3What 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?
4Clinical probability of PE Wells, Ann Intern Med 2001 Leg swelling, tenderness 3Pulse >Immobilization, surgery 1.5Prior DVT/PEHemoptysis 1Cancer 1No other more likely Dx 3Equal to clinical gestalt if you see a lot of these patients< 2 = Low probability2-6 = Moderate> 6 = High
5VQ scan for PE PIOPED, 1990 Clinical Suspicion VQ Well studied; appropriate in outpatients w/ normal CXRRule in PE when clinical suspicion correlates w/ VQ resultNon-diagnostic in 640/887 (72%) patients
6Lower Extremity Veins Iliac Deep (Common) Femoral Internal Saphenous (Superficial)FemoralPoplitealThis 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
7Lower Extremity Ultrasound for PE 90% PE’s originate in lower extremity DVT1st symptomatic DVTSensitivity 95%, specificity 96%Increased sensitivity:serial US at 5-7 dayscombining with clinical suspicionWe 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 veinSerial US if sx persist: identify 1-2% w/ DVT missed on initial study.
8Ultrasound after Non-diagnostic VQ After non-diagnostic lung scan, serial US has NPV of 99.5% (Wells, Ann Intern Med, 1998)Avoids angiogram71% vs. 29% require angio (Stein, Arch Intern Med, 1995)Caution:Recurrent DVT: 50% US still abnormal at 1 yearAsymptomatic DVT: lower sensitivityIsolated calf DVT: lower sensitivitySerial US not for high cardiopulmonary riskData 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%
9D-dimers: what is the role? D-dimer: degradation product of cross-linked fibrinThe appeal: a simple blood testHigh sensitivity, low specificityQuantitative D-dimer < 500 ng/ml makes PE less likelyElevated d-dimer common w/o clot - especiallyCancerPost-opPregnancyInpatientsPrior DVTQuant d-dimer - cutoff point depends on assay used
10D-dimers: use selectively Multiple assaysCan’t generalize from one to anotherGoal: high negative predictive valueTo rule out clotUse D-dimers with clinical suspicion or other testingIn outpatients, EDMultiple assays: ELISA: sens 96%, spec 23%Whole blood SimpliRED agglutination/immunoturbideimetric assay - generally spec around 50% at best, sens lowerGOAL: use for NEG preditive valueINPTS: a neg d-dimer does not lower the probability of VTEStudy from Hopkins AJM 2003;114;276Inpts undergoing DVT evaluation.No utility to D-dimers in pt’s hosp > 3 days, > 60 yo, CRP top 25%
11Pretest probability (930 ED patients) D-dimersPretest probability (930 ED patients)Low: n=527 (57%) Not low: n=403 (43%)D-dimer D-dimer +VQ(-) (+)N=437 (47%)No PE VQWells, Ann Intern Med, 2001However, 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
12The Role of Helical CT in Diagnosing PE Where does Helical CT fit into the algorithm?
13Helical CT: Reviewing the Evidence Rathbun, Ann Intern Med 2000 Mullins, Arch Intern Med 2000 Rathbun MullinsSensitivity 53% - 100% 64% - 93%Specificity 81% - 100% 89% - 100%LimitationsInclude subsegmental PE?Sensitivity for central PE = 83% - 100%, PPV = 95%Sensitivity for subsegmental PE = 29%Variations in quality of technology, reader
14CT: the Primary Diagnostic Test? van Strijen, Ann Intern Med 2003 510 patients with suspected PEHelical CTPE alternate Dx normal124 (24%) 130 (26%) 248 (49%)2 DVT on USMulticenter prospective study in NetherlandsUS 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
15Helical 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
16The Role of Helical CT in Diagnosing PE -->Unstable patient: Helical CTStable patientEquivocal V/Q <--Helical CTMake sure you feel confident in your radiologists and CT scanner
18A 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
19Clues to Inherited Hypercoagulability Age < 50Unusual location or severity“Idiopathic” thrombosisBUT, inherited disorders augment other risks - i.e. surgery, pregnancyRecurrent thrombosisFamily historyUnusual location or severity: not necessarily UE, bec/ usually due to line or anatomic factor, or overuse50% of clots in setting of inherited thrombophilia occur with acquired risk factorFH: if you get it it’s helpful, but lit suggests not reliable
