Proximal versus Calf Vein

Thrombosis: Differences in

Management

Marc A. Passman, M.D.

Associate Professor of Surgery

University of Alabama at Birmingham

Disclosure

Marc Passman, M.D.

I have no financial relationship(s) to disclose.

Learning Objectives

• Review currently available anticoagulation options and role in VTE treatment.

• Implement current evidence based guideline recommendations for VTE treatment

• Understand difference between proximal and calf DVT and controversies in treatment options.

Acute VTE Treatment Modalities

• Untreated DVT PE approximately 50% of patients– Death in 20%

• Initial Treatment = ANTICOAGULATION

• Anticoagulation reduces risk of PE to 1-2% in adequately dosed patients

5

Acute VTETreatment Modalities

The mainstay of therapy

• Full-dose anticoagulation

• Compression

Optional interventions

• Thrombolytic therapy (catheter-directed or

systemic)

• Thrombectomy (percutaneous or surgical)

• Angioplasty and stenting

• Inferior vena cava interruption

6

Treatment of VTE

Current Anticoagulants• Glycosaminoglycans (act mostly by

stimulating AT III)

– Unfractionated heparin (UFH)

– Low-molecular–weight heparin (LMWH)

– Fondaparinux (pentasaccharide)

• Synthetic anticoagulants (for patients

with heparin-induced thrombocytopenia)

– Direct (ie, ATIII-independent) antithrombins

(argatroban, lepirudin, bivalirudin)

• Vitamin K antagonists

– Warfarin

Glycosaminoglycans

UFH LMWH Fondaparinux

Source Porcine/bovine Altered UFH Synthetic

Mean no. of 36 13 5

saccharides

Action ATIII, IIa>Xa ATIII, Xa>IIa ATIII, Xa

Plasma protein binding +++ + +

Bioavailability Variable 90% 100%

Half-life, h Variable (SQ) ~6 (SQ) ~17 (SQ)

<1-3 (IV)

PF4 binding ++ ++ ++

GAG/PF4 antibodies ++ ++ ++

HIT 1%-5% 0.3%-0.8% Almost never

Effect of renal dysfunction ++ ++ ++

Monitoring PTT Anti-Xa Anti-Xa

Protamine as antidote ++ + –

Pregnancy category C B B

Warfarin

Advantages:

Oral

Effective

Antidotes exist(vitamin K, fresh frozen plasma, “4-factor” concentrates)

Long half-life

• Disadvantages:

Long half-life

Not immediately active

Very low therapeutic index

Very significant drug / dietary interactions

Very significant effect of hepatobiliary and gastrointestinal function

Requires close monitoring

Protein C / S deficiency - paradoxically hypercoagulable

Vitamin K IV, FFP, and “4-factor” concentrates have risks

Pregnancy category X (“warfarin embryopathy,” midface hypoplasia and skeletal defects, especially weeks 6-9); fetal hemorrhaging (3rd trimester)

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Direct Thrombin Inhibitors

Argatroban Lepirudin Bivalirudin

Standard loading dose None 0.2 mg/kga 0.75 mg/kg

Standard infusion dose 2 µg/kg/min 0.1 mg/kg/h 1.75 mg/kg/h

How monitored PTTb PTT PTT

Target PTT range 1.5-3.0 x 1.5-2.5 x 1.5-2.5 x

Antidote None None None

Pregnancy category B B B

Half-life 45 min 75 min 25 min

Effect of renal dysfunction – ++++a ++a

Effect of liver dysfunction ++a – –

Antibodies No Occasionalb Rare

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The New Anticoagulants

New Anticoagulants

Rivaroxaban: oral anti-Xa

Apixaban: oral anti-Xa

Dabigatran: oral antithrombin

Principal areas of study

VTE prophylaxis

Treatment of acute VTE and extended prophylaxis

Stroke prevention in chronic atrial fibrillation

Acute coronary syndrome

DabigatranFDA Approval

FDA NEWS RELEASE

• For Immediate Release: Oct. 19, 2010

Consumer Inquiries: 888-INFO-FDA

FDA approves Pradaxa to prevent stroke in

people with atrial fibrillation

– The U.S. Food and Drug Administration today

approved Pradaxa capsules (dabigatran etexilate)

for the prevention of stroke and blood clots in

patients with abnormal heart rhythm (atrial

fibrillation).

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Acute DVT/PE: Initial

Anticoagulant Therapy

Short-term treatment with SC LMWH, IV UFH, or SC fondaparinux

(Grade 1A)

– LMWH SC once or twice daily over UFH as an outpatient if possible

(Grade 1C) and as an inpatient if necessary (Grade 1A), unless renal

failure (Grade 2C)

– IV UFH: continuous infusion with aPTT monitoring (Grade 1C)

If clinical suspicion of DVT is high, treatment should be initiated

while awaiting results of diagnostic tests (Grade 1C)

Treat for at least 5 d with LMWH, UFH, or fondaparinux until the

INR ≥2.0 for 24 h (Grade 1C)

Start warfarin on first treatment day together with LMWH, UFH, or

fondaparinux (Grade 1A)

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Acute DVT / PE: Duration & Intensity

