Chest 2008 Warfarin in DVT

DOI 10.1378/chest.08-0658 2008;133;454S-545SChest

Gary E. Raskob and Anthony J. ComerotaClive Kearon, Susan R. Kahn, Giancarlo Agnelli, Samuel Goldhaber, Clinical Practice Guidelines (8th Edition)

Evidence-BasedCollege of Chest Physicians : American*Thromboembolic Disease

Antithrombotic Therapy for Venous

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Antithrombotic Therapy for VenousThromboembolic Disease*

American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition)

Clive Kearon, MB, PhD; Susan R. Kahn, MD; Giancarlo Agnelli, MD;Samuel Goldhaber, MD, FCCP; Gary E. Raskob, PhD;and Anthony J. Comerota, MD

This chapter about treatment for venous thromboembolic disease is part of the American College of ChestPhysicians Evidence-Based Clinical Practice Guidelines (8th Edition). Grade 1 recommendations are strongand indicate that the benefits do or do not outweigh risks, burden, and costs. Grade 2 suggests that individualpatient values may lead to different choices (for a full understanding of the grading, see “Grades ofRecommendation” chapter). Among the key recommendations in this chapter are the following: for patientswith objectively confirmed deep vein thrombosis (DVT) or pulmonary embolism (PE), we recommendanticoagulant therapy with subcutaneous (SC) low-molecular-weight heparin (LMWH), monitored IV, or SCunfractionated heparin (UFH), unmonitored weight-based SC UFH, or SC fondaparinux (all Grade 1A). Forpatients with a high clinical suspicion of DVT or PE, we recommend treatment with anticoagulants whileawaiting the outcome of diagnostic tests (Grade 1C). For patients with confirmed PE, we recommend earlyevaluation of the risks to benefits of thrombolytic therapy (Grade 1C); for those with hemodynamiccompromise, we recommend short-course thrombolytic therapy (Grade 1B); and for those with nonmassivePE, we recommend against the use of thrombolytic therapy (Grade 1B). In acute DVT or PE, werecommend initial treatment with LMWH, UFH or fondaparinux for at least 5 days rather than a shorterperiod (Grade 1C); and initiation of vitamin K antagonists (VKAs) together with LMWH, UFH, orfondaparinux on the first treatment day, and discontinuation of these heparin preparations when theinternational normalized ratio (INR) is > 2.0 for at least 24 h (Grade 1A). For patients with DVT or PEsecondary to a transient (reversible) risk factor, we recommend treatment with a VKA for 3 months overtreatment for shorter periods (Grade 1A). For patients with unprovoked DVT or PE, we recommendtreatment with a VKA for at least 3 months (Grade 1A), and that all patients are then evaluated for the risksto benefits of indefinite therapy (Grade 1C). We recommend indefinite anticoagulant therapy for patientswith a first unprovoked proximal DVT or PE and a low risk of bleeding when this is consistent with thepatient’s preference (Grade 1A), and for most patients with a second unprovoked DVT (Grade 1A). Werecommend that the dose of VKA be adjusted to maintain a target INR of 2.5 (INR range, 2.0 to 3.0) for alltreatment durations (Grade 1A). We recommend at least 3 months of treatment with LMWH for patientswith VTE and cancer (Grade 1A), followed by treatment with LMWH or VKA as long as the cancer is active(Grade 1C). For prevention of postthrombotic syndrome (PTS) after proximal DVT, we recommend use ofan elastic compression stocking (Grade 1A). For DVT of the upper extremity, we recommend similartreatment as for DVT of the leg (Grade 1C). Selected patients with lower-extremity (Grade 2B) andupper-extremity (Grade 2C). DVT may be considered for thrombus removal, generally using catheter-basedthrombolytic techniques. For extensive superficial vein thrombosis, we recommend treatment with prophy-lactic or intermediate doses of LMWH or intermediate doses of UFH for 4 weeks (Grade 1B).

(CHEST 2008; 133:454S–545S)

Key words: cancer; chronic thromboembolic pulmonary hypertension; deep vein thrombosis; fondaparinux; low-molecular-weightheparin; plasminogen activator; pulmonary embolism; thrombectomy; thrombolytic therapy; thrombophlebitis; unfractionated heparin;vena caval filter; venous thromboembolism; vitamin K antagonist

Abbreviations: APTT � activated partial thromboplastin time; CDT � catheter-directed thrombolysis; CI � confidence interval;CTPH � chronic thromboembolic pulmonary hypertension; DVT � deep venous thrombosis; INR � international normalized ratio;IPC � intermittent pneumatic compression; IVC � inferior vena cava; LMWH � low-molecular-weight heparin;MPFF � micronized purified flavonoid fraction; NSAID � nonsteroidal antiinflammatory drug; OR � odds ratio; PE � pulmonaryembolism; PTS � postthrombotic (phlebitic) syndrome; QOL � quality of life; RCT � randomized controlled trial; RR � relative risk;rt-PA � recombinant tissue plasminogen activator; SC � subcutaneous; SVC � superior vena cava; SVT � superficial venous throm-bosis; tPA � tissue plasminogen activator; UEDVT � upper-extremity deep vein thrombosis; UFH � unfractionated heparin;VKA � vitamin K antagonist; VTE � venous thromboembolism

SupplementANTITHROMBOTIC AND THROMBOLYTIC THERAPY 8TH ED: ACCP GUIDELINES

454S Antithrombotic and Thrombolytic Therapy 8th Ed: ACCP Guidelines



Summary of Recommendations

1.1 Initial Anticoagulation of Acute DVT of the Leg

1.1.1. For patients with objectively confirmedDVT, we recommend short-term treatmentwith SC LMWH (Grade 1A), IV UFH (Grade 1A),monitored SC UFH (Grade 1A), fixed-dose SCUFH (Grade 1A), or SC fondaparinux (Grade 1A)rather than no such short-term treatment.1.1.2. For patients with a high clinical suspicionof DVT, we recommend treatment with antico-agulants while awaiting the outcome of diagnos-tic tests (Grade 1C).1.1.3. In patients with acute DVT, we recom-mend initial treatment with LMWH, UFH, orfondaparinux for at least 5 days and until theINR is > 2.0 for 24 h (Grade 1C).1.1.4. In patients with acute DVT, we recom-mend initiation of VKA together with LMWH,UFH, or fondaparinux on the first treatmentday rather than delayed initiation of VKA(Grade 1A).

1.2 IV UFH for the Initial Treatment of DVT

1.2.1. In patients with acute DVT, if IV UFH ischosen, we recommend that after an initial IVbolus (80 U/kg or 5,000 U), it be administeredby continuous infusion (initially at a dose of 18U/kg/h or 1,300 U/h) with dose adjustment toachieve and maintain an activated partialthromboplastin time (APTT) prolongation thatcorresponds to plasma heparin levels of 0.3 to0.7 IU/mL anti-Xa activity by the amidolyticassay rather than administration as IV bolusesthroughout treatment, or administration with-out coagulation monitoring (Grade 1C).

1.3 SC UFH Compared With IV Heparin for theInitial Treatment of DVT

1.3.1. In patients with acute DVT, if monitored SCUFH is chosen, we recommend an initial dose of17,500 U, or a weight-adjusted dose of about 250U/kg bid, with dose adjustment to achieve andmaintain an APTT prolongation that correspondsto plasma heparin levels of 0.3 to 0.7 IU/mLanti-Xa activity when measured 6 h after injectionrather than starting with a smaller initial dose (seealso Section 1.5) [Grade 1C].1.3.2. In patients with acute DVT, if fixed-dose,unmonitored SC UFH is chosen, we recommendan initial dose of 333 U/Kg followed by 250 U/kgbid rather than non–weight-based dosing (seealso Section 1.5) [Grade 1C].

1.4 LMWH for the Initial Treatment of DVT

1.4.1. In patients with acute DVT, we recom-mend initial treatment with LMWH SC once ortwice daily, as an outpatient if possible (Grade1C), or as an inpatient if necessary (Grade 1A),rather than treatment with IV UFH.1.4.2. In patients with acute DVT treated withLMWH, we recommend against routine moni-toring with anti-factor Xa level measurements(Grade 1A).1.4.3. In patients with acute DVT and severerenal failure, we suggest UFH over LMWH(Grade 2C).

1.9 Catheter-Directed Thrombolysis for Acute DVT

1.9.1. In selected patients with extensive acuteproximal DVT (eg, iliofemoral DVT, symptoms for< 14 days, good functional status, life expectancy of> 1 year) who have a low risk of bleeding, wesuggest that catheter-directed thrombolysis (CDT)may be used to reduce acute symptoms and post-thrombotic morbidity if appropriate expertise andresources are available (Grade 2B).1.9.2. After successful CDT in patients withacute DVT, we suggest correction of underlyingvenous lesions using balloon angioplasty and stents(Grade 2C).1.9.3. We suggest pharmacomechanical throm-bolysis (eg, with inclusion of thrombus fragmen-tation and/or aspiration) in preference to CDTalone to shorten treatment time if appropriateexpertise and resources are available (Grade 2C).1.9.4. After successful CDT in patients with acuteDVT, we recommend the same intensity andduration of anticoagulant therapy as for compa-rable patients who do not undergo CDT (Grade1C).

*From McMaster University Clinic (Dr. Kearon), HendersonGeneral Hospital, Hamilton, ON, Canada; Thrombosis Clinicand Centre for Clinical Epidemiology and Community Studies(Dr. Kahn), Sir Mortimer B. Davis Jewish General Hospital,Montreal, QC, Canada; University of Perugia (Dr. Agnelli),Perugia, Italy; Brigham and Women’s Hospital (Dr. Goldhaber),Boston, MA; College of Public Health, University of OklahomaHealth Science Center (Dr. Raskob), Oklahoma City, OK; andJobst Vascular Center (Dr. Comerota), Toledo, OH.Manuscript accepted December 20, 2007.Reproduction of this article is prohibited without written permissionfrom the American College of Chest Physicians (www.chestjournal.org/misc/reprints.shtml).Correspondence to: Clive Kearon, MB, PhD, Hamilton HealthSciences, Henderson Division, 711 Concession St, Hamilton, ON,L8V 1C3, Canada; e-mail: [email protected]: 10.1378/chest.08-0658

www.chestjournal.org CHEST / 133 / 6 / JUNE, 2008 SUPPLEMENT 455S



1.10 Systemic Thrombolytic Therapy forAcute DVT

1.10.1. In selected patients with extensive prox-imal DVT (eg, symptoms for < 14 days, goodfunctional status, life expectancy of > 1 year)who have a low risk of bleeding, we suggest thatsystemic thrombolytic therapy may be used toreduce acute symptoms and postthromboticmorbidity if CDT is not available (Grade 2C).

1.11 Percutaneous Venous Thrombectomy

1.11.1. In patients with acute DVT, we suggestthat they should not be treated with percutaneousmechanical thrombectomy alone (Grade 2C).

1.12 Operative Venous Thrombectomy forAcute DVT

1.12.1. In selected patients with acute iliofemoralDVT (eg, symptoms for < 7 days, good functionalstatus, and life expectancy of > 1 year), we sug-gest that operative venous thrombectomy may beused to reduce acute symptoms and postthrom-botic morbidity if appropriate expertise and re-sources are available (Grade 2B). If such patientsdo not have a high risk of bleeding, we suggestthat catheter-directed thrombolysis is usuallypreferable to operative venous thrombectomy(Grade 2C).1.12.2. In patients who undergo operative venousthrombectomy, we recommend the same inten-sity and duration of anticoagulant therapy after-wards as for comparable patients who do notundergo venous thrombectomy (Grade 1C).

1.13 Vena Caval Filters for the Initial Treatmentof DVT

1.13.1. For patients with DVT, we recommendagainst the routine use of a vena cava filter inaddition to anticoagulants (Grade 1A).1.13.2. For patients with acute proximal DVT,if anticoagulant therapy is not possible be-cause of the risk of bleeding, we recommendplacement of an inferior vena cava (IVC) filter(Grade 1C).1.13.3. For patients with acute DVT who havean IVC filter inserted as an alternative toanticoagulation, we recommend that theyshould subsequently receive a conventionalcourse of anticoagulant therapy if their risk ofbleeding resolves (Grade 1C).

1.14 Immobilization for the Treatment ofAcute DVT

1.14.1. In patients with acute DVT, we recom-mend early ambulation in preference to initialbed rest when this is feasible (Grade 1A).

2.1 Duration of Anticoagulant Therapy

2.1.1. For patients with DVT secondary to atransient (reversible) risk factor, we recom-mend treatment with a VKA for 3 months overtreatment for shorter periods (Grade 1A).2.1.2. For patients with unprovoked DVT, werecommend treatment with a VKA for at least 3months (Grade 1A). We recommend that after 3months of anticoagulant therapy, all patients withunprovoked DVT should be evaluated for therisk-benefit ratio of long-term therapy (Grade 1C).For patients with a first unprovoked VTE that is aproximal DVT, and in whom risk factors forbleeding are absent and for whom good anticoag-ulant monitoring is achievable, we recommendlong-term treatment (Grade 1A).Values and preferences: This recommendation attachesa relatively high value to prevention of recurrent VTEand a lower value to the burden of long-term antico-agulant therapy.

For patients with a second episode of unpro-voked VTE, we recommend long-term treat-ment (Grade 1A). For patients with a first iso-lated distal DVT that is unprovoked, we suggestthat 3 months of anticoagulant therapy is suffi-cient rather than indefinite therapy (Grade 2B).2.1.3. For patients with DVT and cancer, werecommend LMWH for the first 3 to 6 monthsof long-term anticoagulant therapy (Grade 1A).For these patients, we recommend subsequentanticoagulant therapy with VKA or LMWH in-definitely or until the cancer is resolved (also,see Section 2.4) [Grade 1C].2.1.4. In patients who receive long-term anticoagu-lant treatment, the risk-benefit ratio of continuingsuch treatment should be reassessed in the individ-ual patient at periodic intervals (Grade 1C).

2.2 Intensity of Anticoagulant Effect

2.2.1. In patients with DVT, we recommendthat the dose of VKA be adjusted to maintain atarget INR of 2.5 (range, 2.0 to 3.0) for alltreatment durations (Grade 1A). For patientswith unprovoked DVT who have a strong pref-erence for less frequent INR testing to monitortheir therapy, after the first 3 months of con-




ventional-intensity anticoagulation (INR range,2.0 to 3.0), we recommend low-intensity ther-apy (range, 1.5 to 1.9) with less frequent INRmonitoring over stopping treatment (Grade 1A).We recommend against high-intensity VKAtherapy (INR range, 3.1 to 4.0) compared to anINR range of 2.0 to 3.0 (Grade 1A).

2.6 Treatment of Asymptomatic DVT of the Leg

2.6.1. In patients who are unexpectedly foundto have asymptomatic DVT, we recommend thesame initial and long-term anticoagulation asfor comparable patients with symptomatic DVT(Grade 1C).

3.1 Elastic Stockings and Compression BandagesTo Prevent PTS

3.1.1. For a patient who has had a symptomaticproximal DVT, we recommend the use of anelastic compression stocking with an ankle pres-sure gradient of 30 to 40 mm Hg if feasible(Grade 1A). Compression therapy, which mayinclude use of bandages acutely, should bestarted as soon as feasible after starting antico-agulant therapy and should be continued for aminimum of 2 years, and longer if patients havesymptoms of PTS. (Note: feasibility, both shortand long term, refers to ability of patients andtheir caregivers to apply and remove stockings.)Values and preferences: This recommendation at-taches a relatively high value to long-term preventionof the PTS and a low value to the burden (eg,inconvenience or discomfort) associated with wear-ing stockings.

3.2 Physical Treatment of PTS Without Venous LegUlcers

3.2.1. For patients with severe edema of the legdue to PTS, we suggest a course of intermittentpneumatic compression (IPC) [Grade 2B].3.2.2. For patients with mild edema of the legdue to PTS, we suggest the use of elastic com-pression stockings (Grade 2C).

3.3 Physical Treatment of Venous Leg Ulcers

3.3.1. In patients with venous ulcers resistant tohealing with wound care and compression, wesuggest the addition of IPC (Grade 2B).

3.4 Hyperbaric Oxygen and the Management ofPatients With Venous Ulcers

3.4.1. For patients with venous ulcers, we suggestthat hyperbaric oxygen not be used (Grade 2B).

3.5.1. Pentoxifylline

3.5.1. In patients with venous leg ulcers, wesuggest pentoxifylline, 400 mg po tid, in addi-tion to local care and compression and/or IPC(Grade 2B).

3.5.2. Micronized Purified Flavonoid Fraction orSulodexide for the Treatment of Venous Leg Ulcers

3.5.2. In patients with persistent venous ulcers,we suggest that rutosides, in the form of mi-cronized purified flavonoid fraction adminis-tered orally, or sulodexide administered intra-muscularly and then orally, be added to localcare and compression (Grade 2B).

4.1 IV or SC UFH, SC LMWH, SC Fondaparinux,and VKA for the Initial Treatment of PE

4.1.1. For patients with objectively confirmed PE,we recommend short-term treatment with SCLMWH (Grade 1A), IV UFH (Grade 1A), moni-tored SC UFH (Grade 1A), fixed-dose SC UFH(Grade 1A), or SC fondaparinux (Grade 1A) ratherthan no such acute treatment. Patients with acutePE should also be routinely assessed for treat-ment with thrombolytic therapy (see Section 4.3for related discussion and recommendations).4.1.2. For patients in whom there is a high clinicalsuspicion of PE, we recommend treatment withanticoagulants while awaiting the outcome of di-agnostic tests (Grade 1C).4.1.3. In patients with acute PE, we recommendinitial treatment with LMWH, UFH or fondapa-rinux for at least 5 days and until the INR is > 2.0for at least 24 h (Grade 1C).4.1.4. In patients with acute PE, we recommendinitiation of VKA together with LMWH, UFH, orfondaparinux on the first treatment day ratherthan delayed initiation of VKA (Grade 1A).4.1.5. In patients with acute PE, if IV UFH ischosen, we recommend that after an initial IVbolus (80 U/kg or 5,000 U), it be administered bycontinuous infusion (initially at dose of 18 U/kg/hor 1,300 U/h) with dose adjustment to achieve andmaintain an APTT prolongation that correspondsto plasma heparin levels of 0.3 to 0.7 IU/mLanti-Xa activity by the amidolytic assay ratherthan administration as IV boluses throughouttreatment, or administration without coagulationmonitoring (Grade 1C).4.1.6. In patients with acute PE, if monitored SCUFH is chosen, we recommend an initial dose of17,500 U, or a weight-adjusted dose of approxi-mately 250 U/kg bid, with dose adjustment to




achieve and maintain an APTT prolongation thatcorresponds to plasma heparin levels of 0.3 to 0.7IU/mL anti-Xa activity when measured 6 h afterinjection rather than starting with a smaller initialdose (Grade 1C).4.1.7. In patients with acute PE, if fixed-dose,unmonitored SC UFH is chosen, we recommendan initial dose of 333 U/Kg followed by a twice-daily dose of 250 U/kg rather than non–weight-based dosing (Grade 1C).4.1.8. In patients with acute nonmassive PE, werecommend initial treatment with LMWH over IVUFH (Grade 1A). In patients with massive PE, inother situations where there is concern about SCabsorption, or in patients for whom thrombolytictherapy is being considered or planned, we sug-gest IV UFH over SC LMWH, SC fondaparinux,or SC UFH (Grade 2C).4.1.9. In patients with acute PE treated withLMWH, we recommend against routine monitor-ing with anti-factor Xa level measurements (Grade1A).4.1.10. In patients with acute PE and severe renalfailure, we suggest UFH over LMWH (Grade 2C).

4.3 Systemically and Locally AdministeredThrombolytic Therapy for PE

4.3.1. All PE patients should undergo rapidrisk stratification (Grade 1C). For patientswith evidence of hemodynamic compromise,we recommend use of thrombolytic therapyunless there are major contraindications ow-ing to bleeding risk (Grade 1B). Thrombolysisin these patients should not be delayed be-cause irreversible cardiogenic shock may en-sue. In selected high-risk patients withouthypotension who are judged to have a low riskof bleeding, we suggest administration ofthrombolytic therapy (Grade 2B). The decisionto use thrombolytic therapy depends on theclinician’s assessment of PE severity, progno-sis, and risk of bleeding. For the majority ofpatients with PE, we recommend against us-ing thrombolytic therapy (Grade 1B).4.3.2. In patients with acute PE, when a thrombo-lytic agent is used, we recommend that treatmentbe administered via a peripheral vein rather thanplacing a pulmonary artery catheter to administertreatment (Grade 1B).4.3.3. In patients with acute PE, with administra-tion of thrombolytic therapy, we recommend useof regimens with short infusion times (eg, a 2-hinfusion) over those with prolonged infusiontimes (eg, a 24-h infusion) [Grade 1B].

4.4 Catheter Extraction or Fragmentation for theInitial Treatment of PE

4.4.1. For most patients with PE, we recom-mend against use of interventional catheteriza-tion techniques (Grade 1C). In selected highlycompromised patients who are unable to re-ceive thrombolytic therapy because of bleedingrisk, or whose critical status does not allowsufficient time for systemic thrombolytic ther-apy to be effective, we suggest use of interven-tional catheterization techniques if appropriateexpertise is available (Grade 2C).

4.5 Pulmonary Embolectomy for the InitialTreatment of PE

4.5.1. In selected highly compromised patientswho are unable to receive thrombolytic therapybecause of bleeding risk, or whose critical sta-tus does not allow sufficient time for systemicthrombolytic therapy to be effective, we suggestthat pulmonary embolectomy may be used ifappropriate expertise is available (Grade 2C).

4.6 Vena Caval Filters for the Initial Treatmentof PE

4.6.1. For most patients with PE, we recom-mend against the routine use of a vena cavalfilter in addition to anticoagulants (Grade 1A).4.6.2. In patients with acute PE, if anticoagu-lant therapy is not possible because of risk ofbleeding, we recommend placement of an IVC filter(Grade 1C).4.6.3. For patients with acute PE who have an IVCfilter inserted as an alternative to anticoagulation,we recommend that they should subsequently re-ceive a conventional course of anticoagulant ther-apy if their risk of bleeding resolves (Grade 1C).

5.0 Long-term Treatment of Acute PE

5.1.1. For patients with PE secondary to a tran-sient (reversible) risk factor, we recommend treat-ment with a VKA for 3 months over treatment forshorter periods (Grade 1A).5.1.2. For patients with unprovoked PE, we rec-ommend treatment with a VKA for at least 3months (Grade 1A). We recommend that after 3months of anticoagulant therapy, all patients withunprovoked PE should be evaluated for the risk-benefit ratio of long-term therapy (Grade 1C). Forpatients with a first unprovoked episode of VTEthat is a PE, and in whom risk factors for bleedingare absent and for whom good anticoagulant




monitoring is achievable, we recommend long-term treatment (Grade 1A).Values and preferences: This recommendation attachesa relatively high value to prevention of recurrent VTEand a lower value to the burden of long-term antico-agulant therapy.

For patients with a second episode of unpro-voked VTE, we recommend long-term treatment(Grade 1A).5.1.3. For patients with PE and cancer, we recom-mend LMWH for the first 3 to 6 months of long-term anticoagulant therapy (Grade 1A). For thesepatients, we recommend subsequent anticoagulanttherapy with VKA or LMWH indefinitely or untilthe cancer is resolved (Grade 1C).5.1.4. In patients who receive long-term anticoagu-lant treatment, the risk-benefit ratio of continuingsuch treatment should be reassessed in the individ-ual patient at periodic intervals (Grade 1C).5.1.5. In patients with PE, we recommend that thedose of VKA be adjusted to maintain a target INRof 2.5 (INR range, 2.0 to 3.0) for all treatmentdurations (Grade 1A). For patients with unpro-voked PE who have a strong preference for lessfrequent INR testing to monitor their therapy,after the first 3 months of conventional-intensityanticoagulation (INR range, 2.0 to 3.0), we rec-ommend low-intensity therapy (INR range, 1.5 to1.9) with less frequent INR monitoring over stop-ping treatment (Grade 1A). We recommendagainst high-intensity VKA therapy (INR range,3.1 to 4.0) compared with an INR range of 2.0 to3.0 (Grade 1A).5.1.6. In patients who are unexpectedly found tohave asymptomatic PE, we recommend the sameinitial and long-term anticoagulation as for com-parable patients with symptomatic PE (Grade 1C).

6.1 Pulmonary Thromboendarterectomy, VKA, andVena Caval Filter for the Treatment of ChronicThromboembolic Pulmonary Hypertension

6.1.1. In selected patients with chronic throm-boembolic pulmonary hypertension (CTPH),such as those with central disease under thecare of an experienced surgical/medical team,we recommend pulmonary thromboendarterec-tomy (Grade 1C).6.1.2. For all patients with CTPH, we recom-mend life-long treatment with a VKA targetedto an INR of 2.0 to 3.0 (Grade 1C).6.1.3. For patients with CTPH undergoing pulmo-nary thromboendarterectomy, we suggest theplacement of a permanent vena caval filter beforeor at the time of the procedure (Grade 2C).

6.1.4. For patients with inoperable CTPH, wesuggest referral to a center with expertise inpulmonary hypertension so that patients can beevaluated for alternative treatments, such as va-sodilator therapy or balloon pulmonary angio-plasty (Grade 2C).

7.1 Treatment of Infusion Thrombophlebitis

7.1.1. For patients with symptomatic infusionthrombophlebitis as a complication of IV infu-sion, we suggest oral diclofenac or another non-steroidal antiinflammatory drug (Grade 2B), topi-cal diclofenac gel (Grade 2B), or heparin gel(Grade 2B) until resolution of symptoms or for upto 2 weeks. We recommend against the use ofsystemic anticoagulation (Grade 1C).

7.2 Treatment of SVT

7.2.1. For patients with spontaneous superficialvein thrombosis, we suggest prophylactic orintermediate doses of LMWH (Grade 2B) orintermediate doses of UFH (Grade 2B) for atleast 4 weeks. We suggest that as an alternativeto 4 weeks of LMWH or UFH, VKA (target INR,2.5; range, 2.0 to 3.0) can be overlapped with 5days of UFH and LMWH and continued for 4weeks (Grade 2C). We suggest that oral nonste-riodal antiinflammatory drugs should not beused in addition to anticoagulation (Grade 2B).We recommend medical treatment with antico-agulants over surgical treatment (Grade 1B).

Remark: It is likely that less extensive superficial veinthrombosis (ie, where the affected venous segment isshort in length or further from the saphenofemoraljunction) does not require treatment with anticoagu-lants. It is reasonable to use oral or topical nonsteriodalantiinflammatory drugs for symptom control in suchcases.

8.1. IV UFH or LMWH for the Initial Treatmentof Upper-Extremity DVT

8.1.1. For patients with acute upper-extremityDVT (UEDVT), we recommend initial treat-ment with therapeutic doses of LMWH, UFH,or fondaparinux as described for leg DVT (seeSection 1) [Grade 1C].

8.2 Thrombolytic Therapy for the Initial Treatmentof UEDVT

8.2.1. For most patients with acute UEDVT, werecommend against the routine use of systemic orcatheter-directed thrombolytic therapy (Grade 1C).




8.2.2. In selected patients with acute UEDVT (eg, inthose with a low risk of bleeding and severe symp-toms of recent onset), we suggest that CDT may beused for initial treatment if appropriate expertiseand resources are available (Grade 2C).

8.3 Catheter Extraction, Surgical Thrombectomy,Transluminal Angioplasty, Stent Placement, StagedApproach of Lysis Followed by Interventional orSurgical Procedure, Superior Vena Cava FilterInsertion for the Initial Treatment of UEDVT

8.3.1. For most patients with acute UEDVT, werecommend against the routine use of catheterextraction, surgical thrombectomy, transluminalangioplasty, stent placement, staged approach oflysis followed by interventional or surgical proce-dure, or superior vena cava (SVC) filter place-ment (Grade 1C).8.3.2. In selected patients with acute UEDVT(eg, those with primary UEDVT and failure ofanticoagulant or thrombolytic treatment whohave severe persistent symptoms), we suggestthat catheter extraction, surgical thrombec-tomy, transluminal angioplasty, or a stagedapproach of lysis followed by a vascular inter-ventional or surgical procedure may be usedif appropriate expertise and resources areavailable (all Grade 2C).8.3.3. In selected patients with acute UEDVT(eg, those for whom anticoagulant treatmentis contraindicated and there is clear evidenceof DVT progression or clinically significantPE), we suggest placement of an SVC filter(Grade 2C).

8.4 Anticoagulants for the Long-term Treatment ofUEDVT

8.4.1. For patients with acute UEDVT, we rec-ommend treatment with a VKA for > 3 months(Grade 1C).

Remark: A similar process as for lower-extremityDVT (see Section 2) should be used to determinethe optimal duration of anti-coagulation.8.4.2. For most patients with UEDVT in associ-ation with an indwelling central venous cathe-ter, we suggest that the catheter not be re-moved if it is functional and there is an ongoingneed for the catheter (Grade 2C).8.4.3. For patients who have UEDVT in asso-ciation with an indwelling central venouscatheter that is removed, we do not recom-mend that the duration of long-term antico-agulant treatment be shortened to < 3months (Grade 2C).

8.5 Prevention of PTS of the Arm

8.5.1. For patients at risk for PTS after UEDVT,we do not suggest routine use of elastic com-pression or venoactive medications (Grade 2C).

8.6 Treatment of PTS of the Arm

8.6.1. In patients with UEDVT who have persis-tent edema and pain, we suggest elastic bandagesor elastic compression sleeves to reduce symp-toms of PTS of the upper extremity (Grade 2C).

T his section will describe the role of antithromboticagents as well as devices or surgical techniques that

are used in the treatment of patients with acute venousthromboembolism (VTE), a disease that encompassesboth deep venous thrombosis (DVT) and pulmonaryembolism (PE). In addition, the treatment of patients withacute upper-extremity DVT (UEDVT), superficial veinthrombosis (SVT), and the two most important long-termcomplications of VTE, postthrombotic syndrome (PTS)and chronic thromboembolic pulmonary hypertension(CTPH), are discussed. In this chapter, consistent withmost previous reports, patients with VTE are dichoto-mized into those with symptoms of PE (with or withoutconcomitant symptoms of DVT), and those who presentonly with symptoms of DVT. Table 1 describes theeligibility criteria for the studies considered in each sectionof the recommendations that follow.

