Venous Thromboembolism: Deep Venous Thrombosis and Pulmonary Embolism

Venous Thromboembolism: Deep Venous Thrombosis and Pulmonary Embolism MD Cardiovascular Interventions Orlando 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. 1

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 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. 2

Cancer Paralysis or plaster immobilization Bedrest > 3d or surgery in past 4 wks Localized tenderness DVT Wells Score The following were assigned a point value of 1 if present: 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) Stein PD, Hull RD, Patel KC, et al. D-dimer for the exclusion of acute venous thrombosis and pulmonary embolism: a systematic Dr. review. Pradip Jamnadas Ann Int Med. 2004;140(8):589-602 3

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 Sensitive d-dimer testing can rule out DVT in lowmoderate risk patients Our patient has a positive quantitative ELISA Unfortunately a positive d-dimer is not helpful diagnostically An imaging study is done DVT Case 1 DVT Imaging 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 4

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 5

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 PIOPED Study. JAMA. 1990;263(20):2753-59. Stein PD, Goldhaber SZ, Henry JW. Chest 1995;107:139-43 6

S1Q3T3 CXR FINDINGS Hampton s Hump: -wedge-shaped configuration at lung periphery due to infarcted lung Westermark sign: -pulmonary oligemia 7

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 8

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 9

PE Imaging Studies PIOPED study quantified the value of V/Q scans in diagnosing PE Normal/near-normal scans exclude PE in lowmoderate risk patients High probability scans confirm PE in moderatehigh 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 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. 10

PE PIOPED II Published June 2006 in NEJM 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 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 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 11

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. 45 40 35 30 25 20 15 10 5 0 US 1991 US 2001 Canada 2002 UK 2005 Anderson & Wheeler. Arch Surg 1992. Rahim, et al. Thromb Res 2003. Tapson, et al. Blood 2004 DVT / Pulmonary Embolism Diagnosed Clinically Stable Heparin Therapy Anticoagulation Contraindicated Interrupt IVC Shock, Clinically Unstable Thrombolytic Therapy Heparin Therapy Complication Adjust Dose Bleeding Recurrent PE Adjust Dose Complication Complication Adjust Dose Longterm Oral Anticoagulation Prophylaxis of Venous Thromboembolism Surgical Patients Risk Category Prophylactic Regimen Relative Risk Reduction Grade (Level of Evidence) Low risk Early ambulation C (III) Moderate risk LDUH, LMWH*, IPC, elastic stockings 60%-72% A (I) High risk LDUH, LMWH, IPC 60%-72% A (I) Highest risk LMWH, warfarin, IPC + LDUH or LMWH, adjusted-dose heparin 60%-72% B/A (I/I) Modified from Clagett GP, Anderson FA Jr, Geerts W, Heit JA, Knudson M, Lieberman JR, et al. Prevention of venous thromboembolism. Chest. 1998;114:531S-60S. 12

Prophylaxis of Venous Thromboembolism Surgical Patients Elective hip or knee replacement Hip fracture LMWH (start 12 to 24 h post-operatively) or warfarin (INR, 2.0-3.0; start preoperatively or immediately postoperatively) for at least 7 to 10 days; or adjusted-dose heparin. IPC and elastic stockings may be additive 45%-78% A (I) LMWH (preoperatively) or warfarin (INR, 2.0-3.0; start preoperatively or immediately postoperatively) 44%-50% A (I) LMWH 30%-58% A (I) Trauma IPC if LMWH is contraindicated Unclear C (III) IVC filter if DVT but LMWH is contraindicated Unclear C (III) Acute spinal cord injury Neurosurgical patients LMWH Unclear B (I) IPC + elastic stockings if anti-coagulants are contraindicated Unclear C (II) IPC 74% A (I) LMWH or LDUH may be acceptable, without added risk of bleeding Modified from Clagett GP, Anderson FA Jr, Geerts W, Heit JA, Knudson M, Lieberman JR, et al. Prevention of venous thromboembolism. Chest. 1998;114:531S-60S. Prophylaxis of Venous Thromboembolism Medical Patients Risk Category Prophylactic Regimen Relative Risk Reduction Grade (Level of Evidence) Acute myocardial infarction LDUH 71% A (I) Ischemic stroke LDUH or LMWH 63%-75% A (I) IPC + elastic stockings Unclear B (I) General medical patients LDUH or LMWH 55%-85% Long-term indwelling central venous catheter Warfarin (1 mg/d) or LMWH (once a day) A (I) (at risk) 75% A (I) For prevention of upper-extremity thrombosis. Modified from Clagett GP, Anderson FA Jr, Geerts W, Heit JA, Knudson M, Lieberman JR, et al. Prevention of venous thromboembolism. Chest. 1998;114:531S-60S. 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 13

