New Developments in New Developments in Venous Thromboembolic Venous Thromboembolic

DiseaseDisease

Karen Hauer, MD

University of California,

San Francisco

OutlineOutline

• Diagnosis– VQ, Ultrasound, Helical CT, D-dimer

• Risk factors• Treatment

– Heparins– Warfarin: duration of treatment– New agents

• Prophylaxis• IVC filters

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 clinical suspicion of PE?

What is your next diagnostic step?What is your next diagnostic step?

Clinical probability of PEWells, Ann Intern Med 2001

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

< 2 = Low probability2-6 = Moderate> 6 = High

VQ scan for PEVQ scan for PEPIOPED, 1990PIOPED, 1990

High Intermed Low

High 96% 88% 56%

Intermed 66% 28% 16%

Low 40% 16% 4%

Normal 0 6% 2%

Non-diagnostic in 640/887 (72%) patients

VQ

Clinical Suspicion

Lower Extremity Veins Iliac

(Superficial)Femoral

Deep (Common) Femoral

External Saphenous

Internal Saphenous

Popliteal

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

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

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

D-dimers: use selectivelyD-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

D-dimersD-dimersPretest 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

The Role of Helical CT in Diagnosing PE

Angiographyinvasive

Serial USunsafe if unstable patient

D-dimernegative may rule out PE

V/Q scan60-70% nondiagnostic

Suspected PE

Where does Helical CT fit into the algorithm?

Helical CT: Reviewing the EvidenceRathbun, Ann Intern Med 2000 Mullins, Arch Intern Med 2000

Rathbun MullinsSensitivity 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

CT: the Primary Diagnostic Test?van Strijen, Ann Intern Med 2003

510 patients with suspected PEHelical CT

PE alternate Dx normal124 (24%) 130 (26%) 248 (49%)

2 DVT on US

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

The Role of Helical CT in Diagnosing PE

Suspected PE

Angiography

Serial US D-dimer

V/Q scan

-->Unstable patient: Helical CT

Stable patientEquivocal V/Q <--Helical CT

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 malignancyC. Test for Factor V Leiden, prothrombin mutationD. All of the aboveE. None of the above

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

Inherited Hypercoagulability Prevalence

with VTE Prevalence w/o VTE

Diagnosis

Factor V Leiden 12-21% 6% PCR

Prothrombin mutation

6-8% 2% PCR

Homocysteinemia Homocysteine level

Protein C, S deficiency

2-4% < 1% Pro C, S levels

Antithrombin III deficiency

1-2% <1% ATIII level

Any thrombophilia 24-37% 10%

Antiphospholipid antibody: ACLA, PTT or other twice over 6 weeks

Acquired risk factors: oral contraceptives

0

5

10

15

20

25

30

35

Relative risk

1st/2nd genprog

3rd gen FV Leiden OCP + FVLeiden

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

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 0

1

2

3

<6 >6

months after PE/DVT

Risk of cancer after PE/DVT

Relativerisk

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 testsB. Potential for home therapy C. Reduced mortality riskD. Easier reversal of anticoagulation in case of

bleedingE. Lower risk of heparin induced-thrombocytopenia

LMWHAdvantages

• 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

LMWH vs. UFH: 13 Studies Dolovich, Arch Int Med 2000

Pooled Relative Risk0.50 1.501.00

DVT/PE

PE

Major bleeding

Minor bleeding

Thrombocytopenia

Total mortality

LMWH better UFH better

Treating to preventPost thrombotic syndrome

• Venous insufficiency after DVT• Risk factors

– Elderly– Recurrent DVT– Obesity– Proximal thrombosis

• Chronic pain, edema, ulcers, skin discoloration

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

Duration of Treatment: VTE as a Chronic Disease

0

5

10

15

20

25

30

35

40

45

6 12 18 24

months

Warfarin 3 mo

Warfarin-extended

Recu

rrence rate Warfarin 6 mo

Warfarin-extended

Recurrent VTE

1st VTE

Kearon, NEJM, 1999Schulman, NEJM 1997

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 2003ELATE, Blood 2003

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

Lifelong

The Decision to Stop Warfarin:

• Risk factors for clot recurrence1. Initial clot burden2. Modifiable vs. persistent, major vs. minor3. 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 2004Hron, JAMA 2006

Young, J Thromb Haemost 2006

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 G20212A21% 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

Treatment of Thromboembolism with Cancer: LMWH Superior

Lee. NEJM 2003

02468

101214161820

1 2 3 4 5 6 7

months

recurrent clot (%)

DalteparinWarfarin

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?

A. Reassure her - these are common symptoms in pregnancy

B. MRI of the lower extremitiesC. D-dimer D. V/Q scanE. IV Heparin

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

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

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

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 ambulationB. IV heparinC. UFH 5000 u SQ bidD. Enoxaparin 30 mg SQ bid + ted hose,

early ambulation

DVT prophylaxis: Surgery

• Low risk– Age < 40 AND surgery <30 min

• Moderate risk– Non major surgery or age 40-60 or other risks*

• High risk– Age >60, LE ortho or cancer surgery, other risks*

*e.g. thrombophilia, CHF, malignancy

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

LMWH in Medical Patients at LMWH in Medical Patients at Moderate Risk for DVTModerate 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 effectsBUT. . . mostly asymptomatic, distal DVT

no UFH comparison group

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

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:

A. Unfractionated heparin, goal aPTT 50-60, followed by LMWHB. IVC filter, avoid anticoagulationC. IVC filter, initiate anticoagulation when bleeding controlledD. Unfractionated heparin, warfarin with goal INR 1.5-2

Indications for IVC filter

• Clot with active bleeding

• Clot despite anticoagulation

• Massive PE with chronically compromised pulmonary vasculature?

• Prevention?

IVC filters: benefits and risks Decousus, NEJM 1998

400 patients with proximal DVT, 50% with PEFilter 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

Retrievable IVC filters• FDA approved

• Ideal for young patients with reversible PE risk factors

• Left in, they become permanent– Current duration < 2 weeks

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