1. New Developments in Venous Thromboembolic Disease
Karen Hauer, MD
University of California,
San Francisco

2. Outline Diagnosis Risk factors Treatment Prophylaxis IVC filters
VQ, Ultrasound, Helical CT, D-dimer
Risk factors
Treatment
Heparins
Warfarin: duration of treatment
New agents
Prophylaxis
IVC filters

3. What is your clinical suspicion of PE?
48 year old woman presents with 2 weeks right LE pain, 2 days “trouble catching my breath.”
PMH: dysfunctional uterine bleeding due to fibroids, recently treated with OCPs.
PE: afebrile. BP 120/70, HR 110, RR 20,
O2 95% RA. Normal chest & CV exam, CXR.
What is your clinical suspicion of PE?
What is your next diagnostic step?

4. Clinical probability of PE Wells, Ann Intern Med 2001
Leg swelling, tenderness 3
Pulse >
Immobilization, surgery 1.5
Prior DVT/PE
Hemoptysis 1
Cancer 1
No other more likely Dx 3
Equal to clinical gestalt if you see a lot of these patients
< 2 = Low probability
2-6 = Moderate
> 6 = High

5. VQ scan for PE PIOPED, 1990 Clinical Suspicion VQ
Well studied; appropriate in outpatients w/ normal CXR
Rule in PE when clinical suspicion correlates w/ VQ result
Non-diagnostic in 640/887 (72%) patients

6. Lower Extremity Veins Iliac Deep (Common) Femoral Internal Saphenous
(Superficial)
Femoral
Popliteal
This slide reviews anatomy of LE veins. 50% prox DVTs embolize to lung. 20% calf vein DVTs embolize to prox veins, meaning that only 10% cause PE. Study has shown that PCPs misinterpret US results diagnosing superficial femoral clot as unimportant.
External Saphenous

7. Lower Extremity Ultrasound for PE
90% PE’s originate in lower extremity DVT
1st symptomatic DVT
Sensitivity 95%, specificity 96%
Increased sensitivity:
serial US at 5-7 days
combining with clinical suspicion
We commonly use US as a diagnostic test for DVT, but how good is it as a diagnostic test for PE?
90%. … AND studies show that 40% patients presenting with PE who have NO leg symptoms have a DVT if you look for it.
Dx = noncompressibility of a deep vein
Serial US if sx persist: identify 1-2% w/ DVT missed on initial study.

8. Ultrasound after Non-diagnostic VQ
After non-diagnostic lung scan, serial US has NPV of 99.5% (Wells, Ann Intern Med, 1998)
Avoids angiogram
71% vs. 29% require angio (Stein, Arch Intern Med, 1995)
Caution:
Recurrent DVT: 50% US still abnormal at 1 year
Asymptomatic DVT: lower sensitivity
Isolated calf DVT: lower sensitivity
Serial US not for high cardiopulmonary risk
Data shows that US can be useful part of algorithm for diagnosing PE.
Sensitivity of US for asymp DVT: about 60%
Sensitivity of US for calf vein DVT: about 80%

9. D-dimers: what is the role?
D-dimer: degradation product of cross-linked fibrin
The appeal: a simple blood test
High sensitivity, low specificity
Quantitative D-dimer < 500 ng/ml makes PE less likely
Elevated d-dimer common w/o clot - especially
Cancer
Post-op
Pregnancy
Inpatients
Prior DVT
Quant d-dimer - cutoff point depends on assay used

10. D-dimers: use selectively
Multiple assays
Can’t generalize from one to another
Goal: high negative predictive value
To rule out clot
Use D-dimers with clinical suspicion or other testing
In outpatients, ED
Multiple assays: ELISA: sens 96%, spec 23%
Whole blood SimpliRED agglutination/immunoturbideimetric assay - generally spec around 50% at best, sens lower
GOAL: use for NEG preditive value
INPTS: a neg d-dimer does not lower the probability of VTE
Study from Hopkins AJM 2003;114;276
Inpts undergoing DVT evaluation.
No utility to D-dimers in pt’s hosp > 3 days, > 60 yo, CRP top 25%

