1. Deep Venous Thrombosis Anthony J. Comerota, MD, FACS, FACC
OVERVIEW (…of treatment)
Anthony J. Comerota, MD, FACS, FACC
Director,
Jobst Vascular Center
Adjunct Professor of Surgery,
University of Michigan

2. Anthony J. Comerota, MD, RVT
DISCLOSURES
Anthony J. Comerota, MD, RVT
Consulting Fees
Aastrom, Cook Medical, Covidien, Bristol-Myers Squibb, sanofi-aventis U.S. LLC, Talecris Biotherapeutics, Inc.
Honoraria
Bristol-Myers Squibb, Covidien, Otsuka, sanofi-aventis U.S. LLC, Servier, ZymoGenetics
Grants/Contracted Research
Aastrom Biosciences, Inc., Abbott Vascular, Baxter Healthcare, Bristol-Myers Squibb, Boehringer Ingelheim, BSN, Colorado Prevention Center, CVRx, ev3, Inc., Lombard Medical, Medtronic CardioVascular, Inc., National Institutes of Health, Pfizer, sanofi-aventis U.S. LLC, Schering-Plough Corp. / Merck & Co., Inc., Talecris Biotherapeutics, Inc.

3. Acute Deep Venous Thrombosis - Treatment -
Not all DVTs are the same!

4. Acute DVT Management ACCP 2008 Initial anticoagulation Immobilization
Duration of anticoagulation
Intensity of long-term anticoagulation
Compression stockings

5. Early Anticoagulation Long-Term Anticoagulation
Acute DVT
ACCP 2008
Early Anticoagulation
“Initial Treatment”
Objectives
Prevent: • Thrombus extension • Embolization • Recurrent DVT Early Late
Long-Term Anticoagulation
Objectives
• Reduce recurrence

6. Importance of Early Therapeutic Rx
Acute DVT
Importance of Early Therapeutic Rx
Recurrent VTE*
PTT <1.5x (24 hrs.)
24.5%
(15:1)
PTT >1.5x
1.6%
<0.001
* • most occur > 4 weeks,
• association with poor initial response not appreciated by attending MDs
Hull, RD et al
NEJM 1990

7. Duration of Initial Heparin
Acute DVT
Background: Anticoagulation
Duration of Initial Heparin
Two randomized trials: Proximal DVT
Result
IV UFH x 5-7 days is as effective as IV UFH x 14 days… …provided adequate long-term anticoagulation
Gallus A S et al Lancet 1986;2:1293
Hull R D et al NEJM 1990;322:1260

8. Initial Anticoagulation
Acute DVT
Background: Anticoagulation
Initial Anticoagulation
SQ LMWH (Grade 1A)
IV UFH (Grade 1A)
Monitored SQ UFH (Grade 1A)
Weight adjusted SQ UFH (Grade 1A)
SQ Fondaparinux (Grade 1A) …at least 5 days overlap with VKA, and …INR ≥ 2.0 for 24 hours
2008
Kearon C et al
CHEST 2008;133:4545

9. Anticoagulation…how long?
Acute DVT
Duration of Anticoagulation
Anticoagulation…how long?
Studies have shown…
…the longer the better!

10. Anticoagulation for DVT 4 Weeks vs. 3 Months: Study Design
406 Proximal DVT
(venogram)
3 mos. better than 4 weeks
4 Weeks Anticoagulation
IPG
Positive (N=192)
Negative (N=214)
All patients receiving 3 months of anticoagulation
who had recurrence had continuing risk factors
Anticoagulation (8 Weeks)
Randomize
Placebo (N=105)
Anticoag x 8 Wks (N=109)
Recurrence
@ 8 wks
@ 11 mos
8.6%
11.5%
vs.
0.9% 6%
P =.009
P =.3
Levine MN et al
Thromb Haemost 1995; 74: 6061

11. Anticoagulation for VTE 6 Weeks vs. 6 Months: Study Design
Multicenter, randomized trial
1st episode VTE (DVT-790; PE-107)
6 weeks vs. 6 months oral anticoagulation
Endpoints: 2 yrs Bleeding
Schulman S et al
NEJM 1995; 332:1661

12. Anticoagulation for VTE 6 Weeks vs. 6 Months: Results at 2 Years
Odds Ratio
Recurrence
P-Value
All
18.1%
9.5%
2.1
<.001
6 mos. better than 6 weeks
Month
0.7%
0.9% — —
Month
9.5%
0.4% — —
Month 6-24
7.9
8.1 — —
Major Bleed
0.2
1.1
0.2
0.23
Schulman S et al
NEJM 1995; 332:1661

13. 3 mos vs. Indefinite Anticoagulation
Anticoagulation for Acute DVT
Duration of Warfarin: Randomized Trial
3 mos vs. Indefinite Anticoagulation
Study Interim Analysis!
Percent per Patient Year
Endpoint
3 Mos
>1 Year
RRR
P-value
Recurrent VTE
24.1
1.3
95%
<0.001
Major Bleed
3.8 -
0.09
(non-fatal)
Indefinite better than 3 months (more bleeding)
Kearon C et al
NEJM 1999;340;901

14. Low-Intensity vs. Placebo
Acute DVT
Intensity of Anticoagulation
Low-Intensity vs. Placebo
Long-Term Low-Intensity Warfarin Therapy for the Prevention of Recurrent Venous Thromboembolism (INR vs. Placebo)
Ridker PM, Goldhaber SZ, Danielsen E, et al and the PREVENT Investigators
New England Journal of Medicine 2003; 348:15