1.0 Initial Treatment of Acute DVT of theLeg

1.1. Initial Anticoagulation of Acute DVT of theLeg

Anticoagulation is the main therapy for acute DVT ofthe leg. The main objectives of anticoagulant therapy inthe initial treatment of this disease are to preventthrombus extension and early and late recurrences ofVTE. The evidence for the need for anticoagulation inpatients with DVT is based on studies performed � 40years ago. The first and only trial1 that comparedanticoagulant therapy with no anticoagulant therapy inpatients with symptomatic DVT or PE was published in1960 (Barritt and Jordan; Table 15). This trial ofpatients with acute PE showed that 1.5 days of heparinand 14 days of vitamin K antagonist (VKA) therapymarkedly reduced recurrent PE and mortality. Subse-quent uncontrolled studies2–4 support that mortality isreduced when heparin is used to treat VTE andreported a high mortality when patients did not receiveanticoagulant therapy. Comparatively recently, the re-quirement for an initial course of heparin in addition to




Table 1—Question Definition and Eligibility Criteria (Section: Introduction)

Section Population Intervention or Exposure Outcome Methodology

1.1 Initial treatment ofacute DVT of the leg

IV UFH or LMWH, fondaparinux, and VKA (directcomparison of any of these treatments or theircombinations with a shorter or no treatment )

Recurrent DVT and PE, majorbleeding, total mortality,QOL, and PTS

RCTs


IV UFH; comparison of different regimens of IVUFH


RCTs


SC UFH vs IV UFH Recurrent DVT and PE, majorbleeding, total mortality,QOL, and PTS

RCTs


LMWH vs IV UFH, SC UFH, and comparison ofdifferent regimens of SC LMWH


RCTs


SC UFH vs SC LMWH Recurrent DVT and PE, majorbleeding, total mortality,QOL, and PTS

RCTs


New antithrombotic agents Recurrent DVT and PE, majorbleeding, total mortality,QOL, and PTS

RCTs


Fondaparinux vs UFH or LMWH Recurrent DVT and PE, majorbleeding, total mortality,QOL, and PTS

RCTs


CDT vs placebo or systemically administeredthrombolysis


RCTs and cohortstudies


Systemically administered thrombolysis vsanticoagulant therapy alone




Percutaneous venous thrombectomy vs otherendovascular techniques or anticoagulant therapyalone




Operative venous thrombectomy vs any other modeof treatment

Recurrent DVT and PE, totalmortality, QOL, and PTS



Vena caval filter insertion vs no venal caval filter Recurrent DVT and PE, totalmortality, QOL, and PTS



Immobilization vs active mobilization Recurrent DVT and PE, totalmortality, QOL, and PTS


2.1 Long-term treatment ofacute DVT of the leg

Comparison of different durations of VKA therapy Recurrent DVT and PE, majorbleeding, total mortality,QOL, and PTS

RCTs


Comparison of intensities of VKA therapy Recurrent DVT and PE, majorbleeding, total mortality,QOL, and PTS

RCTs


SC UFH vs VKA Recurrent DVT and PE, majorbleeding, total mortality,QOL, and PTS

RCTs


LMWH vs VKA Recurrent DVT and PE, majorbleeding, total mortality,QOL, and PTS

RCTs


New antithrombotic agents (eg, ximelagatran,idraparinux) vs no treatment or otheranticoagulants


RCTs

2.6 Treatment ofasymptomatic DVT

Treatment with any anticoagulant therapy vs notreatment



3.1 Prophylaxis for PTS Compression stockings vs no stockings Symptomatic PTS RCTs3.2 Treatment of PTS Physical measures vs no intervention in patients

without leg ulcersSymptomatic relief, QOL and

ulcerationRCTs and cohort

studies3.3 Treatment of PTS Physical measures vs no intervention in patients

with leg ulcersSymptomatic relief, ulcer

healing, QOL, and ulcerationRCTs and cohort

studies3.4 Treatment of PTS Hyperbaric oxygen vs no hyperbaric oxygen in

patients with leg ulcersSymptomatic relief, ulcer

healing, QOL, and ulcerationRCTs and cohort

studies




Table 1—Continued

Section Population Intervention or Exposure Outcome Methodology

3.5TC Treatment of PTS Drug therapies vs control in patients with leg ulcers Symptomatic relief, QOL, andulceration


4.1 Initial treatment ofacute PE

IV UFH, LMWH, fondaparinux, and/or VKA vs noanticoagulation; comparisons among these agents,and of different regimens of the same agent

Recurrent DVT and PE, majorbleeding, total mortality,QOL, and CTPH

RCTs


New antithrombotic agent (eg, ximelagatran,idraparinux) compared to no treatment orconventional therapy

Recurrent DVT and PE, majorbleeding, total mortality,QOL, and CTPH



Systemically and locally administered thrombolytictherapy compared to anticoagulant therapy alone,or comparisons of different thrombolytic agents ordifferent regimens of the same agent

Recurrent DVT and PE, totalmortality, QOL, and CTPH



Catheter extraction or fragmentation vs no suchtherapy

Recurrent DVT and PE, totalmortality, QOL, and CTPH



Pulmonary embolectomy vs no such surgery Recurrent DVT and PE, totalmortality, QOL, and CTPH



Vena caval filter insertion vs no vena caval filter Recurrent DVT and PE, totalmortality, QOL, and CTPH


5.1 Long-term treatment ofacute PE

Comparison of different durations of VKA therapy Recurrent DVT and PE, majorbleeding, total mortality,QOL, and PTS

RCTs


LMWH vs VKA therapy Recurrent DVT and PE, majorbleeding, total mortality,QOL, and PTS

RCTs


New antithrombotic agents (eg, ximelagatran,idraparinux) compared to no treatment orconventional therapy


RCTs

5.4 Treatment ofasymptomatic PE

Treatment with any anticoagulant therapy vs notreatment



6.1 CTPH Pulmonary thrombo endarterectomy, vasodilatorsand/or vena caval filter vs not using theseinterventions

Mortality, recurrent DVT andPE, and QOL


7.1 Treatment of infusionthrombophlebitis

VKA, UFH, LMWH, NSAIDs, aspirin, vs no suchtreatment, each other, or different durations orregimens of the same agent

Extension of thrombus,symptomatic relief,symptomatic DVT and PE,major bleeding


7.2 Treatment of SVT VKA, UFH, LMWH, NSAIDs, aspirin, vs no suchtreatment, each other, or different durations orregimens of the same agent

Extension of thrombus,symptomatic relief,symptomatic DVT and PE,major bleeding


8.1 Initial treatment ofacute UEDVT

IV UFH or LMWH compared to placebo or eachother

Recurrent DVT and PE, majorbleeding, total mortality, andPTS of the arm



Thrombolytic therapy compared to no thrombolytictherapy




Catheter extraction, surgical thrombectomy,transluminal angioplasty, stent placement, stagedapproach of lysis followed by interventional orsurgical procedure, SVC filter insertion, comparedwith no interventions



8.4 Long-term treatment ofacute UEDVT

VKA, UFH, LMWH or fondaparinux; comparisonsof different durations or different agents



8.5 Prevention of PTS ofthe arm

Compression glove or elastic bandages vs nocompression therapy

Symptomatic PTS RCTs and cohortstudies

8.6 Treatment of PTS of thearm

Compression glove or elastic bandages vs nocompression therapy

Symptomatic relief, QOL RCTs and cohortstudies




VKA, as compared to starting treatment with VKAtherapy alone, was established in a randomized con-trolled study5 that reported a threefold-higher rate ofrecurrent VTE in patients who received VKA only.Patients with DVT should be treated with anticoagu-lants as soon as the diagnosis is confirmed by objectivetesting. If the clinical suspicion is high, or if there is adelay before diagnostic testing can be performed,treatment should be started before such testing. Fiveoptions are available for the initial treatment of DVT:(1) low-molecular-weight heparin (LMWH), adminis-tered subcutaneous (SC), without monitoring; (2) IVunfractionated heparin (UFH), with monitoring; (3) SCUFH, with monitoring (4); weight-based SC UFH,without monitoring; and (5) SC fondaparinux, withoutmonitoring.

In relationship to the duration of initial heparintherapy, two randomized clinical trial (RCTs)6,7 inpatients with proximal DVT reported that IV UFHadministered for 5 to 7 days is as effective as UFHadministered for 10 to 14 days, providing that it isfollowed by adequate long-term anticoagulant therapy.The efficacy of this therapeutic approach is supportedby subsequent studies that showed acceptable rates ofrecurrent VTE during 3 months of VKA therapy after 5to7 days of heparin. Shortening the duration of initialheparin therapy from approximately 10 to 5 days isexpected to have the added advantage of reducing therisk of heparin-induced thrombocytopenia. The cur-rently recommended approach is to start both heparinand VKA at the time of diagnosis, and to discontinueheparin after 5 days provided the international normal-ized ratio (INR) is � 2.0 for at least 24 h.

Warfarin is generally started at a dose of 2.5 to10 mg. Two trials9,10 performed in hospitalizedpatients showed that starting warfarin at a dose of5 mg, compared to 10 mg, is associated with lessexcessive anticoagulation (see also chapter byAnsell et al8 in this supplement). A similar study11

in outpatients failed to demonstrate an advantageto starting warfarin at a dose of 5 mg comparedwith 10 mg. Observational studies8,12 have shownthat lower VKA maintenance doses are required inolder patients, women, and those with impairednutrition and vitamin K deficiency. Taken to-gether, these data suggest that warfarin can usuallybe started at a dose of 10 mg in younger (eg, � 60years), otherwise healthy outpatients, and at a doseof 5 mg in older patients and in those who arehospitalized. Subsequent doses should be adjustedto maintain the INR at a target of 2.5 (range 2.0 to3.0) [see Section 2.2].

Recommendations

1.1.1. For patients with objectively confirmedDVT, we recommend short-term treatment

with SC LMWH (Grade 1A), IV UFH (Grade 1A),monitored SC UFH (Grade 1A), fixed-dose SCUFH (Grade 1A), or SC fondaparinux (Grade 1A)rather than no such short-term treatment.1.1.2. For patients with a high clinical suspicionof DVT, we recommend treatment with antico-agulants while awaiting the outcome of diagnos-tic tests (Grade 1C).1.1.3. In patients with acute DVT, we recom-mend initial treatment with LMWH, UFH, orfondaparinux for at least 5 days and until theINR is > 2.0 for 24 h (Grade 1C).1.1.4. In patients with acute DVT, we recommendinitiation of VKA together with LMWH, UFH, orfondaparinux on the first treatment day ratherthan delayed initiation of VKA (Grade 1A).

1.2. IV UFH for the Initial Treatment of DVT

Heparin was initially administered by intermittentIV boluses, but this practice was replaced by contin-uous IV infusion, which was shown to be associatedwith a lower risk of bleeding.13 Initially, continuousIV infusions of UFH were administered at a startingdose of 1,000 U/h. A prospective observationalstudy14 showed that adjustment of the initial infusionrate of 1,000 U/h to achieve an activated partialthromboplastin time (APTT) ratio � 1.5 improvedefficacy. Such adjustment also resulted in patientsreceiving a mean UFH dose of adpproximately 1,300U/h, rather than the initial infusion dose of 1,000U/h,and the higher initial infusion rate was adopted inclinical practice.15 Adjustment of initial heparindose in proportion to body weight has also beenshown to be of value.8,16,17 When patients aretreated with an initial heparin infusion of at least1,250 U/h (corresponding to 30,000 U/d), or 18U/kg/h, it is uncertain if adjustment of heparin dosein response to the APTT or heparin levels im-proves efficacy or safety.18 –21 However, as allstudies that have used continuous IV UFH fortreatment of thrombosis have adjusted UFH dosein response to coagulation monitoring, this prac-tice is standard and uniformly recommended.Single randomized trials support the following: (1)use of a weight-adjusted initial infusion dose ofUFH in preference to starting with an infusiondose of 1,000 U/h17; and (2) that it is not necessaryto increase UFH infusion dose � 1,667 U/h (cor-responding to 40,000 U/d) if the anti-factor Xaheparin level is at least 0.35 U/mL even if theAPTT ratio is below the therapeutic range.22

The starting dose of IV UFH for the treatment ofDVT is either of the following: (1) a bolus dose of 5,000U, followed by a continuous infusion of at least 30,000U for the first 24 h; or (2) a weight-adjusted regimen of




a 80 U/kg bolus, followed by 18 U/kg/h. With both ofthese regimens, the infused dose of UFH should beadjusted using a standard nomogram to rapidly reach,and maintain, the APTT at levels that correspond totherapeutic heparin levels.8,15,17 As noted in the pre-ceding section, the requirement for an initial course ofheparin was confirmed in a randomized controlledstudy5 that reported a threefold-higher rate of recur-rent VTE in patients who received VKA only.

Recommendation

1.2.1. In patients with acute DVT, if IV UFH ischosen, we recommend that after an initial IVbolus (80 U/kg or 5,000 U), it be administeredby continuous infusion (initially at a dose of 18U/kg/h or 1,300 U/h), with dose adjustment toachieve and maintain an APTT prolongationthat corresponds to plasma heparin levels of 0.3to 0.7 IU/mL anti-Xa activity by the amidolyticassay rather than administration as IV bolusesthroughout treatment, or administration with-out coagulation monitoring (Grade 1C).

1.3 SC UFH Compared With IV Heparin for theInitial Treatment of DVT

UFH can be administered SC twice daily as analternative to continuous IV infusion for the initialtreatment of DVT. The relative value of IV and SCadministration of UFH has been evaluated in eightclinical studies that included a total of 972 patients, andwere reviewed in a metaanalysis.23 SC UFH adminis-tered twice daily appeared to be more effective (rela-tive risk [RR] of extension or recurrence of VTE, 0.62;95% confidence interval [CI], 0.39 to 0.98), and at leastas safe (RR of major bleeding, 0.79; 95% CI, 0.42 to1.48) as IV UFH, provided an adequate starting dose ofSC UFH was administered. The usual regimen in thesestudies included an initial IV bolus of approximately5,000 U followed by an SC dose of approximately17,500 U bid on the first day, with subsequent adjust-ment to achieve a 1.5 to 2.5 prolongation of the APTTdrawn 6 h after the morning dose. More recently, SCUFH, with24 and without25 dose adjustment in re-sponse to APTT measurements, has been comparedwith LMWH (see Section 1.5).

Recommendations

1.3.1. In patients with acute DVT, if monitoredSC UFH is chosen, we recommend an initialdose of 17,500 U, or a weight-adjusted dose ofapproximately 250 U/kg bid, with dose adjust-ment to achieve and maintain an APTT prolon-gation that corresponds to plasma heparin lev-els of 0.3 to 0.7 IU/mL anti-Xa activity whenmeasured 6 h after injection rather than start-

ing with a smaller initial dose (see also Section1.5) [Grade 1C].1.3.2. In patients with acute DVT, if fixed-dose,unmonitored SC UFH is chosen, we recommendan initial dose of 333 U/Kg followed by a twice-daily dose of 250 U/kg rather than non–weight-based dosing (see also Section 1.5) [Grade 1C].

1.4 LMWH for the Initial Treatment of DVT

LMWHs have more predictable pharmacokineticsand greater bioavailability than UFH.8 Due to thesepharmacologic features, body weight-adjusted doses ofLMWH can be administered SC once or twice dailywithout laboratory monitoring in the majority of pa-tients. However, in certain clinical situations, such assevere renal failure26 or pregnancy (see chapter byBates and colleagues in this supplement27), LMWHdose adjustment may be required using anti-Xa heparinlevels. The usual time to perform the anti-Xa assay is4 h after an injection, when heparin levels are expectedto be at their highest. A target range of 0.6 to 1.0IU/mL is suggested for twice-daily administration, anda target range of 1.0 to 2.0 IU/mL is suggested foronce-daily administration, although neither recommen-dation is firmly founded.8

A large number of well-designed studies28–44 havecompared the efficacy and safety of body weight-adjusted LMWH, administered SC without monitor-ing, with IV UFH administered with monitoring andsubsequent dose adjustment. The results of these stud-ies have been combined in a number of recent meta-analyses.45–47 The most recent such analysis included17 studies28–44,48 in which UFH was administered IV(3,614 patients) and 3 older studies48–50 in which UFHwas administered SC (206 patients).47 LMWH wasassociated with fewer thrombotic complications (3.6%vs 5.4%; odds ratio [OR], 0.68; 95% CI, 0.55 to 0.84),less major bleeding (1.2% vs 2.0%; OR, 0.57; 95% CI,0.39 to 0.83), and fewer deaths (4.5% vs 6.0%; OR,0.76; 95% CI, 0.62 to 0.92).47 The mortality advantagewith LMWH compared to UFH appeared to be con-fined to those with (OR, 0.53; 95% CI, 0.33 to 0.85)rather than without (OR, 0.97; 95% CI, 0.61 to 1.56)cancer.47

Direct Comparisons Among LMWH Regimens forInitial Treatment of VTE

Once-daily and twice-daily administration of thesame LMWH have been directly compared in sixstudies28,39,51–54 (the same total daily dose of LMWHhas not always been compared within studies). Ametaanalysis55 of five of these studies39,51–54 that hadunconfounded comparisons between once- and twice-daily administration found no difference in recurrent




VTE (3 months: OR, 0.85; 95% CI, 0.48 to 1.49), majorbleeding (at 10 days: OR, 1.2; 95% CI, 0.4 to 3.2), ormortality (3 months: OR, 1.05; 95% CI, 0.53 to 2.09).Outpatient and inpatient administration of LMWH(three preparations were used) were compared in asingle study56 of 201 patients: one recurrent VTE andtwo major bleeds occurred in the inpatient group, andtwo recurrent VTEs and two major bleeds occurred inthe outpatient group.

Dalteparin and tinzaparin, each administered oncedaily, have been compared for outpatient treatmentof VTE in a study57 of 497 patients. There was noapparent difference in recurrent VTE at 3 months(4.5% vs 5.9%; RR, 0.91; 95% CI, 0.38 to 2.2), majorbleeding at 7 days (0.4% vs 1.2%; RR, 0.34; 95% CI,0.04 to 3.26), or death at 3 months (4.8% vs 5.5%;RR, 0.0.87; 95% CI, 0.41 to 1.84). Indirect compar-isons across studies also support that there is similarefficacy and safety with the following: (1) once- andtwice-daily administration, (2) outpatient and inpa-tient administration, and (3) use of different prepa-rations of LMWH.45–47

Recommendations

1.4.1. In patients with acute DVT, we recom-mend initial treatment with LMWH SC once ortwice daily, as an outpatient if possible (Grade1C), or as an inpatient if necessary (Grade 1A),rather than treatment with IV UFH.1.4.2. In patients with acute DVT treated withLMWH, we recommend against routine monitoringwith anti-factor Xa level measurements (Grade 1A).1.4.3. In patients with acute DVT and severe renalfailure, we suggest UFH over LMWH (Grade 2C).

1.5 SC UFH Compared With SC LMWH for theInitial Treatment of DVT

Four randomized trials24,25,50,58 that included a totalof 1,645 patients have compared SC UFH with SCLMWH (Table 2). Two of these trials50,58 were small(total of 217 patients) and were performed � 15 yearsago, and two were large studies24,25 (total of 1,428patients) and were recently performed. In the Galileistudy,24 UFH was administered as an initial IV bolusfollowed by twice-daily SC injections of 12,500, 15,000,or 17,500 U initially, depending on the patient’s weight;subsequent UFH dosing was adjusted in response toAPTT measurements. There was no difference inrecurrent VTE, major bleeding, or deaths during fol-low-up (Table 2). The upper 95% CI on the differenceindicated that, compared with LMWH, monitored SCUFH was unlikely to be associated with an absoluteincrease of recurrent VTE of � 3.1% or major bleedingof � 1.7% at 3 months24 (judged Grade 1B evidencefor noninferiority). In the FIDO study, 25 UFH was

administered at an initial SC dose of 333 U/kg (no IVbolus), followed by a fixed SC dose of 250 U/kg bid;subsequent UFH dosing was kept constant, withoutcoagulation monitoring. There was no difference inrecurrent VTE, major bleeding, or death during fol-low-up (Table 2). The upper 95% CI on the differenceindicated that, compared with LMWH, unmonitored,fixed-dose, SC UFH was unlikely to be associated withan absolute increase of recurrent VTE of � 3.3% ormajor bleeding of � 0.8% at 3 months25 (judged Grade1B evidence for noninferiority).

1.6 Fondaparinux Compared With LMWH for theInitial Treatment of DVT

The synthetic pentasaccharide fondaparinux hasbeen evaluated for short-term treatment of DVT andPE (see Section 4.1) in the Matisse studies.59,60 Inthe Matisse DVT trial,59 2,205 patients were treatedwith a once-daily SC dose of fondaparinux (7.5 mg if50 to 100 kg; 5.0 mg if � 50 kg; 10 mg if � 100 kg)or twice-daily SC LMWH (enoxaparin 1 mg/kg) forat least 5 days using a blinded design. With fondapa-rinux vs LMWH, there was no difference in recur-rent VTE at 3 months (3.9% vs 4.1%; difference,� 0.15%; 95% CI, – 1.8 to 1.5%]), major bleedingduring treatment (1.1% vs 1.2%; difference, – 0.1%;95% CI, – 1.0 to 0.8%), or death at 3 months (3.8%vs 3.0%; difference, 0.8%; 95% CI, – 0.8 to 2.3%)59

(judged Grade 1A for noninferiority).

1.7 New Antithrombotic Agents for the Short-termTreatment of DVT

A comparison of 6 months of ximelagatran61 (sincewithdrawn because of hepatic toxicity) with standardtherapy in patients with DVT, and a comparison of 3months or 6 months of idraparinux62 with standardtherapy, are described in Section 2.5.

1.8 Treatment Strategies of Thrombus Removal forAcute DVT

Treatments that actively remove thrombus in pa-tients with acute DVT have the potential to reduceacute symptoms and the risk for PTS. Thrombusremoval directly reverses venous obstruction and canrestore function in valves that were immobilized bythrombus. Indirectly, early removal of thrombus ob-struction can prevent late development of venous val-vular incompetence secondary to venous dilatation indistal venous segments that were never involved withthrombosis.63–71 Randomized trials,72,73 patient regis-tries,74,75 and studies of other designs76–81 support thatsuccessful thrombus removal, using a variety of tech-niques, can improve patient outcomes (see follow-ing).79,81–83 It is also possible that thrombus removal




and relief of venous obstruction may reduce the risk ofrecurrent VTE. Patients with iliofemoral DVT are thesubset of patients with the largest thrombus burdenand highest risk for postthrombotic morbidity, with upto 75% having chronic painful edema and 40% havingvenous claudication when treated with anticoagulanttherapy alone.84–87

1.9 Catheter-Directed Thrombolysis for Acute DVT

The rationale for catheter-directed thrombolysis(CDT), which was established in patients with acutearterial occlusion,88 is that rapid lysis is achieved withlower doses of thrombolytic therapy, resulting in fewerserious bleeding complications. A single-center trial72

Table 2—Comparison of SC LMWH and SC UFH for Short-term Treatment of VTE: Clinical Description andResults (Section 1.5)*

Author/yr(Acronym) Interventions

PatientsAnalyzed†

Recurrent DVTor PE Major Bleeding Total Mortality Comments

Lopaciuk et al50/1992

UFH at 5,000 U IV followedby 250 U/kg SC bidinitially and adjusted toAPTT for 10 d

Fraxiparine at 97 IU/kg SCbid for 10 d

72/75

74/74

1/72 (1.4)

0/74RR, 3.1 (95%CI, 0.1–7.5)

1/72 (1.4)

0/74;RR, 3.1 (95%CI, 0.1–7.5)

3/72 (4.2)

0/74RR, 7.2 (95%CI, 0.4–137)

Population: femoralDVT in 81% andpopliteal or moredistal DVT in19%

Primary outcomewas repeatvenography

Faivre et al58/1988

UFH at 5,000 U IV followedby 250 U/kg SC bid andadjusted to APTT for 10 d

CY222 at 2,000 IU IVfollowed by 150 IU/kg SCbid for 10 d

29/35

30/33

1/35

1/33RR, 0.9 (95%CI, 0.1–14.5)

3/35

0/33RR, 6.6 (95%CI, 0.3–123)

1/35

0/33RR, 2.8 (95%CI, 0.1–67)

Population:DVT (proportionof proximal anddistal not reported)

Primary outcome wasrepeat venography

Prandoni et al24/2004 (Galilei)

UFH IV (� 50 kg, 4,000 U;50 to 70 kg, 5,000 U;� 70 kg, 6,000 U) followedby SC bid doses (initially:� 50 kg, 12,500 U; 50 to70 kg, 15,000 U; � 70 kg,17,500 U) adjusted toAPTT for approximately5 d

Nadroparin at 85 IU/kg SCbid for approximately 6.5 d

360/360

360/360

15/360 (4.2)

14/360 (3.9)RR, 1.1 (95%CI, 0.5–2.2)

5/360 (1.4)

7/360 (1.9)RR, 0.7 (95%CI, 0.2–2.2)

12/360 (3.3)

12/360 (3.3)RR, 1.0; 95%CI, 0.5–2.2)

Population:proximal DVT in65%, distal DVTin 18%, PE in17%

Kearon et al25/2006 (FIDO)

UFH at 333 U/kg SCfollowed by 250 U/kg SCbid (no adjustment) for6.3 d

Dalteparin (n � 261) orenoxaparin (n � 91) at 100IU/kg SC bid for 7.1 d

345/355

352/353

13/345 (3.8)

12/352 (3.4)RR, 1.1 (95%CI, 0.5–2.3)

6/348 (1.7)

12/352 (3.4)RR, 0.5 (95%CI, 0.2–1.3)

18/348 (5.2)

22/352 (6.3)RR, 0.8 (95%CI, 0.4–1.5)

Population:proximal DVTin 77%,asymptomatic ordistal DVT in4%, PE in 19%

70% of patientswere treatedentirely as anoutpatient (76%of DVT and 39%of PE)

Postrandomizationexclusions in 10UFH patients and1 LMWH patient

*Data are presented as No. of patients/total patients (%) unless otherwise indicated. The methodologic quality description portion of this tablecan be found in the online version of this article as a data supplement.†Follow-up was for 3 mo except for the study by Faivre et al,58 for which it was 10 days.




randomized 35 patients with acute iliofemoral DVTto catheter-directed, pulse-spray, intrathrombusstreptokinase or to anticoagulation alone. Six-monthpatency was improved in the thrombolysis group(72% vs 12%, p � 0.001), as was preservation ofnormal venous valve function (89% vs 59%,p � 0.04); postthrombotic symptoms were not eval-uated. In the 19 studies72,75,76,78,81,89–102 of heteroge-neous designs listed in Table 3, significant lysis wasobserved in 79% of the 945 limbs treated with CDT.In an evaluation of 98 patients with iliofemoral DVTtreated with CDT (n � 68) or anticoagulation(n � 30), quality of life (QOL) was better in patientstreated with CDT and correlated with the degree oflysis.79

In the National Venous Registry, patientstreated with short-term thrombosis (� 10 days)had better outcomes than those with older clot andcorrection of underlying venous lesions after suc-cessful thrombolysis, usually with intravascularstenting, appeared to be beneficial.75 Althoughbleeding complications are the major concern withlytic therapy, reports published during the past 6have shown bleeding complication rates less thanhalf (ie, average of 4.8%; Table 4) the rates inearlier reports, which is likely due to more appro-priate patient selection and experience with thetechnique. Data are not available for comparingone plasminogen activator to another or a partic-ular catheter or catheter-based technique to oth-ers, and there are inadequate data to assess thebenefit or risk of inferior vena cava (IVC) filters inthis setting (recommended by manufacturer withsome endovascular devices and techniqueswhereas not with others).

The addition of mechanical thrombus fragmentation,with or without aspiration, during CDT is commonlyused as part of the procedure (collectively referred to aspharmacomechanical thrombolysis). While random-ized comparisons of CDT alone vs pharmacomechani-cal thrombolysis are not available, retrospective analy-ses95,96 suggest they are associated with similar rates ofsuccessful thrombolysis (70 to 80%) and of majorbleeding (5 to 8%); however, pharmacomechanicalthrombolysis is associated with shorter treatment times,shorter ICU and hospital stays, and reduced costs. Norandomized trial has compared CDT with systemicthrombolysis (see following); however, a single-center,retrospective study81 suggests that CDT achieves betterlysis (50% vs 31%) and preservation of valve function(44% vs 13%).

Recommendations

1.9.1. In selected patients with extensive acuteproximal DVT (eg, iliofemoral DVT, symptoms

for < 14 days, good functional status, life ex-pectancy > 1 year) who have a low risk ofbleeding, we suggest that CDT may be used toreduce acute symptoms and postthromboticmorbidity if appropriate expertise and re-sources are available (Grade 2B).1.9.2. After successful CDT in patients withacute DVT, we suggest correction of underlyingvenous lesions using balloon angioplasty and stents(Grade 2C).1.9.3. We suggest pharmacomechanical throm-bolysis (eg, with inclusion of thrombus fragmen-tation and/or aspiration) in preference to CDTalone to shorten treatment time if appropriateexpertise and resources are available (Grade 2C).1.9.4. After successful CDT in patients with acuteDVT, we recommend the same intensity andduration of anticoagulant therapy as for compa-rable patients who do not undergo CDT (Grade1C).

1.10 Systemic Thrombolytic Therapy for Acute DVT

In 15 trials81,103–120 that randomized a total of 811patients with acute DVT to systemic thrombolytictherapy or to anticoagulant therapy alone, as assessedby early repeat phlebography, systemic thrombolytictherapy achieved a higher frequency of complete orsignificant lysis (54% vs 4%) or partial lysis (18% vs14%) [Table 4]. Three of the randomized trialsreported postthrombotic symptoms after follow-upof 1.0 year,115 1.6 years,107 and 6.5 years103 (Table 4).A Cochrane analysis121 that included two of thesestudies103,115 and a total of 101 patients suggests thatthrombolytic therapy reduced postthrombotic mor-bidity (RR, 0.7; 95% CI, 0.5 to 0.9) and leg ulceration(RR, 0.5; 95% CI, 0.1 to 2.4).

In the same Cochrane analysis,121 which in-cluded a total of 12 studies and 701 patients(number of included studies and patients differedwith the outcome assessed), the following esti-mates were obtained with thrombolytic therapy(various agents, mostly administered systemically)vs anticoagulation alone: early PE: RR, 1.2 (95%CI, 0.3 to 4.4; 382 patients in 5 trials); laterecurrent DVT: RR, 1.4 (95% CI, 0.4 to 5.4; 35patients in 1 trial); and early significant or majorbleeding: RR, 1.7 (95% CI, 1.04 to 2.9; 668patients in 10 trials); intracranial bleeding: RR, 1.7(95% CI, 0.2 to 14; 701 patients in 5 trials). Therehave been no direct comparisons of differentthrombolytic agents; however, prolonged infusionsof streptokinase that were used predominantly inthe earlier studies appear to be associated withhigher bleeding rates than other regimens(Table 4).




Tab

le3—

Cat

hete

r-D

irec

ted

Thr

omb

olys

isfo

rA

cute

DV

T:

Cli

nica

lD

escr

ipti

onan

dR

esu

lts

(Sec

tion

1.9)

*

Aut

hor/

yrT

ype

ofSt

udy

Part

icip

ants

Inte

rven

tions

Out

com

esF

ollo

w-u

pR

esul

ts

Sem

baan

dD

ake98

/19

94Pr

ospe

ctiv

ere

gist

ry21

patie

nts

(27

limbs

)w

ithili

ofem

oral

DV

T�

14d

(n�

20)

or�

14d

(n�

7)du

ratio

n

4.9

mill

ion

Uof

urok

inas

e(m

ean)

infu

sed

over

30h

(mea

n),f

ollo

wed

byhe

pari

nan

dth

enw

arfa

rin

for

8–12

wk

Adj

unct

ive

ther

apy:

limbs

w/

resi

dual

sten

oses

�50

%re

ceiv

edan

giop

last

y(n

�2)

orst

entin

g(n

�14

)

Clo

tly

sis,

com

plic

atio

ns3

mo

Sign

ifica

ntly

sis:

18/2

5(7

2%)�

25/2

7lim

bstr

eate

dw

ithC

DT

;2co

uld

not

becr

osse

dw

ithgu

ide

wir

e�Pa

rtia

llys

is:5

/25

(20%

)N

oly

sis:

2/25

(8%

)C

ompl

icat

ions

:one

smal

lhem

atom

aat

punc

ture

site,

noin

terv

entio

n/tr

ansf

usio

nSe

mba

and

Dak

e99/

1996

Cas

ese

ries

32pa

tient

s(4

1lim

bs)

with

iliof

emor

alD

VT

�14

d(n

�25

)or

�14

d(n

�16

)du

ratio

n

3.5

mill

ion

Uof

urok

inas

e(m

ean)

infu

sed

over

30h

(mea

n),f

ollo

wed

byw

arfa

rin

with

INR

2.0–

3.0

for

�6

mo

Adj

unct

ive

ther

apy:

limbs

with

resi

dual

sten

oses

of�

50%

rece

ived

angi

opla

sty

(n�

2)or

angi

o/st

entin

g(n

�20

)

Clo

tly

sis,

com

plic

atio

ns6

mo

Sign

ifica

ntly

sis:

21/3

2(6

6%)

�32

limbs

trea

ted

with

CD

T;4

coul

dno

tbe

cros

sed

with

guid

ewir

e,5

trea

ted

with

angi

opla

sty

and

sten

tal

one�

Part

iall

ysis

:9/3

2(2

8%)

No

lysi

s:2/

32(6

%)

Com

plic

atio

ns:0

Ver

haeg

heet

al10

2 /19

97Pr

ospe

ctiv

est

udy

24pa

tient

sw

ithili

ofem

oral

DV

T�

14d

(n�

16)

or�

14d

(n�

8)du

ratio

n

3m

g/h

rt-P

A(m

ean,

86m

g)in

fuse

dw

ith1,

000

U/h

ofIV

hepa

rin,

follo

wed

byhe

pari

n,ad

just

edto

APT

TA

djun

ctiv

eth

erap

y:hy

drod

ynam

icth

rom

bect

omy

(n�

3)an

dst

ents

(n�

9)

Clo

tly

sis,

blee

ding

13m

o(m

ean)

Sign

ifica

ntly

sis:

19/2

4(7

9%)

Part

iall

ysis

:5/2

4(2

1%)

Ble

edin

g:6/

24(2

5%)

Pate

ncy

at3

mo,

84%

Pate

ncy

at1

yr,7

8%B

jarn

ason

etal

76/

1997

Pros

pect

ive

regi

stry

77pa

tient

s(8

7lim

bs)

with

iliof

emor

alD

VT

�14

d(n

�69

)or

�14

d(n

�18

)dur

atio

n

2,00

0–2,

500

U/k

g/h

urok

inas

ein

fuse

dfo

r75

h(m

ean)

,with

5,00

0IU

bolu

she

pari

npl

usin

fusi

onad

just

edto

APT

TA

djun

ctiv

eth

erap

y:an

giop

last

y(5

2lim

bs),

sten

t(3

8lim

bs),

AV

F(1

5lim

bs),

surg

ical

thro

mbe

ctom

y(1

3lim

bs),

mec

hani

cal

thro

mbe

ctom

y(4

limbs

),su

rgic

alby

pass

(3lim

bs)

Clo

tly

sis,

PE,

blee

ding

1yr

Ear

lyre

sults

:Si

gnifi

cant

lysi

s:69

/87

(79%

)Il

iac

(63%

)F

emor

al(4

0%)

No

lysi

s:18

/87

(21%

)PE

:n�

1(1

%)

Ble

edin

g:M

ajor

:5/7

7(6

%)

Min

or:1

1/77

(14%

)Pa

tenc

yat

1yr

:Il

iac

(63%

)F

emor

al(4

0%)

Mew

isse

net

al75

/19

99(N

atio

nal

mul

tice

nter

regi

stry

)

Pros

pect

ive

mul

ticen

ter

regi

stry

287

patie

nts

(312

infu

sion

s)w

ithlo

wer

-lim

bD

VT

�10

d(n

�18

8)or

�10

d(n

�99

)du

ratio

n

7.8

mill

ion

Uof

urok

inas

e(m

ean)

infu

sed

for

53.4

h(m

ean)

in29

7lim

bsIn

6lim

bs,o

nly

syst

emic

infu

sion

(no

CD

T)

Adj

unct

ive

ther

apy:

sten

ts(1

04lim

bs),

syst

emic

infu

sion

(54

limbs

)

Clo

tly

sis,

PE,

blee

ding

,de

ath

1yr

Ear

lyre

sults

:50

–100

%ly

sis:2

58/3

12(8

3%)

�50

%ly

sis:5

4/31

2(1

7%)

PE:6

/473

(1%

)�ca

lcul

ated

from

tota

lNo.

ofpa

tient

sin

Veno

usR

egist

ry�

Ble

edin

g:54

/473

(11%

)�ca

lcul

ated

from

tota

lN

o.of

patie

nts

inVe

nous

Reg

istry

�D

eath

:2/4

73(�

1%)

�Cal

cula

ted

from

tota

lNo.

ofpa

tient

sin

Veno

usR

egist

ry�;

Pate

ncy

at1

yrIli

ac(6

4%)

Fem

oral

(47%

)C

omer

ota

and

Kag

an78

/200

0R

etro

spec

tive

stud

y54

patie

nts

(54

limbs

)w

ithili

ofem

oral

DV

T,a

vera

gedu

ratio

nof

leg

sym

ptom

sof

5.2

d

250,

000–

500,

000

Uof

urok

inas

ebo

lus

follo

wed

by25

0,00

0–30

0,00

0U

/hof

cont

inuo

usin

fusio

nfo

r30

h(m

ean)

in47

patie

nts;

allp

atie

nts

rece

ived

hepa

rinin

fusio

nat

500–

1,00

0U

/hor

4-to

8-m

gbo

lus

ofrt

-PA

follo

wed

by2–

4m

g/h

in7

patie

nts,

with

hepa

rinas

note

dab

ove

Adj

unct

ive

ther

apy:

surg

ical

thro

mbe

ctom

y(n

�5)

Clo

tly

sis,

com

plic

atio

nsN

DE

arly

resu

lts:

Sign

ifica

ntly

sis:

45/5

4(8

3%)

Ilia

c(7

8%)

Com

plic

atio

ns:

Maj

orbl

eed:

4/54

(7%

)H

emat

oma,

punc

ture

site

:8(1

5%)

Hem

atom

a,in

guin

al:1

(2%

)




Tab

le3—

Con

tinu

ed

Aut

hor/

yrT

ype

ofSt

udy

Part

icip

ants

Inte

rven

tions

Out

com

esF

ollo

w-u

pR

esul

ts

Hor

neet

al92

/200

0Pr

ospe

ctiv

e,st

udy

10pa

tient

s(1

0lim

bs)

with

low

er-e

xtre

mity

DV

T�

14d

dura

tion

rt-P

Ado

seof

0.6

mg/

kgto

am

axim

umof

50m

g/kg

per

leg

infu

sed

via

daily

pulse

-spr

ayca

thet

erfo

rup

to4

dof

trea

tmen

t;he

parin

was

adju

sted

toa

prot

hrom

bin

time

of1.