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 CLASSIFICATIONS OF ANTICOAGULANTS Platelet Aggregation Inhibitors Plavix, Effient, Aspirin, Brilinta Direct Thrombin Inhibitors Angiomax & Pradaxa Factor Xa Inhibitors Eliquis, Savaysa, Xarelto Vitamin K Dependent Factor Inhibitors Coumadin Platelet Aggregation Inhibitors Dosing Onset Indications Pharmacodynamics Bioavailability Antidote Plavix 75 mg/qd 3 to 7 Days MI, CVA, PAD P2Y12 Inhibitor 50% Irreversible Effient 90 mg BID 6 Hours ACS w/pci P2Y12 Inhibitor 78% Irreversible Aspirin 81-325 mg/qd 1-2 Hours CVA Prevention, ACS, PVD, PCI w/stent COX-1 Inhibitor 50-75% Irreversible Brilinta 90 mg BID 2 Hours ACS P2Y12 Inhibitor 30-42% Irreversible 14

Direct Thrombin Inhibitors Dosing Onset Indications Pharmacodynamics Bioavailability Antidote Angiomax 1.75 mg/kg 15 Minutes HIT Inhibits Soluble & Clot-Bound Thrombin N/A Irreversible Pradaxa 150 mg BID 2-4 Hours CVA Prevention w/af Inhibits Soluble & Clot-Bound Thrombin 3-7% Idarucizumab Factor Xa Inhibitors Dosing Onset Indications Pharmacodynamics Bioavailability Antidote Eliquis 5-10 mg BID 3-4 Hours Non- Valvular AF, DVT FXa Inhibitor 50% Irreversible Savaysa 60 mg/qd 1-2 Hours Non- Valvular AF, DVT FXa Inhibitor 62% Irreversible Xarelto 10 mg/qd 36-72 Hours Non- Valvular AF, DVT FXa Inhibitor 80% Irreversible Vitamin K Dependent Factor Inhibitors Dosing Onset Indications Pharmacodynamics Bioavailability Antidote Coumadin 2-5 mg/qd then Adjust to INR 36-72 Hours DVT, PE, AF thromboembolic event prevention Reduced Synthesis Functional Clotting Factors II, XII, IX, and X Almost 100% Vitamin K 15

WHY USE NEW ANTICOAGULANTS Rapid Onset/Shorter Half-Life Fewer Drug and No Food Interactions No Lab Monitoring Equivalent to Warfarin Prevention of Stroke, VTE Bleeding Rates NEW ANTICOAGULANT DISADVANTAGES No Proven Reversal Agents No Monitoring DOSING ADJUSTMENTS Recommended dose of PRADAXA Based on Age and Renal Function CrCl > 30 ml/min CrCl 15-30 ml/min 150 mg twice daily 75 mg twice daily 16