11. Pretest probability (930 ED patients)
D-dimers
Pretest probability (930 ED patients)
Low: n=527 (57%) Not low: n=403 (43%)
D-dimer D-dimer +VQ
(-) (+)
N=437 (47%)
No PE VQ
Wells, Ann Intern Med, 2001
However, there is a role for d-dimers in the ED setting, where patients are generally healthier and probability of finding clot is lower.
simplired- whole blood agglutination

12. The Role of Helical CT in Diagnosing PE
Where does Helical CT fit into the algorithm?

13. Helical CT: Reviewing the Evidence Rathbun, Ann Intern Med 2000 Mullins, Arch Intern Med 2000
Rathbun Mullins
Sensitivity 53% - 100% 64% - 93%
Specificity 81% - 100% 89% - 100%
Limitations
Include subsegmental PE?
Sensitivity for central PE = 83% - 100%, PPV = 95%
Sensitivity for subsegmental PE = 29%
Variations in quality of technology, reader

14. CT: the Primary Diagnostic Test? van Strijen, Ann Intern Med 2003
510 patients with suspected PE
Helical CT
PE alternate Dx normal
124 (24%) 130 (26%) 248 (49%)
2 DVT on US
Multicenter prospective study in Netherlands
US at presentation and Day 4, 7: positive in < 1% at presentation, none at FU, therefore unnecessary. 0.4% w/ normal CT developed PE, none fatal.
Alternate Dx’s - PNA, malignancy, pl effusion

15. Helical CT: Evidence-based Practice
Does a normal helical CT rule out PE?
Enough to withhold anticoagulation? Stop workup?
Yes.
Does a positive helical CT rule in PE?
Yes, no need for further testing.
At centers with CT experience - radiology, scanner

16. The Role of Helical CT in Diagnosing PE
-->Unstable patient: Helical CT
Stable patient
Equivocal V/Q <--
Helical CT
Make sure you feel confident in your radiologists and CT scanner

18. A 48 year old Caucasian woman recently started on OCPs presents with symptoms of acute DVT and PE.
V/Q scan is high probability for PE, LE ultrasound is diagnostic of DVT, and helical CT shows a saddle PE. You initiate anticoagulation, stop the OCP’s, and consider whether she has a hypercoagulable state. Do you. . .
A. Send protein C, protein S, antithrombin III levels B. “Pan scan” for malignancy C. Test for Factor V Leiden, prothrombin mutation D. All of the above E. None of the above

19. Clues to Inherited Hypercoagulability
Age < 50
Unusual location or severity
“Idiopathic” thrombosis
BUT, inherited disorders augment other risks - i.e. surgery, pregnancy
Recurrent thrombosis
Family history
Unusual location or severity: not necessarily UE, bec/ usually due to line or anatomic factor, or overuse
50% of clots in setting of inherited thrombophilia occur with acquired risk factor
FH: if you get it it’s helpful, but lit suggests not reliable

20. Inherited Hypercoagulability
If you look for a source Among all pt’s with clot, 24-37% have thrombophilia, vs. 10% of the general pop (w/ clot, 80% of all comers have a cause acquired or genetic)
FV Leiden - 5-6% of Whites, rare in Asian, AA. Causes resistance to protein C.
Lifetime risk of clot increased 2.2X (vs. Pro C, S 7-8X)
inc risk by in heterozygotes
Prothrombin mutation: leads to PT levels 30% higher than controls
Homocystein - due to genetic abnormality most commonly of MTHFR enzyme, or deficiency of B6, B12, or folic acid
About 1/3 w/ SLE have ACLA and 1/3 have LA
Half w/ SLE and APS will clot
Also, elevated F8 level >150% nl, linked to blood group other than 0, presumed genetic
50-60% of inherited thrombophilia is due to FV Leiden or the Prothrombin mutation
Antiphospholipid antibody: ACLA, PTT or other
twice over 6 weeks

21. Acquired risk factors: oral contraceptives
Pt I described recently started OCPs; Risk greatest in 1st year, returns to baseline after d/c.
However, absolute risk is low at 1-4 per 10,000, higher if obese or inherited thrombophilia
1/2nd gen: levonorgestrel, norethindrone
3rd gen: desogestrel (raise HDL - good for arterial dz risk). Therefore don’t use 3rd gen as your first line OCP
RR with OCP plus inherited thrombophilia = 6-40
Estrogen plus prog higher risk than estrogen alone
To screen:
NOT family history: poor predictive value (archives)