5–2.

5�

base

line

Clo

tly

sis,

PE,

blee

ding

2–6

mo

Sign

ifica

ntly

sis:

9/10

(90%

)Pa

rtia

llys

is:1

/10

(10%

)PE

:2/1

0(2

0%)

Ble

edin

g:1/

10(1

0%)

Kas

iraj

anet

al94

/20

01R

etro

spec

tive

regi

stry

Nin

epa

tient

sw

ith�

90%

thro

mbu

sex

trac

tion

follo

win

gpe

rcut

aneo

usm

echa

nica

lthr

ombe

ctom

yfo

rili

ofem

oral

/IV

CD

VT

Uro

kina

se,r

t-PA

,or

rPA

for

mea

nof

20h

Com

plet

e,pa

rtia

l,no

lysi

s

9m

o(m

ean)

Com

plet

ely

sis:

7/9

(78%

)Pa

rtia

llys

is:1

/9(1

1%)

No

lysi

s:1/

9(1

1%)

Abu

Rah

ma

etal

89/

2001

Pros

pect

ive

stud

y51

patie

nts

(51

limbs

)w

ithili

ofem

oral

DV

Tgi

ven

choi

cebe

twee

nco

nven

tiona

lthe

rapy

(hep

arin

plus

war

fari

n)or

lysi

spl

usan

gio/

sten

t(if

need

ed);

lysi

sof

fere

don

lyto

patie

nts

with

DV

T�

14d

dura

tion

and

noco

ntra

indi

catio

ns

Ant

icoa

gula

tion:

33pa

tient

sad

min

ister

ed1,

000–

2,00

0U

/hof

hepa

rinin

fusio

nfo

r5–

7d

CD

T:18

patie

nts

adm

inist

ered

load

ing

dose

of4,

500

Uof

urok

inas

efo

llow

edby

4,50

0U

/kg/

hfo

r24

–48

h,or

4-to

8-m

gbo

lus

ofrt

-PA

follo

wed

by2

to4/

mg/

hin

fusio

nA

djun

ctiv

eth

erap

y:pa

tient

sw

ithre

sidua

lste

nosis

�50

%re

ceiv

edst

ents

(n�

10)

Clo

tly

sis,

PE,

blee

ding

Ant

icoa

gula

tion

for

6m

oC

DT

for

6m

o

Ant

icoa

gula

tion:

30-d

sign

ifica

ntly

sis:

1/33

(3%

)6-

mo

pate

ncy:

8/33

(24%

)B

leed

ing:

2/33

(6%

)PE

:2/3

3(6

%)

CD

T:

30-d

sign

ifica

ntly

sis:

15/1

8(8

3%)

6-m

opa

tenc

y:15

/18

(83%

)B

leed

ing:

2/18

(11%

)

Ved

anth

amet

al10

1 /20

02R

etro

spec

tive

stud

y20

patie

nts

(28

limbs

)w

ithsy

mpt

omat

iclo

wer

-ex

trem

ityD

VT

Intr

athr

ombu

sde

liver

yof

eith

erof

the

follo

win

g:(1

)ur

okin

ase,

mea

n16

6,00

0U

/h(7

limbs

)(2

)tP

Am

ean

1.74

mg/

h(7

limbs

)(3

)rP

Am

ean

0.89

U/h

(14

limbs

)A

djun

ctiv

eth

erap

y:m

echa

nica

lthr

ombe

ctom

yby

cath

eter

(28

proc

edur

es);

iliac

sten

ts(1

5pa

tient

s)

Proc

edur

alsu

cces

s(�

30%

resid

ual

sten

osis)

,maj

orbl

eedi

ng

Aft

erpr

oced

ure

Proc

edur

alsu

cces

s:23

/28

(82%

)M

ajor

blee

ding

:14%

Els

hara

wy

and

Elz

ayat

72/2

002

RC

T,s

ingl

ece

nter

35pa

tient

sw

ithD

VT

�10

ddu

ratio

nra

ndom

ized

toC

DT

oran

ticoa

gula

tion

alon

e

CD

T:1

8pa

tient

sre

ceiv

edap

prox

imat

ely

1m

illio

nU

ofst

rept

okin

ase

puls

esp

ray

for

1h,

follo

wed

by10

0,00

0U

/hof

stre

ptok

inas

ein

fusi

onun

tilco

mpl

ete

lysi

s,no

chan

gein

12h,

orco

mpl

icat

ion;

adju

nctiv

eth

erap

y:an

giop

last

y/st

ent

(n�

1)A

ntic

oagu

latio

n:17

patie

nts

rece

ived

5,00

0U

ofhe

pari

nbo

lus,

follo

wed

byhe

pari

nad

just

edto

APT

T

Clo

tly

sis,

PE,

blee

ding

1w

eek

and

6m

oC

DT

at1

wk

Com

plet

ely

sis:

11/1

8(6

1%)

No

lysi

s:0

(0%

)PE

:0B

leed

ing:

0A

ntic

oagu

latio

nat

1w

k:C

ompl

ete

lysi

s:0/

17(0

%)

No

lysi

s:17

/17

(100

%)

PE:1

/17

(6%

)B

leed

ing:

0C

DT

at6

mo:

Com

plet

ely

sis:

13/1

8(7

2%)

No

lysi

s:0

(0%

)A

ntic

oagu

latio

nat

6m

o:Si

gnifi

cant

lysi

s:2/

17(1

2%)

No

lysi

s:7/

17(4

1%)

Cas

tane

daet

al90

/20

02Pr

ospe

ctiv

est

udy

15pa

tient

sw

ithac

ute

orch

roni

cD

VT

oflo

wer

extr

emity

(n�

14)

orIV

C(n

�1)

16.5

U/h

(med

ian)

ofrt

-PA

infu

sed

over

29h

(med

ian)

with

hepa

rin

dose

sof

300–

400

U/h

Adj

unct

ive

ther

apy:

sten

ting

(n�

4);

angi

opla

sty/

sten

t(n

�6)

Clo

tly

sis,

PE,

blee

ding

Aft

erpr

oced

ure

Sign

ifica

ntly

sis:

15/1

5(1

00%

)PE

:0B

leed

ing:

0




Tab

le3—

Con

tinu

ed

Aut

hor/

yrT

ype

ofSt

udy

Part

icip

ants

Inte

rven

tions

Out

com

esF

ollo

w-u

pR

esul

ts

Gru

nwal

dan

dH

ofm

ann91

/200

5R

etro

spec

tive

stud

y74

patie

nts

(82

limbs

)w

ithD

VT

ofup

per

(n�

23)

orlo

wer

(n�

59)

extr

emity

,with

dura

tion

of�

14d

(n�

74)

or�

14d

(n�

8)

Uro

kina

se:1

1.3

U/h

ofur

okin

ase

for

40.6

h(3

8lim

bs)

with

ther

apeu

tiche

pari

ndo

sing

tPA

:0.5

7m

g/h

tPA

for

30.8

h(3

2lim

bs)

with

subt

hera

peut

iche

pari

nrt

-PA

:0.7

4U

/hrt

-PA

for

24.3

h(1

2lim

bs)

with

subt

hera

peut

iche

pari

nA

djun

ctiv

eth

erap

y:m

echa

nica

lthr

ombo

lysi

s,an

giop

last

y,st

entin

g;ur

okin

ase

(n�

30),

tPA

(n�

24),

rt-P

A(n

�12

)

Clo

tly

sis,

PE,

blee

ding

Aft

erpr

oced

ure

Uro

kina

se:

Sign

ifica

ntly

sis:

27/3

871

%)

PE:0

Ble

edin

g:2/

38(5

%)

tPA

:Si

gnifi

cant

lysi

s:21

/32

(66%

)PE

:0B

leed

ing:

1/32

(3%

)rt

-PA

:Si

gnifi

cant

lysi

s:6/

12(5

0%)

PE:0

Ble

edin

g:1/

12(8

%)

Lai

hoet

al81

/200

4R

etro

spec

tive

stud

y32

patie

nts

with

iliof

emor

alD

VT

�14

din

dura

tion

rece

ived

eith

erca

thet

er-

dire

cted

(n�

16)

orsy

stem

ic(n

�16

)th

rom

boly

sis

CD

Ttr

eatm

ent:

73m

g(m

ean)

rt-P

Afo

r33

h(m

ean)

via

cath

eter

deliv

ery,

with

LM

WH

and

oral

antic

oagu

lant

s

Clo

tly

sis,

PE,

blee

ding

,va

lvul

arco

mpe

tenc

e

2–3

yrC

DT

trea

tmen

tSi

gnifi

cant

lysi

s:8/

16(5

0%)

PE:2

/16

(13%

)B

leed

ing:

2/16

(13%

)V

alvu

lar

com

pete

nce:

7/16

(44%

)A

nyde

epve

inin

com

pete

nce:

44%

Sille

sen

etal

100 /2

005

Ret

rosp

ectiv

est

udy

45pa

tient

sw

ithili

ofem

oral

DV

T�

14d

indu

ratio

n1

mg

rt-P

Ast

artin

gdo

sepl

us1,

000–

5,00

0U

ofU

FH

follo

wed

byco

ntin

uous

infu

sion

of1

mg

rt-P

Aan

d1,

000

Uof

UF

Hpe

rho

ur(n

�9)

10m

grt

-PA

pulse

spra

ypl

us1,

000–

5,00

0U

ofU

FH

for

initi

al15

–30

min

,fol

low

edby

cont

inuo

usin

fusio

nof

1m

grt

-PA

and

1,00

0U

UF

Hpe

rho

ur(n

�36

)A

djun

ctiv

eth

erap

y:an

giop

last

y/st

entin

g(n

�30

)

Clo

tly

sis,

PE,

blee

ding

,de

ath

24m

o(m

edia

n)Si

gnifi

cant

lysi

s:42

/45

(93%

)PE

:1/4

5(2

%)

Min

orbl

eedi

ng:4

(8%

)

Jack

son

etal

93/2

005

Ret

rosp

ectiv

est

udy

28pa

tient

sw

ithlo

wer

-ex

trem

ityD

VT

of�

14d

(n�

20)

or�

14d

indu

ratio

n(n

�4)

orre

curr

ent

DV

T(n

�4)

60,0

00–1

80,0

00U

/hur

okin

ase

infu

sed

over

24–4

8h

(n�

2)1–

2m

g/h

tPA

for

24–4

8h

(n�

16)

1–2

U/h

rt-P

Afo

r24

–48

h(n

�9)

Mec

hani

calt

hrom

bect

omy

only

(n�

1)A

djun

ctiv

eth

erap

y:m

echa

nica

lthr

ombe

ctom

y(n

�20

),st

entin

g(n

�12

)

Clo

tly

sis,

PE,

blee

ding

,de

ath

15.5

mo

Lys

is�

90%

:6/2

8(2

1%)

Lys

is80

–89%

:2/2

8(7

%)

Lys

is60

–79%

:2/2

8(7

%)

Lys

is�

60%

:11/

28(3

9%)

PE:0

Min

orbl

eedi

ng:2

/28

(7%

)Im

med

iate

pate

ncy:

92%

Lon

g-te

rmpa

tenc

y:80

%O

gaw

aet

al97

/200

5Pr

ospe

ctiv

e,st

udy

24pa

tient

sw

ithlo

wer

-ex

trem

ityD

VT

CD

T:2

40,0

00U

ofur

okin

ase

infu

sed

for

1h,

follo

wed

by2

dof

1-h

infu

sion

of12

0,00

0U

ofur

okin

ase

bid,

with

IVU

FH

tore

ach

APT

Ttim

era

tiofr

om1.

5–2.

0w

ithin

24h

(n�

10)

CD

Tpl

usIP

C/I

VC

:thr

ombo

lysi

spe

rfor

med

asin

CD

T-o

nly

grou

p;te

mpo

rary

IVC

filte

rpl

aced

inin

frar

enal

IVC

and

rem

oved

afte

rC

DT

;IPC

with

foot

-cal

fcy

cle

begu

naf

ter

urok

inas

ein

fusi

onan

dco

ntin

ued

24h/

dun

tilC

DT

stop

ped

(n�

14)

Clo

tly

sis,

PE,

blee

ding

CD

Tgr

oup:

22m

o;

CD

Tpl

usIP

Cgr

oup:

14m

o

CD

T:

100%

lysi

s:0/

10(5

0–99

%)

lysi

s:2/

10(2

0%)

�50

%ly

sis:

8/10

(80%

)PE

:0B

leed

ing:

0C

DT

plus

IPC

/IV

C10

0%ly

sis:

5/14

(36%

)50

–99%

lysi

s:6/

14(4

3%)

�50

%ly

sis:

3/14

(21%

)PE

:0B

leed

ing:

0




Tab

le3—

Con

tinu

ed

Aut

hor/

yrT

ype

ofSt

udy

Part

icip

ants

Inte

rven

tions

Out

com

esF

ollo

w-u

pR

esul

ts

Kim

etal

95/2

006

Ret

rosp

ectiv

est

udy

37pa

tient

s(4

5lim

bs)

with

acut

e(�

14d)

iliof

emor

alD

VT

CD

T:6

.70

�5.

9m

illio

nU

ofur

okin

ase

(mea

n)in

fuse

dfo

rm

ean

of56

.5�

27.4

hin

26lim

bs(2

3pa

tient

s)C

DT

plus

phar

mac

omec

hani

cal:

lytic

trea

tmen

tpe

rfor

med

asde

scri

bed

inC

DT

grou

ppl

usA

ngio

Jet

thro

mbe

ctom

yde

vice

Clo

tly

sis,

blee

ding

,PE

,tr

eatm

ent

dura

tion,

cost

,re

curr

entD

VT

32m

oC

ompl

ete

lysi

s:C

DT

:21/

26(8

1%)

CD

Tpl

usPM

T:1

6/21

(84%

)M

ajor

blee

ding

:C

DT

:2/2

6(7

%)

CD

Tpl

usPM

T:1

/21

(5%

)PE

:C

DT

:1/2

6(4

%)

CD

Tpl

usPM

T:1

/21

(5%

)T

reat

men

tdu

ratio

n:C

DT

:57

hC

DT

plus

PMT

:30

hC

ost

(dru

gpl

usde

vice

):C

DT

:$10

,127

CD

Tpl

usPM

T:$

5,12

8R

ecur

rent

DV

T:

CD

T:4

/16

(25%

)C

DT

plus

PMT:

2/13

(15%

)L

inet

al96

/200

6R

etro

spec

tive

stud

y93

patie

nts

(98

proc

edur

es)

with

sym

ptom

atic

DV

TC

DT

:46

proc

edur

esus

ing

tPA

,rt-

PA,o

rur

okin

ase

PMT

:52

proc

edur

esus

ing

Ang

ioJe

trh

eoly

ticth

rom

bect

omy

syst

emw

ithtP

A,r

t-PA

,or

urok

inas

e

Clo

tly

sis,

No.

ofve

nogr

ams,

imm

edia

tecl

inic

alim

prov

emen

t,bl

eedi

ng,

ICU

/hos

pita

lst

ay,1

-yr

prim

ary

pate

ncy,

cost

1yr

Com

plet

e/pa

rtia

llys

is:

CD

T:3

2/46

(70%

)/14

/46

(30%

)C

DT

plus

PMT

:39/

52(7

5%)/1

3/52

(25%

)N

o.of

veno

gram

s:C

DT

:2.5

CD

Tpl

usPM

T:0

.4(p

�0.

001)

Imm

edia

tecl

inic

alim

prov

emen

t:C

DT

:33/

46(7

2%)

CD

Tpl

usPM

T:4

2/52

(81%

)B

leed

ing:

CD

T:2

/49

(4%

)C

DT

plus

PMT

:3/4

6(7

%)

ICU

stay

:C

DT

:2.4

dC

DT

plus

PMT

:0.6

dH

ospi

tals

tay:

CD

T:8

.4d

CD

Tpl

usPM

T:2

.4d

1-yr

prim

ary

pate

ncy:

CD

T:6

4%C

DT

plus

PMT

:68%

Cos

t:C

DT

:$85

,301

CD

Tpl

usPM

T:$

47,7

42

*ND

�no

tde

term

ined

.The

met

hodo

logi

cqu

ality

desc

ript

ion

port

ion

ofth

ista

ble

can

befo

und

inth

eon

line

vers

ion

ofth

isar

ticle

asa

data

supp

lem

ent.




Tab

le4

—Sy

stem

icT

hrom

bol

ytic

The

rapy

for

Acu

teD

VT

:C

lini

cal

Des

crip

tion

and

Res

ult

s(S

ecti

on1.

9)*

Aut

hor/

yrT

ype

ofSt

udy

Part

icip

ants

Inte

rven

tions

Out

com

esF

ollo

w-u

pR

esul

ts

Bro

wse

etal

105 /

1968

RC

T,s

ingl

ece

nter

10pa

tient

sw

ithlo

wer

-ext

rem

ityD

VT

conf

irm

edby

phle

bogr

aphy

Lys

is:6

00,0

00U

ofst

rept

okin

ase

plus

100

mg

ofhy

droc

ortis

one

for

first

hour

,the

nco

ntin

ued

ever

y6

hfo

r3

d(n

�5)

Ant

icoa

gula

tion:

4-to

6-h

dose

sof

5,00

0U

hepa

rin

for

48h

follo

wed

byw

arfa

rin

(n�

5)

Clo

tly

sis,

PE,

blee

ding

7–10

dT

hrom

boly

sis:

Com

plet

ecl

otly

sis:

3/5

(60%

)Pa

rtia

llys

is:1

/5(2

0%)

No

lysi

s:1

(20%

)PE

:0B

leed

ing:

0A

ntic

oagu

latio

n:C

ompl

ete

clot

lysi

s:0/

5Pa

rtia

llys

is:0

/5N

oly

sis:

5/5

(100

%)

PE:0

Ble

edin

g:0

Rob

erts

onet

al11

3 /19

68R

CT

,sin

gle

cent

er16

patie

nts

with

DV

TT

hrom

boly

sis:

200,

000

Uof

stre

ptok

inas

eov

er90

min

,the

n10

0,00

0U

asm

aint

enan

cedo

sefo

r22

.5h;

500

mg

ofhe

pari

nad

min

iste

red

over

24h,

plus

pred

niso

ne(n

�8)

Ant

icoa

gula

tion:

hepa

rin

plus

pred

niso

ne(n

�8)

Clo

tly

sis,

blee

ding

7d

Thr

ombo

lysi

s:Si

gnifi

cant

lysi

s:5/

8(6

3%)

Part

iall

ysis

:2/8

(25%

)N

oly

sis:

1/8

(12%

)B

leed

ing:

Maj

or:2

/8(2

5%)

Min

or:2

/8(2

5%)

Ant

icoa

gula

tion:

Sign

ifica

ntly

sis:

1/8

(12%

)Pa

rtia

llys

is:2

/8(2

5%)

No

lysi

s:5/

8(6

3%)

Ble

edin

g:M

ajor

:1/8

(12%

)M

inor

:1/8

(12%

)K

akka

ret

al10

9 /19

69R

CT

,sin

gle

cent

er30

patie

nts

with

DV

Tof

�4

dT

hrom

boly

sis:

stre

ptok

inas

eat

500,

000

UIV

over

30m

in,9

00,0

00U

ever

y6

hfo

r5

d(n

�10

)A

rvin

:arv

inlo

adin

gdo

se80

UIV

over

6h,

80U

over

15m

in,4

0to

80U

ever

y6

hfo

r5

d(n

�10

)A

ntic

oagu

latio

n:he

pari

nat

10,0

00U

IVov

er5

min

,the

n10

,000

–15,

000

Uev

ery

6h

for

5d

(n�

10)

Clo

tly

sis,

PE,

blee

ding

,dea

th6–

12m

oT

hrom

boly

sis:

Com

plet

ecl

otly

sis:

6/9

(67%

)Pa

rtia

llys

is:1

/9(1

1%)

No

lysi

s:2/

9(2

2%)

PE:0

Ble

edin

g:4/

10(4

0%)

Dea

th:2

/9(2

2%)

�1pa

tient

excl

uded

from

trea

tmen

t�A

rvin

:C

ompl

ete

lysi

s:1/

10(1

0%)

Part

iall

ysis

:3/1

0(3

0%)

No

lysi

s:6/

10(6

0%)

PE:0

Ble

edin

g:0

Dea

th:0

Ant

icoa

gula

tion:

Com

plet

ecl

otly

sis:

2/9

(22%

)Pa

rtia

llys

is:2

/9(2

2%)

No

lysi

s:5/

9(5

5%)

PE:1

/10

Dea

th:2

/9(2

2%)

Ble

edin

g:2/

9(2

2%)

�not

e:1

patie

ntex

clud

edfr

omtr

eatm

ent�




Tab

le4

—C

onti

nued

Aut

hor/

yrT

ype

ofSt

udy

Part

icip

ants

Inte

rven

tions

Out

com

esF

ollo

w-u

pR

esul

ts

Tsa

poga

set

al11

7 /19

73R

CT

,sin

gle

cent

er34

patie

nts

with

DV

Tof

�5

dT

hrom

boly

sis:

titra

ted

initi

aldo

seof

stre

ptok

inas

eIV

,the

nst

rept

okin

ase

at10

0,00

0U

/hm

aint

aine

dan

dad

just

edup

to72

h;IV

hepa

rin

for

1w

k6–

12h

afte

rst

rept

okin

ase

(n�

19)

Ant

icoa

gula

tion:

hepa

rin

IVin

toaf

fect

edlim

b,7,

000

Ubo

lus

then

1,50

0U

/had

just

ed;c

ontin

ued

for

7d

(n�

15)

Clo

tly

sis,

PE,

blee

ding

7d

Thr

ombo

lysi

s:C

ompl

ete/

part

iall

ysis

:10/

19(5

3%)

No

lysi

s:9/

19(4

7%)

PE:0

Ble

edin

g:m

inor

:3(1

6%)

Ant

icoa

gula

tion:

Com

plet

e/pa

rtia

llys

is:1

/15

(7%

)N

oly

sis:

14/1

5(9

3%)

PE:1

/15

(7%

)B

leed

ing:

0D

ucke

rtet

al10

6 /19

75Pr

ospe

ctiv

est

udy

134

patie

nts

with

acut

eor

suba

cute

DV

T

Thr

ombo

lysi

s:in

itial

dose

ofst

rept

okin

ase

calc

ulat

edac

cord

ing

toto

lera

nce

inje

cted

over

15–3

0m

in;m

aint

enan

cedo

seat

30m

L/h

was

two

thir

dsof

first

dose

(n�

92)

Ant

icoa

gula

tion:

5,00

0U

hepa

rin

for

initi

aldo

sefo

llow

edby

25,0

00U

/24

hin

fusi

on(n

�42

)

Clo

tly

sis,

PE,

blee

ding

App

roxi

mat

ely

7d

Thr

ombo

lysi

s:Si

gnifi

cant

lysi

s:39

/92

(42%

)Pa

rtia

llys

is:2

3/92

(25%

)N

oly

sis:

30/9

2(3

3%)

PE:7

(8%

)B

leed

ing:

Maj

or:5

8(6

2%)

Min

or:2

4(2

6%)

Ant

icoa

gula

tion:

Sign

ifica

ntly

sis:

0/42

(0%

)Pa

rtia

llys

is:4

/42

(10%

)N

oly

sis:

38/4

2(9

0%)

PE:5

/42

(12%

)B

leed

ing:

Maj

or:2

/42

(5%

)M

inor

:4/4

2(1

0%)

Port

eret

al11

2 /19

75R

CT

,sin

gle

cent

er50

patie

nts

with

DV

T�

14d

indu

ratio

n

Thr

ombo

lysi

s:st

rept

okin

ase

IVat

250,

000

Uov

er30

min

,the

n10

0,00

0U

/htit

rate

dfo

r72

h;fo

llow

edby

IVhe

pari

ntit

rate

dov

er7

d(n

�23

)A

ntic

oagu

latio

n:IV

hepa

rin

at15

0U

/kg

load

ing

dose

then

titra

ted

for

10d

(n�

26)

Clo

tly

sis,

PE,

blee

ding

,dea

thdu

eto

trea

tmen

t

10d

Thr

ombo

lysi

s:C

ompl

ete

lysi

s:6/

23(2

6%)

Part

iall

ysis

:15/

23(6

5%)

No

lysi

s:2/

23(9

%)

PE:0

Ble

edin

g:4/

23(1

7%)

Dea

th:1

(4%

)A

ntic

oagu

latio

n:C

ompl

ete

lysi

s:1/

26(4

%)

Part

iall

ysis

:20/

26(7

7%)

No

lysi

s:5/

26(1

9%)

PE:0

Ble

edin

g:1/

26(4

%)

Dea

th:0

Mar

der

etal

111 /

1977

RC

T,s

ingl

ece

nter

24pa

tient

sw

ithD

VT

Thro

mbo

lysis

:ini

tiald

ose

of25

0,00

0U

ofst

rept

okin

ase

for

20m

in,f

ollo

wed

by10

0,00

0U

/hfo

r72

h(n

�12

)A

ntic

oagu

latio

n:in

itial

IVhe

parin

dose

of15

0U

/kg,

follo

wed

bytit

rate

din

fusio

nfo

r72

hC

otre

atm

ent:

100

mg

bolu

shy

droc

ortis

one

prio

rto

trea

tmen

t

Clo

tly

sis,

deat

hdu

eto

trea

tmen

t5

dT

hrom

boly

sis:

Sign

ifica

ntly

sis:

5/12

(42%

)Pa

rtia

llys

is:2

/12

(16%

)N

oly

sis:

5/12

(42%

)D

eath

:1/1

2(8

%)

Ant

icoa

gula

tion:

Sign

ifica

ntly

sis:

0/12

(0%

)Pa

rtia

llys

is:3

/12

(25%

)N

oly

sis:

9/12

(75%

)D

eath

:0




Tab

le4

—C

onti

nued

Aut

hor/

yrT

ype

ofSt

udy

Part

icip

ants

Inte

rven

tions

Out

com

esF

ollo

w-u

pR

esul

ts

Arn

esen

etal

103 /

1978

RC

T,s

ingl

ece

nter

42pa

tient

sw

ithpr

oxim

alD

VT

of�

5d

Thr

ombo

lysis

:250

,000

Ulo

adin

gof

IVst

rept

okin

ase,

then

100,

000

IU/h

IVfo

r72

–96

h(n

�21

)A

ntic

oagu

latio

n:15

,000

IUIV

bolu

she

parin

,the

nto

talo

f30

,000

IUIV

infu

sion

for

72–9

0h

(n�

21)

Clo

tly

sis,

PE,

blee

ding

21d

to6

yrT

hrom

boly

sis:

Sign

ifica

ntly

sis:

15/2

1(7

1%)

No

lysi

s:6/

21(2

9%)

PE:1

/21

(5%

)B

leed

ing:

2/21

(9%

)A

ntic

oagu

latio

n:Si

gnifi

cant

lysi

s:5/

21(2

4%)

No

lysi

s:16

/21

(76%

)PE

:0B

leed

ing:

2/21

(9%

)E

lliot

etal

107 /

1979

RC

T,s

ingl

ece

nter

51pa

tient

sw

ithcl

inic

alhi

stor

yof

DV

Tof

�8

d

Thr

ombo

lysi

s:lo

adin

gdo

seof

600,

000

Uof

stre

ptok

inas

ein

fuse

dov

er30

min

,fol

low

edby

100,

000/

hfo

r3

d;he

pari

nfo

r4

dfo

llow

ing

stre

ptok

inas

e(n

�26

)A

ntic

oagu

latio

n:10

,000

Uof

IVhe

pari

nin

itial

ly,f

ollo

wed

by10

,000

UIV

daily

for

a6-

hin

fusi

onto

mai

ntai

ncl

ottin

gtim

eof

2.5

to3

times

norm

al,f

or7

d(n

�25

)

Imm

edia

te:c

lot

lysi

s,PE

,ble

edin

g

Lon

gte

rm:s

ympt

omfr

ee

Imm

edia

te:5

d

Lon

g-te

rm:1

9m

o(m

ean)

Imm

edia

te:

Thr

ombo

lysi

s:Si

gnifi

cant

lysi

s:17

/26

(65%

)Pa

rtia

llys

is:1

/26

(4%

)N

oly

sis:

8/26

(31%

)PE

:0B

leed

ing:

2(8

%)

Ant

icoa

gula

tion:

Sign

ifica

ntly

sis:

0/25

(0%

)Pa

rtia

llys

is:0

/25

(0%

)N

oly

sis:

25/2

5(1

00%

)PE

:0B

leed

ing:

2/21

(9%

)L

ong-

term

Thr

ombo

lysi

s:Sy

mpt

omfr

ee:1

2/20

(60%

)�f

our

deat

hs,o

ther

caus

es,t

wo

unav

aila

ble

for

follo

w-u

p�;

Tre

atm

ent

2:Sy

mpt

omfr

ee:2

/21

(9%

)�f

our

deat

hs,t

wo

PE,t

wo

othe

rca

uses

�W

atz

etal

120 /

1979

Pros

pect

ive

stud

y35

patie

nts

with

DV

TT

hrom

boly

sis:

initi

aldo

seof

250,

000

Uof

stre

ptok

inas

ein

30m

in,

follo

wed

bym

aint

enan

ceof

100,

000

U/h

for

how

long

????

