Translational Research Center),

U34-HL123831 (C-TRACT Planning Grant)

Research support to Washington University: BSN

Medical, Volcano, Cook, Therakos (nothing to me)

Off-label: Lytic drugs for VTE; stents for iliac vein

Venous Thromboembolism

GOALS OF CARE

ACUTE PHASE

Prevent fatal PE (or PE)

Prevent recurrent VTE

Prevent clot progression

Reduce initial symptoms

CHRONIC PHASE

Prevent recurrent VTE

Prevent PTS

Prevent Venous Ulcer

Prevent CTEPH

Acute Proximal 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

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.

Evidence-Based: Anticoagulation

AC prevents PE, fatal PE, clot progression

Poor INR control & recurrent DVT raise PTS risk– Prandoni P et al. Ann Intern Med 1996; 125:1-7.

– Van Dongen et al. J Throm Haemost 2005; 3:939-942.

Direct-acting oral anticoagulants

– Similarly effective, slightly safer than warfarin

– Convenient: less interactions, no need for monitoring

– But not evaluated for PTS prevention ability

IVC Filters

Rarely indicated in AC candidates

Permanent filters may

reduce PE, increase DVT,

no mortality benefit– Decousus et al. NEJM 1998.

– PREPIC Invest. Circulation 2005.

Retrievable filters do not

prevent recurrent PE or

death in high-risk patients

– Mismetti P et a. JAMA 2015.

Compression Does Not Prevent PTS

Event Active ECS Placebo ECS P Value

PTS (Ginsberg) 14.2% 12.7% NS

PTS (Villalta) 52.6% 52.3% NS

Mod-severe PTS 15.8% 16.5% NS

Leg ulcer 4.1% 4.2% NS

Recurrent VTE 8.1% 9.6% NS

Chg VEINES-QOL 5.8 points 5.9 points NS

Kahn SR; SOX Investigators. Lancet 2014.

PTS – A Consequence of Residual Clot

Despite use of anticoagulant drugs,

blood clots permanently damage the

valves (causing “reflux”) and block

venous blood flow (“obstruction”)

Reflux + obstruction => clinical PTS

Markel A et al. J Vasc Surg 1992.

Meissner MH et al. J Vasc Surg 1998.

Prandoni P et al. J Thromb Hemost 2005.

Catheter-Directed Thrombolysis

CAVENT Trial

CDT Probably Prevents PTSStudy N CDT Arm Control P Value

Major Bleeds 209 3.2% 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

Bleeds: no ICH-death, one surgery, one transfusion

BUT: small sample, Norway, limited device use

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

CAVENT: 5-Year Outcomes (n=176)Outcome CDT (n=87) Control (n=89) P Value

PTS (Any) 42.5% 70.8% < 0.0001

PTS (Moderate + Severe) 6.9% 15.7% Not stated

PTS (Severe) 4.6% 1.1% Not stated

Recurrent VTE 14.9% 23.6% NS

General QOL (EQ-5D) 0.78 0.79 NS

Venous QOL (VEINES-QOL) 50.5 49.6 NS

NNT = 4; Crossovers in 5 Controls & 1 CDT

Haig et al. Lancet 2016.

New Tools – Faster and Safer

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)

NO-PCDT 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)

ATTRACT STUDY SCHEMA

692 PATIENTS56 CLINICAL CENTERS

FULLY ENROLLED

Main Exclusions: Age > 75, cancer, symptoms > 14d, established PTS,

high bleeding risk

Operational separation of PI from study data

Comparable use of AC, anti-platelet therapy, filters

Operational plans for equal surveillance of patients in both arms

Central randomization stratified by site and

thrombus extent

Allocation concealed, explicit

blinding precautions

Systematic Efforts to

Minimize Bias

Study OutcomesOutcome PCDT

(n=336)

No-PCDT

(n=355)

P Value

Any PTS 46.7% 48.2% 0.56

Major Bleeding (10 days) 1.7% 0.3% 0.049

Any Bleeding (10 days) 4.5% 1.7% 0.034

Recurrent VTE 12.5% 8.5% 0.087

Generic QOL (SF-36 PCS) 11.8 10.06 0.37

No fatal or intracranial bleeds in either arm

PCDT Arm: 3/4 transfusions & 2 embolizations

PCDT = less effective in patients > 65 yrs (p = 0.038)

Villalta ≥5 Villalta ≥15Villalta ≥10VCSS ≥4 VCSS ≥8

RR 0.96

(p=0.56)

RR 0.84

(p=0.09)

RR 0.73

(p=0.03)

RR 0.56

(p=0.02)

RR 0.65

(p=0.06)

PCDT Reduces Early Symptoms & PTS Severity

50%

10%

0%

20%

30%

40%

Courtesy C. Kearon

PCDT reduced early swelling

and pain (p = 0.025), and mean

by-visit Villalta (p < 0.01) and

VCSS (p < 0.05) scores at 6-24

mo

Villalta ≥5 Villalta ≥15Villalta ≥10VCSS ≥4 VCSS ≥8

0.96

And We Probably Know Who to Target Iliofemoral versus Femoropopliteal

Courtesy C. Kearon

0.98

0.73

0.46 0.56

0.88

0.75

0.98

0.65

0.95

P=0.81

P=0.12

P=0.20

P=0.31P=0.43

50%

10%

0%

20%

30%

40%

FPDVT: PCDT is ineffective

IFDVT: moderate-severe PTS

is frequent + likely substantial

PCDT effect on its occurrence

PATIENT PRESENTS TO CLINIC

45 year-old woman with RLE DVT one year ago has severe daily pain and swelling that impair ambulation => job loss