CONVERTING PATIENTS ON PRADAXA TO AND FROM OTHER ANTICOAGULANTS Converting FROM warfarin: Discontinue warfarin and start PRADAXA when the INR is < 2.0 Converting TO warfarin: Adjust the starting time of warfarin based on CrCl as follows Recommended starting time of warfarin Creatinine Clearance 3 days before discontinuing PRADAXA > 50 ml/min 2 days before discontinuing PRADAXA 30-50 ml/min 1 days before discontinuing PRADAXA 15-30 ml/min No recommendations can be made < 15 ml/min DISCONTINUING THERAPY IN PATIENTS ON PRADAXA BEFORE SURGERY AND AFTER INTERVENTIONS If possible, discontinue PRADAXA 1 to 2 days (CrCl > 50mL/min) or 3 to 5 days (CrCl < 50 ml/min) before invasive or surgical procedures because of the increased risk of bleeding Consider longer times for patients undergoing major surgery, spinal puncture, or placement of a spinal epidural catheter or port, in whom complete hemostasis may be required XARELTO DOSING ADJUSTMENTS Reduce Stroke Risk in NONVALVULAR AF 20 mg ONCE DAILY CrCl >50 ml/min 15 mg ONCE DAILY CrCl 15-50 ml/min Treatment of DVT and PE Reduce risk of recurrent DVT and PE 15 mg TWICE DAILY 20 mg ONCE DAILY With food for first 21 days On day 22, with food 20 mg ONCE DAILY With food, at approx. same time each day Prophylaxis of DVT which may lead to PE after KNEE or HIP replacement surgery 10 mg ONCE DAILY KNEE: 12 days HIP: 35 days, first dose 6 to 12 hrs after surgery, provided that hemostasis is established 17

6 INDICATIONS APPROVED BY THE FDA 1)To reduce the risk of stroke and systemic embolism in patients with nonvalvular AF. There are limited data on the relative effectiveness of XARELTO and warfarin in reducing the risk of stroke and systemic embolism when warfarin therapy is well controlled 2)For the Treatment of DVT 3)For the treatment of PE 4)For the reduction in the risk of recurrence of DVT and of PE following initial 6 months treatment for DVT and/or PE 5)For the prophylaxis of DVT, which may lead to PE in patients undergoing knee replacement surgery 6)For the prophylaxis of DVT, which may lead to PE in patients undergoing hip surgery SWITCHING PATIENTS TO AND FROM XARELTO Switching to XARELTO From warfarin Stop warfarin and start XARELTO when INR is < 3.0 From unfractionated heparin Stop the infusion and start XARELTO at the same time From other anticoagulants Start XARELTO 0-2 hours prior to the next scheduled evening dose of the other anticoagulant Switching from XARELTO To warfarin One approach is to stop XARELTO and start parental anticoagulant and warfarin at the time of next scheduled XARELTO dose To other anticoagulants Stop XARELTO and start other anticoagulant when the next dose of XARELTO would have been given SAVAYSA DOSING ADJUSTMENTS 60 mg ONCE DAILY 30 mg ONCE DAILY Treatment of NVAF CrCl >50 to < 95 ml/min CrCl 15 to 50 ml/min 60 mg ONCE DAILY 30 mg ONCE DAILY Treatment of DVT and PE Recommended dose CrCl 15 to 50 ml/min or body weight less than or equal to 60 kg or who use certain P-gp inhibitors 18

ELIQUIS DOSING ADJUSTMENTS Stroke risk reduction in NVAF DVT and PE treatment and reduction in risk of recurrence 5 mg TWICE DAILY 2.5 mg TWICE DAILY Recommended dose For patients with at least 2 of the following: age >80 years, body weight < 60 kg, and/or serum creatinine > 1.5 mg/dl 10 mg TWICE DAILY 5 mg TWICE DAILY 2.5 mg TWICE DAILY Days 1-7 Following day 7 Following > 6 months of treatment for DVT or PE Prophylaxis of DVT after HIP or KNEE replacement surgery 2.5 mg TWICE DAILY The initial dose should be taken 12 to 24 hours after hip or knee replacement surgery: 35 day duration for HIP, 12 days duration for KNEE ANTITHROMBOTIC THERAPY FOR VENOUS THROMBOEMBOLIC DISEASES ----- ANTITHROMBOTIC THERAPY AND PREVENTION OF THROMBOSIS: ACCP EVIDENCE-BASED CLINICAL PRACTICE GUIDELINES, 9TH ED Introduction These slides present recommendations for the use of antithrombotic agents, as well as devices or surgical techniques, in the treatment of patients with : deep venous thrombosis (DVT) pulmonary embolism (PE) DVT and PE are collectively referred to as venous thromboembolism (VTE) They also present recommendations for patients with: postthrombotic syndrome (PTS) chronic thromboembolic pulmonary hypertension (CTEPH) incidentally diagnosed (asymptomatic) DVT or PE acute upper extremity DVT (UEDVT) superficial vein thrombosis (SVT) splanchnic vein thrombosis hepatic vein thrombosis 19