?(n

�18

)A

ntic

oagu

latio

n:45

,000

Uof

hepa

rin

daily

with

war

fari

n(n

�17

)

Clo

tly

sis,

PE,

blee

ding

1–2

mo

Thro

mbo

lysis

:Si

gnifi

cant

lysis

:8/1

8(4

4%)

Part

iall

ysis:

4/18

(22%

)N

oly

sis:6

/18

(34%

)PE

:1/1

8(5

%)

Ble

edin

g:m

inor

:3/1

8(1

2%)

Ant

icoa

gula

tion:

Sign

ifica

ntly

sis:1

/17

(6%

)Pa

rtia

llys

is:5/

17(2

9%)

No

lysis

:11/

17(6

5%)

PE:1

/17

(6%

)B

leed

ing:

min

or2/

17(1

2%)




Tab

le4

—C

onti

nued

Aut

hor/

yrT

ype

ofSt

udy

Part

icip

ants

Inte

rven

tions

Out

com

esF

ollo

w-u

pR

esul

ts

Kiil

etal

110 /

1981

RC

T,s

ingl

ece

nter

20pa

tient

sw

ithD

VT

of�

72h

Thr

ombo

lysi

s:ur

okin

ase

at20

0,00

0U

IVfo

r24

h;af

ter

18h,

hepa

rin

load

ing

dose

of15

,000

U,t

hen

40,0

00U

/dfo

r5

d(n

�11

)A

ntic

oagu

latio

n:he

pari

nat

40,0

00U

/dIV

for

6d

(n�

9)

Clo

tly

sis,

PE,

blee

ding

2w

kT

hrom

boly

sis:

Part

iall

ysis

:1/1

1(9

%)

No

lysi

s:10

/11

(91%

)PE

:0B

leed

ing:

3/11

(27%

)A

ntic

oagu

latio

n:Pa

rtia

llys

is:1

/8(1

2%)

No

lysi

s:7/

8(8

8%)

PE:0

Ble

edin

g:3/

9(3

3%)

�not

e:1

patie

ntex

clud

edfr

omgr

oup�

Arn

esen

etal

104 /

1982

Fol

low

-up

toR

CT

ofA

rnes

en/1

978

(n�

48)

35/4

2pa

tient

sfr

omR

CT

Phle

bogr

aphy

and

clin

ical

exam

inat

ion

bybl

inde

dev

alua

tors

Nor

mal

legs

,PT

Ssy

mpt

oms

6.5

yrT

hrom

boly

sis:

Nor

mal

legs

:13/

17(7

7%)

PTS:

sym

ptom

s(m

oder

ate)

:4/1

7(2

4%)

Ant

icoa

gula

tion:

Nor

mal

legs

:6/1

8(3

3%)

PTS

sym

ptom

s(m

oder

ate)

:9/1

8(5

0%)

Schu

lman

etal

114 /

1986

RC

T,s

ingl

ece

nter

36pa

tient

sw

ithca

lfD

VT

of�

7d

Thr

ombo

lysi

s:st

rept

okin

ase

at50

,000

IUIV

over

15m

in,t

hen

100,

000

IUov

er12

hfo

rup

to7

d,tit

rate

d;ad

min

iste

red

with

5,00

0IU

ofhe

pari

nIV

over

12h

(n�

17)

Ant

icoa

gula

tion:

hepa

rin

at5,

000

IUIV

for

15m

inth

en30

,000

IU/d

,tit

rate

dov

er7

d(n

�19

)

Clo

tly

sis,

blee

ding

,PE

5yr

Thr

ombo

lysi

s:C

ompl

ete

lysi

s:7/

17(4

1%)

Ble

edin

g:3/

17(1

8%);

PE:0

Ant

icoa

gula

tion:

Com

plet

ely

sis:

2/19

(10%

)B

leed

ing:

1/19

(5%

)PE

:0V

erha

eghe

etal

119 /

1989

Pros

pect

ive

coho

rtst

udy

(stu

dyA

)an

dm

ultic

ente

rR

CT

(stu

dyB

)

32pa

tient

sw

ithD

VT

of�

10d

Stud

yA

:O

pen-

labe

lstu

dyw

ithIV

rt-P

A10

0m

gov

er8

h(d

ay1)

,50

mg

rt-P

Aov

er8

h(d

ay2)

;10%

dose

asbo

lus

(n�

11)

Stud

yB

:rt

-PA

at10

0m

g;IV

of10

0m

Lco

ntai

ning

rt-P

A10

0m

gin

fuse

dov

er8

h(d

ay1)

,IV

of10

0m

Lco

ntai

ning

50m

gof

rt-

PAin

fuse

dov

er8

h(d

ay2)

;10%

dose

asbo

lus

(n�

8)rt-

PA50

mg:

IVof

100

mL

cont

aini

ngrt-

PA50

mg

infu

sed

over

8h

onbo

thda

ys1

and

2;10

%do

seas

bolu

s(n

�6)

Plac

ebo:

IVof

100

mL

cont

aini

ngpl

aceb

oin

fuse

dov

er8

hon

both

days

1an

d2

(n�

7)C

otre

atm

ent:

hepa

rinat

5,00

0U

IVbo

lus

then

cont

inuo

usin

fusio

n1,

000

U/h

for

upto

72h

Clo

tly

sis,

blee

ding

72h

Not

e:au

thor

sas

signe

dve

ins

are

lativ

eva

lue

refle

ctin

gde

gree

ofth

rom

bosis

(max

imum

of40

U:c

ompl

ete

thro

mbo

sis);

the

unit

scor

esre

flect

the

redu

ctio

nin

thro

mbo

sisaf

ter

lysis

Stud

yA

:C

hang

ein

unit

scor

e�

3.2

Stud

yB

:rt

-PA

100

mg

Cha

nge

inun

itsc

ore

�24

.3B

leed

ing:

6rt

-PA

:50

mg

Cha

nge

inun

itsc

ore

�34

.3B

leed

ing:

3Pl

aceb

o:C

hang

ein

unit

scor

e�

2.8

Ble

edin

g:0




Tab

le4

—C

onti

nued

Aut

hor/

yrT

ype

ofSt

udy

Part

icip

ants

Inte

rven

tions

Out

com

esF

ollo

w-u

pR

esul

ts

Gol

dhab

eret

al10

8 /19

90R

CT

,mul

ticen

ter

64pa

tient

s(6

5ra

ndom

izat

ions

)w

ithD

VT

of�

14d

rt-P

A:r

t-PA

0.05

mg/

kg/h

IVfo

r24

h,th

enhe

parin

100

U/k

gbo

lus,

then

1,00

0U

/h,a

djus

ted

(n�

36)

rt-P

Apl

ushe

parin

:rt-P

Aas

ingr

oup

1pl

ushe

parin

conc

omita

ntly

(n�

17)

Ant

icoa

gula

tion:

hepa

rin10

0U

/kg

bolu

s,th

en1,

000

U/h

(n�

12)

Clo

tly

sis,

blee

ding

36h

rt-P

A:

Com

plet

ely

sis:

2/32

(6%

)Pa

rtia

llys

is:1

8/32

(57%

)N

oly

sis:

12/3

2(3

8%)

Ble

edin

g:1/

32(3

%)

rt-P

Apl

ushe

pari

n:C

ompl

ete

lysi

s:1/

17(6

%)

Part

iall

ysis

:8/1

7(4

8%)

No

lysi

s:8/

17(4

8%)

Ble

edin

g:0

Ant

icoa

gula

tion:

Part

iall

ysis

:2/1

1(1

8%)

No

lysi

s:9/

11(8

9%)

Ble

edin

g:0

(not

e:5

of65

veno

gram

sw

ere

not

anal

yzed

)T

urpi

eet

al11

8 /19

90R

CT

,mul

ticen

ter

83pa

tient

sw

ithD

VT

of�

7d

Phas

e1:

Lys

ispl

ushe

pari

n:tw

o-ch

ain

rt-P

A0.

5m

g/kg

IVfo

r4

h(n

�12

)Pl

aceb

opl

ushe

pari

n(n

�12

)Ph

ase

2:L

ysis

plus

hepa

rin:

one-

chai

nrt

-PA

0.5

mg/

kgIV

for

8h

and

repe

ated

in24

h(n

�29

)Pl

aceb

opl

ushe

pari

n(n

�30

)C

otre

atm

ent:

IVhe

pari

n5,

000

Ubo

lus

then

30,0

00U

/24

h,ad

just

edfo

r7–

10d

Clo

tly

sis,

blee

ding

24–4

8h

Phas

e1:

Lys

ispl

ushe

pari

n:�

50%

lysi

s:7/

12(5

8%)

�50

%ly

sis:

2/12

(17%

)N

oly

sis:

3/12

(25%

)B

leed

ing:

4/12

(33%

)Pl

aceb

opl

ushe

pari

n:�

50%

lysi

s:2/

12(1

7%)

No

lysi

s:10

/12

(83%

)B

leed

ing:

1/12

(8%

)Ph

ase

2:L

ysis

plus

hepa

rin:

�50

%ly

sis:

6/29

(21%

);�

50%

lysi

s:7/

29(2

4%)

No

lysi

s:15

/29

(52%

)B

leed

ing:

1/29

(3%

)Pl

aceb

opl

ushe

pari

n:�

50%

lysi

s:2/

30(7

%);

�50

%ly

sis:

5/30

(17%

)N

oly

sis:

23/3

0(7

7%)

Ble

edin

g:1/

30(3

%)

Schw

eize

ret

al11

5 /19

98R

CT

,sin

gle

cent

er69

patie

nts

with

DV

Tof

�7

drt

-PA

:20

mg

IVin

tope

dalv

ein

4h/

dfo

r7

d;he

parin

IVad

min

ister

edco

ncom

itant

ly;w

arfa

rinda

y7

to12

mo

Uro

kina

se:1

00,0

00IU

/hIV

into

peda

lve

inco

ntin

uous

ly7

d;he

parin

IV7

d;pl

asm

inog

enm

onito

red;

war

farin

day

7–12

mo

Ant

icoa

gula

tion:

hepa

rinIV

adju

sted

for

7d;

.war

farin

,day

1to

12m

o

7d:

clot

lysi

s,bl

eedi

ng1

yr:P

TS

sym

ptom

s

7d

and

1yr

rt-P

A:

Com

plet

ely

sis:

6/22

(27%

)B

leed

ing:

1/22

(5%

)PT

Ssy

mpt

oms:

14/2

2(6

4%)

Uro

kina

se:

Com

plet

ely

sis:

11/2

2(5

0%)

Ble

edin

g:1/

22(5

%)

PTS

sym

ptom

s:9/

22(4

1%)

Ant

icoa

gula

tion:

Com

plet

ely

sis:

0B

leed

ing:

0PT

Ssy

mpt

oms:

15/2

2(6

8%)




Tab

le4

—C

onti

nued

Aut

hor/

yrT

ype

ofSt

udy

Part

icip

ants

Inte

rven

tions

Out

com

esF

ollo

w-u

pR

esul

ts

Schw

eize

ret

al11

6 /20

00R

CT

,mul

ticen

ter

250

patie

nts

with

DV

Tof

�9

drt

-PA

:loc

oreg

iona

lrt-P

A20

mg/

dfo

r4

hvi

ape

dalv

ein

for

4–7

d;IV

hepa

rinad

min

ister

edsim

ulta

neou

slyat

1,00

0IU

/h;a

djus

ted

Uro

kina

se:l

ocor

egio

nalu

roki

nase

100,

000

IU/i

nfus

edco

ntin

uous

ly;f

ibrin

ogen

and

plas

min

ogen

mon

itore

d;IV

hepa

rinad

min

ister

edco

ncom

itant

lySy

stem

icst

rept

okin

ase:

3,00

0,00

0U

/dfo

r6

hw

ithhe

parin

for

upto

7d;

prem

edic

atio

ns:h

ydro

cort

isone

at10

0m

g,ra

nitid

ine

at50

mg,

clem

astin

eat

2m

gSy

stem

icur

okin

ase:

5,00

0,00

0IU

/dfo

r4

hup

to7

d;IV

hepa

rinad

min

ister

edco

ncom

itant

lyA

ntic

oagu

latio

n:he

parin

IV,a

djus

ted

Cot

reat

men

t:be

dre

st,c

ompr

essio

nba

ndag

es,c

ompr

essio

nth

erap

y,w

arfa

rinfo

r12

mo

Clo

tly

sis,

blee

ding

,m

orta

lity

1yr

rt-P

A:

Com

plet

ely

sis:

10/5

0(2

0%)

�50

%ly

sis:

7/50

(14%

)�

50%

lysi

s:16

/50

(32%

)N

oly

sis:

13/5

0(2

6%)

Ble

edin

g:2/

50(4

%)

Uro

kina

se:

Com

plet

ely

sis:

10/5

0(2

0%)

�50

%ly

sis:

9/50

(18%

);�

50%

lysi

s:17

/50

(34%

)N

oly

sis:

11/5

0(2

2%)

Ble

edin

g:1/

50(2

%)

Syst

emic

stre

ptok

inas

e:C

ompl

ete

lysi

s:20

/50

(40%

)�

50%

lysi

s:7/

50(1

4%)

�50

%ly

sis:

13/5

0(2

6%)

No

lysi

s:8/

50(1

6%)

Ble

edin

g:5/

50(1

0%)

PE:5

/50

(10%

)Sy

stem

icur

okin

ase:

Com

plet

ely

sis:

17/5

0(3

4%)

�50

%ly

sis:

10/5

0(2

0%)

�50

%ly

sis:

13/5

0(2

6%)

No

lysi

s:8/

50(1

6%)

Ble

edin

g:4/

50(8

%)

PE:4

/50

(8%

)L

aiho

etal

81/

2004

Ret

rosp

ectiv

est

udy,

sing

lece

nter

32pa

tient

sw

ithili

ofem

oral

DVT

�14

din

dura

tion

rece

ived

eith

erC

DT

(n�

16)o

rsy

stem

icth

rom

boly

sis(n

�16

)

Thr

ombo

lysi

s:22

9m

g(m

ean)

ofrt

-PA

(n�

4)or

6.5

mill

ion

Uof

stre

ptok

inas

e(n

�12

)fo

r62

h(m

ean)

plus

LM

WH

and

oral

antic

oagu

lant

s

Clo

tly

sis,

PE,

blee

ding

,val

vula

rco

mpe

tenc

e

2–3

yrT

hrom

boly

sis:

Sign

ifica

ntly

sis:

5/16

(31%

)PE

:5/1

6(3

1%)

Ble

edin

g:1/

16(6

%)

Val

vula

rco

mpe

tenc

e:2/

16(1

3%)

Any

deep

vein

inco

mpe

tenc

e:81

%

*The

met

hodo

logi

cqu

ality

desc

ript

ion

port

ion

ofth

ista

ble

can

befo

und

inth

eon

line

vers

ion

ofth

isar

ticle

asa

data

supp

lem

ent.




Recommendation

1.10.1. In selected patients with extensive prox-imal DVT (eg, symptoms for < 14 days, goodfunctional status, life expectancy of > 1 year)who have a low risk of bleeding, we suggest thatsystemic thrombolytic therapy may be used toreduce acute symptoms and postthromboticmorbidity if CDT is not available (Grade 2C).

1.11 Percutaneous Venous Thrombectomy

Percutaneous mechanical venous thrombectomyrefers to catheter-based fragmentation of thrombus(eg, with pulse-spray or rotational devices) with, orwithout, aspiration of thrombus fragments.101 Percu-taneous mechanical venous thrombectomy is oftencombined with CDT, which, collectively, are re-ferred to as pharmacomechanical thrombolysis. Be-cause pharmacomechanical thrombolysis was in-cluded in the preceding section on CDT (Section1.9), the current section will be confined to percu-taneous mechanical venous thrombectomy withoutconcomitant thrombolysis.

No randomized trials have compared percutaneousmechanical venous thrombectomy with other catheter-based, or noncatheter-based, treatments for DVT.Small retrospective studies suggest that percutaneousmechanical venous thrombectomy alone often fails toremove much of the thrombus94,101 and is associatedwith a high risk of PE.122,123

Recommendation

1.11.1. In patients with acute DVT, we suggestthat they should not be treated with percutaneousmechanical thrombectomy alone (Grade 2C).

1.12 Operative Venous Thrombectomy for Acute DVT

Operative venous thrombectomy is an alternativeapproach for thrombus removal that is generallyreserved for patients with iliofemoral DVT. Contem-porary operative techniques124 and more effectiveanticoagulant regimens have improved outcomescompared to earlier reports.125,126 Iliofemoral venousthrombectomy with a temporary arteriovenous fis-tula plus anticoagulation was compared with antico-agulation alone in a randomized trial of 63 patientswho were followed for a long term.73,82,83 Results at6 months, 5 years, and 10 years were consistent withimproved iliac vein patency, less leg swelling, andfewer leg ulcers (Table 5).73,82,83 In nine nonrandom-ized studies73,80,82,83,127–134 that evaluated venousthrombectomy in 520 limbs of 509 patients, sus-tained patency was achieved in 65 to 85%, and

preservation of femoral-popliteal valve function oc-curred in 65 to 75% of operated patients. Althoughoperative pulmonary embolization is a concern withthis procedure, it is an infrequent complication.130

Recommendations

1.12.1. In selected patients with acute iliofemoralDVT (eg, symptoms for < 7 days, good functionalstatus, and life expectancy > 1 year), we suggestthat operative venous thrombectomy may be usedto reduce acute symptoms and postthromboticmorbidity if appropriate expertise and resourcesare available (Grade 2B). If such patients do nothave a high risk of bleeding, we suggest that CDTis usually preferable to operative venous throm-bectomy (Grade 2C).1.12.2. In patients who undergo operative venousthrombectomy, we recommend the same inten-sity and duration of anticoagulant therapy after-wards as for comparable patients who do notundergo venous thrombectomy (Grade 1C).

1.13 Vena Caval Filters for the Initial Treatment ofDVT

IVCs (and rarely superior vena caval [SVC]) filterscan be used instead of initial anticoagulation (eg, unac-ceptable risk of bleeding), or as an adjunct to anticoag-ulation, in patients with acute DVT. No randomizedtrial or prospective cohort study have evaluated IVCfilters as sole therapy in patients with DVT (ie, withoutconcurrent anticoagulation). Permanent IVC filter in-sertion as an adjunct to anticoagulant therapy has beenevaluated in a single, large RCT of patients with acuteDVT who were considered to be at high risk for PE(PREPIC study; Table 6). The findings of that study,which were reported after 2 years29 and 8 years135 offollow-up (Table 6), provide the strongest evidence toguide use of IVC filters in patients with acute VTE, andcan be summarized as follows. First, routine insertionof filters in patients who are also anticoagulated doesnot alter the frequency of recurrent VTE (RR, 1.34 at2 years; and RR, 1.03 at 8 years) or total mortality (RR,1.08 at 2 years; and RR, 0.95 at 8 years). Second, filtersreduce PE at 12 days (RR, 0.4; this estimate includesasymptomatic PE detected by routine lung scanning), 2years (RR, 0.54), and at 8 years (RR, 0.41). Third, filtersincrease DVT at 2 years (RR, 1.8) and at 8 years (RR,1.3; hazard ratio, 1.5; 95% CI, 1.02 to 2.3 in the originalreport29). Fourth, despite more frequent DVT duringfollow-up and frequent evidence of thrombosis at thefilter site in those with recurrent VTE (43% of cases),filters were not associated with a higher frequency ofPTS (defined as presence of at least one of edema,varicose veins, trophic disorders or ulcers) [hazard




Tab

le5—

Ope

rati

veV

enou

sT

hrom

bec

tom

yfo

rA

cute

DV

T:

Cli

nica

lD

escr

ipti

onan

dR

esu

lts

(Sec

tion

1.12

)*

Aut

hor/

yrT

ype

ofSt

udy

Part

icip

ants

Inte

rven

tions

Out

com

esF

ollo

w-u

pR

esul

ts

Kis

tner

and

Spar

kuhl

130 /

1979

Cas

ese

ries

70pa

tient

s(7

7ex

trem

ities

)w

ithac

ute

iliof

emor

alD

VT

conf

irm

edby

veno

grap

hy

Ope

rativ

eve

nous

thro

mbe

ctom

yPa

tenc

y,cl

inic

alsu

cces

s,op

erat

ive

PE4

yr(m

ean)

Pate

ncy:

75%

Clin

ical

succ

ess:

Exc

elle

nt,5

4%G

ood,

32%

Fai

r,7%

Poor

,7%

Ope

rativ

ePE

:8%

(thr

eeas

ympt

omat

ic)

Plat

eet

al73

/198

4R

CT

,mul

ticen

ter

58pa

tient

sw

ithac

ute

iliof

emor

alve

nous

thro

mbo

sis

Med

ical

:5,0

00U

bolu

she

pari

nfo

llow

edby

500

U/k

g/24

had

just

edto

APT

T,a

ndor

alan

ticoa

gula

tion

(n�

31)

Surg

ical

:ope

rativ

eve

nous

thro

mbe

ctom

yw

ithte

mpo

rary

arte

riov

enou

sfis

tula

plus

antic

oagu

latio

nas

abov

e(n

�27

)

PTS

sequ

elae

:ilio

fem

oral

pate

ncy,

valv

eco

mpe

tenc

e6

mo

Med

ical

:PT

Sse

quel

ae:2

5/27

(93%

)Il

iofe

mor

alpa

tenc

y:9/

26(3

5%)

Val

veco

mpe

tenc

e:7/

27(2

6%)

(PE

in1

patie

nt)

Surg

ical

:PT

Sse

quel

ae:1

4/24

(58%

;p

�0.

005)

Ilio

fem

oral

pate

ncy:

16/2

1(7

6%,

p�

0.02

5)V

alve

com

pete

nce:

13/2

3(5

2%;

p�

0.05

)(v

enou

sga

ngre

nein

1pa

tient

)E

inar

sson

etal

127 /

1986

Pros

pect

ive

regi

stry

70pa

tient

s(7

1le

gs)

with

iliof

emor

alD

VT

(age

ofcl

ot:m

ean

3d)

Ilio

fem

oral

veno

usth

rom

bect

omy

with

tem

pora

ryA

VF

clos

edat

6–8

wk,

hepa

rin

befo

rean

daf

ter

oper

ativ

ion,

plus

war

fari

npo

stop

erat

ivel

y

Ven

ous

pate

ncy,

hem

atom

a,A

VF

pate

ncy,

PE,w

ound

infe

ctio

n56

d(m

ean)

Pate

ntili

acve

in:8

8%H

emat

oma:

11%

AV

Fpa

tenc

y:86

%PE

:4%

Wou

ndin

fect

ion:

26%

:

Ein

arss

onet

al12

8 /19

86F

ollo

w-u

pto

(66)

57pa

tient

s(5

8lim

bs)

with

prio

rop

erat

ive

veno

usth

rom

bect

omy

and

AV

Fcl

osed

at6–

8w

kfo

rili

ofem

oral

DV

T

Clin

ical

PTS;

veno

grap

hy;

veno

uspr

essu

re;v

enou

spl

ethy

smog

raph

y,fo

otvo

lum

etry

Ven

ous

insu

ffic

ienc

y:G

ood,

fair

,poo

r

Ven

ogra

phy

(vei

nse

gmen

t):

Nor

mal

;pos

tthr

ombo

tic,o

cclu

ded

Ven

ous

pres

sure

:N

orm

al;a

bnor

mal

Plet

hysm

ogra

phy:

Nor

mal

,abn

orm

al

Foo

tvo

lum

etry

:N

orm

al,a

bnor

mal

9–10

mo

Ven

ous

insu

ffic

ienc

y:G

ood:

75%

Fai

r:20

%Po

or:5

%V

enog

raph

y(il

iofe

mor

al):

Nor

mal

:61%

Post

thro

mbo

tic:2

3%O

cclu

ded:

39%

IVpr

essu

re:

Nor

mal

:82%

Abn

orm

al:1

8%Pl

ethy

smog

raph

y:N

orm

al:2

9%A

bnor

mal

:71%

Foo

tvo

lum

etry

:N

orm

al:2

9%A

bnor

mal

:71%




Tab

le5—

Con

tinu

ed

Aut

hor/

yrT

ype

ofSt

udy

Part

icip

ants

Inte

rven

tions

Out

com

esF

ollo

w-u

pR

esul

ts

Juha

net

al12

9 /19

87R

etro

spec

tive

stud

y41

patie

nts

with

42ili

ofem

oral

(n�

24)

orili

ocav

al(n

�18

)re

cent

thro

mbo

ses

Ope

rativ

eve

nous

thro

mbe

ctom

yw

ithte

mpo

rary

arte

riov

enou

sfis

tula

(n�

31),

IVC

inte

rrup

tion

(n�

21)

Ven

ous

pate

ncy,

PE,d

eath

,he

mat

oma

4yr

Imm

edia

tePa

tenc

y:Il

iac:

93%

IVC

:100

%Su

perf

icia

lfem

oral

:66%

Popl

iteal

:82%

PE:0

Dea

th:0

Hem

atom

a:6

Lat

efo

llow

-up:

4yr

pate

ncy

(33

patie

nts)

:93%

Tor

ngre

nan

dSw

ende

nbor

g134 /

1988

Ret

rosp

ectiv

est

udy

60pa

tient

sw

ithili

ofem

oral

DV

TO

pera

tive

veno

usth

rom

bect

omy

with

tem

pora

ryA

VF

(clo

sed

at3

mo)

and

antic

oagu

latio

nfo

r6

mo

Ven

ous

pate

ncy

3m

o–5

yrE

arly

:Pa

tenc

y:70

%

Fol

low

-up:

Pate

ncy:

54%

Plat

eet

al82

/19

905-

yrfo

llow

-up

toR

CT

(Pla

te19

84,n

�10

)

41/5

8pa

tient

s(2

2m

edic

al,

19su

rgic

al)

avai

labl

efo

rev

alua

tion

at5

yr

Prio

rtr

eatm

ent

Med

ical

:ant

icoa

gula

tion

alon

e

vs Surg

ical

:ope

rativ

eve

nous

thro

mbe

ctom

ypl

usan

ticoa

gula

tion

PTS

sequ

elae

,ilia

cpa

tenc

y,ve

nous

pres

sure

5yr

Med

ical

:PT

Sse

quel

ae:6

/22

(27%

)Il

iac

pate

ncy:

11/2

2(5

0%)

Ven

ous

pres

sure

:60

mm

Hg

(mea

n)

Surg

ical

:PT

Sse

quel

ae:2

/19

(11%

)Il

iac

pate

ncy:

15/1

9(7

8%)

Ven

ous

pres

sure

:43

mm

Hg

(mea

n;p

�0.

05)

Neg

len

etal

132 /1

991

Pros

pect

ive

regi

stry

48pa

tient

sw

ithili

ofem

oral

DV

Tof

1–14

dO

pera

tive

veno

usth

rom

bect

omy

with

tem

pora

ryA

VF

(clo

sed

6–12

wk

afte

rop

erat

ion)

Adj

unct

ive

ther

apy:

tran

sven

ous

perc

utan

eous

dila

tatio

nof

seve

reili

acst

enos

is(n

�3)

Pate

ncy,

PE,c

linic

alsy

mpt

oms,

norm

alph

otop

leth

ysm

ogra

phy,

succ

essf

ulA

VF

clos

ure

24m

o(m

ean)

Pate

ncy:

Ilio

fem

oral

:88%

Popl

iteal

:94%

PE:1

6%sy

mpt

omat

ic,3

1%as

ympt

omat

icSy

mpt

omfr

ee:8

1%N

orm

alph

otop

leth

ysm

ogra

phy

(no

reflu

x):5

6%A

VF

clos

ure

succ

ess

rate

:87%

Mei

ssne

ran

dH

usze

za13

1 /199

6R

etro

spec

tive

stud

y30

patie

nts

with

acut

eD

VT

ofth

elo

wer

extr

emiti

es

Ope

rativ

eve

nous

thro

mbe

ctom

yw

ithte

mpo

rary

AV

FPa

tenc

y,PE

,sw

ellin

g30

d–12

wk

Ear

ly:

Pate

ncy:

100%

PE:0

Fol

low

-up:

Pate

ncy:

89%




Tab

le5—

Con

tinu

ed

Aut

hor/

yrT

ype

ofSt

udy

Part

icip

ants

Inte

rven

tions

Out

com

esF

ollo

w-u

pR

esul

ts

Plat

eet

al83

/199

710

-yr

follo

w-u

pto

RC

T(P

late

1984

,n�

10;

1990

,n�

20)

30/5

8pa

tient

s(1

7fr

omm

edic

alar

m,1

3fr

omsu

rgic

alar

m)

avai

labl

efo

rev

alua

tion

Prio

rtr

eatm

ent:

Med

ical

:ant

icoa

gula

tion

alon

e

vs Surg

ical

:ope

rativ

eve

nous

thro

mbe

ctom

ypl

usan

ticoa

gula

tion

PTS

sequ

elae

,ilia

cpa

tenc

y,ve

nous

pres

sure

10yr

Med

ical

:PT

Sse

quel

ae:1

5/17

(88%

)Il

iac

pate

ncy:

7/17

(41%

)V

enou

spr

essu

re:6

3m

mH

g(m

ean)

Surg

ical

:PT

Sse

quel

ae:7

/13

(54%

)Il

iac

pate

ncy:

10/1

2(8

3%)

Ven

ous

pres

sure

:55

mm

Hg

(mea

n)Ju

han

etal

80/1

997

Ret

rosp

ectiv

est

udy

75pa

tient

s(7

7lim

bs)

with

acut

eili

ofem

oral

veno

usth

rom

bosi

s

Ope

rativ

eve

nous

thro

mbe

ctom

yw

ithA

VF

ligat

edat

6–8

wk

Ilio

fem

oral

syst

empa

tenc

y,va

lvul

arco

mpe

tenc

e,C

VI

8.5

yr(m

ean)

5-yr

resu

lts(4

4lim

bs):

Ilio

fem

oral

pate

ncy:

84%

Val

vula

rco

mpe

tenc

e:80

%C

VI,

Gra

de0/

1:93

%

10-y

rre

sults

(16

limbs

):Il

iofe

mor

alpa

tenc

y:84

%V

alvu

lar

com

pete

nce:

56%

CV

I,G

rade

0/1:

94%

Schw

arzb

ach

etal

133 /2

005

Ret

rosp

ectiv

est

udy

20pa

tient

sw

ithac

ute

iliof

emor

alor

ilioc

aval

thro

mbo

sis

Ope

rativ

eve

nous

thro

mbe

ctom

yw

ithen

dova

scul

arco

rrec

tion

ofre

sidu

alle

sion

s

Prim

ary

and

seco

ndar

ypa

tenc

y,cl

inic

alou

tcom

epe

rC

EA

Pst

age

21m

o(m

ean)

Pate

ncy:

Prim

ary:

80%

Seco

ndar

y:90

%

Clin

ical

outc

ome:

13pa

tient

s,as

ympt

omat

ic1

patie

nt;r

etic

ular

vein

s4

patie

nts;

asym

ptom

atic

edem

a4

patie

nts;

sym

ptom

atic

edem

a,pa

in

*AV

F�

arte

riov

enou

sfis

tula

;CV

I�

chro

nic

veno

usin

suff

icie

ncy;

V-Q

�ve

ntila

tion-

perf

usio

n;C

EA

P�

clin

ical

etio

logi

can

atom

icpa

thop

hysi

olog

ic(c

lass

ifica

tion)

.The

met

hodo

logi

cqu

ality

desc

ript

ion

port

ion

ofth

ista

ble

can

befo

und

inth

eon

line

vers

ion

ofth

isar

ticle

asa

data

supp

lem

ent.




ratio, 0.87; 95% CI, 0.66 to 1.13]. Fifth, 2.5% (fivepatients) of the nonfilter group and 1.0% (two patients)of the filter group died of PE during 8 years offollow-up. Sixth, other complications of filter place-ment are rare (none were reported).

A comprehensive review136 of mostly retrospec-tive case series of vena caval filter insertions (atotal of 6,500 patients in 89 reports who had filtersinserted for many different reasons) suggests thatvenous thrombosis at the site of filter insertionsites is common (eg, approximately 10% of pa-tients), that filters can be placed above the renalveins if necessary, and that it is feasible to placefilters in the SVC. Epidemiologic data suggest thatIVC filters are not associated with an increasedrisk of recurrent VTE in patients who present withDVT.137 If an IVC filter is being inserted in apatient with acute DVT or PE because anticoagu-lant therapy is temporarily contraindicated (eg,active bleeding), there is the option of inserting aretrievable filter and removing the filter when it issafe to start anticoagulant therapy. However, therisks and benefits of using a retrievable filtercompared with a permanent filter in this settingare uncertain.

Recommendations

1.13.1. For patients with DVT, we recommendagainst the routine use of a vena cava filter inaddition to anticoagulants (Grade 1A).1.13.2. For patients with acute proximal DVT ifanticoagulant therapy is not possible because ofrisk of bleeding, we recommend placement ofan IVC filter (Grade 1C).1.13.3. For patients with acute DVT who havean IVC filter inserted as an alternative to anti-coagulation, we recommend that they shouldsubsequently receive a conventional course ofanticoagulant therapy if their risk of bleedingresolves (Grade 1C).

1.14 Immobilization for the Treatment of AcuteDVT

The early treatment of acute DVT with bed restand anticoagulation has given way to anticoagula-tion with early mobilization. Randomized trials138 –

142 and observational studies143–145 show fasterresolution of pain and swelling with early ambula-tion and leg compression compared with immobi-lization, and a similar incidence of new PE onroutine repeat lung scanning after 10 days oftreatment (Table 7). These observations suggestthat mobile patients with DVT should remainambulant.

Recommendation

1.14.1. In patients with acute DVT, we recom-mend early ambulation in preference to initialbed rest when this is feasible (Grade 1A).

2.0 Long-term Treatment of Acute DVT ofthe Leg

In this review, long-term treatment refers to treat-ments that are continued after initial therapy, such aswith heparin or thrombolytic agents, has been com-pleted. Long-term therapy has two goals: (1) tocomplete treatment of the acute episode of VTE;and (2) to prevent new episodes of VTE that are notdirectly related to the acute event. During the earlyphase of long-term treatment (ie, first 3 months),treatment of the acute episode of VTE predomi-nates. During the late phase of long-term treatment(ie, after the first 3 months), prevention of newepisodes of VTE predominates. We will use the termindefinite anticoagulation to refer to anticoagulationthat is continued without a scheduled stop date, butwhich may be stopped because of a subsequentincrease in the risk of bleeding or change in patientpreference.

The need for long-term anticoagulant treatment ofDVT after 5 to 10 days of initial heparin therapy issupported by three lines of evidence from RCTs: (1)a randomized trial in which no long-term anticoag-ulant treatment was administered to patients withsymptomatic calf-vein thrombosis, which docu-mented a 20% rate of symptomatic extension and/orrecurrence of thrombosis within 3 months146; (2) arandomized trial that evaluated SC low-dose UFH(5,000 U bid) as an alternative to VKA for long-termtreatment after proximal DVT, in which the low-doseUFH regimen proved ineffective and resulted in ahigh rate of recurrent VTE (47% within 3months)147; and (3) randomized trials in which re-duced durations of treatment of 4 or 6 weeksresulted in clinically important increases in recurrentVTE, compared to conventional durations of treat-ment of 3 months or 6 months.148–150

In this section, we will address three issuesrelating to long-term anticoagulant therapy forDVT: (1) the optimal duration of treatment (usu-ally with VKA), (2) the optimal intensity of treat-ment with VKA, and (3) the relative effectivenessand safety of alternative approaches to long-termVKA treatment, particularly LMWH. We will re-view studies that included patients with symptom-atic DVT, or both symptomatic DVT and PE.Studies that only included patients with symptom-atic PE, with or without concomitant symptomaticDVT, are considered in later sections of this




Tab

le6

—R

ando

miz

edT

rial

ofIV

CF

ilte

ras

anA

dju

nct

toA

ntic

oagu

lati

onin

Pat

ient

sW

ith

DV

T:

Cli

nica

lD

escr

ipti

onan

dR

esu

lts

(Sec

tion

1.13

)*

Stud

y/yr

Inte

rven

tions

Patie

nts

Ana

lyze

dL

engt

hof

Fol

low

-up

Rec

urre

ntV

TE

Maj

orB

leed

ing

Tot

alM

orta

lity

Com

men

ts

PRE

PIC

29/

1998

Perm

anen

tIV

Cfil

ter

(56%

Ven

aT

ech

LG

M;2

6%G

reen

field

;16%

Car

dial

orB

irds

Nes

t;2%

nofil

ter)

No

IVC

filte

r

12d

372

patie

nts

(rea

sons

why

28pa

tient

sw

ere

not

anal

yzed

are

desc

ribe

d;es

timat

edth

at18

3fil

ter

and

189

nofil

ter

wer

ean

alyz

ed)

12d

All

PEat

12d

Filt

er:2

/183

(1.1

%)

No

filte

r:9/

189

(4.8

%)

RR

,0.2

3(9

5%C

I,0.

05–1

.05)

Sym

ptom

atic

PEat

12d

Filt

er:2

/183

(1.1

%)

No

filte

r:5/

189

(2.6

%)

RR

,0.4

1(9

5%C

I,0.

08–2

.1)

Maj

orbl

eedi

ngat

12d

Filt

er:9

/200

No

filte

r:6/

200

RR

:1.5

(95%

CI,

0.54

–4.

14)

Mor

talit

yat

12d

Filt

er:5

/200

No

filte

r:5/

200

RR

,1.0

(95%

CI,

0.29

–3.