22. Screening for hypercoagulability before oral contraceptives
Pro
Thrombophilia common
PE: high morbidity, mortality
Con
Cost
Risk of clot low
Difficulty predicting who will clot
H/o DVT/PE: already a contraindication
May still miss thrombophilia
Pro: thrombophilia is common and OCP use is common.
Risk of clot among all OCP users still low: 3-4/10,000 per year
Number needed to screen >500,000 for FV Leiden to prevent one death from PE

23. Acquired risk factors - cancer
Cancer in patients with DVT/PE:
Higher risk of metastases, worse prognosis
Recommendation: careful H & P, routine cancer screening
Sorensen, NEJM 2000
Relative
risk
In the case I described, do we need to screen for cancer?
Approx 20% w/ cancer will develop clot. However, 75% of cancer pt’s with clot already have Dx of cancer. Among pt’s w/ clot, worry more in older pt or pt w/idiopathic clot.
Lrg population based study from Sweden

24. A healthy 48 year old with acute DVT and PE is treated with warfarin and heparin. Potential benefits of LMWH for this patient include all of the following except:
A. Fewer lab tests
B. Potential for home therapy
C. Reduced mortality risk
D. Easier reversal of anticoagulation in case of bleeding
E. Lower risk of heparin induced-thrombocytopenia

25. LMWH Advantages Disadvantages Longer half life No need to monitor PTT
Better bioavailability after SQ injection
Less heparin-induced thrombocytopenia
Less osteoporosis
Better outcomes with cancer
Disadvantages
Incompletely reversed by protamine
Unpredictable response with renal failure, obesity
GFR < 30, decrease dose to weight based from 1 mg/kg SQ bid to qd, for prevention 30 qd. Not FDA approved for HD pts.
Weight limit enoxaparin 144 kg

26. LMWH vs. UFH: 13 Studies Dolovich, Arch Int Med 2000
DVT/PE PE
Major bleeding
Minor bleeding
Total mortality
Thrombocytopenia
1.00
LMWH better
0.50
1.50
UFH better
Pooled Relative Risk

27. Treating to prevent Post thrombotic syndrome
Venous insufficiency after DVT
Risk factors
Elderly
Recurrent DVT
Obesity
Proximal thrombosis
Chronic pain, edema, ulcers, skin discoloration

28. Compression hose prevent post thrombotic syndrome
1st proximal DVT, anticoagulated >= 3 months
Intervention
Below-knee elastic stocking on affected leg for 2 years, started 5-10 days after DVT diagnosis
Stockings reduced post thrombotic syndrome:
49% vs. 26% (NNT = 4 to prevent 1 case)
Compression hose well tolerated
No difference in rate of recurrent DVT
Prandoni, Ann Intern Med 2004
reduced severe sequelae 12%-> 3.5%
Most cases w/in 1 year of DVT DX
Incidence of post thrombotic syndrome similar to prior studies in which shorter durations of anticoagulation were used
Much lower risk of post thrombotic syndrome w/ asymptomatic DVT
Avoid hose w/ occlusive arterial disease

29. Duration of Treatment: VTE as a Chronic Disease
Recurrence rate
1st VTE
Recurrent VTE
Warfarin 6 mo
Kearon - 1st idiopathic DVT. 3 mo vs. 2 year warfarin. Warfarin 95% risk reduction; 3.8% vs. 0% non-fatal major bleeding w/ warfarin. Study concluded that 3 mo too short, longer Rx indicated.
Schulman: 6 mo vs. indefinite, similar findings.
Warfarin-
extended
Kearon, NEJM, 1999
Schulman, NEJM 1997

30. Warfarin for Secondary Prevention after Idiopathic DVT/PE
Recurrence/year Bleeding/year
Placebo 7%
INR % 1%
INR % 1%
PREVENT, NEJM 2003
ELATE, Blood 2003
Extended treatment - also referred to as secondary prevention.
Bleeding = major bleeding
Conclusion: ACCP recommends full intensity warfarin
Placebo: higher risk recurrence if idiopathic clot, or if h/o mult clot.