Initial Anticoagulation for Patients With Acute DVT of the Leg In patients with acute DVT of the leg treated with VKA therapy, we recommend initial treatment with parenteral anticoagulation (LMWH, fondaparinux, IV UFH, or SC UFH) over no such initial treatment (Grade 1B). Parenteral Anticoagulation Prior to Receipt of the Results of Diagnostic Work-up for VTE In patients with a high clinical suspicion of acute VTE, we suggest treatment with parenteral anticoagulants compared with no treatment while awaiting the results of diagnostic tests (Grade 2C). Parenteral Anticoagulation Prior to Receipt of the Results of Diagnostic Workup for VTE In patients with a low clinical suspicion of acute VTE, we suggest not treating with parenteral anticoagulants while awaiting the results of diagnostic tests, provided test results are expected within 24 h (Grade 2C). 20

Anticoagulation in Patients With Isolated Distal DVT In patients with acute isolated distal DVT of the leg and without severe symptoms or risk factors for extension, we suggest serial imaging of the deep veins for 2 weeks over initial anticoagulation (Grade 2C). Anticoagulation in Patients With Isolated Distal DVT In patients with acute isolated distal DVT of the leg and severe symptoms or risk factors for extension (see text), we suggest initial anticoagulation over serial imaging of the deep veins (Grade 2C). Remarks: Patients at high risk for bleeding are more likely to benefit from serial imaging. Patients who place a high value on avoiding the inconvenience of repeat imaging and a low value on the inconvenience of treatment and on the potential for bleeding are likely to choose initial anticoagulation over serial imaging. Anticoagulation in Patients With Isolated Distal DVT In patients with acute isolated distal DVT of the leg who are managed with initial anticoagulation, we recommend using the same approach as for patients with acute proximal DVT (Grade 1B). 21

Anticoagulation in Patients With Isolated Distal DVT In patients with acute isolated distal DVT of the leg who are managed with serial imaging, we recommend no anticoagulation if the thrombus does not extend (Grade 1B); we suggest anticoagulation if the thrombus extends but remains confined to the distal veins (Grade 2C); we recommend anticoagulation if the thrombus extends into the proximal veins (Grade 1B). Anticoagulation in Patients With Isolated Distal DVT In patients with acute isolated distal DVT of the leg who are managed with initial anticoagulation, we recommend using the same approach as for patients with acute proximal DVT (Grade 1B). Anticoagulation in Patients With Isolated Distal DVT In patients with acute isolated distal DVT of the leg who are managed with serial imaging, we recommend no anticoagulation if the thrombus does not extend (Grade 1B); we suggest anticoagulation if the thrombus extends but remains confined to the distal veins (Grade 2C); we recommend anticoagulation if the thrombus extends into the proximal veins (Grade 1B). 22