For transient, reversible risk factor, anticoagulation for at least 3 months (Grade 1A), then evaluate risk-benefit equation for longer treatment (Grade 1C)

For an unprovoked proximal DVT or PE, long-term anticoagulation (Grade 1A)

For a second episode of VTE, long-term anticoagulation (Grade 1A)

For an unprovoked distal DVT, anticoagulation for at least 3 months (Grade 2B)

Warfarin INR target 2.0-3.0, not 3.0-4.0 (both Grade 1A)

For cancer-related VTE, anticoagulation with a LMWH (rather than warfarin) for 3-6 months (Grade 1A), then reassess

Additional factors that may prompt longer

treatment

Residual significant venous obstruction

Hypercoagulable state(s)

Ongoing estrogenic drugs, thalidomide or lenalidomide

Immobile status

Significantly elevated or rising D-dimers when

anticoagulation is stopped

Patient preference

Acute DVT / PE: Duration & Intensity

Goals of these procedures

• To reduce acute symptoms

• To reduce risk of postthrombotic syndrome

Eligibility

• Extensive femoral or iliofemoral DVT

• Duration <14 days

• Good performance status

• Low bleeding risk (for thrombolytic therapy)

• Life expectancy >1 year

Acute DVT / PE: Lysis, Thrombectomy, Stents

Acute DVT / PE:

IVC Interruption

Routine use of an IVC filter as an adjunct to anticoagulation is not advised (Grade 1A)

For proximal DVT, IVC filter indicated if a bleeding risk precludes use of anticoagulation (Grade 1C)

If an IVC filter is placed, the bleeding risk subsides, and anticoagulation is no longer precluded, then anticoagulation is advisable (Grade 1C)

Calf Vein DVT – Evidence?

• Definition?– Infrapopliteal

– Intramuscular

– Plantar

• Incidence?– Asymptomatic

12%-40%

– Symptomatic 8-49%

• PE?– 0-6.3%

• Propagation?– 4%-15%

• Postthrombotic Syndrome– 8% - 57% C2-C3

– 3%- 5% C4 – C6

Calf Vein DVT – Evidence?

• Definition?– Nicos

• Incidence?– Nicos

• PE?– Nicos

– Passman

• Propagation– Nicos

• Postthrombotic Syndrome– Nicos

– Passman

Calf Vein DVTEvidence Based Outcomes

Study DVT

Location

N Treatment F/U DVT

Recurrence

PE

Galanaud et al. Thromb Haemost, 2009

Infrapopliteal 787 81% oral

anticoagulation

3% None

3 months 1.0% 1.1%

Schwartz et al. J

Vasc Surg 2010

Intramuscular 109 Group 1: LMWH 10

days + compression

Group 2: compression

3 months Group 1: 3.7%

Group 2: 3.8%

Group 1: 0%

Group 1: 0%

Baglin et al. J Thormb Haemost 2010

Distal DVT 171 Heparin 5-10 days then

oral anticoagulation 3

months

5 years 6.4% 1.2%

Gillet et al. J Vasc Surg 2007

Intramuscular 131 Oral anticoagulation 1-

3 months +

compression

3 years 18.8% 4.5%

Pinede et al. Circulation 2001

Infrapopliteal 197 Group 1: LMWH or

UFH 12 weeks

Group 2: 6 weeks

LMWH or UFH

15 months Group 1: 2.3%

Group 2: 2.0%

Group 1: 1.1%

Group 2: 0%

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Calf Vein DVT Duration & Intensity

For transient, reversible risk factor, anticoagulation for at least 3 months (Grade 1A), then evaluate risk-benefit equation for longer treatment (Grade 1C)

For an unprovoked proximal DVT or PE, long-term anticoagulation (Grade 1A)

For a second episode of VTE, long-term anticoagulation (Grade 1A)

For an unprovoked distal DVT, anticoagulation for at least 3 months (Grade 2B)

Warfarin INR target 2.0-3.0, not 3.0-4.0 (both Grade 1A)

For cancer-related VTE, anticoagulation with a LMWH (rather than warfarin) for 3-6 months (Grade 1A), then reassess

Calf Vein DVT Treatment Algorithm

Calf DVT

Infrapopliteal

Unprovoked

Anticoagulation 12 weeks – 3 months then re-evaluate

- Leg sxs

- Respiratory sxs

- PE

Anticoagulation 3 months then re-

evaluate

- Propagation

- Recurrence

Anticoagulation 3 months then re-

evaluate

- Asymptomatic

- Transient, Reversible Risk

Factor

Bleeding Risk Low:

consider anticoagulation vs

surveillance

Bleeding Risk High:

Surveillance

Intramuscular

Surveillance

Proximal vs Calf DVTConclusion

• Iliofemoral DVT:

– anticoagulation

– consider catheter clot removal options

– compression

• Femoral – Popliteal DVT:

– anticoagulation• transient reversible risk

factor: – 3 months then re-

evaluate

• unprovoked or recurrent: – long-term

– compression

• Calf DVT:

– more evidence needed

– anticoagulation• unprovoked:

– 12 weeks to 3 months

• PE, leg symptoms, recurrence or propagation:

– 3 months then re-evaluate

– surveillance• transient reversible risk

factor

• asymptomatic

• intramuscular

– compression