New Developments in Venous Thromboembolic Disease

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New Developments in Venous Thromboembolic Disease

• Karen Hauer, MD
• University of California,
• San Francisco

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Outline

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

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• 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?
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Clinical probability of PEWells, Ann Intern Med
2001

• Leg swelling, tenderness 3
• Pulse gt 100 1.5
• Immobilization, surgery 1.5
• Prior DVT/PE 1.5
• Hemoptysis 1
• Cancer 1
• No other more likely Dx 3

lt 2 Low probability 2-6 Moderate gt 6 High
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VQ scan for PEPIOPED, 1990
Clinical Suspicion
VQ
Non-diagnostic in 640/887 (72) patients
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Lower Extremity Veins
Iliac
Deep (Common) Femoral
Internal Saphenous
(Superficial) Femoral
Popliteal
External Saphenous
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Lower Extremity Ultrasound for PE

• 90 PEs originate in lower extremity DVT
• 1st symptomatic DVT
• Sensitivity 95, specificity 96
• Increased sensitivity
• serial US at 5-7 days
• combining with clinical suspicion

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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

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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 lt 500 ng/ml makes PE less
  likely
• Elevated d-dimer common w/o clot - especially
• Cancer
• Post-op
• Pregnancy
• Inpatients
• Prior DVT

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D-dimers use selectively

• Multiple assays
• Cant 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

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D-dimers

• Pretest probability (930 ED patients)
• Low n527 (57) Not low n403 (43)
• D-dimer D-dimer VQ
• (-) ()
• N437 (47)
• No PE VQ
• Wells, Ann Intern Med, 2001

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The Role of Helical CT in Diagnosing PE

Where does Helical CT fit into the algorithm?
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Helical CT Reviewing the EvidenceRathbun, 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

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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

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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

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The Role of Helical CT in Diagnosing PE

--gtUnstable patient Helical CT
Stable patient Equivocal V/Q lt-- Helical CT
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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 OCPs, and consider whether she has a
hypercoagulable state. Do you. . .
A. Send protein C, protein S, antithrombin III
levels B. Pan scan for malignancyC. Test for
Factor V Leiden, prothrombin mutationD. All of
the aboveE. None of the above
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Clues to Inherited Hypercoagulability

• Age lt 50
• Unusual location or severity
• Idiopathic thrombosis
• BUT, inherited disorders augment other risks -
  i.e. surgery, pregnancy
• Recurrent thrombosis
• Family history

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Inherited Hypercoagulability
Antiphospholipid antibody ACLA, PTT or other
twice over 6 weeks
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Acquired risk factors oral contraceptives

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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

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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
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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
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LMWH

• Advantages
• 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

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

• Venous insufficiency after DVT
• Risk factors
• Elderly
• Recurrent DVT
• Obesity
• Proximal thrombosis
• Chronic pain, edema, ulcers, skin discoloration

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Compression hose prevent post thrombotic
syndrome

• 1st proximal DVT, anticoagulated gt 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

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Duration of Treatment VTE as a Chronic Disease
Recurrence rate
1st VTE
Recurrent VTE
Warfarin 6 mo
Warfarin- extended
Kearon, NEJM, 1999 Schulman, NEJM 1997
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Warfarin for Secondary Prevention after
Idiopathic DVT/PE

• Recurrence/year Bleeding/year
• Placebo 7
• INR 1.5-2 2-2.6 1
• INR 2-3 0.6 1
• PREVENT, NEJM 2003
• ELATE, Blood 2003

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Duration of Treatment Guidelines
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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

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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

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Treatment of Thromboembolism with Cancer LMWH
Superior

• Lee. NEJM 2003

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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

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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

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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 lt 30

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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

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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
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DVT prophylaxis Surgery

• Low risk
• Age lt 40 AND surgery lt30 min
• Moderate risk
• Non major surgery or age 40-60 or other risks
• High risk
• Age gt60, LE ortho or cancer surgery, other risks
• e.g. thrombophilia, CHF, malignancy

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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

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LMWH in Medical Patients at Moderate Risk for
DVTSamama, 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

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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

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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

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Indications for IVC filter

• Clot with active bleeding
• Clot despite anticoagulation
• Massive PE with chronically compromised pulmonary
  vasculature?
• Prevention?

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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

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Retrievable IVC filters

• FDA approved
• Ideal for young patients with reversible PE risk
  factors
• Left in, they become permanent
• Current duration lt 2 weeks

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Summary

• Diagnosis
• 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