Timing of Initiation of VKA and Associated Duration of Parenteral Anticoagulant Therapy In patients with acute DVT of the leg, we recommend early initiation of VKA (eg, same day as parenteral therapy is started) over delayed initiation, and continuation of parenteral anticoagulation for a minimum of 5 days and until the international normalized ratio (INR) is 2.0 or above for at least 24 h (Grade 1B). Choice of Initial Anticoagulant Regimen in Patients With Proximal DVT In patients with acute DVT of the leg, we suggest LMWH or fondaparinux over IV UFH (Grade 2C) and over SC UFH (Grade 2B for LMWH; Grade 2C for fondaparinux). Remarks: Local considerations such as cost, availability, and familiarity of use dictate the choice between fondaparinux and LMWH. LMWH and fondaparinux are retained in patients with renal impairment, whereas this is not a concern with UFH. Choice of Initial Anticoagulant Regimen in Patients With Proximal DVT In patients with acute DVT of the leg treated with LMWH, we suggest once- over twice-daily administration (Grade 2C). Remarks: This recommendation only applies when the approved once-daily regimen uses the same daily dose as the twice-daily regimen (ie, the once-daily injection contains double the dose of each twice-daily injection). It also places value on avoiding an extra injection per day. 23

At-Home vs In-Hospital Initial Treatment of Patients With DVT In patients with acute DVT of the leg and whose home circumstances are adequate, we recommend initial treatment at home over treatment in hospital (Grade 1B). Remarks: The recommendation is conditional on the adequacy of home circumstances: well-maintained living conditions, strong support from family or friends, phone access, and ability to quickly return to the hospital if there is deterioration. It is also conditional on the patient feeling well enough to be treated at home (eg, does not have severe leg symptoms or comorbidity). Catheter-Directed Thrombolysis for Patients With Acute DVT In patients with acute proximal DVT of the leg, we suggest anticoagulant therapy alone over catheter-directed thrombolysis (CDT) (Grade 2C). Remarks: Patients who are most likely to benefit from CDT (see text), who attach a high value to prevention of postthrombotic syndrome (PTS), and a lower value to the initial complexity, cost, and risk of bleeding with CDT, are likely to choose CDT over anticoagulation alone. Systemic Thrombolytic Therapy for Patients With Acute DVT In patients with acute proximal DVT of the leg, we suggest anticoagulant therapy alone over systemic thrombolysis (Grade 2C). Remarks: Patients who are most likely to benefit from systemic thrombolytic therapy (see text), who do not have access to CDT, and who attach a high value to prevention of PTS, and a lower value to the initial complexity, cost, and risk of bleeding with systemic thrombolytic therapy, are likely to choose systemic thrombolytic therapy over anticoagulation alone. 24

Operative Venous Thrombectomy for Acute DVT In patients with acute proximal DVT of the leg, we suggest anticoagulant therapy alone over operative venous thrombectomy (Grade 2C). Anticoagulation in Patients Who Have Had Any Method of Thrombus Removal Performed In patients with acute DVT of the leg who undergo thrombosis removal, we recommend the same intensity and duration of anticoagulant therapy as in comparable patients who do not undergo thrombosis removal (Grade 1B). Vena Cava Filters for the Initial Treatment of Patients With DVT In patients with acute DVT of the leg, we recommend against the use of an IVC filter in addition to anticoagulants (Grade 1B). 25

Vena Cava Filters for the Initial Treatment of Patients With DVT In patients with acute proximal DVT of the leg and contraindication to anticoagulation, we recommend the use of an IVC filter (Grade 1B). Vena Cava Filters for the Initial Treatment of Patients With DVT In patients with acute proximal DVT of the leg and an IVC filter inserted as an alternative to anticoagulation, we suggest a conventional course of anticoagulant therapy if their risk of bleeding resolves (Grade 2B). Remarks: We do not consider that a permanent IVC filter, of itself, is an indication for extended anticoagulation. Early Ambulation of Patients With Acute DVT In patients with acute DVT of the leg, we suggest early ambulation over initial bed rest (Grade 2C). Remarks: If edema and pain are severe, ambulation may need to be deferred. As per section 4.1, we suggest the use of compression therapy in these patients. 26

