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New Developments in Venous Thromboembolic Disease

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

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  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 PEWells, Ann Intern Med 2001 Leg swelling, tenderness 3 Pulse > 100 1.5 Immobilization, surgery 1.5 Prior DVT/PE 1.5 Hemoptysis 1 Cancer 1 No other more likely Dx 3 • < 2 = Low probability • 2-6 = Moderate • > 6 = High

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

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

  7. 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 Lower Extremity Ultrasound for PE

  8. 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 Ultrasound after Non-diagnostic VQ

  9. 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: what is the role?

  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

  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 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

  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

  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

  17. 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

  18. Age < 50 Unusual location or severity “Idiopathic” thrombosis BUT, inherited disorders augment other risks - i.e. surgery, pregnancy Recurrent thrombosis Family history Clues to Inherited Hypercoagulability

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

  20. Acquired risk factors: oral contraceptives

  21. 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 Screening for hypercoagulability before oral contraceptives

  22. 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

  23. 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

  24. 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 LMWH

  25. 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

  26. Treating to preventPost thrombotic syndrome • Venous insufficiency after DVT • Risk factors • Elderly • Recurrent DVT • Obesity • Proximal thrombosis • Chronic pain, edema, ulcers, skin discoloration

  27. 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

  28. 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

  29. 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

  30. Duration of Treatment Guidelines

  31. 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

  32. 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

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

  34. 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

  35. 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

  36. 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

  37. 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

  38. 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

  39. 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

  40. 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

  41. 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

  42. 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

  43. 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

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

  45. 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

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

  47. 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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