31. Duration of Treatment Guidelines
1st event, reversible risk factor
3-6 months
1st event, spontaneous
>= 6 months
2nd event
>=12 months or lifelong
2nd spontaneous event, or 1st spontaneous and life threatening
Lifelong
3rd event or
Ongoing risk factors
Duration of Rx: influenced largely by whether clot was provoked or idiopathic/spontaneous.
1st event, spon, life threatening - consider lifelong
2nd event - lifelong if both spontaneous

32. The Decision to Stop Warfarin:
Risk factors for clot recurrence
Initial clot burden
Modifiable vs. persistent, major vs. minor
Thrombophilia
Indicators of increased risk
Elevated d-dimers 1 mo after stopping anticoag
Residual thrombosis on ultrasound after anticoag
Other markers of coagulation activity
ACCP 2004
Hron, JAMA 2006
Young, J Thromb Haemost 2006
Initial clot burden - if PE, likelihood of recurrence presenting as PE higher than if initial is DVT

33. Inherited risk factors and recurrent venous thromboembolism
Meta-analysis of 10 studies evaluating risk of recurrent clot in 3000 patients after anticoagulation stopped - with or without genetic mutation
Factor V Leiden Prothrombin G20212A
21% of patients 10% of patients
Odds of recurrence: 1.4 Odds of recurrence: 1.7
Elevated risk, but not enough to warrant lifelong anticoagulation
Ho, Arch Intern Med, 2006
Risks vary from not at all to 3
To test or not to test
Reasons to do so: family screening
May not impact Rx decisions

34. Treatment of Thromboembolism with Cancer: LMWH Superior
Lee. NEJM 2003
Venous thromboembolism and cancer - problems w/ warfarin
High recurrence rate
Challenge to maintain stable INR
Dalteparin 200 IU QD X q mo then 150 IU QD SQ
6 mo recurrence rate cut in half w/ LMWH
Use LMWH if pt willing to have SQ injections

35. Thrombosis in Pregnancy
A 34 year old woman G1 who is 35 weeks pregnant presents with left leg swelling, dyspnea, and right sided pleuritic chest pain.
How do you proceed?
Reassure her - these are common symptoms in pregnancy
MRI of the lower extremities
D-dimer
V/Q scan
IV Heparin
Risk 2X as high after Csxn vs. vag birth
DVT risk; left > right LE

36. Thrombosis in Pregnancy
Challenges in diagnosis
Edema, tachypnea, dyspnea common
D-dimer levels rise during pregnancy
Test as you would for non-pregnant patient
Ultrasound for DVT, PE
Consider MRI
V/Q or CT for PE
Treat with LMWH, heparin, fondaparinux
D-dimer peaks at 685 at delivery, early postpartum
Missing Dx is potentially worse than risk of exposing fetus to ionizing radiation
estimated fetal radiation exposure from the combination of a chest radiograph, V/Q scanning, and pulmonary arteriography is less than 5000 mcGy (500 mrad)]. This is 100 to 200 times less than the dose thought to produce a significant risk of fetal anomalies.CT: estimated mean radiation dose to the fetus is 3 to 131 mcGy across pregnancy; these values are less than those calculated for V/Q scanning

37. On the horizon. . . New therapies
Fondaparinux
Synthetic Factor Xa inhibitor
FDA approved for prophylaxis, treatment
Prophylaxis: 2.5/d SQ
Treatment: weight based 5, 7.5 or 10/d SQ
Start warfarin simultaneously, continue 5-7 days as with heparin
Avoid with GFR < 30
Factor 10: common pathway. Factor 2 = thrombin. Fondaparinux binds to antithrombin and makes it a more potent inhibitor of factor Xa.
Fondaparinux: single sq injection QD (does 2.5 for prevention, 5-10 for Rx based on body weight), 100% bioavailable after SQ injection. FDA approved 2001 for prevention, 2004 for Rx. up to 50-60% better than heparin in ortho pts, but more bleeding complications. Studies excluded pts w/ Cr > renally cleared. Should be ok with HIT (doesn’t bind plt or plt factor 4)
Studied for Rx - effective, but expensive, not better than LMWH, no antidote. Pregnancy category B. no inc in PTT w/ prophylactic dose (2.5) but may bump PTT w/ therapeutic dose.
Ximelagatran: 1st oral anticoagulant since warfarin