40)

400

patie

nts

with

prox

imal

DV

T:

fem

oral

orm

ore

prox

imal

vein

invo

lved

in94

%;c

onco

mita

ntsy

mpt

omat

icPE

in36

%;m

ean

age,

72yr

;all

patie

nts

wer

etr

eate

dw

ithL

MW

Hor

UF

H(r

ando

miz

edal

loca

tion;

fact

oria

ldes

ign)

follo

wed

byV

KA

s(I

NR

2–3)

for

atle

ast

3m

o;pr

imar

you

tcom

ew

assy

mpt

omat

icor

asym

ptom

atic

PEat

12d

Oth

erth

anth

rom

bosi

sat

the

filte

rsi

teth

atw

asde

tect

edin

16of

the

37fil

ter

patie

nts

with

recu

rren

tV

TE

,“no

othe

rm

ajor

com

plic

atio

nsw

ere

obse

rved

”in

the

filte

rgr

oup.

Enr

ollm

ent

was

stop

ped

at40

0in

stea

dof

800

patie

nts

beca

use

ofsl

owre

crui

tmen

t2

yr39

9pa

tient

san

alyz

edfo

rde

ath;

deno

min

ator

sar

ees

timat

edfr

ompe

rcen

tage

san

dre

ason

for

diffe

renc

esar

eno

tdes

crib

ed

2yr

Sym

ptom

atic

PEat

2yr

Filt

er:6

/176

(3.4

%)

No

filte

r:12

/190

(6.3

%)

RR

,0.5

4(9

5%C

I,0.

21–1

.41)

Sym

ptom

atic

DV

Tat

2yr

Filt

er:3

7/17

8(2

0.8%

)N

ofil

ter:

21/1

81(1

1.6%

)R

R,1

.78

(95%

CI,

1.09

–2.9

4)

Sym

ptom

atic

VT

Eat

2yr

Filt

er:3

7/17

8(2

0.8%

)N

ofil

ter:

29/1

87(1

5.5%

)R

R,1

.34

(95%

CI,

0.86

–2.0

8)

Maj

orbl

eedi

ngat

2yr

Filt

er:1

7/19

3(8

.8%

)N

ofil

ter:

22/1

86(1

1.8%

)R

R,0

.74

(95%

CI,

0.41

–1.3

6)

Mor

talit

yat

2yr

Filt

er:4

3/19

9(2

1.6%

)N

ofil

ter:

40/1

99(2

0.1)

RR

,1.0

8(9

5%C

I,0.

73–1

.58)




chapter (Sections 4.0 and 5.0). However, for thereasons noted in Section 4.0, the results of allstudies of VTE have been considered when for-mulating recommendations for long-term treat-ment of DVT and PE, and the main recommen-dations for long-term anticoagulant therapy do notdiffer for proximal DVT or PE.

2.1. Duration of Anticoagulant Therapy

Anticoagulant therapy for VTE should be contin-ued for the following: (1) until its benefits (reductionof recurrent VTE) no longer clearly outweigh itsrisks (increase in bleeding), or (2) it is patientpreference to stop treatment even if continuingtreatment is expected to be of net benefit. In orderto assess if the benefits of continuing anticoagulanttherapy will outweigh its risks, the increase in recurrentVTE and the decrease in bleeding that will occur withstopping treatment need to be known or estimated. Inaddition, the consequences of a new episode of VTEand of an episode of bleeding need to considered.151,152

In patients with an average risk of bleeding whilereceiving anticoagulant therapy, therefore, the decisionto stop or continue therapy is dominated by the risk ofrecurrent VTE if treatment is stopped.

Current evidence suggests that the risk of recur-rence after stopping therapy is largely determined bytwo factors: (1) whether the acute episode of VTEhas been effectively treated; and (2) the patient’sintrinsic risk of having a new episode of VTE (ie, notarising directly from the episode of thrombosis forwhich patients have been receiving treatment). Iftherapy is stopped before the acute episode ofthrombosis is adequately treated, the risk of recur-rent VTE will be higher than if anticoagulants werestopped after a longer course of treatment. If pa-tients have a persistently high intrinsic risk forthrombosis, even if the acute episode of thrombosishas effectively been treated, they will have a high riskof recurrence once anticoagulant therapy is stopped;if this risk is sufficiently high relative to the patient’srisk of bleeding, long-term anticoagulant therapy willbe indicated.

During the past 15 years, a series of trials148–150,153–162

have compared different durations of antico-agulant therapy for VTE (Table 8). Most of thesestudies163–166 excluded patients with active cancerbecause they were judged to require long-termanticoagulant therapy because of a high risk ofrecurrence. The earlier trials,148,149,162 in addition tocomparing outcomes with different durations oftreatment, identified that the risk of recurrentVTE after stopping VKA therapy was much lowerif VTE had been provoked by a reversible riskfactor, such as surgery, rather than if the episode

Tab

le6

—C

onti

nued

Stud

y/yr

Inte

rven

tions

Patie

nts

Ana

lyze

dL

engt

hof

Fol

low

-up

Rec

urre

ntV

TE

Maj

orB

leed

ing

Tot

alM

orta

lity

Com

men

ts

PRE

PIC

135 /

2005

Sam

epa

tient

sas

for

PRE

PIC

1998

399

anal

yzed

for

deat

hD

enom

inat

ors

are

estim

ated

from

perc

enta

ges

and

reas

onfo

rdi

ffere

nces

are

notd

escr

ibed

8yr

Sym

ptom

atic

PEat

8yr

Filt

er:9

/145

(6.2

%)

No

filte

r:24

/159

(15.

1%)

RR

,0.4

1(9

5%C

I,0.

20–0

.86)

Sym

ptom

atic

DV

Tat

8yr

Filt

er:5

7/16

0(3

5.7%

)N

ofil

ter:

41/1

50(2

7.5%

)R

R,1

.3(9

5%C

I:0.

93–1

.82)

Sym

ptom

atic

DV

Tan

dPE

at8

yrF

ilter

:58/

159

(36.

4%)

No

filte

r:55

/155

(35.

4%)

RR

,1.0

3(9

5%C

I,0.

72–1

.38)

Maj

orbl

eedi

ngat

8yr

Filt

er:2

6/16

9(1

5.4%

)N

ofil

ter:

31/1

68(1

8.5%

)R

R,0

.83

(95%

CI.

0.52

–1.3

4)

Mor

talit

yat

8yr

Filt

er:9

8/20

0(4

9%)

No

filte

r:10

3/20

0(5

1%)

RR

,0.9

5(9

5%C

I,0.

78–1

.16)

Fat

alPE

at8

yrF

ilter

:2/2

00(1

.0%

)N

ofil

ter:

5/20

0(2

.5%

)R

R,0

.40

(95%

CI,

0.08

–2.0

4)

Lon

g-te

rmfo

llow

-up

ofPR

EPI

Cst

udy;

VK

As

wer

est

oppe

dat

3m

oin

38%

offil

ter

grou

pan

d36

%of

no-f

ilter

grou

p;V

KA

sw

ere

used

thro

ugho

ut8

yrfo

llow

-up

by35

%of

both

grou

ps;e

last

icst

ocki

ngs

wer

ew

orn

thro

ugho

ut8-

yrfo

llow

-up

by45

%of

filte

ran

d47

%of

no-

filte

rgr

oup

*The

met

hodo

logi

cqu

ality

desc

ript

ion

port

ion

ofth

ista

ble

can

befo

und

inth

eon

line

vers

ion

ofth

isar

ticle

asa

data

supp

lem

ent.




Tab

le7—

Imm

obil

izat

ion

for

the

Tre

atm

ent

ofA

cute

DV

T:

Cli

nica

lD

escr

ipti

onan

dR

esu

lts

(Sec

tion

1.14

)*

Aut

hor/

yrT

ype

ofSt

udy

Part

icip

ants

Inte

rven

tions

Out

com

esF

ollo

w-u

pR

esul

ts

Sche

llong

etal

142 /

1999

RC

T,s

ingl

ece

nter

126

patie

nts

with

acut

epr

oxim

alD

VT

Am

bula

tion:

leg

elev

atio

nun

tilda

y2,

then

ambu

latio

n,co

mpr

essi

on(n

�64

)B

edre

st:B

edre

stfo

r8

dw

ithle

gel

evat

ion,

com

pres

sion

(n�

62)

PEby

vent

ilatio

n/pe

rfus

ion

scan

10d

Am

bula

tion:

PE:1

0/59

(17%

)

Bed

rest

:PE

:14/

63(2

2%)

Part

sch

and

Bla

ttle

r141 /

2000

RC

T,m

ultic

ente

r45

patie

nts

with

prox

imal

DV

T�

14d

dura

tion

Am

bula

tion

plus

band

ages

:ine

last

icU

nna

boot

band

ages

plus

wal

king

exer

cise

s,(n

�15

)

Am

bula

tion

plus

stoc

king

s:el

astic

com

pres

sion

stoc

king

spl

usw

alki

ngex

erci

ses

(n�

15)

Bed

rest

:bed

rest

,no

com

pres

sion

,L

MW

H(n

�15

)

Wal

king

dist

ance

,pai

nle

vels

,leg

circ

umfe

renc

e,cl

inic

alsc

ores

,PE

,si

deef

fect

s

9d

Sum

mar

yre

sults

betw

een

grou

ps:

Wal

king

dist

ance

,pai

n,le

gci

rcum

fere

nce

and

clin

ical

scor

essi

gnifi

cant

lyim

prov

edin

grou

psA

and

Bco

mpa

red

togr

oup

C

PE,g

roup

A:2

/15

(13%

)PE

,gro

upB

:1/1

5(7

%)

PE,g

roup

C:1

/15

(7%

)

Asc

hwan

den

etal

138 /2

001

RC

T,s

ingl

ece

nter

129

patie

nts

with

acut

eD

VT

Am

bula

tion:

Am

bula

tion

�4

h/d

for

4d

unde

rsu

perv

isio

n,L

MW

H(n

�69

)

Bed

rest

:B

edre

stfo

r4

(n�

60)

New

PEbe

twee

nba

selin

ean

dda

y4

byve

ntila

tion/

perf

usio

nsc

an

3m

oA

mbu

latio

n:PE

:10/

69(1

4%)

Bed

rest

PE:6

/60

(10%

)

Not

e:ne

wPE

sw

ere

asym

ptom

atic

;12/

16pa

tient

sha

dba

selin

ePE

sPa

rtsc

h143 /2

001

Pros

pect

ive

stud

y1,

289

patie

nts

with

acut

eD

VT

All

trea

ted

with

LM

WH

,co

mpr

essi

on,a

ndim

med

iate

ambu

latio

n

PEon

vent

ilatio

n/pe

rfus

ion

scan

atho

spita

ladm

issio

nan

daf

ter

10d

oftr

eatm

ent

10d

PEat

adm

issi

on:6

29/1

,270

(50%

)PE

at10

d:77

/1,2

56(6

1%)

Not

e:in

itial

lung

scan

sw

ere

perf

orm

edin

1,27

0/1,

289

patie

nts;

f/usc

ans

wer

epe

rfor

med

in1,

256/

1,28

9pa

tient

s.B

latt

ler

and

Part

sch13

9 /200

3R

CT

53pa

tient

sw

ithpr

oxim

alD

VT

Am

bula

tion

plus

band

ages

:fir

min

elas

ticba

ndag

es,

ambu

latio

n(n

�18

)

Am

bula

tion

plus

stoc

king

s:el

astic

com

pres

sion

stoc

king

s,am

bula

tion

(n�

18)

Bed

rest

only

(n�

17)

Wal

king

dist

ance

,wel

l-be

ing

and

DV

T-

rela

ted

QO

L,l

egpa

inby

VA

S,ed

ema,

clin

ical

scor

es,

thro

mbu

spr

ogre

ssio

n

9d

Wel

l-bei

ng/Q

OL

:Im

prov

edw

ithst

ocki

ngs

(p�

0.05

)ba

ndag

es(p

�0.

01)

Leg

pain

:D

ecre

ased

fast

erdu

ring

first

4d

with

band

ages

and

stoc

king

svs

bed

rest

(p[lt

0.01

);ne

arab

senc

eof

pain

at9

dac

hiev

edw

ithba

ndag

eson

lyE

dem

a:M

arke

dre

duct

ion

inle

gsi

zew

ithba

ndag

esan

dst

ocki

ngs

vsbe

dre

st(p

�0.

001)

Clin

ical

scor

es:

Impr

oved

with

band

ages

and

stoc

king

svs

bed

rest

(p�

0.00

1)T

hrom

bus

prog

ress

ion:

Impr

oved

with

band

ages

and

stoc

king

svs

bed

rest

(p�

0.01

)PE

:N

odi

ffer

ence

betw

een

grou

ps




Tab

le7—

Con

tinu

ed

Aut

hor/

yrT

ype

ofSt

udy

Part

icip

ants

Inte

rven

tions

Out

com

esF

ollo

w-u

pR

esul

ts

Part

sch

etal

144 /

2004

2-yr

follo

w-u

pto

RC

T(n

�77

)37

patie

nts

follo

wed

up2

yraf

ter

RC

T

Ant

icoa

gula

tion

and

bed

rest

vs Ant

icoa

gula

tion

and

ambu

latio

nw

ithco

mpr

essi

onba

ndag

esor

stoc

king

s

PTS

asse

ssm

ent

(Vill

alta

-Pra

ndon

isc

ale)

Pain

asse

ssm

ent

byV

AS

and

mod

ified

Low

enbe

rgte

st

Thr

ombu

sre

gres

sion

2yr

PTS

scor

es:

Am

bula

tory

grou

p(m

ean

scor

e,5.

1)ha

dim

prov

edou

tcom

evs

bed

rest

grou

p(m

ean

scor

e,8.

2)�p

�0.

01�

Pain

:L

ower

pain

leve

lsin

mob

ilegr

oup

vsbe

dre

st(n

otsi

gnifi

cant

)T

hrom

bus

exte

nsio

n:N

odi

ffer

ence

inth

rom

bus

regr

essi

onof

thro

mbu

sre

mna

nts

betw

een

grou

psT

rujil

lo-S

anto

set

al14

5 /200

5Pr

ospe

ctiv

est

udy

2,65

0pa

tient

sw

ithac

ute

DV

T(n

�20

38,7

7%)

orPE

(n�

612

,23

%)

DV

Tgr

oup:

bed

rest

oram

bula

tion:

1,05

0(5

2%)

patie

nts

rece

ived

bed

rest

and

988

patie

nts

(48%

)w

ere

ambu

late

d;al

lrec

eive

dL

MW

H.

PEgr

oup,

bed

rest

oram

bula

tion:

385

patie

nts

(63%

)re

ceiv

edbe

dre

st,a

nd22

7pa

tient

s(3

7%)

wer

eam

bula

ted;

allr

ecei

ved

LM

WH

Sym

ptom

atic

,co

nfir

med

PEdu

ring

first

15d

ofth

erap

y

3m

oD

VT

grou

p:be

dre

st:

PE:7

/1,0

50(0

.7%

)D

VT

grou

p:am

bula

te:

PE:4

/988

(0.4

%)

PEgr

oup:

bed

rest

:PE

:2/3

85(0

.5%

)PE

grou

p:am

bula

te:

PE:2

/227

(0.9

%)

Jung

eret

al14

0 /20

06R

CT

,mul

ticen

ter

open

desi

gnst

ratif

ied

byag

e

103

patie

nts

with

prox

imal

DV

TB

edre

st:5

0pa

tient

sre

ceiv

ed5

dof

stri

ctbe

dre

st,L

MW

H,

com

pres

sion

band

ages

Am

bula

tion:

52pa

tient

sam

bula

ted

for

5d,

LM

WH

,com

pres

sion

band

ages

PE,p

rogr

essi

onof

orne

wth

rom

bosi

s,in

fect

ion

orse

riou

sad

vers

eev

ent

5d

New

PEB

edre

st:8

/50

(16%

)A

mbu

latio

n:2/

52(4

%)

Prim

ary

targ

etva

riab

leB

edre

st:1

4/50

(28%

)A

mbu

latio

n:7/

52(1

3%)

*VA

S�

visu

alan

alog

uesc

ale.

The

met

hodo

logi

cqu

ality

desc

ript

ion

port

ion

ofth

ista

ble

can

befo

und

inth

eon

line

vers

ion

ofth

isar

ticle

asa

data

supp

lem

ent.




Tab

le8

—C

ompa

riso

nsof

Du

rati

ons

and

Inte

nsit

ies

ofA

ntic

oagu

lant

The

rapy

for

DV

Tan

dP

E:

Cli

nica

lD

escr

ipti

onan

dR

esu

lts

(Sec

tion

2.1)

*

Aut

hor/

yr(A

cron

ym)

Inte

rven

tion

Pate

ints

Ana

lyze

d,N

o.L

engt

hof

Fol

low

-up

Rec

urre

ntD

VT

orPE

,No.

(Tot

al)

Maj

orB

leed

ing,

No.

(Tot

al)

Tot

alM

orta

lity,

No.

(%)

Com

men

ts

Shor

t(4

wk

or6

wk)

vsin

term

edia

te(3

mo

or6

mo)

dura

tion

sof

anti

coag

ulat

ion

Kea

ron

etal

157 /2

004

(SO

FA

ST)

VK

Ast

oppe

d(p

lace

bo)

VK

A(I

NR

,2.0

–3.0

)fo

r2

mor

em

o

84/8

4

81/8

1

11m

o

11m

o.

5/84

(6%

)

3/81

(4%

)R

R,0

.6(9

5%C

I,0.

1–2.

5)

0/84

0/81

RR

,1.0

(95%

CI,

0.0–

51.6

)

0/84

1/81

(1%

)R

R3.

1(9

5%C

I,0.

1–74

.4)

Popu

latio

n:fir

stD

VT

orPE

:tr

eate

dfo

r1

mo;

VT

Ew

asas

ympt

omat

icin

9%,a

ndis

olat

edca

lfD

VT

in18

%;o

neV

TE

occu

rred

whi

ledu

ring

war

fari

ntr

eatm

ent

Pine

deet

al16

0 /200

1(D

OT

AV

K)

VK

A(I

NR

,2.0

–3.0

)fo

r1.

5m

o.

VK

A(I

NR

,2.0

–3.0

)fo

r3

mo

105/

105

92/9

2

15m

o2/

105

(2%

)

3/92

RR

,1.7

(95%

CI,

0.3–

10.0

)

1/10

5(1%

)

3/92

RR

,3.4

(95%

CI,

0.4–

33.4

)

Not

spec

ified

Popu

latio

n:fir

stis

olat

edca

lfD

VT

Schu

lman

etal

162 /

1995

(DU

RA

C1)

VK

A(I

NR

,2.0

–2.8

5)fo

r1.

5m

o

VK

A(I

NR

,2.0

–2.8

5)fo

r6

mo

443/

443

454/

454

2yr

80/4

43(1

8%)

43/4

54(9

%)

RR

,0.5

(95%

CI,

0.4–

0.7)

1/44

3

5/45

4(1

%)

RR

,4.9

(95%

CI,

0.6–

41.6

)

22/4

43(5

%)

17/4

54(4

%)

RR

0.75

(95%

CI,

0.4–

1.4)

Fir

stV

TE

:DV

T(d

ista

lor

prox

imal

)or

PE;o

nly

aske

dab

out

blee

ding

whi

lere

ceiv

ing

VK

As

Lev

ine

etal

148 /1

995

VK

Ast

oppe

d(p

lace

bo)

VK

A(I

NR

,2.0

–3.0

)fo

r2

mor

em

o

105/

107

109/

113

9m

o12

/105

(11%

)

7/10

9(6

%)

RR

,0.6

(95%

CI,

0.2–

1.4)

0/10

5

1/10

9(1

%)

RR

,2.9

(95%

CI,

0.1–

70.2

)w

ithin

2m

oof

rand

omiz

atio

n

9/10

5(9

%)

9/10

9(8

%)

RR

,1.0

(95%

CI,

0.4–

2.5)

Prox

imal

DV

T(f

irst

epis

ode

in91

%);

canc

erin

21%

Bri

tish

Tho

raci

cSo

ciet

y149

VK

A(I

NR

,2.0

–3.0

)fo

r1

mo

VK

A(I

NR

,2.0

–3.0

)fo

r3

mo

358/

358

354/

354

1yr

1yr

28/3

58(1

1%)

14/3

54(4

%)

RR

,0.5

(95%

CI,

0.3–

0.9)

5/35

8(1

%)

4/35

4(1

%)

RR

,0.8

(95%

CI,

0.2–

3.0)

26/3

58(7

%)

28/3

54(8

%)

RR

,1.1

(95%

CI,

0.6–

1.8)

Popu

latio

n:D

VT

orPE

;onl

y71

%ob

ject

ivel

ydi

agno

sed;

prop

ortio

nw

itha

prev

ious

VT

Eno

tkn

own.

All

blee

dsw

ere

rece

ivin

gV

KA

;on

lyon

ere

curr

ent

VT

Eam

ong

116

patie

nts

with

post

oper

ativ

eV

TE

Sum

mar

y2,

198

RR

0.53

(0.4

0,0.

70)

RR

1.84

(0.7

6,4.

50)

RR

1.04

(0.7

4,1.

48)

For

alla

naly

ses,

p�

�0.

1fo

rhe

tero

gene

ity.S

OF

AST

80no

tin

clud

edin

estim

ate

for

maj

orbl

eedi

ngas

noev

ents

inei

ther

grou

p




Tab

le8

—C

onti

nued

Aut

hor/

yr(A

cron

ym)

Inte

rven

tion

Pate

ints

Ana

lyze

d,N

o.L

engt

hof

Fol

low

-up

Rec

urre

ntD

VT

orPE

,No.

(Tot

al)

Maj

orB

leed

ing,

No.

(Tot

al)

Tot

alM

orta

lity,

No.

(%)

Com

men

ts

Dif

fere

ntin

term

edia

tedu

rati

ons

(6m

oor

12m

ovs

3m

o)of

anti

coag

ulat

ion

Cam

pbel

let

al15

5 /200

7V

KA

(IN

R2.

.0–3

.5)

for

3m

o

VK

A(I

NR

2.0–

3.5)

for

6m

o

369/

396

380/

414

1yr

1yr

31/3

69(8

%)

29/3

80(8

%)

RR

,0.9

(95%

CI,

0.6–

1.5)

0/36

9(d

urin

g3

mo

oftr

eatm

ent)

8/38

0(2

%)

duri

ng6

mo

oftr

eatm

ent

RR

,16.

5(9

5%C

I,(1

.0–2

85)

15/3

69(4

%)

9/36

9(5

%)

RR

,1.3

(95%

CI,

0.6–

2.5)

Popu

latio

n:D

VT

orPE

;pro

port

ion

with

calf

DV

Tno

tkn

own;

Onl

ybl

eedi

ngdu

ring

trea

tmen

tis

repo

rted

.20%

ofV

TE

outc

omes

wer

eno

tob

ject

ivel

yve

rifie

dA

gnel

liet

al15

3 /200

3(W

OD

IT-P

E)

VK

Ast

oppe

d

VK

A(I

NR

,2.0

–3.0

)fo

r9

mor

em

o

91/9

1

90/9

0

2.6

yr(m

ean)

2.9

yr(m

ean)

11/9

1(1

2%)

11.9

0(1

2%)

RR

,1.0

(95%

CI,

0.5–

2.2)

1/91

(1%

)

2/90

(2%

)R

R,2

.0(9

5%C

I,0.

5–21

.9)

7/91

(8%

)

8/90

(9%

)R

R,1

.16

(95%

CI,

0.4–

3.0)

Popu

latio

n:fir

stun

prov

oked

PE;

trea

ted

for

�3

mo;

amon

gth

efo

urgr

oups

,onl

yon

ere

curr

ent

VT

Ew

hile

rece

ivin

gV

KA

VK

Ast

oppe

d

VK

A(I

NR

,2.0

–3.0

)fo

r3

mor

em

o

70/7

0

75/7

5

2.8

yr(m

ean)

2.9

yr(m

ean)

7/70

(10%

)

4/75

(5%

)R

R,0

.5(9

5%C

I,0.

2–1.

7)

0/70

(0%

)

1/75

(1%

)R

R,1

.9(9

5%C

I,0.

1–56

)

0/70

(0%

)

4/75

(5%

)R

R,8

.4(9

5%C

I,0.

5–15

3)

Popu

latio

n:fir

stpr

ovok

edPE

;tr

eate

dfo

r�

3m

o(s

eepr

evio

us)

Agn

elli

etal

154 /2

001

(WO

DIT

–D

VT

)V

KA

stop

ped

VK

A(I

NR

,2.0

–3.0

)fo

r9

mo

133/

133

134/

134

3.2

yr(m

ean)

3.1

yr(m

ean)

21/1

33(1

6%)

21/1

34(1

6%)

RR

,1.0

(95%

CI,

0.6–

1.7)

2/13

3(2

%)

4/13

4(3

%)

RR

,2.0

(95%

CI,

0.4–

10.7

)

7/13

3(5

%)

7/13

4(5

%)

RR

,1.0

(95%

CI,

0.4–

2.8)

Popu

latio

n:F

irst

unpr

ovok

edpr

oxim

alD

VT

trea

ted

for

3m

o;on

epa

tient

had

recu

rren

tV

TE

whi

lere

ceiv

ing

VK

A;b

leed

ing

inth

ein

terv

entio

ngr

oup

was

whi

lere

ceiv

ing

VK

APi

nede

etal

160 /2

001

(DO

TA

VK

)V

KA

(IN

R,2

.0–3

.0)

for

3m

oV

KA

(IN

R,1

.0–3

.0)

for

6m

o

270/

270

269/

269

15m

o21

/270

(8%

)

23/2

69(9

%)

RR

,1.1

(95%

CI,

0.6–

1.9)

5/27

0(2

%)

7/26

9(3

%)

RR

,1.4

(95%

CI,

0.4–

4.4)

Not

spec

ified

Popu

latio

n:fir

stpr

oxim

alD

VT

orPE

;rec

urre

ntV

TE

occu

rred

afte

rV

KA

in26

/28

ofth

esh

ort-

dura

tion

grou

psan

d21

/27

ofth

elo

ng-d

urat

ion

grou

psSu

mm

ary

1,88

1R

R,0

.95

(95%

CI,

0.72

–1.2

6)R

R,2

.53

(95%

CI,

1.18

–5.4

6)R

R,1

.3(9

5%C

I,0.

82–2

.08)

For

alla

naly

ses,

p�

0.1

for

hete

roge

neity

Inde

fini

tevs

inte

rmed

iate

dura

tion

sof

anti

coa

gula

tion

(IN

R,

appr

oxim

atel

y20

–3.0

)Pa

lere

tiet

al15

9 /200

6(P

RO

LO

NG

)R

emai

nof

f(s

top)

VK

A

Res

tart

Inde

finite

VK

A(I

NR

,2.

0–3.

0)no

tbl

inde

d

103/

105

120/

122

1.4

yr(m

ean)

,m

axim

um1.

5yr

18/1

03(1

7%)

2/12

0(2

%)

RR

,0.1

(95%

CI,

0.0–

0.4)

0/10

3

1/12

0(1

%)

RR

,2.6

(95%

CI,

0.1–

62.6

)

1/10

3(1

%)

1/12

0(1

%)

RR

,0.9

(95%

CI,

0.1–

13.6

)

Popu

latio

n:F

irst

unpr

ovok

edpr

oxim

alD

VT

orPE

;tre

ated

for

�3

mo;

VK

Ast

oppe

dan

dd-

dim

erpo

sitiv

e1

mo

late

r

Eig

htco

ntro

lpat

ient

s;re

star

ted

VK

A,s

ome

afte

rsu

perf

icia

lph

lebi

tis;o

nere

curr

ent

VT

Ein

VK

Agr

oup

afte

rV

KA

stop

ped.




Tab

le8

—C

onti

nued

Aut

hor/

yr(A

cron

ym)

Inte

rven

tion

Pate

ints

Ana

lyze

d,N

o.L

engt

hof

Fol

low

-up

Rec

urre

ntD

VT

orPE

,No.

(Tot

al)

Maj

orB

leed

ing,

No.

(Tot

al)

Tot

alM

orta

lity,

No.

(%)

Com

men

ts

Kea

ron

etal

156 /1

999

(LA

FIT

)V

KA

stop

ped

(Pla

cebo

)

VK

A(I

NR

,2.0

–3.0

)fo

r2

mor

eyr

83/8

379

/79

10m

o(m

ean)

,m

axim

um2

yr)

17/8

3(2

0%)

1/79

(1%

)R

R,0

.1(9

5%C

I,0.

0–0.

5)

0/83

3/79

(4%

)R

R,7

.4(9

5%C

I,0.

4–14

0)

3/83

(4%

)

1/79

(1%

)R

R,0

.3(9

5%C

I,0.

0–3.

3)

Popu

latio

n:fir

stun

prov

oked

prox

imal

DV

Tor

PE(5

%)

had

prev

ious

prov

oked

VT

E;

recu

rren

tV

TE

inth

eV

KA

patie

ntw

asaf

ter

stop

ping

VK

A

Schu

lman

etal

150 /1

997

(DU

RA

C2)

VK

A(I

NR

,2.0

–2.8

5)fo

r6

mo

VK

A(I

NR

,2.0

–2.8

5)In

defin

itely

111/

111

116/

116

4yr

23/1

11(2

%)

3/11

6(3

%)

RR

,0.1

(95%

CI,

0.0–

0.4)

3/11

1(3

%)

10/1

16(9

%)

RR

,3.2

(95%

CI,

0.9–

11.3

)

16/1

11(1

4%)

10/1

16(9

%)

RR

,0.6

(95%

CI,

0.3–

1.3)

Seco

ndV

TE

:DV

T(d

ista

lor

prox

imal

)or

PE;a

llre

curr

ent

VT

Es

inth

ein

defin

iteV

KA

grou

pw

ere

afte

rst

oppi

ngV

KA

s;bl

eedi

ngdu

ring

the

first

6m

oof

VK

Ain

one

patie

nts

in6-

mo

grou

pan

dsi

xpa

tient

sin

inde

finite

grou

p(o

nly

aske

dab

out

blee

ding

whi

lere

ceiv

ing

VK

As)

Sum

mar

yR

R,0

.1(9

5%C

I,0.

04–0

.22)

RR

,3.6

1(9

5%C

I,1.

22–1

0.7)

RR

,0.5

8(9

5%C

I,0.

29–1

.14)

For

alla

naly

ses,

p�

0.1

for

hete

roge

neity

Inde

fini

tevs

inte

rmed

iate

dura

tion

sof

anti

coag

ulat

ion

(IN

R,

appr

oxim

atel

y5–

2.0

afte

rin

itia

lIN

Rof

2.0–

3.0

inbo

thgr

oups

)R

idke

r161 /2

003

(PR

EV

EN

T)

VK

Ast

oppe

dor

not

rest

arte

d(P

lace

bo)

VK

A(I

NR

,1.5

–2.0

)

253/

253

255/

255

2.1

yr(m

ean)

,m

axim

um,

4.3

yr

37/2

53(1

5%)

14/2

55(5

%)

RR

,0.4

(95%

CI,

0.2–

0.7)

2/25

3(1

%)

5/25

5(2

%)

RR

,2.5

(95%

CI,

0.5–

12.7

)

8/25

3(3

%)

4/25

5(2

%)

RR

,0.5

(95%

CI,

0.1–

1.6)

Popu

latio

n:U

npro

voke

dD

VT

(dis

talo

rpr

oxim

al)

orPE

(fir

step

isod

ein

38%

);ei

ght

recu

rren

tV

TE

sin

the

VK

Agr

oup

afte

rst

oppi

ngV

KA

sL

ow-i

nten

sity

(IN

R,

1.5–

1.9)

vsco

nven

tion

alin

tens

ity

(IN

R,

2.0–

3.0)

Kea

ron18

5 /200

3(E

LA

TE

)V

KA

(IN

R,1

.5–1

.9)

VK

A(I

NR

,2.0

–3.0

),bl

inde

d

369/

369

369/

369

2.4

yr(m

ean)

16/3

69(4

%)

6/36

9(2

%)

RR

,0.4

(95%

CI,

0.1–

0.9)

9/36

9(2

%)

8/36

9(2

%)

RR

,0.9

(95%

CI,

0.3–

2.3)

16/3

69(4

%)

8/36

9(2

%)

RR

,0.5

(95%

CI,

0.2–

1.2)

Popu

latio

n:U

npro

voke

dpr

oxim

alD

VT

orPE

(fir

step

isod

ein

31%

);tr

eate

dfo

r�

3m

o.V

KA

(IN

R,2

.0–

3.0)

;mea

n,12

mo;

five

recu

rren

tV

TE

sin

INR

of1.

5–1.

9an

dth

ree

inIN

Rof

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of VTE was unprovoked (also called idiopathicVTE). This observation was also made in a numberof other prospective studies166,167 during the sameperiod. Consequently, many of the more recenttrials that compared durations of VKA therapyselectively enrolled patients with either unpro-voked VTE,153,154,156,158,159,161 or VTE that wasprovoked by a reversible risk factor157 (Table 8).Longer or indefinite durations of anticoagulanttherapy were generally evaluated in patients withunprovoked VTE, and shorter durations of therapywere evaluated in patients with a reversible provok-ing factor. Because the presence of a reversibleprovoking risk factor,148,149,160,162,163,165–170 unpro-voked VTE,148,149,160,162,163,165–170 and presence ofactive cancer163–166 were used to select patients formany of the studies, and have been shown to be themost important factors that influence risk of recur-rent VTE after stopping VKA, separate recommen-dations for duration of anticoagulant therapy will bemade for each of these three categories of patientswith VTE. Reversible provoking risk factors includethe following: major factors such as surgery, hospi-talization, or plaster cast immobilization, all within 1month; and minor factors such as estrogen therapy,pregnancy, prolonged travel (eg, � 8 h), or thepreviously noted major factors when they have oc-curred 1 to 3 months before diagnosis of VTE. Thegreater the provoking reversible risk factor (eg, suchas recent major surgery), the lower the expected riskof recurrence after stopping anticoagulant thera-py.168 Within each of these three groups, we willconsider if there are additional factors that influencethe risk of recurrence enough to modify recommen-dations about duration of therapy. The most impor-tant of such factors are the following: (1) whetherDVT was confined to the distal veins (often calledisolated calf DVT) or involved the proximalveins,160,162,170 and (2) whether the DVT was a firstepisode of VTE or a second or subsequent episode ofVTE.161,164,171 The presence of hereditary thrombo-philia has not been used as a major factor to guideduration of anticoagulation for VTE in these guide-lines because evidence from prospective stud-ies156,161,168,169,172–180 suggests that these factors arenot major determinants of the risk of recurrence.

