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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 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

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