15. Intensity of Anticoagulation
Acute DVT
Intensity of Anticoagulation
Placebo
(n = 253)
Warfarin
(n = 255)
RRR
P-value
Recurrent DVT
Major Bleed
Death
Composite
14.6%
0.8%
0.32%
16.2%
5.5%
1.9%
0.16%
8.6%
62%
-253%
50%
48%
<0.001
0.25
0.26
0.01
Indefinite low-intensity anticoagulation better than 3-6 months for idiopathic VTE
Ridker PM, et al
NEJM 2003; 348:15

16. Low-Intensity vs. Conventional
Acute DVT
Intensity of Anticoagulation
Low-Intensity vs. Conventional
Randomized, blinded study
738 pts - 1st unprovoked VTE
Randomized after 3 months anticoag.
Low-intensity – INR
Conventional – INR
Endpoints: Recurrence Death Bleeding
Follow-up 2.4 yrs
Kearon et al
NEJM 2003;349:631

17. Low-Intensity vs. Conventional
Acute DVT
Intensity of Anticoagulation
Low-Intensity vs. Conventional
2.4 yrs No/100 person yr
Low (N=369)
Conventional (N=369)
Hazard Ratio
P-value
Recurrent VTE
1.9
0.7
2.8
0.03
Death
1.9
0.9
2.1
0.09
Major bleed
1.1
0.9
1.2
0.76
Kearon et al
NEJM 2003;349:631

18. Duration of Anticoagulation
Acute DVT: First-Time DVT
ACCP 2008
Duration of Anticoagulation
Transient risk: Recommend VKA for 3 mos. over shorter periods (Grade 1A)
Unprovoked DVT: VKA for at least 3 mos. (Grade 1A)…then eval. for risk/benefit of continued Rx (1C)
Isolated distal DVT, rec. 3 mos. (2B)
For proximal DVT in patients at low risk for bleeding, rec. “long-term” (1A)
2008
First Slide after Title Slide only (or first slide with title)! Use only once.
Kearon C et al
CHEST 2008;133:4545

19. Acute DVT: Unprovoked DVT CHEST 2008
VKA to target INR – 2.5 for all treatment durations (Grade 1A)
For patients with strong preference for less INR testing after 1st 3 mos., rec. low-intensity [INR ] over stopping VKA (Grade 1A)
Recommend “against high-intensity” VKA therapy [INR ] (Grade 1A)
2008
First Slide after Title Slide only (or first slide with title)! Use only once.

20. Acute DVT : Recurrent (Unprovoked) Duration of Anticoagulation
6 Months vs. Indefinite
4 yrs
6 mos (N=111)
Indefinite (N=369) RR
P-value
Recurrent VTE
21% 3%
8.0
<.001
Death
14% 9%
1.7
0.21
Major bleed 3% 9%
0.3
0.0084
Schulman S et al
NEJM 1997;336:393

21. Duration of Anticoagulation
Acute DVT: Recurrent (Unprovoked)
ACCP 2008
Duration of Anticoagulation
For Recurrent DVT
Recommend long-term, indefinite Rx (Grade 1A)
For patients on long-term Rx, reassess risk/benefit at periodic intervals
2008
First Slide after Title Slide only (or first slide with title)! Use only once.
Kearon C et al
CHEST 2008;133:4545

22. LMWH vs. Coumadin: Results
VTE in Cancer Patients
LMWH vs. Coumadin: Results
Dalteparin (N=338)
Coumadin (N=338)
Hazard Ratio
P-Value
Recurrent VTE 8%
15.8%
0.48
0.002
Major Bleed 6% 4% ―
0.27
Mortality
39%
41% ―
0.53
Lee AY et al
NEJM 2003;349:146

23. Acute DVT: Cancer CHEST 2008 DVT and Cancer 2008
Recommend LMWH for the first mos. (Grade 1A)
Recommend subsequent Rx with VKA or LMWH indefinitely or until cancer is resolved (Grade 1C)
2008
First Slide after Title Slide only (or first slide with title)! Use only once.

24. Acute DVT ACCP 2008 DVT and Ambulation 2008
Recommend early ambulation in preference to initial bed rest (Grade 1A)
2008
First Slide after Title Slide only (or first slide with title)! Use only once.
Kearon C et al
CHEST 2008;133:4545

25. Immobilization vs. Ambulation
Acute DVT
ACCP 2008
Immobilization vs. Ambulation
Randomized trials (N=5)
Observational studies (N=3)
Result
Early ambulation with compression shows:
1. Faster resolution of pain 2. More rapid resolution of swelling 3. No increased risk of PE
Kearon C et al
CHEST 2008;133:4545

26. Postthrombotic Syndrome
Acute DVT: Compression Stockings
ACCP 2008
Randomized Trials
Lancet 1997;349:759
<.01
51%
24%
49%
55%
21%
47%
P-value
RRR
Stocking
Control
Postthrombotic Syndrome
Prandoni P
(N=194)
(N=170)
Patho Hemst Thromb 2002;32(suppl 2):72
Brandjes DP

27. Compression Stockings
Acute DVT: Compression Stockings
ACCP 2008
Compression Stockings
“…we recommend the use of an elastic compression stocking with an ankle gradient of 30-40mmHg pressure…for a minimum of 2 years”
…GRADE 1A…
2008
First Slide after Title Slide only (or first slide with title)! Use only once.

28. Acute DVT
ACCP 2008
Summary
More aggressive recommendations for management of acute DVT…strategy of thrombus removal
Emphasize need for:
Early therapeutic anticoagulation
Long-term anticoagulation for unprovoked DVT and cancer patients
Good compression (30-40mmHg)
Early ambulation
2008
First Slide after Title Slide only (or first slide with title)! Use only once.
Kearon C et al
CHEST 2008;133:4545

29. End Slide