VKAs for the Long-term Treatment of DVT

Clinical trials that have evaluated different dura-tions of anticoagulant therapy can be divided intothree categories according to the durations oftherapy that were compared: (1) short vs intermedi-ate durations, (2) different intermediate durations,and (3) indefinite therapy vs intermediate durations.Within each of these categories we will first consider

studies that included heterogeneous (ie, less se-lected) patients with VTE, and then studies thatenrolled subgroups of (ie, selected) patients whowere expected to have either a lower (eg, associatedwith reversible risk factors) or a higher (eg,unprovoked, or second episodes, of VTE) risk ofrecurrence.

Short (4 Weeks or 6 Weeks) vs Intermediate (3Months or 6 Months) Durations of Therapy

Five trials148,149,160,162 have evaluated shortening theduration of oral anticoagulant therapy from 3 or 6months to 4 or 6 weeks in patients with mostly firstepisodes of VTE (Table 8). The first three studies(British Thoracic Society, Levine, DURAC 1; Table 8),which mainly enrolled unselected patients with proxi-mal DVT or PE, found that shortening the duration ofanticoagulation was associated with about double thefrequency of recurrent VTE during follow-up of 1 to 2years (an absolute risk increase of approximately5%).148,149,162 Major bleeding was uncommon duringthe incremental period of anticoagulation in these threestudies (estimated at seven episodes among 1,009patients during 259 patient-years of additional treat-ment [2.7%/yr]).148,149,162 Therefore, the main findingof these studies was that anticoagulant therapy shouldnot be shortened to 4 or 6 weeks in patients with VTE.

Subgroup analyses of one of the above studies (DU-RAC 1) suggests that isolated distal DVT provoked bya major transient risk factor can safely be treated withonly 6 weeks of therapy.162 A subsequent study,160

(component of DOTVAK), which compared 6 vs 12weeks of therapy in patients with isolated calf DVT(unprovoked or provoked; mostly diagnosed by ultra-sound), found no suggestion that shortening therapyincreased the risk of recurrence (RR, 0.6; 95% CI, 0.01to 3.4) and, in general, observed a low frequency ofrecurrent VTE with isolated calf DVT (approximately2% in the first year) compared to proximal DVT or PE(approximately 6% in the first year). These findingssuggest that if anticoagulants need to be stopped after6 weeks of therapy in patients with isolated distal DVT,the subsequent risk of recurrence is not expected to beexcessive. The fifth of these studies157 enrolled onlypatients with VTE associated with a major reversiblerisk factor (SOFAST; Table 8); however, because only165 patients were enrolled, its findings were not defin-itive. A metaanalysis of five studies (retrospective iden-tification of the patient’s subgroup in four stud-ies,148,149,162,181 selective enrollment of patients in 1study157) that compared 4 or 6 weeks with 3 or 6months of treatment among 725 patients with VTEprovoked by a reversible risk factor found that theshorter durations of therapy were associated with more




than double the risk of recurrent VTE during the nextyear (OR, 2.9; 95% CI, 1.2 to 6.9; absolute increase ofapproximately 3.4%).157

Different Intermediate Durations of Therapy (6Months or 12 Months vs 3 Months)

Two studies155,160 have compared 6 months vs 3months of anticoagulant therapy in patients withpredominantly first episodes of DVT or PE (unpro-voked, or provoked by a reversible risk factor)[DOTAVK, Campbell; Table 8]. There was no dif-ference in the risk of recurrence during follow-up inboth studies, and one study155 reported a lowerrisk of bleeding in the 3-month group (Campbell;Table 8).

Agnelli and colleagues154 compared stopping antico-agulant therapy at 3 months with continuing it foranother 9 months after a first episode of unprovokedproximal DVT (WODIT-DVT; Table 8). At the end ofthe first year, recurrent VTE was less frequent in thegroup that remained on anticoagulant therapy (3.0% vs8.3%), but this benefit was lost 2 years after thesepatients stopped anticoagulant therapy (RR, 1.0; 95%CI, 0.6 to 1.7). The same investigators obtained similarresults in a comparable study153 of patients with unpro-voked PE (WODIT PE; Section 5.1, Table 8).

Based on the findings of these five studies (the“provoked” and “unprovoked” components of theWODIT-PE study are have been condidered separatestudies),153–155,160 anticoagulants are very effective atpreventing recurrence while patients are receiving ther-apy; but, at the end of extended follow- up after stoppingtreatment, a similar risk of recurrence is expected ifanticoagulants are stopped at 6 or 12 months, com-pared to at 3 months (RR for the five studies, 0.95;95% CI, 0.72 to 1.26; Table 8), including amongpatients with unprovoked proximal DVT or PE.

Indefinite vs Intermediate Durations ofAnticoagulant Therapy

Four trials have compared indefinite (where indef-inite refers to extended therapy without scheduledstopping of treatment) anticoagulation (target INRs,2.0 to 2.85,150 2.0 to 3.0,156,159 and 1.5 to 2.0161) withstopping therapy in patients with VTE who werebelieved to have a high risk of recurrence becausethrombosis was a second episode,150 unpro-voked,156,161 or was unprovoked and had a positived-dimer result 1 month after stopping therapy159

(DURAC 2, LAFIT, PREVENT, PROLONG; Table8). The results indicate that randomization to indef-inite treatment with conventional-intensity VKA (tar-get INR, 2.5) reduces recurrent VTE by approxi-mately 90% (RR for the three studies, 0.10; 95% CI,

0.04 to 0.22; Table 8),150,156,159 and randomization tolow-intensity therapy (target INR, 1.75) reducesVTE by 64% (95% CI for HR, 23 to 81%)161 (Table8; both RRs are appreciably greater among patientswho remain on VKA therapy).

The benefit of indefinite treatment with VKA ispartially offset by the risk of major bleeding. In thetwo initial studies150,156,182 of extended treatment(DURAC 2, LAFIT; Table 8), the incidence of majorbleeding was approximately 3%/yr during extendedtreatment with conventional-intensity warfarin (in-cluded bleeding during the first 6 months of therapyin DURAC 2). However, in the more recent PRO-LONG study159 and a randomized comparison ofconventional-intensity and low-intensity VKA (ELATE;Table 8),158 extended treatment with conventional-intensity VKA was associated with a risk of majorbleeding of approximately 1% per patient-year (low-intensity VKA is considered in Section 2.2). A meta-analysis184 of seven studies115,148,154,156,161,171,183 thatcompared durations of conventional-intensity antico-agulant therapy for VTE estimated the rate of majorbleeding to be 1.1% per patient-year (18 episodes in1,571 patient-years) during the extended phase ofanticoagulation compared with 0.6% per patient-year (9 episodes during 1,497 patient-years) withoutanticoagulation (RR, 1.80; 95% CI, 0.72 to 4.51).Thus, for patients with unprovoked DVT (and PE),the benefit of long-term treatment is partially offsetby a higher risk of bleeding, and patients loseprotection against recurrent VTE if anticoagulantsare withdrawn. For these reasons, values and pref-erences regarding preventing recurrent thromboem-bolism, avoiding bleeding complications and incon-venience of treatment, bear on the recommendationfor long-term anticoagulant treatment for unpro-voked VTE, particularly after a first episode of DVT(lower risk of recurrence than after a second episodeof VTE,161,164,171 and expected to have a lower risk ofdeath with a recurrence than after a first episode ofPE164,185).186 Individual patient risk of recurrentVTE and of major bleeding may differ from theaverage values that have been reported in the previ-ously noted trials and, in selected patients, mayinfluence the decision to continue or stop anticoag-ulant therapy once 3 months of initial treatment hasbeen completed, or subsequently.

Of factors that have been evaluated as risk factors forrecurrent VTE among patients with unprovoked DVT,the following appear to have the greatest potential to beclinically useful: isolated calf DVT vs proximal DVT(RR, approximately 0.5)160,162,170; one or more previousepisodes of VTE (RR, approximately 1.5)161,164,171;negative d-dimer findings 1 month after withdrawal ofVKA (RR, approximately 0.4)159,177,187,188; antiphos-pholipid antibody (RR, approximately 2)156,179,189;




hereditary thrombophilia (RR, approximately1.5)156,161,168,169,173–175,177; males vs females (relativerisk 1.6)190; Asian ethnicity (RR, approximately0.8)191; and residual thrombosis in the proximal veins(RR, approximately 1.5).153,156,157,192–194

Of factors that have been evaluated as risk factorsfor major bleeding during anticoagulant therapy, thefollowing appear to have the greatest potential to beclinically useful markers of increased risk: older age,particularly after 75 years; previous GI bleeding,particularly if not associated with a reversible cause;previous noncardioembolic stroke; chronic renal orhepatic disease; concomitant antiplatelet therapy (tobe avoided if possible); other serious acute orchronic illness; poor anticoagulant control; subopti-mal monitoring of anticoagulant therapy (see chapteron Hemorrhagic Complications of Anticoagulant andThrombolytic Therapy195).158,195–202

Recommendations

2.1.1. For patients with DVT secondary to atransient (reversible) risk factor, we recom-mend treatment with a VKA for 3 months overtreatment for shorter periods (Grade 1A).2.1.2. For patients with unprovoked DVT, werecommend treatment with a VKA for at least 3months (Grade 1A). We recommend that after 3months of anticoagulant therapy, all patientswith unprovoked DVT should be evaluated forthe risk-to-benefit ratio of long-term therapy(Grade 1C). For patients with a first unprovokedVTE that is a proximal DVT, and in whom riskfactors for bleeding are absent and for whomgood anticoagulant monitoring is achievable,we recommend long-term treatment (Grade 1A).Values and preferences: This recommendation at-taches a relatively high value to prevention of recur-rent VTE and a lower value to the burden oflong-term anticoagulant therapy.

For patients with a second episode of unpro-voked VTE, we recommend long-term treat-ment (Grade 1A). For patients with a first iso-lated distal DVT that is unprovoked, we suggestthat 3 months of anticoagulant therapy is suffi-cient rather than indefinite therapy (Grade 2B).2.1.3. For patients with DVT and cancer, werecommend LMWH for the first 3 to 6 monthsof long-term anticoagulant therapy (Grade 1A).For these patients, we recommend subsequentanticoagulant therapy with VKA or LMWH in-definitely or until the cancer is resolved (also,see Section 2.4) [Grade 1C].2.1.4. For patients who receive long-term anticoag-ulant treatment, the risk-benefit ratio of continuing

such treatment should be reassessed in the individ-ual patient at periodic intervals (Grade 1C).

2.2 Intensity of Anticoagulant Effect

The preferred intensity of the anticoagulant effectof treatment with VKA has been established by theresults of randomized trials.158,203–205 The ELATEstudy was a randomized, blinded trial that comparedlow-intensity VKA (target INR, 1.5 to 1.9) withconventional-intensity VKA (INR, 2.0 to 3.0) forindefinite treatment of patients with unprovokedVTE who had completed at least 3 months of initialconventional-intensity anticoagulation (Table 8). Theincidences of recurrent VTE were 1.9% per patient-year in the low-intensity group, and 0.6% per pa-tient-year in the conventional-intensity group (haz-ard ratio, 3.3; 95% CI, 1.2 to 9.1).158 The incidencesof major bleeding were 0.96% per patient-year in thelow-intensity group and 0.93% per patient-year inthe conventional-intensity group; the correspondingincidences of all bleeding (major and minor) were4.9% per patient-year and 3.6% per patient-year.Thus, low-intensity VKA treatment was less effectivethan conventional-intensity therapy and did not pro-vide a safety advantage.158 The observed incidence ofrecurrent VTE of 1.9% per patient-year in thelow-intensity group is similar to the incidence of2.6% per patient-year in the PREVENT study,161

which compared low-intensity warfarin therapy(INR, 1.5 to 2.0) with placebo (the latter group hadan incidence of recurrent VTE of 7.2% per patient-year; hazard ratio, 0.36 compared with placebo; 95%CI, 0.19 to 0.67). Taken together, the results of thesetwo randomized trials158,161 indicate that after 3months of conventional-intensity therapy, althoughlow-intensity warfarin therapy is much more effec-tive than placebo, it is less effective than convention-al-intensity therapy and does not appear to reducethe incidence of bleeding complications.

In the PREVENT trial,161 low-intensity anticoagula-tion was delivered using a dosing nomogram thatscheduled INR measurements 8 weeks apart, providedthe current INR result was 1.3 to 3.0. This nomogramresulted in an average interval between INR tests of 61days compared with an average interval of 26 days inthe conventional-intensity group of the ELATE trial,158

in which ordering of INR measurements was at thediscretion of the responsible clinician. Thus, the find-ings of the PREVENT trial suggest that anticoagulantmonitoring can be simplified, and made less burden-some to patients and health-care providers, when thetarget INR is 1.75 (range, 1.5 to 2.0) rather than 2.5(range, 2.0 to 3.0). Some patients may prefer to betreated with a lower intensity of VKA therapy that isdelivered with less frequent INR monitoring that to




receive conventional-intensity therapy that, althoughmore effective, requires more frequent INR monitor-ing.

Additional important evidence regarding the opti-mal intensity of anticoagulant therapy with VKA isprovided by the PAPRE203 and WAPS204 random-ized trials that compared conventional-intensity VKAtherapy (INR, 2.0 to 3.0) with high-intensity warfarintherapy (INR, 3.1 to 4.0203 and 3.0 to 4.5204) for theprevention of recurrent thromboembolism in pa-tients with antiphospholipid antibodies and a historyof venous or arterial thromboembolism (Table 9). Inthe two studies combined, there was no evidencethat the higher intensity of anticoagulation was asso-ciated with a lower frequency of recurrent thrombo-embolism (OR, 2.49; 95% CI, 0.93 to 6.67), and nodifference in major bleeding (OR, 0.73; 95% CI, 0.23to 2.31), or minor bleeding (OR, 1.75; 95% CI, 0.93to 3.31).204 However, high-intensity VKA therapy haspreviously been shown to be associated with highrates of bleeding in patients with VTE.147,205,206 Theevidence outlined above provides the basis for therecommendation of an INR of 2.0 to 3.0 as thepreferred intensity of long-term anticoagulant treat-ment with VKA in all patients with VTE.

Recommendation

2.2.1. In patients with DVT, we recommendthat the dose of VKA be adjusted to maintain atarget INR of 2.5 (range, 2.0 to 3.0) for alltreatment durations (Grade 1A). For patientswith unprovoked DVT who have a strong pref-erence for less frequent INR testing to monitortheir therapy, after the first 3 months of con-ventional-intensity anticoagulation (INR range,2.0 to 3.0), we recommend low-intensity ther-apy (INR range, 1.5 to 1.9) with less frequentINR monitoring over stopping treatment (Grade1A). We recommend against high-intensity VKAtherapy (INR range, 3.1 to 4.0) compared to anINR range of 2.0 to 3.0 (Grade 1A).

2.3 SC UFH for the Long-term Treatment of DVT

Adjusted-dose SC UFH is an effective approach forthe long-term treatment of DVT,206 whereas low-doseUFH (5,000 U bid) is inadequate for this pur-pose.147,207 In a study208 of 80 patients with DVT andcontraindications to VKA therapy that compared10,000 U of UFH with 5,000 IU of dalteparin, eachadministered SC twice daily for 3 months, there was asimilar low frequency of recurrent VTE and bleeding inboth groups, but less frequent spinal fracture in theLMWH group. Because of the lower potential forosteoporosis with LMWH and because it can be ad-

ministered once daily without the need for anticoagu-lant monitoring, LMWH is preferred to UFH forlong-term therapy.

2.4 LMWH for the Long-term Treatment of DVT

Twelve randomized trials have compared VKA(INR, 2.0 to 3.0) with widely differing regimens of fiveLMWH preparations (dalteparin,209–211 enoxapa-rin,167,212–214 nadroparin,215,216 tinzaparin,217,218 bemi-parin34). In these studies, the daily LMWH dose was aslow as 4,000 IU167,212 to as high as 200 IU/kg211,216;approximately a 3.5-fold difference. Two metaanalysesof studies that compared LMWH with VKAs, eachadministered for 3 months after initial heparin therapy,have been performed.219,220 In the analysis by Iorioand colleagues,219 which includes seven stud-ies167,209,212,214–217 and a total of 1,379 patients, therewere trends toward less recurrent VTE (OR, 0.66; 95%CI, 0.41 to 1.07) and less major bleeding (OR, 0.45;95% CI, 0.18 to 1.11) with 3 months of LMWHcompared with VKA. Compared with outcomes inpatients who received VKA therapy, between studydifferences of mean daily dose of LMWH had littleeffect on efficacy but did appear to influence the risk ofmajor bleeding (OR, approximately 0.2 with approxi-mately 4,000 IU/d to approximately 0.7 with 12,000IU/d, relative to the VKA groups [p � 0.03]).219 Threesubsequent studies that selectively enrolled a total of1,029 patients with VTE in association with activecancer found that, compared to VKA therapy, 3months213,221 or 6 months211 of therapeutic-doseLMWH was associated with less recurrent VTE in onestudy211 and less bleeding in another study213 (Table10) [RR for the three studies: recurrent VTE, 0.56;95% CI, 0.38 to 0.82; major bleeding, 1.01; 95% CI,0.62 to 1.64; mortality, 0.92; 95% CI, 0.78 to 1.10;Table 4].213,219,221 Randomized trials have not evalu-ated approaches to anticoagulant therapy after the first6 months of VKA or LMWH therapy in patients withVTE and cancer, either to assess duration of therapy orto compare extended therapy with VKA or LMWH.Observational studies163–166 suggest that the risk ofrecurrent VTE is unacceptably high in patients withactive cancer who stop anticoagulant therapy.

2.5 New Antithrombotic Agents for Long-termTreatment of DVT

Ximelagatran (since withdrawn because of hepatictoxicity) has been evaluated for both short-term andlong-term treatment of VTE.61,171 In the short-termtreatment study,61 2,491 patients with acute DVT weretreated for 6 months with ximelagatran, 36 mg bid, orLMWH followed by VKA therapy (INR, 2.0 to 3.0),using a blinded design. The frequency of recurrentVTE at 6 months was similar with ximelagatran (2.1%)




and usual therapy (2.0%), and an “on treatment”analysis (“intention to treat” analysis was not reported)suggested less major bleeding with ximelagatran (1.3%vs 2.2%; 95% CI for difference, � 2.0% to 0.2%). Inthe long-term treatment study,171 18 months of ximel-agatran (24 mg bid) was compared with placebo in1,224 patients with DVT or PE who had completed 6months of initial treatment with VKA. Ximelagatranreduced recurrent VTE by 84% (95% CI, 70 to 91%)without an apparent increase in major bleeding (hazardratio, 1.2; 95% CI, 0.4 to 3.8). Many new anticoagulantsare being evaluated in ongoing trials (see chapter byWeitz et al222 on new anticoagulant drugs).

The long-acting pentasaccharide idraparinuxwas reported to be as effective and as safe as VKAfor the first 3 or 6 months of treatment of DVT(but less effective that VKA in patients withPE).223 After an initial 6 months of treatment witheither idraparinux or warfarin (52% of patientsinitially presented with symptomatic DVT), com-pared with placebo, 6 months of extended therapywith idraparinux markedly reduced recurrent VTEand increased bleeding.223

2.6 Treatment of Asymptomatic DVT of the Leg

Screening of postoperative patients for the pres-ence of asymptomatic DVT is not recommended224;instead, surgical patients should receive appropriateprimary prophylaxis for VTE. If asymptomatic prox-imal DVT is detected, for example, in patients whohave screening performed because they could notreceive recommended VTE prophylaxis or in pa-tients who have imaging studies performed for otherreasons (eg, staging of cancer), care should be takento ensure that DVT is truly present and patientsshould be treated as described elsewhere in thischapter (also see Section 5.4, “Treatment of Asymp-tomatic PE”). Asymptomatic proximal DVT detectedby routine ultrasound screening in the setting of aclinical trial evaluating VTE prophylaxis in hospital-ized medical patients has been shown to be associ-ated with increased mortality at 3 months.225

Recommendation

2.6.1. In patients who are unexpectedly foundto have asymptomatic DVT, we recommend thesame initial and long-term anticoagulation asfor comparable patients with symptomatic DVT(Grade 1C).

3.0 Postthrombotic Syndrome

PTS is a cluster of leg symptoms and signs inpatients with previous DVT. PTS occurs in 20 to

Tab

le9

—C

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2/58

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(10.

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RR

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(95%

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0.6–

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4/58

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48)

Popu

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RR

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CI,

0.5–

7.7)

3/55

(5.5

%)

2/54

(3.7

%);

RR

,0.7

(95%

CI,

0.1–

3.9)

2/55

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)

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1.64

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CI,

0.3–

8.8)

Popu

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n:69

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405

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50% of patients after acute DVT.226 The initialtreatment of acute DVT may influence the presenceand severity of PTS, as discussed earlier (Section2.0). The most prominent symptoms are chronicpostural dependent swelling and pain, ambulatorydiscomfort, and skin pigmentation. The severity ofsymptoms may vary over time, and the most extrememanifestation is a venous ulcer of the lower leg.First, the studies on the prevention of PTS arediscussed, followed by the trials on the treatment ofthis syndrome, with and without venous ulcers.

3.1 Elastic Stockings and Compression BandagesTo Prevent PTS

Four randomized trials144,227–229 have evaluated theefficacy of compression stockings for the prevention ofPTS following DVT (Table 11). Two trials, namelythose of Brandjes et al227 and Prandoni et al,229 ran-domized patients to stockings (30 to 40 mm Hg anklegradient) or no stockings after a first episode ofacute symptomatic proximal DVT. A third trial byGinsberg et al228 evaluated 47 asymptomatic pa-tients with evidence of venous valvular incompe-tence 1 year following their acute DVT. Twenty-six percent of the patients had asymptomatic DVTdetected by phlebography after orthopedic sur-gery. A lower compression stocking of 20 to 30 mmHg ankle pressure was compared with a placebostocking.

Blattler and Partsch139 randomized 53 patients withacute symptomatic DVT to anticoagulation and bedrest for 9 days or anticoagulation and ambulation witheither inelastic bandages or compression stockings (30mm Hg). Early and long-term results favored theambulation-with-compression group (Table 11).144

Brandjes et al227 demonstrated that 47% of thecontrol group had mild-to-moderate PTS comparedwith 20% of patients in the stocking group. Twenty-three percent of patients in the control group vs 11%of patients in the stocking group had severe PTS.Prandoni et al229 made similar observations, in thatPTS developed in 49% of control patients comparedwith 25% in the treatment group after 2 years.

Ginsberg et al228 observed no difference in the 47patients who were randomized to 20 to 30 mm Hgcompression stockings compared with a placebostocking. Since all patients were asymptomatic atentry into the study 1 year after diagnosis, and as26% initially had asymptomatic DVT, it appears thatthe patients in this trial were unlikely to benefit fromany measure to prevent PTS, since PTS was unlikelyto develop without treatment.

A Cochrane review230 that combined the findings ofBrandjes, Prandoni, and Ginsberg (421 patients) esti-mated that stockings markedly reduced the cumulative

incidence of PTS at 2 years (OR, 0.3; 95% CI, 0.2 to0.5). An ongoing placebo-controlled study is furtherevaluating whether routine wearing of graduated com-pression stockings prevents the development of PTS.231

Recommendation

3.1.1. For a patient who has had a symptomaticproximal DVT, we recommend the use of anelastic compression stocking with an anklepressure gradient of 30 to 40 mm Hg iffeasible (Grade 1A). Compression therapy,which may include use of bandages acutely,should be started as soon as feasible afterstarting anticoagulant therapy and should becontinued for a minimum of 2 years, andlonger if patients have symptoms of PTS.(Note: feasibility, both short-term and long-term, refers to ability of patients and theircaregivers to apply and remove stockings.)Values and preferences: This recommendation attachesa relatively high value to long-term prevention of thePTS and a low value to the burden (eg, inconvenienceor discomfort) associated with wearing stockings.

3.2 Physical Treatment of PTS Without Venous LegUlcers

The treatment of PTS has been evaluated onlyin small or methodologically flawed trials. Treat-ment is usually based on physical methods de-signed to counteract the raised venous pressure.Of these approaches, elastic stockings have beenevaluated in asymptomatic and symptomatic pa-tients in a small underpowered trial228; the resultsfailed to show a benefit, possibly due to milddisease and small patient numbers. In a cross-overstudy232 of 15 patients with a severe PTS, inter-mittent pneumatic compression (IPC) at 40 mmHg was more effective than a lower (placebo)pressure. Twelve of 15 patients preferred thetherapeutic pressure.

Recommendations

3.2.1. For patients with severe edema of the leg dueto PTS, we suggest a course of IPC (Grade 2B).3.2.2. For patients with mild edema of the leg due toPTS, we suggest the use of elastic compressionstockings (Grade 2C).

3.3 Physical Treatment of Venous Leg Ulcers

Venous leg ulcers represent the most severe com-plication of PTS. While most reports of venous legulcers fail to differentiate a postthrombotic etiologyfrom primary venous insufficiency, it is recognized thatthe postthrombotic limb is likely to have higher venous




Tab

le10

—L

MW

Hvs

VK

Afo

rL

ong-

Ter

mT

reat

men

tof

VT

Ein

Pat

ient

sW

ith

Act

ive

Can

cer:

Cli

nica

lD

escr

ipti

onan

dR

esu

lts

(Sec

tion

2.4)

*

Aut

hor/

yr(A

cron

ym)

Inte

rven

tions

Patie

nts

Ana

lyze

d,N

o./T

otal

(%)

Len

gth

ofF

ollo

w-u

pR

ecur

rent

DV

Tor

PE,N

o./T

otal

(%)

Maj

orB

leed

ing,

No.

/Tot

al(%

)T

otal

Mor

talit

y,N

o./T

otal

(%)

Com

men

ts

Mey

eret

al21

3 /200

2V

KA

(IN

R,2

.0–3

.0)

for

3m

oaf

ter

initi

alen

oxap

arin

Eno

xapa

rin

at1.

5m

g/kg

once

daily

for

3m

o

75/7

5

71/7

1

3m

o

3m

o.

3/75

(4%

)

2/71

(3%

)R

R,0

.7(9

5%C

I,0.

1–4.

1)

12/7

5(1

6%)

5/71

(7%

)R

R,0

.4(9

5%C

I,0.

2–1.

2)

17/7

5(2

3%)

8/71

(11%

)R

R,0

.5(9

5%C

I,0.

2–1.

1)

Popu

latio

n:D

VT

(pro

port

ion

with

calf

DV

Tno

tkn

own)

orPE

and

activ

eca

ncer

;al

lfat

albl

eedi

ngs

(n�

6)w

ere

inV

KA

grou

p.

Lee

etal

211 /2

003

(CL

OT

)V

KA

(IN

R,2

.0–3

.0)

for

6m

oaf

ter

initi

alda

ltepa

rin

Dal

tepa

rin

at20

0U

/kg

once

daily

for

1m

ofo

llow

edby

150

U/k

gfo

r5

mo

336/

338

336/

338

6m

o

6m

o

53/3

36(1

6%)

27/3

36(8

%)

RR

,0.5

(95%

CI,

0.3–

0.8)

12/3

35(4

%)

19/3

38(6

%)

RR

,1.6

(95%

CI,

0.8–

3.2)

136/

336

(40%

)

130/

336

(37%

)R

R,1

.0(9

5%C

I,0.

8–1.

2)

Popu

latio

n:Pr

oxim

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VT

orPE

and

activ

eca

ncer

Diff

eren

cein

effic

acy

mai

nly

due

tore

curr

ent

DV

T(1

4vs

37ep

isod

es)

Hul

let

al22

1/2

006

(Mai

nL

ITE

-ca

ncer

)

VK

A(I

NR

2.0–

3.0)

for

3m

oaf

ter

initi

alIV

UF

H

Tin

zapa

rin

at17

5m

g/kg

once

for

3m

o

100/

100

100/

100

3m

o

3m

o.

10/1

00(1

0%)

6/10

0(6

%)

RR

,0.6

(95%

CI,

0.2–

1.6)

7/10

0(7

%)

7/10

0(7

%)

RR

,1.0

(95%

CI,

0.4–

2.8)

19/1

00(1

9%)

20/1

00(2

0%)

RR

,1.0

(95%

CI,

0.6–

1.9)

Popu

latio

n:Pr

oxim

alD

VT

and

activ

eca

ncer

Pres

peci

fied,

stra

tific

atio

n,su

bgro

upw

ithin

ala

rger

tria

l;O

utco

mes

at12

mo

wer

eal

sore

port

edSu

mm

ary

RR

,0.7

(95%

CI,

0.4–

0.8)

RR

,1.0

(95%

CI,

0.6–

1.6)

RR

,0.9

(95%

CI,

0.8–

1.1)

*The

met

hodo

logi

cqu

ality

desc

ript

ion

port

ion

ofth

ista

ble

can

befo

und

inth

eon

line

vers

ion

ofth

isar

ticle

asa

data

supp

lem

ent.




pressures and, therefore, more likely to have ulcerationthan patients with primary venous insufficiency.65

Smith et al233 demonstrated that in patients withvenous leg ulcers, IPC for 4 h daily added to standardwound care and compression significantly increasedhealing (p � 0.009) [Table 12]. Kumar et al234 foundthat IPC in addition to standard four-layered compres-sion increased rate of ulcer healing (p � 0.046) andreduced time to a healed ulcer (p � 0.05) [Table 12].In 10 patients with postthrombotic venous ulcers, 60min of IPC was found to increase transcutaneousoxygen tension, reduce edema, and increase skin tem-perature in the short-term (Table 12).235 As compres-sion pressures and cycles have varied in the studies thathave been performed, IPC prescription for treatment

of PTS and venous ulcers has not been standardized.Surgical correction of superficial venous reflux in addi-tion to compression bandaging was shown to reducerecurrent ulceration compared with compression ther-apy alone in a randomized trial236,237 of 500 patientswith open or recently healed leg ulcers and ultrasound-confirmed superficial venous reflux (recurrent ulcer-ation of 31% vs 56% at 4 years; p � 0.01).

Recommendation

3.3.1. In patients with venous ulcers resistant tohealing with wound care and compression, wesuggest the addition of IPC (Grade 2B).

Table 11—Elastic Stockings for the Prevention of PTS: Clinical Description and Results (Section 3.1)*

Author/yrType ofStudy Participants Interventions Outcomes Follow-up Results

Brandjes et al227/1997

RCT 194 patientswith firstsymptomatic,proximal DVT

Compression stockings:below-kneecustomizedelastic compressionstockings withankle pressure30–40 mm Hg(96 patients)

Control group: nointervention (n � 98)

Cumulativeincidence ofmild-to-moderateand severe PTS

3 mo and 6 mo,then every6 mo to amedian of76 mo

Compression stockings:Mild-to-moderate PTS:

20% (RR, 0.42; 95%CI, 0.27–0.66; p �0.001)

Severe PTS: 11% (RR,0.49; 95% CI, 0.25–0.95; p � 0.001)

Control group:Mild-to-moderate PTS:

47%Severe PTS: 23%

Ginsberg et al228/2001

RCT 47 asymptomaticpatients withvalvularincompetence1 yr afterDVT

Compression stockings:below-knee elasticcompression stockings20–30 mm Hg(n � 24)

Placebo: placebostocking (n � 23)

PTS symptoms 57 mo (mean) Compression stockings:PTS symptoms: 0%

Placebo:PTS symptoms: 4%

Prandoni et al229/2004

RCT 180 patients withfirst episode ofsymptomatic,acute proximalDVT

Compression stockings:below-knee elasticcompression stockings30–40 mm Hg(n � 90)

Control group: nointervention(n � 90)

Cumulativeincidence ofmild-to-moderateand severe PTS

3 to 5 yr Compression stockings:PTS symptoms: 25%

(95% CI, 15.6–33.4%)

Control group:PTS symptoms: 49%

(95% CI, 38.7–59.4%)

Partsch et al144/2004

2-yr follow-upto RCT141

37 symptomaticpatients withacute DVTfollowed uplong term

All anticoagulated withLMWH followed byoral anticoagulation

Inelastic bandages plusearly ambulation (n �13)

Elastic stockings (30 mmHg) plus earlyambulation (n � 13)

Bed rest for 9 d, nocompression (n � 11)

Overall leg pain,leg circumference,PTS score(Villalta-Prandoni)

2 yr Leg painNo difference between

groups

Calf circumferenceNo difference between

groups

PTS scoreSignificantly better

outcome withambulation andbandaging or stockingscompared to bed rest(p � 0.01)

*The methodologic quality description portion of this table can be found in the online version of this article as a data supplement.




3.4 Hyperbaric Oxygen and the Management ofPatients With Venous Ulcers

Only one small trial238 of acceptable methodologicquality has evaluated hyperbaric oxygen in the treatmentof patients with venous leg ulcers, and this study of 16patients failed to show any benefit on the rate of healing.

Recommendation

3.4.1. For patients with venous ulcers, we suggestthat hyperbaric oxygen not be used (Grade 2B).

3.5 Pharmacologic Treatment of Venous Ulcers

Not all venous ulcers heal in a timely manner withcompression and/or IPC, and such patients maybenefit from the addition of pharmacologic agents.