20Inherited 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 heterozygotesProthrombin mutation: leads to PT levels 30% higher than controlsHomocystein - due to genetic abnormality most commonly of MTHFR enzyme, or deficiency of B6, B12, or folic acidAbout 1/3 w/ SLE have ACLA and 1/3 have LAHalf w/ SLE and APS will clotAlso, elevated F8 level >150% nl, linked to blood group other than 0, presumed genetic50-60% of inherited thrombophilia is due to FV Leiden or the Prothrombin mutationAntiphospholipid antibody: ACLA, PTT or othertwice over 6 weeks
21Acquired 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 thrombophilia1/2nd gen: levonorgestrel, norethindrone3rd gen: desogestrel (raise HDL - good for arterial dz risk). Therefore don’t use 3rd gen as your first line OCPRR with OCP plus inherited thrombophilia = 6-40Estrogen plus prog higher risk than estrogen aloneTo screen:NOT family history: poor predictive value (archives)
22Screening for hypercoagulability before oral contraceptives ProThrombophilia commonPE: high morbidity, mortalityConCostRisk of clot lowDifficulty predicting who will clotH/o DVT/PE: already a contraindicationMay still miss thrombophiliaPro: thrombophilia is common and OCP use is common.Risk of clot among all OCP users still low: 3-4/10,000 per yearNumber needed to screen >500,000 for FV Leiden to prevent one death from PE
23Acquired risk factors - cancer Cancer in patients with DVT/PE:Higher risk of metastases, worse prognosisRecommendation: careful H & P, routine cancer screeningSorensen, NEJM 2000RelativeriskIn 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
24A 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 therapyC. Reduced mortality riskD. Easier reversal of anticoagulation in case of bleedingE. Lower risk of heparin induced-thrombocytopenia
25LMWH Advantages Disadvantages Longer half life No need to monitor PTT Better bioavailability after SQ injectionLess heparin-induced thrombocytopeniaLess osteoporosisBetter outcomes with cancerDisadvantagesIncompletely reversed by protamineUnpredictable response with renal failure, obesityGFR < 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
26LMWH vs. UFH: 13 Studies Dolovich, Arch Int Med 2000 DVT/PEPEMajor bleedingMinor bleedingTotal mortalityThrombocytopenia1.00LMWH better0.501.50UFH betterPooled Relative Risk
27Treating to prevent Post thrombotic syndrome Venous insufficiency after DVTRisk factorsElderlyRecurrent DVTObesityProximal thrombosisChronic pain, edema, ulcers, skin discoloration
28Compression hose prevent post thrombotic syndrome 1st proximal DVT, anticoagulated >= 3 monthsInterventionBelow-knee elastic stocking on affected leg for 2 years, started 5-10 days after DVT diagnosisStockings reduced post thrombotic syndrome:49% vs. 26% (NNT = 4 to prevent 1 case)Compression hose well toleratedNo difference in rate of recurrent DVTPrandoni, Ann Intern Med 2004reduced severe sequelae 12%-> 3.5%Most cases w/in 1 year of DVT DXIncidence of post thrombotic syndrome similar to prior studies in which shorter durations of anticoagulation were usedMuch lower risk of post thrombotic syndrome w/ asymptomatic DVTAvoid hose w/ occlusive arterial disease
29Duration of Treatment: VTE as a Chronic Disease Recurrence rate1st VTERecurrent VTEWarfarin 6 moKearon - 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-extendedKearon, NEJM, 1999Schulman, NEJM 1997
30Warfarin for Secondary Prevention after Idiopathic DVT/PE Recurrence/year Bleeding/yearPlacebo 7%INR % 1%INR % 1%PREVENT, NEJM 2003ELATE, Blood 2003Extended treatment - also referred to as secondary prevention.Bleeding = major bleedingConclusion: ACCP recommends full intensity warfarinPlacebo: higher risk recurrence if idiopathic clot, or if h/o mult clot.