Long-term Anticoagulation in Patients With Acute DVT of the Leg In patients with acute VTE who are treated with anticoagulant therapy, we recommend long-term therapy (see section 3.1 for recommended duration of therapy) over stopping anticoagulant therapy after about 1 week of initial therapy (Grade 1B). Duration of Long-term Anticoagulant Therapy In patients with a proximal DVT of the leg provoked by surgery, we recommend treatment with anticoagulation for 3 months over (i) treatment of a shorter period (Grade 1B), (ii) treatment of a longer time-limited period (eg, 6 or 12 months) (Grade 1B), or (iii) extended therapy (Grade 1B regardless of bleeding risk). Duration of Long-term Anticoagulant Therapy In patients with a proximal DVT of the leg provoked by a nonsurgical transient risk factor, we recommend treatment with anticoagulation for 3 months over (i) treatment of a shorter period (Grade 1B), (ii) treatment of a longer timelimited period (eg, 6 or 12 months) (Grade 1B), and (iii) extended therapy if there is a high bleeding risk (Grade 1B). We suggest treatment with anticoagulation for 3 months over extended therapy if there is a low or moderate bleeding risk (Grade 2B). 27

Duration of Long-term Anticoagulant Therapy In patients with an isolated distal DVT of the leg provoked by surgery or by a nonsurgical transient risk factor (see remark), we suggest treatment with anticoagulation for 3 months over treatment of a shorter period (Grade 2C) and recommend treatment with anticoagulation for 3 months over treatment of a longer time-limited period (eg, 6 or 12 months) (Grade 1B) or extended therapy (Grade 1B regardless of bleeding risk). Duration of Long-term Anticoagulant Therapy In patients with an unprovoked DVT of the leg (isolated distal [see remark] or proximal), we recommend treatment with anticoagulation for at least 3 months over treatment of a shorter duration (Grade 1B). After 3 months of treatment, patients with unprovoked DVT of the leg should be evaluated for the risk-benefit ratio of extended therapy. Duration of Long-term Anticoagulant Therapy In patients with a first VTE that is an unprovoked proximal DVT of the leg and who have a low or moderate bleeding risk, we suggest extended anticoagulant therapy over 3 months of therapy (Grade 2B). 28

Duration of Long-term Anticoagulant Therapy In patients with a first VTE that is an unprovoked proximal DVT of the leg and who have a high bleeding risk, we recommend 3 months of anticoagulant therapy over extended therapy (Grade 1B). Duration of Long-term Anticoagulant Therapy In patients with a first VTE that is an unprovoked isolated distal DVT of the leg (see remark), we suggest 3 months of anticoagulant therapy over extended therapy in those with a low or moderate bleeding risk (Grade 2B) and recommend 3 months of anticoagulant treatment in those with a high bleeding risk (Grade 1B). Duration of Long-term Anticoagulant Therapy In patients with a second unprovoked VTE, we recommend extended anticoagulant therapy over 3 months of therapy in those who have a low bleeding risk (Grade 1B), and we suggest extended anticoagulant therapy in those with a moderate bleeding risk (Grade 2B). 29

Duration of Long-term Anticoagulant Therapy In patients with a second unprovoked VTE who have a high bleeding risk, we suggest 3 months of anticoagulant therapy over extended therapy (Grade 2B). Duration of Long-term Anticoagulant Therapy In patients with DVT of the leg and active cancer, if the risk of bleeding is not high, we recommend extended anticoagulant therapy over 3 months of therapy (Grade 1B), and if there is a high bleeding risk, we suggest extended anticoagulant therapy (Grade 2B). Remarks (3.1.3, 3.1.4, 3.1.4.3): Duration of treatment of patients with isolated distal DVT refers to patients in whom a decision has been made to treat with anticoagulant therapy; however, it is anticipated that not all patients who are diagnosed with isolated distal DVT will be given anticoagulants (see section 2.3). In all patients who receive extended anticoagulant therapy, the continuing use of treatment should be reassessed at periodic intervals (eg, annually). Intensity of Anticoagulant Effect In patients with DVT of the leg who are treated with VKA, we recommend a therapeutic INR range of 2.0 to 3.0 (target INR of 2.5) over a lower (INR < 2) or higher (INR 3.0-5.0) range for all treatment durations (Grade 1B). 30