Pentoxifylline

Pentoxifylline affects the membrane of blood cells,resulting in changes in the rheology of blood and themicrocirculation.239 A Cochrane review evaluatedeight randomized studies240–247 with a total of 547patients with venous leg ulcers who were treatedwith pentoxifylline vs placebo and in which there wasobjective measurement of wound healing (Table 13).Compression therapy was used in five of the eighttrials,241–244,246 and in three trials no compressionwas used.240,245,247 There was a tendency for com-plete healing or significant improvement to occurmore frequently in pentoxifylline-treated patients(RR, 1.5; 95% CI, 1.1 to 2.0). In the five studies inwhich compression was used, the addition of pen-toxifylline resulted in an RR of healing of 1.3 (95%

Table 12—Physical Treatment of PTS With Venous Ulcers: Clinical Description and Results (Section 3.3)*

Author/yrType ofStudy Participants Interventions Outcomes Follow-up Results

Kolari et al235/1988

Prospectivestudy

10 patients (studygroup) withPTS leg ulcers,and 9 patientswith noevidence ofperipheralarterial disease

1 h of IPC at 50 mm Hg(inflation time of 12 s,deflation time of 18 s);leg volume and skintemperature measuredbefore and aftercompression

Before/afterinterventionTcPO2 (supineat ulcer edge),leg volume(waterdisplacement),skintemperature

Immediately afterprocedure

Before/after TcPO2:Study group: before,

26.2 � 7.0, after, 42.7� 6.4 (p � 0.005)

Control subjects: before,59.7 � 2/9; after, ND

Change in TcPO2correlated significantlywith reduction inedema and inversechange in skintemperature (R �0.912, p � 0.002)

Smith et al233/1990

RCT 45 patients withnonhealingvenous ulcers

Stockings: ulcerdebridement, cleaning,nonadherent dressing,graduated compressionstockings 30–40 mmHg

Stockings plus IPC: sameprotocol ascompression group plusIPC 4 h/d

Healed ulcer,median rate ofhealing perweek

3.7 yr (mean) StockingsHealed ulcer: 1/24 (4%)Median healing rate:

2.1%

Stockings plus IPCHealed ulcer: 10/21

(48%) �p � 0.009�Median healing rate:

19.8% (p � 0.046)

Kumar et al234/2002


Bandages: weekly four-layer bandaging

Bandages plus IPC:weekly four-layerbandaging plus IPC for1 h bid at 60 mm Hg

Mean number ofdays to healedulcer, meanrate of healing

4 mo BandagesMean days to healed

ulcer: 73.7 dMean rate of healing:

0.05 cm2/d (95% CI,0.03–0.07; SD �0.046)

Bandages plus IPCMean days to healed

ulcer: 53.5 dMean rate of healing:

0.14 cm2/d (95% CI,0.03–0.25; SD � 0.22)�p � 0.05�

*TcPO2 � transcutaneous oxygen pressure; ECS � elastic compression stocking; IPC � intermittent pneumatic compression; ND � not determined.The methodologic quality description portion of this table can be found in the online version of this article as a data supplement.




CI, 1.1 to 1.5). In the three studies in whichcompression was not used as standard therapy, pen-toxifylline also promoted healing (RR, 2.4; 95% CI,1.3 to 4.3). A subsequent trial248 of 80 patientsshowed similar results.

Micronized Purified Flavonoid Fraction orSulodexide for the Treatment of Venous Leg Ulcers

Hydroxyrutosides are a class of flavonoid drugproduced from plant glycosides. Although theirmechanism of action is not entirely known, theyappear to reduce capillary permeability, reduceinflammation, improve lymphatic function, andimprove symptoms relating to chronic venousinsufficiency249,250 (Table 14). Micronization ofthe flavonoid compound improves intestinal ab-sorption and bioavailability and, therefore, isthought to improve clinical effects.251 A meta-analysis252 of five studies evaluated micronizedpurified flavonoid fraction (MPFF) in the manage-ment of patients with venous ulceration who wereall treated with compression. Two of the fivestudies were placebo-controlled trials, whereasthree studies did not incorporate a placebo. At 6months, complete ulcer healing had occurred in61% of the MPFF patients and in 48% of thecontrol patients (RR reduction for persistent ul-ceration, 32%; 95% CI, 3 to 70%; p � 0.03).Subgroup analyses suggested that the benefits ofMPFF were greatest in ulcers � 5 cm2 and � 6months in duration. Sulodixide, a glycosaminogly-can preparation that is administered intraamuscu-larly or orally, was shown to increase venous ulcerhealing in a placebo-controlled trial253 of 235patients (RR for healing, 1.37; 95% CI, 1.07 to1.74) without an apparent increase in side effects.

Recommendations

3.5.1. In patients with venous leg ulcers, wesuggest pentoxifylline, 400 mg po tid, in ad-dition to local care and compression and/orIPC (Grade 2B).3.5.2. In patients with persistent venous ul-cers, we suggest that rutosides, in the form ofMPFF adminstered orally, or sulodexide ad-ministered intramuscularly and then orally,be added to local care and compression(Grade 2B).

4.0 Initial Treatment of Acute PE

Treatment regimens for DVT and PE are similarbecause the two conditions are manifestations of the

same disease process. When patients with VTE arecarefully studied, the majority of those with proximalDVT also have PE (symptomatic or asymptomatic) andvice versa.185 Furthermore, clinical trials of anticoagu-lant therapy have yielded similar estimates for efficacyand safety in patients with DVT alone, in those withboth DVT and PE, and in patients with only PE. Therisk of recurrence also appears to be similar after PEand after proximal DVT.164,185 The vast majority ofpatients with VTE who receive adequate anticoagula-tion survive. However, there are some important dif-ferences between patients who present with PE andthose who present with DVT that justify separateconsideration of treatment for PE. First, the risk ofearly death (within 1 month) from VTE, due to eitherthe initial acute episode or recurrent VTE, is muchgreater after presenting with PE than after DVT164; thisdifference may justify more aggressive initial treatmentfor PE (eg, thrombolytic therapy, insertion of an IVCfilter, more intensive anticoagulant therapy) com-pared with DVT. Second, recurrent episodes ofVTE are about three times as likely to be PE afteran initial PE than after an initial DVT (ie, approx-imately 60% after a PE vs 20% after a DVT)164,185;this difference may justify more aggressive, ormore prolonged, long-term therapy. Third, thelong-term sequelae of PE are cardiorespiratoryimpairment, especially due to pulmonary hyper-tension, rather than PTS of the legs or arms. As therecommendation for anticoagulant therapy andIVC filter insertion in patients with PE are partlybased on studies that enrolled DVT patients alone,or both DVT and PE patients, see correspondingsections for treatment of patients with DVT.

4.1 IV or SC UFH, SC LMWH, SC Fondaparinux,and VKA for the Initial Treatment of PE

Anticoagulant Therapy vs No Anticoagulant Therapy

In their landmark RCT, Barritt and Jordan1

showed that short-term treatment with intermittentboluses of IV UFH and VKA therapy was effective inpatients with a clinical diagnosis of PE (Table 15);this trial also reported very favorable outcomes in acohort of 38 patients with severe PE who were alltreated with anticoagulants (one nonfatal recurrentPE, and one death not due to PE or bleeding) afterthe RCT was stopped early because of benefit fromactive therapy.

SC LMWH vs IV UFH

Consistent with findings in patients with DVT,LMWH has been found to be at least as effective




and safe as IV UFH in studies that included bothpatients with PE and/or DVT, or only patients withPE (Table 15). In a metaanalysis259 of 12 stud-ies29,30,33,35,39,43,44,254 –258 that included a total of1,951 patients with either submassive symptomaticPE, or asymptomatic PE in conjunction withsymptomatic DVT, at the end of treatment (5 to 14days), LMWH was associated with a tendency toless recurrent VTE (OR, 0.63; 95% CI, 0.33 to1.18), less major bleeding (OR, 0.67; 95% CI, 0.36to 1.27), and similar all-cause mortality (OR, 1.20;95% CI, 0.59 to 2.45).

SC UFH vs SC LMWH

Two recent large studies of patients with acuteVTE (total of 1,478 patients, of whom 253 presentedwith PE) found no difference in recurrent VTE,bleeding, or all-cause mortality between patientswho were treated with either partially24 or fully25

weight-adjusted SC UFH (dose adjusted to APTTresults in one study,24 and in fixed-doses withoutAPTT monitoring in the other study25), comparedwith those who were treated with LMWH (Galilie,FIDO; Table 2) [judged Grade 1B evidence fornoninferiority of monitored and fixed-dose SC UFHcompared with LMWH].

Fondaparinux vs IV UFH

The Matisse PE study,60 an open-label trial thatenrolled 2,213 patients with acute PE (including majorPE, provided thrombolytic therapy was not required),found that partially weight-adjusted, fixed-dose, SCfondaparinux was associated with a similar frequency ofrecurrent VTE (3.8% vs 5.0% at 3 months) and majorbleeding (1.3% vs 1.1% during initial treatment) asadjusted-dose IV UFH (Table 15) [judged Grade 1Aevidence for noninferiority of fondaparinux comparedwith IV UFH or SC LMWH].

Treatment of PE on an Outpatient Basis

No published trials have specifically randomizedpatients with acute PE to either be treated in hospitalor at home. Two randomized trials25,57 included pa-tients with acute PE who were treated as outpatients.The first trial,57 which compared two LMWH prepa-rations for outpatient treatment of acute VTE, in-cluded 90 patients with acute PE. The second trial,25

which compared subcutaneous fixed-dose UFH andLMWH in patients with acute VTE, included 52patients with acute PE who were treated entirely asoutpatients. Among the 142 patients, there was a lowfrequency of recurrent VTE (3.5%) and major bleed-ing (1.4%). The feasibility of treating a substantial

proportion of patients with symptomatic PE withLMWH at home is also supported by the findingsof three observational studies260 –262 in which 158patients (35% of total) with PE were treatedentirely at home. Two prediction rules have beendeveloped to aid with selection of patients withacute PE who are suitable for treatment out ofhospital.263–265 Recommendations about the initi-ation of UFH or LMWH as well as the overlapwith VKA and monitoring of the anticoagulanteffects are largely based on the findings in patientswith DVT and, therefore, are the same as for DVT(see Section 1).

Recommendations

4.1.1. For patients with objectively confirmedPE, we recommend short-term treatment withSC LMWH (Grade 1A), IV UFH (Grade 1A),monitored SC UFH (Grade 1A), fixed-dose SCUFH (Grade 1A), or SC fondaparinux (Grade 1A)rather than no such short-term treatment. Pa-tients with acute PE should also be routinelyassessed for treatment with thrombolytic ther-apy (see Section 4.3 for related discussion andrecommendations).4.1.2. For patients for whom there is a highclinical suspicion of PE, we recommend treat-ment with anticoagulants while awaiting theoutcome of diagnostic tests (Grade 1C).4.1.3. In patients with acute PE, we recommendinitial treatment with LMWH, UFH, orfondaparinux for at least 5 days and until theINR is > 2.0 for at least 24 h (Grade 1C).4.1.4. In patients with acute PE, we recommendinitiation of VKA together with LMWH, UFH, orfondaparinux on the first treatment day ratherthan delayed initiation of VKA (Grade 1A).4.1.5. In patients with acute PE, if IV UFH ischosen, we recommend that after an initial IVbolus (80 U/kg or 5,000 U), it be administeredby continuous infusion (initially at dose of 18U/kg/h or 1,300 U/h) with dose adjustment toachieve and maintain an APTT prolongationthat corresponds to plasma heparin levels of0.3 to 0.7 IU/mL anti-Xa activity by the amido-lytic assay rather than administration as IVboluses throughout treatment, or administra-tion without coagulation monitoring (Grade1C).4.1.6. In patients with acute PE, if monitoredSC UFH is chosen, we recommend an initialdose of 17,500 U, or a weight-adjusted dose ofabout 250 U/kg bid, with dose adjustment toachieve and maintain an APTT prolongationthat corresponds to plasma heparin levels of




Table 13—Pentoxifylline for the Treatment of PTS With Venous Ulcers: Clinical Description and Results(Section 3.5.1)*

Author/yr Type of Study Participants Interventions Outcomes Follow-up Results

Weitgasser247/1983

RCT 60 patients withnonhealingvenous legulcers

Pentoxifylline: 400 mg tid(n � 30)

Placebo (n � 30)

Healed ulcer (ulcerclosed or sizeconsiderablyreduced)

6–8 wk PentoxifyllineComplete ulcer healing:

20/30 (67%)

PlaceboComplete ulcer healing:

7/29 (24%)Schürman

et al246/1986RCT 24 patients with

nonhealingvenous ulcers

Pentoxifylline pluscompression: 400 mgTID plus compression(n � 12)

Placebo plus compression(n � 12)

Healed ulcer 8 wk Pentoxifylline pluscompression

Complete ulcer healing:2/12 (16%)

Placebo plus compression:Complete ulcer healing:

3/12 (25%)Arenas and

Atoche240/1988


Pentoxifylline: 400 mgTID (n � 18)

Placebo (n � 12)

Healed ulcer 6 mo PentoxifyllineComplete ulcer healing:

7/18 (39%)


3/12 (25%)Colgan242/

1990RCT,

multicenter80 patients with


Pentoxifylline pluscompression: 400 mgTID plus layeredcompression (n � 38)

Placebo plus compression:placebo plus layeredcompression (n � 42)



Placebo plus compressionComplete ulcer healing:

12/42 (29%)Barbarino241/

1992RCT 12 patients with


Pentoxifylline pluscompression: 400 mgTID plus layeredcompression (n � 6)

Placebo plus compression:placebo plus layeredcompression (n � 6)

Healed ulcer 2–3 mo Pentoxifylline pluscompression

Complete ulcer healing: 4/6(66%)

Placebo plus compressionComplete ulcer healing: 1/6

(17%)Apollonio and

Angeletti385/1992


Defibrotide: 800 mg intwo doses daily(n � 12)

Pentoxifylline: 400 mgof pentoxifylline tid(n � 11)

Healed ulcer 6 mo DefibrotideComplete ulcer healing:

11/12 (92%)

PentoxifyllineComplete ulcer healing:

9/11 (82%)Herdy et al245/

1997RCT 12 patients with


Pentoxifylline: 400 mgpentoxifylline TID(n � 6)

Placebo (n � 6)

Reduction in ulcerarea

12 wk PentoxifyllineUlcer reduction: 2.2 cm2

PlaceboUlcer reduction: 0.4 cm2

Dale et al243/1999

Factorial RCT,multicenter

200 patientswithnonhealingvenous ulcers

Pentoxifylline pluscompression: 400 mgTID plus compressionplus wound dressing(n � 101)

Placebo plus compression:placebo plus compressionplus wound dressing(n � 99)



Placebo plus compressionComplete ulcer healing:

52/99 (52%)




0.3 to 0.7 IU/mL anti-Xa activity when mea-sured 6 h after injection rather than startingwith a smaller initial dose (Grade 1C).4.1.7. In patients with acute PE, if fixed-dose,unmonitored SC UFH is chosen, we recom-mend an initial dose of 333 U/Kg followed bya twice-daily dose of 250 U/kg rather thannon–weight-based dosing (Grade 1C).4.1.8. In patients with acute nonmassive PE, werecommend initial treatment with LMWH over IVUFH (Grade 1A). In patients with massive PE, inother situations where there is concern about SCabsorption, or in patients for whom thrombolytictherapy is being considered or planned, we sug-gest IV UFH over SC LMWH, SC fondaparinux,or SC UFH (Grade 2C).4.1.9. In patients with acute PE treated withLMWH, we recommend against routine monitoringwith anti-factor Xa level measurements (Grade 1A).4.1.10. In patients with acute PE and severe renalfailure, we suggest UFH over LMWH (Grade 2C).

4.2 New Antithrombotic Agents for the InitialTreatment of PE

In addition to the synthetic pentasaccharidefondaparinux (Section 4.1), several other new anti-thrombotic agents have recently been developed(see chapter by Weitz et al222 in this supplement). Aspreviously noted (Section 2.5), ximelagatran hasbeen compared with LMWH and VKA therapy forthe initial 6 months of short-term treatment of DVT,and one third of these patients had concomitant PE(not available for clinical use because of associatedliver toxicity).61 The long-acting pentasaccharideidraparinux was reported to be less effective thanstandard therapy with heparins and VKA for the first3 to 6 months of treatment of PE.62

4.3 Systemically and Locally AdministeredThrombolytic Therapy for PE

Thrombolytic therapy for PE remains controver-sial. The fundamental problem is that � 800 PE

Table 13—Continued

Author/yr Type of Study Participants Interventions Outcomes Follow-up Results

Falanga etal244/1999


Placebo plus compression(n � 45)



Healed ulcer 24 wk Placebo plus compressionComplete ulcer healing:

28/45 (63%)

Pentoxifylline 400 mg tidplus compression:


Pentoxifylline 800 mg tidplus compression


Belcaro etal386/2002



Placebo (n � 88)


67%


31%De Sanctis et

al387/2002RCT 85 patients with



Placebo (n � 39)


88%


44%Nikolovska et

al248/2002RCT 80 patients with



Placebo (n � 40)


23/40 (58%)

PlaceboComplete ulcer healing: 11/

40 (28%)





patients have been enrolled in randomized trials ofthrombolysis plus anticoagulation vs anticoagulationalone (Table 16). The results of such trials havebeen summarized in three recently publishedmetaanalyses.266–268 In one overview, which included11 studies269–278 totalling 748 patients with PE ofvarying severity, thrombolysis was associated withtrends toward reduction in recurrent PE (2.7% vs

4.3%; OR, 0.67; 95% CI, 0.33 to 1.37), reduction inall-cause mortality (4.3% vs 5.9%; OR, 0.70; 95%CI, 0.37 to 1.30), and an increase in major bleed-ing (9.1% vs 6.1%; OR, 1.42; 95% CI, 0.81 to2.46). In the subset of five trials269,271,273,275,278

(total of 254 patients) that focused on patients withmore severe PE, the reduction in mortality (6.2%vs 12.7%; OR, 0.47; 95% CI, 0.20 to 1.10) and the

Table 14—MPFF for the Treatment of PTS With Venous Ulcers: Clinical Description and Results (Section 3.5)*

Author/yr Type of Study Participants Interventions OutcomesFollow-

up Results

Guilhou etal388/1997

RCT, placebocontrolled,multicenter

105 patients withvenous ulcers,stratified byulcer size: �10cm (n � 91),� 10 cm (n � 14)

MPFF pluscompression:500 mg bid pluscompression

Placebo pluscompression

Complete ulcerhealing

Symptoms of CVI,time to heal

2 mo Healed ulcersTreatment: 14/44 (32%)Control: 6/47 (13%)p � 0.028;

No ulcer � 10 cm2

Glinski etal389/2001

RCT, open label 140 patients withvenous leg ulcers,stratified byulcer size:� 3 cm, 3–6 cm,� 6 cm

MPFF pluscompression: 500 mgbid plus compression

Compression alone

Complete ulcerhealing

Reduction in ulcersize, cost-effectiveness

6 mo Healed ulcersTreatment: 47%Control: 28%(p � 0.05; RR, 2.3; 95% CI,

1.1–4.6)

Ulcer: � 3 cmTreatment: 71%Control: 50%

Ulcer 3–6 cmTreatment: 60%Control: 32%

Ulcer � 6 cmTreatment: 9%Control: 13%

Cost per healed ulcerTreatment: €1026.20Control: €1871.80

Roztocil etal390/2003

RCT, openlabel,multicenter

150 patients withvenous legulcers 2–10 cmin diameter

MPFF pluscompression

Complete healingat 6 mo

6 mo Healed ulcersTreatment: 65%Control: 41%(p � 0.004)

Days to achieve healingTreatment: 137 dControl: 166 d(p � 0.004)

Coleridge-Smithet al252/2005

Metaanalysis,three trialssummarizedabove, plustwounpublishedtrials

723 patients withvenous legulcers

Two studiesMPFF plus compression

vs compression plusplacebo

Three studiesMPFF plus compression

vs compression alone

Complete healing 2–6 mo Healing increased by 32%(RR, 1.3.2; 95% CI, 1.03–1.70) at 6 mo

Healing time shortened by 5wk

Healing increased in ulcers� 5 cm2 (RR, 1.53; 95%CI, 1.15–2.03) and � 6mo old (RR, 1.41; 95%CI, 1.09–1.81)





increase in major bleeding (21.9% vs 11.9%; OR,1.98; 95% CI, 1.00 to 3.92) were more markedwith thrombolytic therapy.268

MAPPET-3,279 the largest and most recent random-ized trial of thrombolytic therapy vs heparin alone,studied patients with the combination of normal BPand either echocardiographic or ECG evidence of rightventricular dysfunction (Table 16). The principal endpoint was escalation of therapy, defined as the need forpressors, mechanical ventilation, cardiopulmonary re-suscitation, or open-label thrombolysis. Tissue plasmin-ogen activator (tPA), compared with placebo, halvedthe frequency of escalation of therapy and did notincrease major bleeding. However, open-label throm-bolysis as rescue therapy was the main form of escala-tion of therapy, and as the decision to use open label“rescue thrombolysis” was subjective and could bemake after unblinding, this component of the primaryoutcome has been criticized.279

In the International Cooperative Pulmonary Em-bolism Registry, which enrolled 2,454 PE patientsfrom 52 hospitals in seven countries, intracranialbleeding occurred in 3.0% of the 304 patients whoreceived thrombolytic therapy, compared with 0.3%of the nonthrombolysis treated patients.280 The over-all mortality rate from PE was approximately 8%after 3 months,281 about double the frequency re-ported in randomized trials; this higher mortalityrate probably reflects exclusion of the sickest pa-tients from participating in randomized trials43,60

(Table 16). There was no apparent survival benefitfrom thrombolysis in this registry, even among thesickest patients with massive PE.280

There is widespread agreement that thrombolytictherapy should be used to treat PE associated withhemodynamic compromise. Justification for this is that,compared with anticoagulation alone, thrombolytictherapy has demonstrated the following: (1) accelera-tion of thrombus lysis as evidenced by more rapidresolution of perfusion scan abnormalities, decrementin angiographic thrombus, reduction in elevated pul-monary artery pressures, and normalization of rightventricular dysfunction (Table 16); and (2) trends to-ward improved clinical outcomes in subgroups of pa-tients with hemodynamic compromise. However, de-laying thrombolytic therapy until patients with PE arepressor dependent is detrimental because prolongedinadequate tissue perfusion can cause irreversible mul-tisystem organ failure. Consequently, selection of pa-tients with PE to receive thrombolytic therapy requiresrapid and accurate risk stratification of the competingrisks of death from PE and of bleeding.

The risk of death is very high in the presence ofsustained hypotension and cardiogenic shock.280,281

However, such patients are rare, accounting forapproximately 5% of patients with a diagnosis ofPE.280,281

In the presence of normal systemic arterial pressure,prognostication depends on the following: (1) clinicalevaluation,281 (2) cardiac biomarkers such as tropo-nin,282–286 and (3) assessment of right ventricular sizeand function.280,283,285,287–289 Clinical evaluation beginswith general appearance, BP, heart rate, respiratoryrate, temperature, and pulse oximetry. The next step isphysical examination to detect findings of right ventric-ular dysfunction such as distended jugular veins, asystolic murmur of tricuspid regurgitation, or an accen-tuated P2. Clues on the ECG include right-bundle-branch block, SIQIIITIII, and T wave inversion in leadsV1 through V4. Elevation of cardiac troponins indicatesright ventricular microinfarction; echocardiographymay show right ventricular hypokinesis; both are inde-pendent risk factors for early mortality and are associ-ated with a worse outcome when they occur togeth-er.282–286 Right ventricular enlargement on the CTpulmonary angiogram, defined as a right ventriculardiameter � 90% than the left ventricular diameter,appears to be an independent risk factor for death andnonfatal clinical complications.280,288

Among patients without hemodynamic compromise,poor prognostic indicators include the following: (1)patients who appear ill, with marked dyspnea, anxiety,and low oxygen satuartion; (2) elevated troponin, indi-cating right ventricular microinfarction; (3) right ven-tricular dysfunction on echocardiography; and (4) rightventricular enlargement on chest CT. These sick pa-tients are at high risk for an adverse outcome and mayderive benefit from thrombolytic therapy, even if theyinitially maintain systemic arterial pressure. Conse-quently, in distinction to the last version of theseguidelines that generally discouraged treatment of PEwith thrombolytic therapy unless there was hemody-namic compromize, we suggest administration ofthrombolytic therapy in selected high-risk patientswithout hypotension who are judged to have a low riskof bleeding.

Assessment of bleeding risk with thrombolytictherapy is similar in patients with PE and withacute ST-segment elevation myocardial infarc-tion.290,291 Major contraindications to thrombolytictherapy include intracranial disease, uncontrolledhypertension at presentation, and recent majorsurgery or trauma.291

Because of the inadequacy of currently availabledata, further studies are required to determine therisk and benefits of thrombolytic therapy in patientswith severe PE who do not have hemodynamiccompromise. In 2007, a European trial began enroll-ing patients with submassive PE who had preservedsystolic BP, elevated troponin levels, and right ven-




Tab

le15

—R

CT

sof

Init

ial

Tre

atm

ent

ofA

cute

PE

:C

lini

cal

Des

crip

tion

and

Res

ult

s(S

ecti

on4.

1.1)

*

Aut

hor/

yrIn

terv

entio

nsPa

tient

sA

naly

zed,

No.

/Tot

alL

engt

hof

Fol

low

-up

Rec

urre

ntD

VT

and

PE,

No.

/Tot

alM

ajor

Ble

edin

g,N

o./T

otal

Tot

alM

orta

lity,

No.

/Tot

alC

omm

ents

Ant

icoa

gula

tion

vsno

anti

coag

ulat

ion

Bar

ritt

and

Jord

an1 /

1960

UF

Hat

10,0

00U

IVq6

hfo

r1.

5d

and

nico

umal

one

adju

sted

topr

othr

ombi

ntim

efo

r14

d

Unt

reat

edco

ntro

ls

16/1

6

19/1

9

App

roxi

mat

ely

14d

Rec

urre

ntPE In

t:0/

16C

ontr

:10/

16R

R,0

.05

(95%

CI,

0.00

–0.7

5)

Fat

alPE

Int:

0/16

Con

tr:5

/19

RR

,0.1

1(9

5%C

I,0.

01–1

.80)

NR (1

/16

fata

lble

eds)

NR (0

/19

fata

lble

eds)

Int:

1/16

Con

tr:5

/19

RR

,0.3

2(9

5%C

I,0.

06–1

.73)

Popu

latio

n:cl

inic

aldi

agno

sis

ofac

ute

PE(r

ight

hear

tfa

ilure

,pu

lmon

ary

infa

rctio

n)

LM

WH

vsU

FH

Pere

zde

Lla

noet

al25

7 /200

3E

noxa

pari

nat

1m

g/kg

SCbi

d

UF

Hat

5,00

0IU

follo

wed

byin

fusi

onof

appr

oxim

atel

y35

,000

IU/2

4h

Eno

xapa

rin:

29/2

9U

FH

:21

/21

6m

oE

noxa

pari

n:3/

29(1

0%)

UF

H:

2/21

(10%

)

RR

,1.0

9(9

5%C

I,0.

20–5

.94)

Eno

xapa

rin:

0/29

(0%

);U

FH

:0/

21(0

%)

Eno

xapa

rin:

2/29

(8%

)U

FH

:0/

21(0

%)

RR

,3.6

7(9

5%C

I,0.

19–7

2.63

)

Fou

rpa

tient

sw

ithdr

awn

and

two

unav

aila

ble

for

follo

w-u

p;al

loca

tion

grou

pno

tre

port

ed

Sim

onne

auet

al43

/19

97T

inza

pari

n:17

5IU

/kg

SCqd

UF

H:5

0IU

/kg

follo

wed

byin

fusi

onof

500

IU/k

g/24

h

LM

WH

:30

4/30

4U

FH

:30

8/30

8

90d

LM

WH

:5/

304

(2%

)

UF

H:

6/30

8(2

%)

RR

,0.8

4(9

5C

I,0.

26–2

.74)

LM

WH

:6/

304

(2.0

%);

UF

H:

8/30

8(3

%)

RR

,0.7

6(9

5%C

I,0.

27–2

.16)

LM

WH

:12

/304

(4%

)U

FH

:14

/308

(5%

)R

R,0

.87

(95%

CI,

0.41

–1.8

5)

Mey

eret

al25

6 /199

5D

alte

pari

n:12

0an

ti-X

aIU

/kg

SCbi

d

UF

H:i

nfus

ion

of50

0IU

/kg

/24

h(n

obo

lus)

LM

WH

:29

/29

UF

H:

31/3

1

3m

oL

MW

H:

0/29

(0%

)

UF

H:

0/31

(0%

)

LM

WH

:0/

29(0

%)

UF

H:

0/31

(0%

)

LM

WH

:1/

29(3

%)

UF

H:

1/31

(3%

)

RR

,1.0

7(9

5%C

I,0.

07–1

6.31

)

Dal

tepa

rin

dose

ishi

gher

than

iscu

rren

tlyre

com

men

ded




Tab

le15

—C

onti

nued

Aut

hor/

yrIn

terv

entio

nsPa

tient

sA

naly

zed,

No.

/Tot

alL

engt

hof

Fol

low

-up

Rec

urre

ntD

VT

and

PE,

No.

/Tot

alM

ajor

Ble

edin

g,N

o./T

otal

Tot

alM

orta

lity,

No.

/Tot

alC

omm

ents

The

ryet

al25

8 /199

2G

roup

1:U

FH

at50

IU/k

gfo

llow

edby

infu

sion

of60

0IU

/kg/

24h

Gro

up2:

nadr

opar

inat

appr

oxim

atel

y16

0IU

/kg

SCbi

d

Gro

up3:

nadr

opar

in,a

ppro

xim

atel

y24

0IU

/kg

SCtid

Gro

up4:

nadr

opar

in,a

ppro

xim

atel

y36

0IU

/kg

SCtid

Gro

up1:

33/3

3

Gro

up2:

35/3

5

Gro

up3:

26/2

6

Gro

up4:

0/7

14d

Gro

up1:

0/33

(0%

)

Gro

up2:

0/35

(0%

);

Gro

up3:

0/26

(0%

);

Gro

up4:

0/7

(0%

)

Gro

up1:

2/33

(6%

);

Gro

up2:

0/35

(0%

)R

R,0

.19

(95%

CI,

0.01

–3.7

9)G

roup

3:5/

26(1

9%)

RR

,3.1

7(9

5%C

I,0.

67–1

5.06

)G

roup

4:4/

7(5

7%)

RR

,9.4

3(9

5%C

I,2.

13–4

1.78

)

Gro

up1:

1/33

(3)

Gro

up2:

1/35

(3)

RR

,0.9

4(9

5%C

I,0.

06–1

4.47

)G

roup

3:0/

26(0

%)

RR

,0.4

2(9

5%C

I,0.

02–9

.90)

;G

roup

4:1/

7(1

4%)

RR

,4.7

1(9

5%C

I,0.

33–6

6.67

)

Enr

ollm

ent

stop

ped

beca

use

ofbl

eedi

ngin

grou

ps3

and

4;do

ses

ingr

oups

1,3,

and

4ar

ehi

gher

than

curr

ently

reco

mm

ende

d

Fon

dapa

rinu

xvs

UF

HB

ulle

ret

al60

/20

03F

onda

pari

nux

at7.

5m

g(5

0-10

0kg

)or

5.0

mg

(�50

kg),

or10

.0m

g(�

100

kg)

SCda

ily

UF

Hby

IVin

fusi

onad

just

edto

APT

T

1,10

3/1,

103

1,11

0/1,

110

3m

oIn

t:43

/1,1

03C

ontr

:56/

1,11

0R

R,0

.77

(95%

CI,

0.52

–1.1

4)

Int:

14/1

,103

Con

tr:1

2/1,

110

RR

,1.1

7(9

5%C

I,0.

55–2

.53)

Int:

57/1

,103

Con

tr:4

8/1,

110

RR

,1.2

0(9

5%C

I,0.

82–1

.74)

Ave

rage

dose

ofU

FH

was

26,1

00U

onth

ese

cond

day

oftr

eatm

ent

*Int

�in

terv

entio

n;co

ntr

�co

ntro

l.T

hem

etho

dolo

gic

qual

ityde

scri

ptio

npo

rtio

nof

this

tabl

eca

nbe

foun

din

the

onlin

eve

rsio

nof

this

artic

leas

ada

tasu

pple

men

t.




Tab

le16

—R

ando

miz

edT

rial

sof

Thr

omb

olyt

icT

hera

pyvs

No

Thr

omb

olyt

icT

hera

pyfo

rA

cute

PE

:C

lini

cal

Des

crip

tion

and

Res

ult

s(S

ecti

on4.

3)*

Aut

hor/

yrIn

terv

entio

nsPa

tient

sA

naly

zed,

No.

/Tot

al(%

)L

engt

hof

Fol

low

-up

Rec

urre

ntD

VT

and

PE,N

o./T

otal

(%)

Maj

orB

leed

ing,

No.

/Tot

al(%

)T

otal

Mor

talit

y,N

o./T

otal

(%)

Com

men

ts

Stre

ptok

inas

epl

ushe

pari

nvs

hepa

rin

Tib

butt

etal

277 /1

974

Stre

ptok

inas

eat

600,

000

Uin

trap

ulm

onar

yfo

llow

edby

100,

000

Ufo

r72

h

Hep

arin

at5,

000

Uin

trap

ulm

onar

y,fo

llow

edby

2,50

0U

for

72h

Stre

ptok

inas

e:11

/13

(84.

6%)

Hep

arin

:12/

17(7

0.6%

)

72h

Stre

ptok

inas

e:0/

11

Hep

arin

:0/

12

Stre

ptok

inas

e:1/

11:(9

.1%

)

Hep

arin

:1/

12(8

.3%

)

RR

,0.9

2(9

5%C

I,0.

06–1

2.95

)

Stre

ptok

inas

e:0/

11

Hep

arin

:0/

12

All

hydr

ocor

tison

eat

100

mg

and

at60

hof

trea

tmen

t;w

arfa

rin

initi

aldo

se25

mg

for

6m

o

Seve

npa

tient

sfa

iled

toco

mpl

ete

the

trea

tmen

tre

gim

enan

dw

ere

excl

uded

from

the

anal

ysis

Patie

nts

repo

rtin

gm

ajor

blee

ding

requ

ired

abl

ood

tran

sfus

ion

Som

e6-

mo

follo

w-u

pda

taav

aila

ble

Ly

etal

275 /1

978

Stre

ptok

inas

eat

250,

000

Ufo

llow

edby

100,

000

U/h

for

72h

Hep

arin

at15

,000

Ufo

llow

edby

1,25

0U

/hfo

r7

d

Stre

ptok

inas

e:14

/14

Hep

arin

:11/

11

10d

Stre

ptok

inas

e:1/

14(7

.1%

)

Hep

arin

:2/

11(1

8.2%

)

RR

,2.5

5(9

5%C

I,0.

26–2

4.56

)

Stre

ptok

inas

e:4/

14(2

8.6%

)

Hep

arin

:2/

11(1

8.2%

)

RR

,0.6

4(9

5%C

I,0.

