Venous Thromboembolism: Deep Venous Thrombosis and Pulmonary Embolism 2006 Capital Conference Andrews Air Force Base CDR Kenneth S. Yew MC, USN Uniformed Services University Edited by Paul Saleeb

Objectives Recognize common presentations of deep venous thrombosis (DVT) and pulmonary embolus (PE) Understand evidence-based diagnostic and therapeutic strategies for DVT/PE Understand the role of prevention for DVT/PE and use of prevention strategies

Case 1 37 yo moderately obese female on OCP presents to your office with a two day history of painless R leg swelling. She’s been elevating her leg several days after a severe ankle sprain during a mother-daughter soccer game. No prior medical history, recent surgery or weight loss. She is a non-smoker and drinks rarely. Exam is notable for R ankle splint and pitting edema in R calf, which is 1.5 cm larger than the L.

DVT – Epidemiology and Etiology Annual incidence of venous thromboembolism (VTE) is 1/1000 DVT accounts for one half of VTE Carefully evaluated, up to 80% of patients with VTE have one or more risk factors Majority of lower extremity DVT arise from calf veins but ~20% begin in proximal veins About 20% of calf-limited DVTs will propagate proximally

DVT – VTE Risk Factors Malignancy Surgery Trauma Pregnancy Oral contraceptives or hormonal therapy Immobilization Inherited thrombophillia Presence of venous catheter Congestive failure Antiphospholipid antibody syndrome Hyperviscosity Nephrotic syndrome Inflammatory bowel disease In addition a study in a Nurses Health study cohort noted obesity, smoking and HTN as risk factors for PE in women.

DVT – Clinical Presentation Classically = calf pain, tenderness, swelling, redness and Homan’s sign Overall sens/spec = 3-91% Unreliable for diagnostic decisions Wells developed and tested a clinical prediction model for DVT Wells PS, Anderson DR, Bormanis J, et al. Value of assessment of pretest probability of deep-vein thrombosis in clinical management. Lancet 1997;350 (9094):1795-8.

DVT – Wells Score Cancer Paralysis or plaster immobilization The following were assigned a point value of 1 if present: Cancer Paralysis or plaster immobilization Bedrest > 3d or surgery in past 4 wks Localized tenderness Entire leg swollen Calf > 3cm larger than unaffected leg Pitting edema greater than unaffected leg Collateral superficial veins Alternative diagnosis more likely than DVT = - 2 points Probability High (≥ 3), Moderate (1-2) or Low (0 or less) DVT risk: High – 75%, Moderate – 17%, Low – 3% Wells PS, Andersen DR, Bormanis J et al. Lancet. 1997;350:1795-8

DVT – Case 1 Our patient has 2-3 risk factors (OCP, +/- immobilization and trauma Her Wells score gives her a moderate pretest probability for DVT A d-dimer test is performed…

DVT – D-Dimer Fibrin degradation product elevated in active thrombosis Negative test can help exclude VTE Preferred test Quantitative Rapid ELISA – sensitivity 96/95% for DVT/PE Other methods include latex agglutination and RBC agglutination (SimpliRED) Less helpful in malignancy and recent surgery. Rapid RBC agglutination (SimpliRED) – sensitivity 87/78% for DVT/PE 1st generation ELISA accurate but slow Latex agglutination only useful if quantitative Stein PD, Hull RD, Patel KC, et al. D-dimer for the exclusion of acute venous thrombosis and pulmonary embolism: a systematic review. Ann Int Med. 2004;140(8):589-602

DVT – D-Dimer In 283 patients with suspected DVT, low-moderate Wells DVT score and negative d-dimer only 1 (NPV 99.6%) had DVT over next 3 months 556 consecutive patients with suspected DVT, 283 (51%) had low-mod prob and neg d-dimer Used a quantitative latex agglutination test (sens 97.1% in this study; method sens 85%/89% for DVT/PE in Stien SR) Sensitive d-dimer testing can rule out DVT in low-moderate risk patients Bates SM, Kearon C, Crowther M, et al. Ann Intern Med. 2003;138:787-94

DVT – Case 1 Our patient has a positive quantitative ELISA Unfortunately a positive d-dimer is not helpful diagnostically An imaging study is done…

