By: Mark Meissner, M.D. Visit VeinGlobal at http://www.veinglobal.com/ for more presentations and videos on this topic, or for more information on venous disease news, education and research.

1. Disclosure
Mark Meissner, M.D.
I have no financial relationship(s) to disclose.

2. Mark H. Meissner, MD
Professor of Surgery
University of Washington School of Medicine
Seattle, WA
VTE & Duration of Anticoagulation

3. 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)

4. But Are The Guidelines Always Helpful?
What does “assess for long-term” anticoagulation
REALLY mean?

5. 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%

6. 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

7. 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

8. 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

9. 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

10. 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

11. 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

12. 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

13. 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%

14. 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