31Duration of Treatment Guidelines 1st event, reversible risk factor3-6 months1st event, spontaneous>= 6 months2nd event>=12 months or lifelong2nd spontaneous event, or 1st spontaneous and life threateningLifelong3rd event orOngoing risk factorsDuration of Rx: influenced largely by whether clot was provoked or idiopathic/spontaneous.1st event, spon, life threatening - consider lifelong2nd event - lifelong if both spontaneous
32The Decision to Stop Warfarin: Risk factors for clot recurrenceInitial clot burdenModifiable vs. persistent, major vs. minorThrombophiliaIndicators of increased riskElevated d-dimers 1 mo after stopping anticoagResidual thrombosis on ultrasound after anticoagOther markers of coagulation activityACCP 2004Hron, JAMA 2006Young, J Thromb Haemost 2006Initial clot burden - if PE, likelihood of recurrence presenting as PE higher than if initial is DVT
33Inherited 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 mutationFactor V Leiden Prothrombin G20212A21% of patients 10% of patientsOdds of recurrence: 1.4 Odds of recurrence: 1.7Elevated risk, but not enough to warrant lifelong anticoagulationHo, Arch Intern Med, 2006Risks vary from not at all to 3To test or not to testReasons to do so: family screeningMay not impact Rx decisions
34Treatment of Thromboembolism with Cancer: LMWH Superior Lee. NEJM 2003Venous thromboembolism and cancer - problems w/ warfarinHigh recurrence rateChallenge to maintain stable INRDalteparin 200 IU QD X q mo then 150 IU QD SQ6 mo recurrence rate cut in half w/ LMWHUse LMWH if pt willing to have SQ injections
35Thrombosis 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 pregnancyMRI of the lower extremitiesD-dimerV/Q scanIV HeparinRisk 2X as high after Csxn vs. vag birthDVT risk; left > right LE
36Thrombosis in Pregnancy Challenges in diagnosisEdema, tachypnea, dyspnea commonD-dimer levels rise during pregnancyTest as you would for non-pregnant patientUltrasound for DVT, PEConsider MRIV/Q or CT for PETreat with LMWH, heparin, fondaparinuxD-dimer peaks at 685 at delivery, early postpartumMissing Dx is potentially worse than risk of exposing fetus to ionizing radiationestimated 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
37On the horizon. . . New therapies FondaparinuxSynthetic Factor Xa inhibitorFDA approved for prophylaxis, treatmentProphylaxis: 2.5/d SQTreatment: weight based 5, 7.5 or 10/d SQStart warfarin simultaneously, continue 5-7 days as with heparinAvoid with GFR < 30Factor 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
38Off the horizon 2006. . . Ximelagatran Direct thrombin inhibitorsAlternative to warfarinOral - fixed doseAcute clot or orthopedic prophylaxis: 36 mg bidSecondary prevention: 24 mg bidNo monitoring, no initial heparinSafety questionsNo antidoteCan elevate LFTsDirect 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’dXimelagatran 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).
39Preparing for surgeryDeemed 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
40DVT prophylaxis: Surgery Low riskAge < 40 AND surgery <30 minModerate riskNon major surgery or age or other risks*High riskAge >60, LE ortho or cancer surgery, other risks**e.g. thrombophilia, CHF, malignancyLow risk = ambulatory surgeryHigh risk: elderly, ortho, cancer, or multiple other risks
41DVT prophylaxis: Surgery Low riskEarly ambulationModerate riskUFH 5000 u SQ bid or LMWH, IPC, ted hoseHigh riskLMWH - may combine with IPC, ted hoseACCP recommends combining Rx
42LMWH in Medical Patients at Moderate Risk for DVT Samama, NEJM. 1999 866 patients: respiratory failure, infection, CHF, treated 6-14 daysDVT 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 DVTno UFH comparison group
43Preventing DVT in Medical Patients UFH or LMWH effective60% risk reduction in DVT, PEBorderline decrease in hemorrhage with LMWHTarget high risk patientsCHFSevere respiratory diseaseBedridden plus additional risk factorConsider compression hose for low risk patientsEnoxaparin recommended at 40 mg/kg sq, or UFH
44CaseA 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 LMWHIVC filter, avoid anticoagulationIVC filter, initiate anticoagulation when bleeding controlledUnfractionated heparin, warfarin with goal INR 1.5-2
45Indications for IVC filter Clot with active bleedingClot despite anticoagulationMassive PE with chronically compromised pulmonary vasculature?Prevention?
46IVC filters: benefits and risks Decousus, NEJM 1998 400 patients with proximal DVT, 50% with PEFilter No filter pPE at day 12 1% 5% 0.03PE at 2 years 3% 6% NSDVT at 2 years 21% 12% 0.02Death 22% 21% NSMajor bleed 9% 12% NS
47Retrievable IVC filters FDA approvedIdeal for young patients with reversible PE risk factorsLeft in, they become permanentCurrent duration < 2 weeks
48Summary Diagnosis Risk factors Treatment Prophylaxis Combine clinical suspicion, test resultsRisk factorsHigher yield for inherited thrombophiliaTreatmentLMWH as good, possibly superior to UFHWarfarin: Longer treatment courseProphylaxisRisk stratify