DVT – Imaging Compression US – first line test, high sens/spec Available imaging and ancillary tests: Compression US – first line test, high sens/spec Venography – gold standard MRI – Lower quality evidence only at present Impedance plesmythography – not in US Complete lower extremity US – experimental Compression US with doppler or duplex – good for symptomatic proximal DVT, only 70% sens for calf-limited DVT. Venography less common due to time, difficulty, invasiveness, but still best for recurrences, high prob patients with neg or incomplete US or eval for calf-limited DVT. MRI – may have limited availability, more expensive. Available studies examining accuracy of this method not same quality as for US and venography, but have suggested high sens/spec for DVT. Complete LE US, has been studied in a couple of centers with low rates of subsequent VTE events after a single negative study. Technically demanding and may not catch on.

DVT – Case 1 Compression US negative Options include: Venography or MRI Serial compression US – single US done at 5-7 days reliably excludes calf-limited DVT Follow clinically for resolution of symptoms – riskier, no data supporting safety of this option American Thoracic Society guidelines: The approach to acute venous thromboembolism. Am J Respir Crit Care Med. 1999;160:1043. Fraser JD, Anderson DR. Radiology. 1999;211(1):9-24

Diagnostic algorithm using D-dimer testing and ultrasound imaging in patients with suspected DVT                                                                                                                                  * Imaging done from proximal veins to calf trifurcation. Reproduced with permission from Scarvelis, D, Wells, P. Diagnosis and treatment of deep-vein thrombosis. CMAJ 2006; 175:1087. Copyright © 2006 Canadian Medical Association.

Case 2 The patient in Case 1 elected to be followed clinically. She returned to clinic 3 days later with persistent swelling, but no new symptoms She was to return the following week, but instead you are called to the ER 10 days later after she presents with acute onset of dyspnea and pleuritic chest pain

PE – Epidemiology and Etiology 100-200,000 deaths per year due to PE Most PE arise from lower extremity DVT In patients with DVT, 40-60% will have a PE on V/Q scanning “Pulmonary embolus is not a disease. It is a complication of DVT.” Ken Moser MD

PE – Clinical Presentation Dyspnea, pleuritic pain and cough most common symptoms Tachypnea, rales and tachycardia most common signs ABG limited value for diagnosis EKG and CXR often abnormal, but usually lacking specificity to aid diagnosis Pneumonia/pleurisy syndrome – 65% Unexplained dyspnea syndrome – 22% Central catastrophic syndrome – 8% Chronic pulmonary hypertension syndrome Pulmonary sepsis syndrome – T<102 in 14% † Percentages specified are from those observed in the PIOPED study. AA gradient normal in 8-23% of patients with angiographically proven PE. PIOPED Study. JAMA. 1990;263(20):2753-59. Stein PD, Goldhaber SZ, Henry JW. Chest 1995;107:139-43

S1Q3T3

CXR FINDINGS Hampton’s Hump: -wedge-shaped configuration at lung periphery due to infarcted lung Westermark sign: -pulmonary oligemia

PE – Case 2 Findings in the ER Alert white female, mildly anxious T 101, HR 105, RR 18 R LE edema and redness Lungs clear to auscultation ABG – mild respiratory alkalosis; aA gradient = 17 CXR showing mild atelectasis D-dimer positive as before, troponin normal

PE – Assigning Pretest Probability Single most important step in the diagnosis of pulmonary embolism May be done based on clinical judgment or aided by a clinical scoring system Modified Wells Criteria is the most widely used and studied Reliably stratifies patients by likelihood of PE to allow selection of safe (<2% VTE risk if no anticoagulation) management strategy Low(57%) 1.3%; Moderate(36%) 16.2% and High(7%) 37.5%

PE – Assigning Pretest Probability

PE – Use of D-Dimer Not helpful when positive, but sensitive assay can exclude PE in low risk patient In patients with moderate pretest probability only rapid quantitative ELISA can adequately exclude PE Patients judged to be high risk for PE would still have a posttest PE probability of 5-20% even after negative ELISA and require further testing Roy PM, Colombet I, Durieux R, et al. Systematic review and meta-analysis of strategies for the diagnosis of suspected pulmonary embolism. BMJ. 2005;331(7511):259

PE – Case 2 High risk for PE by Modified Wells Criteria (Wells score = 9) Positive D-dimer, but negative test would not have safely excluded PE Options include: CT angiogram V/Q scan Lower extremity compression US

