VTE & Duration of Anticoagulation

Disclosure Mark Meissner, M.D.

I have no financial relationship(s) to disclose.

Mark H. Meissner, MD Professor of Surgery

University of Washington School of Medicine

Seattle, WA

VTE & Duration of Anticoagulation

DVT – Duration of Treatment ACCP Guidelines, Chest 2008

• Duration of anticoagulation guided by randomized trials

• RCT endpoints

• Recurrent VTE

• Bleeding

• 2008 recommendations

• Reversible factors – VKA for 3 months (1A)

• Unprovoked DVT

First episode – VKA for 3 months (1A) with re-evaluation for long-

term treatment (1C)

Second episode – Long-term treatment (1A)

Isolated calf thrombosis – VKA for 3 months (2B)

• Cancer – LMWH for 3 – 6 months (1A) , subsequent

LMWH or VKA indefinitely or until cancer resolved (1C)

But Are The Guidelines Always Helpful?

What does “assess for long-term” anticoagulation

REALLY mean?

Do You Test For Thrombophilia?

Undefined - 28%

Factor V - 20%

Factor VIII - 16%

Hyperhomocysteinemia

10%

APLA - 10%

Prothrombin 20210A

6%

Protein C - 5%

Protein S - 3%

AT III - 1%

Disfibrinogenemia - 1%

Risk & Incidence of a First DVT Bauer KA, Ann Intern Med 2001

Variable Relative Risk Annual Incidence

Normal 1 0.008

Hyperhomocysteinemia 2.5 0.02

Homozygous MTHFR 1 0.008

Prothrombin G20210A 2.8 0.02

Oral Contraceptive Use 4 0.03

Heterozygous FV Leiden 3 - 7 0.06

Homozygous FV Leiden 80 0.5 - 1

Factor VIII > 150% 4.8 0.04

AT, Protein C Deficiency 7.3 – 15

Protein S Deficiency 2

Blood Group A 1.9 – 3.2

Recurrent Idiopathic VTE Kearon et al, New Engl J Med 1999

Recurrent VTE (p < 0.001)

Warfarin group - 1.3% / patient-year

Placebo - 27.4% / patient-year

Defect Recurrence

(n = 17)

No Recurrence

(n = 66)

p

V Leiden 19% 29% ns

G20210A 6% 3% ns

APL Antibody 25% 3% 0.03

Warfarin X 3 mo Warfarin X 24 mo (n = 79)

Placebo X 24 mo (n = 83)

History a better predictor than genetic tests

Thrombophilia and Recurrent VTE Simpson EL, Health Technology Assessment 2009

Thrombophilia Incidence in VTE

(%)

Recurrence

(RR)

Change in

Management

FVL Heterozygous 10 – 50% 1.0 No

PTG20210A Heterozygous 5 – 18% 1.48 No

FVL / 20210A Heterozygous - 5.4 Yes

Antiphospholipid Antibodies 5.4% 6.8 Yes

Hyperhomocysteinemia 5.7 - 35% 2.7 Yes

Antithrombin 0.5 – 3% Yes

Protein C Deficiency 3 – 5% 1.44 No

Protein S Deficiency 1 – 5% 1.44 No

Most common defects not associated with significant recurrence

Attributable risk – 9% (1 in 10 recurrent VTE events)

Absence of defect ≠ Absence of thrombophilia

The Thrombophilic Phenotype

Venous thromboembolism Onset at young age (< age 50) Recurrent thrombotic events Family history of VTE DVT at unusual anatomic sites Unprovoked idiopathic DVT

Recurrent 2nd and 3rd trimester pregnancy loss Complications of pregnancy

Preeclampsia Abruptio placenta Intrauterine growth retardation

?? Aseptic necrosis of femoral head

Is Ultrasound Useful? Prandoni et al, Ann Intern Med 2009

• Ultrasound at 3, 9, 15, and 21 months

• Compression of common femoral & popliteal veins

• Recanalization – Single diameter < 2mm or serial diameters < 3mm

• Recurrent VTE (33 mo) in 17.8% (Fixed AC) versus 12.3% (Flexible AC)

• Secondary DVT - HR 0.81 (95% CI 0.32 – 2.06)

• Idiopathic DVT – HR 0.61 (95% CI 0.36 – 1.02)

• No significant difference in major bleeding

• 538 patients randomized

• Fixed duration AC

Secondary DVT – 3 mo

Idiopathic DVT – 6 mo

• Flexible duration AC

Secondary – Up to 12 mo

Idiopathic – Up to 24 months

What Did These Trials Measure?

Author Criteria for Recanalization

Prandoni 2009 Single D2 < 2 mm, Serial D2 < 3 mm

Siragusa 2008 D2 < 40% D1

THROMBUS

THROMBUS

THROMBUS

THROMBUS

UNCOMPRESSED

PROBE COMPRESSION

D1

D2

Point measurements in common femoral & popliteal veins

Residual Thrombus No Residual Thrombus

Residual Venous Obstruction (RVO) & D-Dimer Cosmi et al; Thromb Haemost 2005

• 400 patient with first idiopathic DVT

• 6 months anticoagulation recommended

• Compression U/S at AC withdrawal

• D-Dimer (nl < 500) 30 days after AC withdrawal

Recurrence Hazard Ratio p

(-) D-dimer; (-) RVO 5.7% 1 (reference)

(-) D-dimer; (+) RVO 10.4% 1.66 (0.6 - 4.8) .35

(+) D-dimer; (-) RVO 22.9% 4.3 (1.56 - 11.88) .005

(+) D-dimer; (+) RVO 25.9% 4.76 (1.78 - 12.8) .002

RVO does not independently predict recurrence

D-Dimer & Anticoagulant Duration Palareti et al; N Engl J Med 2006

• 608 pts with first idiopathic DVT

• D-dimer 30 days after anticoagulants discontinued

• Normal - 385 (63%)

• Abnl - 223 (47%)

No anticoagulation - 120

Anticoagulation - 103

• Mean f/u - 1.4 years

• Recurrent VTE + Bleeding

• Nl D-dimer - 6.2%

• Abnl D-dimer (anticoag) - 2.9%

• Abnl D-dimer (no anticoag) - 15.0%

Conclusions - Duration of Anticoagulation

Currently determined by trials balancing recurrent VTE and bleeding

Unprovoked calf vein thrombosis – 3 months

Reversible risk factors – 3 months

Unprovoked DVT

1st episode – Assess risk versus benefits after 3 months

2nd episode – Long-term treatment

Selective thrombophilia testing may be warranted but …

Absence of identified defect ≠ absence of thrombophilia

Limited positive predictive value for recurrence

History is the most important determinant of prognosis

Persistent thrombus on U/S (at least in U.S) is not validated

Promising role for D-dimer