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

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Presentation on theme: "New Developments in Venous Thromboembolic Disease Karen Hauer, MD University of California, San Francisco."— Presentation transcript:

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

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

3 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, tenderness3 Pulse > Immobilization, surgery1.5 Prior DVT/PE1.5 Hemoptysis1 Cancer1 No other more likely Dx3 < 2 = Low probability 2-6 = Moderate > 6 = High

5 VQ scan for PE PIOPED, 1990 Non-diagnostic in 640/887 (72%) patients VQ Clinical Suspicion

6 Lower Extremity Veins Iliac (Superficial) Femoral Deep (Common) Femoral External Saphenous Internal Saphenous Popliteal

7 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

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

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

10 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

11 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

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 RathbunMullins 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 patients with suspected PE Helical CT PE alternate Dxnormal 124 (24%)130 (26%)248 (49%) 2 DVT on US

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


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 OCPs, 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

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

21 Acquired risk factors: oral contraceptives

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

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

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 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

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

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

29 Duration of Treatment: VTE as a Chronic Disease Recurrence rate Warfarin 6 mo Warfarin- extended Recurrent VTE 1st VTE Kearon, NEJM, 1999 Schulman, NEJM 1997

30 Warfarin for Secondary Prevention after Idiopathic DVT/PE Recurrence/yearBleeding/year Placebo7% INR %1% INR %1% PREVENT, NEJM 2003 ELATE, Blood 2003

31 Duration of Treatment Guidelines 1st event, reversible risk factor3-6 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

32 The Decision to Stop Warfarin: Risk factors for clot recurrence 1.Initial clot burden 2.Modifiable vs. persistent, major vs. minor 3.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

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 patients10% of patients Odds of recurrence: 1.4Odds of recurrence: 1.7 Elevated risk, but not enough to warrant lifelong anticoagulation Ho, Arch Intern Med, 2006

34 Treatment of Thromboembolism with Cancer: LMWH Superior Lee. NEJM 2003

35 Thrombosis in Pregnancy A 34 year old woman G 1 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 extremities C.D-dimer D.V/Q scan E.IV Heparin

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

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

38 Off the horizon 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

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

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

42 LMWH in Medical Patients at Moderate Risk for DVT LMWH in Medical Patients at Moderate Risk for DVT Samama, NEJM 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

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: A.Unfractionated heparin, goal aPTT 50-60, followed by LMWH B.IVC filter, avoid anticoagulation C.IVC filter, initiate anticoagulation when bleeding controlled D.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 patients with proximal DVT, 50% with PE FilterNo filter p PE at day 121%5%0.03 PE at 2 years3%6%NS DVT at 2 years21%12%0.02 Death22%21%NS Major bleed9%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 –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

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