38. Off the horizon 2006. . . Ximelagatran
Direct thrombin inhibitors
Alternative to warfarin
Oral - fixed dose
Acute clot or orthopedic prophylaxis: 36 mg bid
Secondary prevention: 24 mg bid
No monitoring, no initial heparin
Safety questions
No antidote
Can elevate LFTs
Direct thrombin inhibitors are able to inhibit both free and clot-bound thrombin, thereby producing more effective anticoagulation.
Ximelagatran is the first orally available direct thrombin inhibitor to reach phase 3 clinical trials.
Elevated LFTs in 6% in NEJM - thought to be transient, actually can occur after drug d/c’d
Ximelagatran was generally well tolerated in the trial populations, but a small proportion (5-6%) developed elevated liver enzyme levels, which prompted the FDA to reject an initial application for approval in The further development was discontinued in 2006 after it turned out hepatic damage could develop in the period subsequent to withdrawal of the drug. According to AstraZeneca, a chemically different but pharmacologically similar substance, AZD0837, is undergoing testing for similar indications (AstraZeneca press release 2006).

39. Preparing for surgery
Deemed no longer a candidate for estrogens, the patient is scheduled for hysterectomy due to menorrhagia worsened on anticoagulation. What DVT prophylaxis do you recommend?
A. Ted hose, early ambulation
B. IV heparin
C. UFH 5000 u SQ bid
D. Enoxaparin 30 mg SQ bid + ted hose, early ambulation

40. DVT prophylaxis: Surgery
Low risk
Age < 40 AND surgery <30 min
Moderate risk
Non major surgery or age or other risks*
High risk
Age >60, LE ortho or cancer surgery, other risks*
*e.g. thrombophilia, CHF, malignancy
Low risk = ambulatory surgery
High risk: elderly, ortho, cancer, or multiple other risks

41. DVT prophylaxis: Surgery
Low risk
Early ambulation
Moderate risk
UFH 5000 u SQ bid or LMWH, IPC, ted hose
High risk
LMWH - may combine with IPC, ted hose
ACCP recommends combining Rx

42. LMWH in Medical Patients at Moderate Risk for DVT Samama, NEJM. 1999
866 patients: respiratory failure, infection, CHF, treated 6-14 days
DVT at day 14:
enoxaparin 40 mg/dy: 5.5%
enoxaparin 20 mg/dy, placebo: 15%(p = 0.001)
Similar mortality, side effects
BUT. . . mostly asymptomatic, distal DVT
no UFH comparison group

43. Preventing DVT in Medical Patients
UFH or LMWH effective
60% risk reduction in DVT, PE
Borderline decrease in hemorrhage with LMWH
Target high risk patients
CHF
Severe respiratory disease
Bedridden plus additional risk factor
Consider compression hose for low risk patients
Enoxaparin recommended at 40 mg/kg sq, or UFH

44. Case
A 30 year old woman with ulcerative colitis is admitted with bloody diarrhea. On day 3 she develops dyspnea and hypoxia. Helical CT reveals PE. What is the best management strategy:
Unfractionated heparin, goal aPTT 50-60, followed by LMWH
IVC filter, avoid anticoagulation
IVC filter, initiate anticoagulation when bleeding controlled
Unfractionated heparin, warfarin with goal INR 1.5-2

45. Indications for IVC filter
Clot with active bleeding
Clot despite anticoagulation
Massive PE with chronically compromised pulmonary vasculature?
Prevention?

46. IVC filters: benefits and risks Decousus, NEJM 1998
400 patients with proximal DVT, 50% with PE
Filter No filter p
PE at day 12 1% 5% 0.03
PE at 2 years 3% 6% NS
DVT at 2 years 21% 12% 0.02
Death 22% 21% NS
Major bleed 9% 12% NS

47. Retrievable IVC filters
FDA approved
Ideal for young patients with reversible PE risk factors
Left in, they become permanent
Current duration < 2 weeks

48. Summary Diagnosis Risk factors Treatment Prophylaxis
Combine clinical suspicion, test results
Risk factors
Higher yield for inherited thrombophilia
Treatment
LMWH as good, possibly superior to UFH
Warfarin: Longer treatment course
Prophylaxis
Risk stratify