PE – Imaging Studies PIOPED study quantified the value of V/Q scans in diagnosing PE Normal/near-normal scans exclude PE in low-moderate risk patients High probability scans confirm PE in moderate-high risk patients Drawbacks: more difficult test and 73% patients had indeterminate scans LE compression US showing DVT helps diagnostically, but a negative study insufficient to exclude VTE PIOPED Study. JAMA. 1990;263(20):2753-59

PE – Helical CT (CTA) Eng performed a systematic review (SR) of all studies & SRs on CTA prior to 2003 Only 1/6 SRs and 3/8 primary studies found CTA >90% sensitive for PE In a similar SR in 2005 Roy concluded Negative CTA could safely exclude PE in low risk patients Negative LE US plus negative CTA could exclude PE in moderate risk patients At the time of those SRs no studies of faster multidetector CTA (MDCT) were available Faster scanning times and 50% thinner cuts presumably would result in increased sensitivity for smaller PEs Eng J, Krishnan JA, Segal JB, et al. AJR 2004;183(6):1819-27. Roy PM, Colombet I, Durieux P, et al. BMJ 2005;331(7511):259.

PE – PIOPED II Published June 2006 in NEJM Findings 1090 consecutive patients with suspected PE All given Modified Wells Score MDCT - mostly 4 slice Gold standard – composite - V/Q, angiogram & LE US Findings MDCT: sens 83% & spec 96% for PE Positive predictive value >90% in moderate/high risk Negative predictive value 96% in low risk patients but only 89% in moderate risk patients Findings generally consistent with Roy’s SR Concordant findings helpful - Need neg LE US to exclude in moderate risk patients Discordant findings – low pretest – pos CT or high pretest – neg CT need more testing. Stein PD, Fowler SE, Goodman LR, et al. Multidetector Computed Tomography for Acute Pulmonary Embolism. N Engl J Med 2006;354(22):2317-2327.

PE – Case 2 MDCT – segmental embolus Therapy Enoxaparin 1mg/kg sq every 12 hours for 5 days Warfarin started day 1 at 5 mg a day CBC on day 3-5 and INR every day if inpatient May stop enoxaparin after 5 days if INR > 2.0 Warfarin continued to keep INR at 2.5 (2.0-3.0 range) for 3 months Heparin also an option but since outcome if tied to the rapidity of adequate anticoagulation, LMWH preferred due to its easier dosing. Check q2d CBC if using heparin. NO reason to delay warfarin. NO reason to load warfarin – only leads to higher rate of high INRs and bleeding complications. Must continue heparin or LMWH at least 5 days and ensure INR>2.0 prior to discontinuing.

VTE – Other Therapy Issues Anticoagulation same for DVT & PE Thrombolysis - risk/benefit uncertain; clinical outcomes generally not improved Vena cava filters Contraindication to anticoagulation Rarely survivors of massive PE Rare patients with recurrent VTE on adequate anticoagulation Prophylaxis in certain high risk patients PE – faster clot resolution in short term, but no documented improvement in mortality or symptom resolution DVT – possible isolated indication in massive VTE. NO reduction in postphlebitic syndrome. Contraindication to anicoagulation – recent surgery, CVA or active bleeding High risk patients for filter – cor pulmonale, prior VTE diagnosed with hip fx or cancer

VTE – Prevention Underutilized DVT-FREE prospective registry of 5,451 patients at 183 US hospitals Only 32% of medical patients with DVT received DVT prophylaxis Goldhaber S & Tapson V. Am J Cardiol 2004. Slide adapted from Dr. Michael Streiff. Anderson & Wheeler. Arch Surg 1992. Rahim, et al. Thromb Res 2003. Tapson, et al. Blood 2004

VTE – Prophylaxis in Medical Patients Indications CHF or severe respiratory disease Bedrest with additional risk factor Cancer Prior VTE Acute neurologic disease Inflammatory bowel disease Most ICU patients Options Low dose unfractionated heparin or LMWH Sequential compression devices Graduated compression stockings

Take Home Points DVT and PE are the same disease Assigning pretest probability for VTE is an essential step in diagnosis DVT & PE can diagnosed or excluded in many but not all patients using noninvasive means VTE for can be safely managed with heparin for at least 5 days and simultaneous warfarin without a loading dose Always consider VTE prophylaxis in inpatients