Small anterior calf ulcer

US => small, echogenic, non-compressible right CFV, FV, popliteal vein

Stent Placement Reduced Ambulatory Venous

Pressure and PTS Severity

STUDY ENROLLMENTPatient with SIO-PTS meets eligibility criteria,

completes run-in period, and provides consent

ALL PATIENTSCompression, DVT-appropriate AC, local

preferences for “allowed” PTS treatments

RANDOMIZATION (1:1 Ratio)

CONTROL ARM SUBJECTSContinue conservative therapy with

adjustments at 2-month and 4-month follow-up visits if non-improving

ENDOVASCULAR ARM SUBJECTSIliac vein stent placement

Endovenous saphenous vein ablation Same conservative therapy as Control

FOLLOW-UP VISITS – ALL SUBJECTSScheduled: 2, 4, 6, 12, 18 months post-RAND

Unscheduled: as needed for symptoms & recurrence

OUTCOME ASSESSMENTSPrimary: Change in VEINES-QOL from 0 to 6 months

Secondary: Change VEINES-QOL, VCSS, VillaltaSecondary: Ulcer healing, safety events, costs

C-TRACT

STUDY

Multicenter, open-

label, assessor-

blind RCT (1:1)

Endorsed: AVF, SIR,

SVM, ACP, NATF

Pulmonary Embolism Risk StratificationJaff MR, et al. Circulation 2011

Massive PE = sustained hypotension (SBP < 90 mmHg

> 15 min or needing inotropic support); pulselessness; or

bradycardia (HR < 40 bpm with signs/sx of shock)

Submassive PE = RV dysfunction or myocardial necrosis

– ECHO or CT: RV/LV > 0.9 in apical 4-chamber view

– BNP > 90 pg/ml or pro-BNP > 500 pg/ml

– ECG – new RBBB, anteroseptal ST elevation or

depression, or anteroseptal T-wave inversion

– Troponin I > 0.4 ng/ml or troponin T > 0.1 ng/ml

Meta-Analysis – Systemic LysisChatterjee et al. JAMA 2014

Outcome Lysis (n=1061) Control (n=1054) OR

All-cause mortality 2.17% 3.89% 0.53

Recurrent PE 1.17% 3.05% 0.40

Major Bleeding 9.24% 3.42% 2.73

Intracranial Bleed 1.46% 0.19% 4.78

Thrombolysis => very small survival benefit

Persisted when limited to submassive PE

Increased bleeding driven by patients > 65 yrs

TOPCOAT Study

Double-blind, placebo-controlled RCT (n = 87)

– Submassive PE: TNK + heparin vs heparin alone

Lysis recipients more likely to have normal RV

function, exercise capacity, physical wellness,

better QOL (SF-36 PCS score) at 3 months

– Kline JA et al. J Thromb Haemost 2014.

Could CDT provide long-term functional benefit?

Catheter-Based PE Therapy

Meta-analysis of existing

data => CDT may provide

better safety than systemic

Deeply flawed “studies”

Open label, non-blinded

Only 6 prospective (n=94)

Publication bias certain

Kuo W et al. JVIR 2009.

ULTIMA & SEATTLE Studies

ULTIMA: RCT – US-CDT 10-20 mg TPA

over 15 hr vs heparin - submassive PE

< 14d, central, RV/LV > 10 (n = 50)

Reduced 24-hr end-diastolic RV/LV - no

major bleeds, recurrent PE, or deaths

– Kucher N, et al. Circulation 2014.

SEATTLE II – single-arm 150 patients –

efficacy, 11.4% major bleeds, no ICH

– Piazza G, et al. ACC Abstract 2014.

PE-TRACT Trial (Dr. Akhilesh Sista – NYU)

30-center RCT: acute submassive PE with central thrombus: CDT + AC versus AC alone (n=414)

Primary outcome: 6 minute walk distance (12 months); also, early outcomes, QOL, safety, costs

How can you make a stable patient BETTER?

SUMMARY: BIG DVT Anticoagulation: essential if not contraindicated

Compression: optional (mainly to control swelling)

IVC Filter: only if AC contraindicated

CDT/PCDT: only if acute limb threat or IFDVT with severe

symptoms after 5-7 days of AC, < 65 yrs, low bleed risk

Chronic severe PTS: consider iliac vein stent placement

SUMMARY: BIG PE Anticoagulation: essential if not contraindicated

IVC Filter: only if AC contraindicated

– Unclear if should be used for massive PE

Systemic Thrombolysis: massive PE

Catheter-Based Methods: massive PE with

contraindicated/failed systemic thrombolysis and

low bleed risk (submassive PE needs RCT)

Think Globally, Act Locally

Recognize VTE as a multifaceted disease process

Engage diverse expertise for patient care and research

Track local and national outcomes to improve quality