14–2

.86)

Stre

ptok

inas

e:1/

14(7

.1%

)

Hep

arin

:2/

11(1

8.2%

)

RR

,2.5

5(9

5%C

I,0.

26–2

4.56

)

Prim

ary

outc

ome

was

angi

ogra

phic

repe

rfus

ion

5of

the

25pa

tient

sre

ceiv

edno

nran

dom

ized

ther

apy

Dot

ter

etal

271 /1

979

Stre

ptok

inas

eat

250,

000

Ufo

llow

edby

100,

000

U/h

for

18–7

2h

Hep

arin

at1,

500

Upe

rkg

for

2–7

d

Stre

ptok

inas

e:15

/15

Hep

arin

:16/

16

In-h

ospi

tal

Stre

ptok

inas

e:0/

15

Hep

arin

:1/

16(6

.3%

)

RR

,2.8

2(9

5%C

I,0.

12–6

4.39

)

Stre

ptok

inas

e:3/

15(2

0.0%

)

Hep

arin

:4/

16(2

5.0%

)

RR

,1.2

5(9

5%C

I,0.

33–4

.68)

Stre

ptok

inas

e:1/

15(6

.7%

)

Hep

arin

:2/

16(1

2.5%

)

RR

,1.8

8(9

5%C

I,0.

19–1

8.60

)

All:

war

fari

n/V

KA

:

Prim

ary

outc

ome

was

angi

ogra

phic

repe

rfus

ion

(not

clea

rly

stat

ed)

Jerj

es-S

anch

ezet

al27

3 /199

5St

rept

okin

ase

at1,

500,

000

Uov

er1

hfo

llow

edby

abo

lus

ofhe

pari

n10

,000

Upl

usco

nsta

ntin

fusi

onof

1,00

0U

/h;h

epar

inat

10,0

00U

follo

wed

by1,

000

U/h

Hep

arin

:4/4

Stre

ptok

inas

e:4/

4

In-h

ospi

tal

Stre

ptok

inas

e:0/

40%

)

Hep

arin

:4/

4(1

00%

)

RR

.9.0

0(9

5%C

I,0.

64–1

26.8

5)

Stre

ptok

inas

e:0/

4(0

%)

Hep

arin

:0/

4(0

%)

Stre

ptok

inas

e:0/

4(0

%)

Hep

arin

:4/

4(1

00%

)

RR

,9.0

0(9

5%C

I,0.

64–1

26.8

5)

Prim

ary

outc

ome

not

stat

ed;

tria

lsto

pped

earl

yfo

rbe

nefit

;all

patie

nts

had

card

ioge

nic

shoc

kat

rand

omiz

atio

n;he

pari

n-tr

eate

dpa

tient

sap

pear

toha

vefa

iled

hepa

rin

ther

apy

befo

rera

ndom

izat

ion,

whe

reas

the

stre

ptok

inas

epa

tient

sha

dno

t




Tab

le16

—C

onti

nued

Aut

hor/

yrIn

terv

entio

nsPa

tient

sA

naly

zed,

No.

/Tot

al(%

)L

engt

hof

Fol

low

-up

Rec

urre

ntD

VT

and

PE,N

o./T

otal

(%)

Maj

orB

leed

ing,

No.

/Tot

al(%

)T

otal

Mor

talit

y,N

o./T

otal

(%)

Com

men

ts

Uro

kina

sevs

hepa

rin

UPE

TSt

udy

Gro

up26

9,27

8 /197

0U

roki

nase

:inf

usio

nof

2,00

0C

TA

U/lb

follo

wed

by2,

000

CT

AU

/lb/h

Hep

arin

:inf

usio

nof

75U

/lbfo

llow

edby

10U

/lb/h

Uro

kina

se,8

2/82

Hep

arin

:78/

78

2w

kU

roki

nase

:12

/82

(14.

6%)

Hep

arin

:15

/78

(19.

2%)

RR

,1.3

1(9

5%C

I,0.

66–2

.63)

Uro

kina

se:3

7/82

(45.

1%)

Hep

arin

:21

/78

(26.

9%)

RR

,0.6

0(9

5%C

I,0.

39–0

.92)

Uro

kina

se:6

/82

(7.3

%)

Hep

arin

:7/

78(8

.9%

)

RR

,1.2

3(9

5%C

I,0.

43–3

.49)

All:

hepa

rin

for

am

inim

umof

5d

The

maj

orbl

eedi

ngre

port

edin

clud

esm

oder

ate

plus

seve

rebl

eedi

ng

Ang

iogr

aphi

cda

tafo

llow

-up

data

avai

labl

eup

to12

mo

Mar

inie

tal

276 /1

988

Hig

hdo

se:u

roki

nase

at3,

300,

000

Uov

er12

h

Low

-dos

e:ur

okin

ase

at80

0,00

0U

over

12h

daily

for

3d

Hep

arin

at30

,000

U/d

for

7d

follo

wed

byor

alan

ticoa

gula

nts

Hig

hdo

se:u

roki

nase

:10

/10

Low

dose

:uro

kina

se:

10/1

0

Hep

arin

:10/

10

7d

Hig

hdo

se:u

roki

nase

:0/

10

Low

dose

:uro

kina

se:

0/10

Hep

arin

:0/1

0

Hig

hdo

se:u

roki

nase

:0/

10

Low

dose

:uro

kina

se:

0/10

Hep

arin

:0/1

0

Hig

hdo

se:u

roki

nase

:0/

10

Low

dose

:uro

kina

se:

0/10

Hep

arin

:0/1

0

Prim

ary

outc

ome

was

lung

scan

perf

usio

n

Thr

ombo

lysi

sar

ms

did

not

rece

ive

hepa

rin

All

patie

nts:

oral

Ant

icoa

gula

nts

cont

inue

dfo

r1

yrrt

-PA

plus

hepa

rin

vshe

pari

nD

alla

-Vol

taan

dPa

lla27

0 /199

2rt

-PA

at10

mg

follo

wed

by90

mg

over

2h

Hep

arin

at10

,000

Ufo

llow

edby

1,75

0U

/hfo

r7

to10

d

rt-P

A:2

0/20

Hep

arin

:16/

16

30d

rt-P

A:1

/20

(5.0

%)

Hep

arin

:0/1

6

RR

,2.4

3(9

5%C

I,0.

11–5

5.89

)

rt-P

A:3

/20

(15.

0%)

Hep

arin

:2/1

6(1

2.5%

)

RR

,1.2

0(9

5%C

I,0.

23–6

.34)

rt-P

A:2

/20

(10.

0%)

Hep

arin

:0/1

6

RR

,4.0

5(9

5%C

I,0.

21–7

8.76

)

Prim

ary

outc

ome

was

angi

ogra

phic

repe

rfus

ion

Gol

dhab

eret

al39

1 /19

93rt

-PA

at10

0m

gov

er2

hfo

llow

edby

hepa

rin

at1,

000

U/h

Hep

arin

at5,

000

Ufo

llow

edby

1,00

0U

/h

rt-P

A:4

6/46

Hep

arin

:55/

55

In-h

ospi

tal

14–2

1d

rt-P

A:0

/46;

Hep

arin

:5/5

5(9

.1%

)

RR

,0.1

1(9

5%C

I,0.

01–1

.91)

rt-P

A:3

/46

(6.5

%)

Hep

arin

:1/5

5(1

.8%

)

RR

,3.5

9(9

5%C

I,0.

39–3

3.33

)

rt-P

A:0

/46

Hep

arin

:2/5

53.

6%)

RR

,0.2

4(9

5%C

I,0.

01–4

.84)

Prim

ary

outc

ome

was

echo

card

iogr

aphi

cri

ght

vent

ricu

lar

func

tion

Kon

stan

tinid

eset

al27

9 /200

2rt

-PA

at10

0m

g,fo

llow

edby

alte

plas

eat

90m

gov

er2

hpl

ushe

pari

nat

1,00

0U

/h

Hep

arin

at5,

000

Ufo

llow

edby

1.00

0U

/hpl

uspl

aceb

o

rt-P

A:1

18/1

18

Hep

arin

plus

plac

ebo:

138/

138

30d

rt-P

A:4

/118

(3.4

%)

Hep

arin

plus

plac

ebo:

4/13

8(2

.9%

)

RR

,1.1

7(9

5%C

I,0.

30–4

.57)

rt-P

A:1

/118

(0.8

%)

Hep

arin

plus

plac

ebo:

5/13

8(3

.6%

)

RR

,0.2

3(9

5%C

I,0.

03–1

.97)

rt-P

A:4

/118

(3.4

%)

Hep

arin

plus

plac

ebo:

3/13

8(2

.2%

)

RR

,1.5

6(9

5%C

I,0.

36–6

.83)

Prim

ary

outc

ome

was

deat

hor

need

for

esca

latio

nof

ther

apy

(late

rde

cisi

onco

uld

bem

ade

afte

run

blin

ding

)




tricular enlargement on echocardiography. This trialwill randomize approximately 1,000 patients tothrombolysis with a bolus regimen of tenecteplaseplus heparin vs heparin alone.

In summary, there is good evidence that throm-bolytic therapy accelerates resolution of PE andresults in more rapid hemodynamic improvement.The evidence that thrombolytic therapy improvesclinical outcome is less secure. In the absence of riskfactors for bleeding, patients who are hemodynami-cally compromised are very likely to benefit, as aresick patients with major pulmonary arterial obstruc-tion, although the evidence supporting the lattergroup is indirect.

Choice of Thrombolytic Therapy Regimen

Nine randomized trials292–299 (total of 621 patients)have compared the rate of thrombus resolutionachieved with various IV thrombolytic regimens. Theseregimens included urokinase administered over 2 h 295

or 12 h292,298; streptokinase given over 2 h296, 12 h297 or24 h292; and recombinant tissue plasminogen activator(rt-PA) administered over 15 min293,299 or 2 h.42,293–299

An additional study300 compared IV with catheter-directed pulmonary arterial administration of rt-PA (50mg � 2 h). The results of these studies suggest thefollowing: (1) prolonged infusions of thrombolyticagents (eg, � 12 h) are associated with higher rates ofbleeding292,294; (2) 2-h infusions achieve more rapidclot lysis than 12- or 24- h infusions294,297,298; (3) whena high-concentration, 2-h infusion of thrombolysis isadministered, there is no clear difference in the efficacyor safety of rt-PA vs streptokinase296; (4) the relativeefficacy and safety of bolus rt-PA regimens (eg, approx-imately 50 mg in � 15 min) compared with a 2-hinfusion of 100 mg of rt-PA is uncertain293,299,301; and(5) infusion of rt-PA directly into a pulmonary artery asopposed to a peripheral vein does not acceleratethrombolysis but does cause more frequent bleeding atthe catheter insertion site (there was no attempt toinfuse rt-PA directly into, or to mechanically disrupt,the thrombus in this study from 1988).300 When a lyticagent is appropriate for PE, current evidence supportsthat thrombolytic therapy should be infused into aperipheral vein over 2 h or less. rt-PA, at a dose of 100mg over 2 h, is currently the most widely used andevaluated regimen. In patients with imminent or actualcardiac arrest, bolus infusion of thrombolytic therapy isindicated.

Initial Anticoagulant Therapy in Patients TreatedWith Thrombolytic Therapy

In the absence of a contraindication, anticoagula-tion with UFH, LMWH, or fondaparinux should not

Tab

le16

—C

onti

nued

Aut

hor/

yrIn

terv

entio

nsPa

tient

sA

naly

zed,

No.

/Tot

al(%

)L

engt

hof

Fol

low

-up

Rec

urre

ntD

VT

and

PE,N

o./T

otal

(%)

Maj

orB

leed

ing,

No.

/Tot

al(%

)T

otal

Mor

talit

y,N

o./T

otal

(%)

Com

men

ts

Lev

ine

etal

301 /1

990

rt-P

Aat

0.6

mg/

kgov

er2

min

Plac

ebo

plus

hepa

rinat

5,00

0U

follo

wed

by30

,000

U/d

rt-P

A:3

3/33

Plac

ebo:

25/2

5

10d

rt-P

A:0

/33

Plac

ebo:

0/25

rt-P

A:0

/33

Plac

ebo:

0/25

rt-P

A:1

/33

(3.0

%)

Plac

ebo:

0/25

RR

,2.2

9(9

5%C

I,0.

10–5

4.06

)

Prim

ary

outc

ome

was

lung

scan

repe

rfus

ion

PIO

PED

Inve

stig

ator

s272 /1

990

rt-P

Aat

40–8

0m

gat

1m

g/m

in

Plac

ebo

plus

hepa

rin

(dos

esde

term

ined

byph

ysic

ian)

rt-P

A:9

/9

Plac

ebo:

4/4

7d

rt-P

A:0

/9

Plac

ebo:

0/4

rt-P

A:1

/9(1

1.1%

)

Plac

ebo:

0/4

RR

,1.5

0(9

5%C

I,0.

07–3

0.59

)

rt-P

A:0

/9

Plac

ebo:

0/4

Prim

ary

outc

ome

not

stat

ed(s

eria

lang

iogr

aphi

can

dlu

ngsc

ans

wer

eas

sess

ed)

Hep

arin

dose

sw

ere

dete

rmin

edby

atte

ndin

gph

ysic

ian

inbo

thgr

oups

One

deat

hoc

curr

ed19

daf

ter

trea

tmen

t

*CT

A�

Com

mitt

eeon

Thr

ombo

lytic

Age

nts.

The

met

hodo

logi

cqu

ality

desc

ript

ion

port

ion

ofth

ista

ble

can

befo

und

inth

eon

line

vers

ion

ofth

isar

ticle

asa

data

supp

lem

ent.




be delayed until diagnostic testing for PE has beencompleted (see Section 4.1). IV UFH has been usedin conjunction with thrombolytic therapy in the trialsthat have evaluated thrombolysis for PE (Table 16).Consequently, initial anticoagulation with IV UFH isappropriate if thrombolytic therapy is being consid-ered. Different regimens of IV UFH have not beencompared in randomized trials in patients with PEwho are treated with thrombolytic therapy.

Before thrombolytic therapy is administered, IVUFH should be administered in full therapeuticdoses (eg, bolus of 80 U/kg followed by 18U/kg/hinitially [Sections 1.1 and 4.1]). During administra-tion of thrombolytic therapy, it is acceptable to eithercontinue, or suspend, the UFH infusion (these twopractices have never been compared). During a 2-hinfusion of 100 mg of tPA, US regulatory bodiesrecommend suspension of IV UFH, whereas IVUFH is continued during the tPA infusion in manyother countries. After administration of thrombolytictherapy, IV UFH should be restarted or continued.In the United States, it is recommended that theAPTT is checked immediately after completion ofthe tPA infusion and that, provided the APTT is not� 80 s, IV UFH is restarted without a bolus at thesame rate of infusion as was being used before tPAwas started. If UFH has not been suspended, theinfusion is continued at the same rate with ongoingadjustment according to APTT results.

Recommendations

4.3.1. All PE patients should undergo rapid riskstratification (Grade 1C). For patients with evi-dence of hemodynamic compromise, we recom-mend use of thrombolytic therapy unless thereare major contraindications owing to bleedingrisk (Grade 1B). Thrombolysis in these patientsshould not be delayed because irreversible car-diogenic shock may ensue. In selected high-riskpatients without hypotension who are judged tohave a low risk of bleeding, we suggest admin-istration of thrombolytic therapy (Grade 2B).The decision to use thrombolytic therapy de-pends on the clinician’s assessment of PE sever-ity, prognosis, and risk of bleeding. For themajority of patients with PE, we recommendagainst using thrombolytic therapy (Grade 1B).4.3.2. In patients with acute PE, when a throm-bolytic agent is used, we recommend that treat-ment be administered via a peripheral veinrather than placing a pulmonary artery catheterto administer treatment (Grade 1B).4.3.3. In patients with acute PE, with adminis-tration of thrombolytic therapy, we recommenduse of regimens with short infusion times (eg, a

2-h infusion) over those with prolonged infusiontimes (eg, a 24-h infusion) [Grade 1B].

4.4 Catheter Extraction or Fragmentation for theInitial Treatment of PE

Interventional catheterization techniques for massivePE include mechanical fragmentation of thrombuswith a standard pulmonary artery catheter, clot pulver-ization with a rotating basket catheter, percutaneousrheolytic thrombectomy, or pigtail rotational catheterembolectomy.302–305 Pharmacologic thrombolysis andmechanical interventions can be combined whenbleeding risk is not high. The goal of catheter extractionof thrombus is to reduce pulmonary arterial resistanceenough to reduce pulmonary artery hypertension, alle-viating right ventricular dilatation and dysfunction, andrapidly increase cardiac output. Catheter embolectomyrarely results in extraction of massive pulmonary arte-rial thrombus. More often, clot fragments are suctionedthrough the catheter or displaced distally with modestangiographic improvement.

There are no randomized trials or prospective cohortstudies that have evaluated interventional catheteriza-tion techniques for massive PE. Case series302–305 thathave included modest numbers of patients (eg, � 50)suggest that these techniques can be lifesaving.

Recommendation

4.4.1. For most patients with PE, we recom-mend against use of interventional catheteriza-tion techniques (Grade 1C). In selected highlycompromised patients who are unable to re-ceive thrombolytic therapy because of bleedingrisk, or whose critical status does not allowsufficient time for systemic thrombolytic ther-apy to be effective, we suggest use of interven-tional catheterization techniques if appropriateexpertise is available (Grade 2C).

4.5 Pulmonary Embolectomy for the InitialTreatment of PE

Emergency surgical embolectomy with cardiopul-monary bypass is another management strategy forwith massive PE.306–308 This operation is also suited foracute PE patients who require surgical excision of aright atrial thrombus or impending paradoxical arterialembolism, or closure of a patent foramen ovale. Surgi-cal embolectomy can also be performed to rescuepatients in whom thrombolysis has been unsuccessful.Outcomes are better when patients are referred beforethe onset of cardiogenic shock. At one hospital, 47patients underwent surgical embolectomy in a 4-yearperiod with a 96% survival rate.306 The procedure is




best performed on a warm, beating heart, withoutaortic cross-clamping, cardioplegia, or fibrillatory ar-rest.

Recommendation4.5.1. In selected highly compromised patientswho are unable to receive thrombolytic therapybecause of bleeding risk, or whose critical sta-tus does not allow sufficient time for systemicthrombolytic therapy to be effective, we suggestthat pulmonary embolectomy may be used ifappropriate expertise is available (Grade 2C).

4.6 Vena Caval Filters for the Initial Treatment ofPE

As previously noted in section 1.13, vena cavalfilters can be used instead of initial anticoagulanttherapy (eg, unacceptable risk of bleeding) or as anadjunct to anticoagulation in patients with acuteVTE. As for acute DVT, no randomized trials orprospective cohort studies have evaluated IVC filtersas sole therapy for acute PE (ie, without concurrentanticoagulation). As described in Section 1.13 andTable 6, the PREPIC study,29,135 which evaluatedIVC filters as an adjunct to anticoagulation in 400high-risk patients with proximal DVT, showed thatfilters reduced PE, increased DVT, and did notchange overall frequency of VTE (DVT and/or PEcombined). The PREPIC study29 included 145 pa-tients (36% of total) with symptomatic PE and 52patients (13% of total) with asymptomatic PE atenrolment in addition to proximal DVT. Multivari-able analyses did not find an association between thepresence of PE at entry and the frequency of PE at2 years; however, such an association was presentafter 8 years of follow-up.135

There is uncertainty about the risk and benefits ofinserting an IVC filter as an adjunct to anticoagulantand thrombolytic therapy in patients with massivePE. Among patients with hemodynamic compromisein the International Cooperative Pulmonary Embo-lism Registry, insertion of an IVC filter was associ-ated with a reduction of early recurrent PE anddeath.280 Epidemiologic data suggest that insertionof an IVC filter in patients who present with PE (withor without symptomatic DVT) is associated with abouta doubling of the frequency of VTE during follow-up;most of this increase is due to a higher frequency ofDVT (approximately 2.6-fold increase) rather than PE(approximately 1.3-fold increase).137

Recommendations4.6.1. For patients with PE, we recommendagainst the routine use of a vena caval filter inaddition to anticoagulants (Grade 1A).

4.6.2. In patients with acute PE, if anticoagulanttherapy is not possible because of risk of bleed-ing, we recommend placement of an IVC filter(Grade 1C).4.6.3. For patients with acute PE who have anIVC filter inserted as an alternative to antico-agulation, we recommend that they should sub-sequently receive a conventional course of an-ticoagulant therapy if the risk of bleedingresolves (Grade 1C).

5.0 Long-term Treatment of Acute PE

In the following sections, studies that were per-formed exclusively in patients with PE will be em-phasized. In addition, subgroup analyses of PE pa-tients enrolled in studies that included patients whoonly presented with symptoms of DVT will bepresented. As the findings of studies with DVTpatients are relevant to PE patients, and as thefindings of studies performed exclusively in patientswith PE have been consistent with studies thatincluded DVT patients, the recommendations forlong-term treatment of PE are the same as for DVT(see corresponding sections for treatment of DVT).

5.1 VKA for the Long-term Treatment of PE

There has been only one evaluation of duration ofVKA therapy exclusively in patients with PE. After 3months of initial treatment, patients with PE pro-voked by a temporary risk factor were randomized tostop or to receive 3 more months of therapy, andthose with unprovoked PE were randomized to stopor to receive 6 more months of therapy (WODITPE; Table 8). Consistent with studies that includedpatients who presented with DVT, extended VKAtherapy was effective while treatment was beingreceived. However, extending the duration of treat-ment beyond 3 months did not lower the rates ofrecurrence that were observed when anticoagulantswere subsequently stopped.

5.2 LMWH for the Long-term Treatment of PE

Two small studies309,310 from the same investigatorgroup have compared long-term LMWH (enoxaparin,1 mg/kg SC bid for approximately 14 days, followed by1.5 mg/kg/d SC) with long-term VKA exclusively inpatients who presented with PE. The combined resultsof these two studies are that there was a similarfrequency of recurrent VTE (enoxaparin: 4/60; VKA:1/40) and major bleeding (enoxaparin: 1/60; VKA: 2/40)with the two treatments.309 Of the 12 other studies thatcompared LMWH with VKA therapy for long termtreatment of VTE (see Section 2.3), only 2 studies211,213




included patients with PE; in these 2 studies, allpatients had cancer and 295 patients had PE (36% ofall enrolled patients; some PE may have been asymp-tomatic in one study213); subgroup analyses were notreported for the PE patients.

5.3 New Antithrombotic Agents for the Long-termTreatment of PE

Fondaparinux has not been evaluated as a long-termtreatment for VTE. As previously noted (Section 2.5),ximelagatran has been shown to markedly reduce re-current VTE (hazard ratio, 0.16) without increasingbleeding in patients with VTE who had completed 6months of initial treatment with VKAs.171 In this study,ximelagatran was noted to be equally effective in thesubgroup of 447 patients with PE (35% of total) as inthe patients with DVT alone.171 As previously noted(Section 4.2), the long-acting pentasaccharide idrapa-rinux was reported to be less effective than standardtherapy with heparins and VKA for the first 3 to 6months of treatment of PE.62 After an initial 6 monthsof treatment with either idraparinux or warfarin (48%of patients initially presented with symptomatic PE),compared with placebo, 6 months of extended therapywith idraparinux markedly reduced recurrent VTE andincreased bleeding.223

5.4 Treatment of Asymptomatic PE

Diagnosis of unexpected PE when contrast-en-hanced CT is performed for other indications hasbecome relatively common.311–314 Usually (eg, ap-proximately 80% of cases), CT has been performedto evaluate known cancer, and the prevalence ofincidental PE is higher in inpatients that in outpa-tients (eg, approximately 4% vs 1% of CTscans).311,314 When there is evidence of an unex-pected PE, the first priority is to review the CT scansto determine if the findings are convincing for acutePE. Other recent CT scans may be available forcomparison, or the current scan may also reveal DVTin the central deep veins (eg, subclavian, IVC, iliac).If there is any uncertainty about the presence ofacute PE, additional diagnostic testing is required(eg, d-dimer, ultrasonography of the deep veins,dedicated CT pulmonary angiography). When PE isdiagnosed unexpectedly in patients with cancer, theclinical history often reveals symptoms suggestive ofPE.312

Recommendations

5.1.1. For patients with PE secondary to atransient (reversible) risk factor, we recom-mend treatment with a VKA for 3 months overtreatment for shorter periods (Grade 1A).

5.1.2. For patients with unprovoked PE, werecommend treatment with a VKA for at least 3months (Grade 1A). We recommend that after 3months of anticoagulant therapy, all patientswith unprovoked PE should be evaluated forthe risk-benefit ratio of long-term therapy(Grade 1C). For patients with a first unprovokedepisode of VTE that is a PE, and in whom riskfactors for bleeding are absent and for whomgood anticoagulant monitoring is achievable,we recommend long-term treatment (Grade 1A).Values and preferences: This recommendation at-taches a relatively high value to prevention of recur-rent VTE and a lower value to the burden oflong-term anticoagulant therapy.

For patients with a second episode of unpro-voked VTE, we recommend long-term treat-ment (Grade 1A).5.1.3. For patients with PE and cancer, we recom-mend LMWH for the first 3 to 6 months oflong-term anticoagulant therapy (Grade 1A). Forthese patients, we recommend subsequent antico-agulant therapy with VKA or LMWH indefinitelyor until the cancer is resolved (Grade 1C).5.1.4. In patients who receive long-term anticoag-ulant treatment, the risk-benefit ratio of continu-ing such treatment should be reassessed in theindividual patient at periodic intervals (Grade 1C).5.1.5. In patients with PE, we recommend that thedose of VKA be adjusted to maintain a target INRof 2.5 (INR range, 2.0 to 3.0) for all treatmentdurations (Grade 1A). For patients with unpro-voked PE who have a strong preference for lessfrequent INR testing to monitor their therapy,after the first 3 months of conventional-intensityanticoagulation (INR range, 2.0 to 3.0), we rec-ommend low-intensity therapy (INR range, 1.5 to1.9) with less frequent INR monitoring over stop-ping treatment (Grade 1A). We recommendagainst high-intensity VKA therapy (INR range,3.1 to 4.0) compared with an INR range of 2.0 to3.0 (Grade 1A).5.1.6. In patients who are unexpectedly found tohave asymptomatic PE, we recommend the sameinitial and long-term anticoagulation as for com-parable patients with symptomatic PE (Grade 1C).

6.0 Chronic Thromboembolic PulmonaryHypertension

CTPH occurs much more frequently after acutePE than had previously been believed. The oldteaching was that CTPH had a prevalence of notmore than 1 in 500 cases of acute PE; however,data from prospective cohort studies indicate




the frequency is approximately 3%.315–317 Afteracute PE initiates CTPH, pulmonary vascularremodeling may cause severe pulmonary hyper-tension out of proportion to pulmonary vascularthrombosis.318

6.1 Pulmonary Thromboendarterectomy, VKA, andVena Cava Filter for the Treatment of CTPH

Primary therapy for CTPH is pulmonary throm-boendarterectomy, which, if successful, can re-duce and sometimes cure pulmonary hyperten-sion.318 The operation requires a mediansternotomy, institution of cardiopulmonary bypass,deep hypothermia with circulatory arrest periods,and exploration of both pulmonary arteries. Pul-monary thromboendarterectomy removes orga-nized thrombus by establishing an endarterectomyplane in all involved vessels. At the most experi-enced centers, the mortality rate is � 5%.318 Themost common postoperative problem is reperfu-sion pulmonary edema, generally managed withsupportive care that requires several days of me-chanical ventilation. When pulmonary thromboen-darterectomy is successful, patients can usuallyresume normal daily activities and experience agreatly improved quality of life. Management usu-ally includes insertion of a permanent vena cavafilter before or during pulmonary endarterectomyand indefinite anticoagulant therapy with a targetINR of 2.5.319 No randomized trials of CTPHtherapy have been undertaken. Patients with CTPHwho are not candidates for pulmonary endarterectomybecause of comorbid disease or surgically inaccessiblelesions may be candidates for pulmonary artery angio-plasty.320

Some patients with CTPH have predominantlydistal (ie, subsegmental) vascular involvement. Thepathophysiology of pulmonary microvascular diseaseremains uncertain but may involve release of medi-ators by endothelial cells or platelets, or plexiformlesions similar to idiopathic pulmonary hyperten-tion.321,322 It is possible that some of the medicaltherapies for idiopathic pulmonary hypertensionmight have a beneficial role in CTPH, especially inthose patients who are not surgical candidates or whohave a poor response to thrombendarterectomy dueto distal microvascular disease. Novel therapies in-clude prostacyclin analogs such as epoprostenol,beraprost, iloprost and treprostinil, endothelin re-ceptor antagonists such as bosentan, and phosphodi-esterase-5 inhibitors such as sildenafil.322–324 A co-hort study325 of 47 patients with inoperable CTPHwho were treated with bosentan therapy showedsustained functional and hemodynamic improve-ment with 96% survival after 1 year.

Recommendations

6.1.1. In selected patients with CTPH, such asthose with central disease under the care of anexperienced surgical/medical team, we recom-mend pulmonary thromboendarterectomy(Grade 1C).6.1.2. For all patients with CTPH, we recom-mend life-long treatment with a VKA targetedto an INR of 2.0 to 3.0 (Grade 1C).6.1.3. For patients with CTPH who undergopulmonary thromboendarterectomy, we sug-gest the placement of a permanent vena cavalfilter before or at the time of the procedure(Grade 2C).6.1.4. For patients with inoperable CTPH, wesuggest referral to a center with expertise inpulmonary hypertension so that patients can beevaluated for alternative treatments, such asvasodilator therapy or balloon pulmonary an-gioplasty (Grade 2C).

7.0 Superficial Vein Thrombosis

7.1 Treatment of Infusion Thrombophlebitis

Peripheral vein infusion thrombophlebitis is esti-mated to occur in 25 to 35% of hospitalized patientswho have peripheral IV catheters.326 In a three-armrandomized trial327 of 120 hospitalized patients withinfusion thrombophlebitis, diclofenac emulsion gelused topically three times daily and oral diclofenac (75mg bid) were superior to placebo in relieving localsymptoms of thrombophlebitis at 48 h, with positiveresponses in 60% in both active treatment groups vsonly 20% in the control group. Three other controlledtrials have assessed the effects of various topical gels orcreams compared with placebo for relief of symptomsor clinical resolution of SVT. The largest of thesetrials328 randomized 126 inpatients with infusionthrombophlebitis to heparin sodium gel or placebo gelthree times daily. At 7 days, phlebitis had resolved in44% of the heparin group and 26% of the placebogroup (p � 0.03). In a trial329 that included 68 patientswith spontaneous or infusion-related thrombophlebitiswho were randomized to heparinoid cream, piroxicamgel, or placebo, there were no differences amongtreatment groups in symptoms or size of affected areaat 14 days. Finally, a small trial330 of 23 patients withinfusion thrombophlebitis who were randomized totopical essaven gel (contains aescinate, phospholipids,heparin) or placebo found significant improvement inintensity of local symptoms in the group that receivedessaven. In this study, all patients were also treated withenoxaparin 0.1 mL/10 kg body weight daily (equivalentof 1 mg/kg) for 4 weeks (Table 17). No controlled trials




Table 17—Infusion Thrombophlebitis Treatment: Clinical Description and Results (Section 7.1)*

Author/yrType ofStudy† Participants Intervention‡ Outcomes§ Follow-up Results

Becherucci etal327/2000

Parallel RCT,singlecenter

120 hospitalizedpatients withinfusionthrombophlebitis

Topical diclofenacemulsion gelq8h for six doses(n � 40)

Oral diclofenac at75 mg bid forfour doses(n � 40)

Untreated controls(n � 40)

Intensity of localsymptoms (flushing,swelling, warmth,pain)

48 h Intensity of local symptoms:

Topical diclofenac:60% reduction

Oral diclofenac:60% reduction

Control: 20% reduction

(p � 0.0001 for both treatmentgroups vs control)

De Sanctis etal330/2001


23 patients withconfirmedinfusionthrombophlebitis

Topical essavengel (containsaescinate,phospholipids,heparin) oncedaily (n � 12)

Placebo gel oncedaily (n � 11)

Each administeredfor 4 wk, alongwith enoxaparin1 mg/kg for 4 wk

Temperature ofaffected area

Symptom score(based on localpain, disability, andswelling)

4 wk Temperature at 4 wk:Essaven gel: 71% of baselinePlacebo: 86% of baseline

(p � 0.05)

Symptom score at 4 wk:Essaven gel: 33% of baselinePlacebo: 80% of baseline

(p � 0.05)

Vilardell etal328/1999


126 inpatientswithsuperficialphlebitissecondary toindwellingcatheter

Heparin sodiumgel (1,000 IU/g);

Placebo gel;

Each applied tiduntil resolutionof phlebitis or7 d maximum

Resolution ofphlebitis

7 d Resolution of phlebitis:Heparin gel: 27/61 (44.3%)Placebo: 17/65 (26.1%)RR, 1.69 (95% CI, 1.03–2.78;

p � 0.03)

Note: large No. of withdrawalsdue to hospital dischargecounted as “non-resolution”

Bergqvist etal329/1990


68 patients(30 inpatientswith infusionthrombophlebitisand 38outpatientswith spontaneousthrombophlebitis)

Topical piroxicamgel (0.5%; n �22), heparinoidcream (n � 22)or placebo (n �24) applied bidfor 14 d or untilsymptomsdisappeared

Intensity of localsymptoms

Size ofthrombophlebiticarea

Pain intensityby VAS

Approximately14 d

Intensity of local symptoms:Piroxicam gel: 50% of day 0;Heparinoid cream: 60%

of day 0Control: 45% of day 0

Size of involved area:Piroxicam gel: 5.4% of day 0Heparinoid cream: 7.8% of

day 0Control: 4.6% of day 0

Pain intensity:Piroxicam gel: 8.8% of day 0;Heparinoid cream: 2.9%

of day 0Control: 5.2% of day 0(p � not significant

for all comparisons)

*The methodologic quality description portion of this table can be found in the online version of this article as a data supplement.†Study design: RCT, cohort.‡Drugs: NSAIDs, topical treatments, vs placebo, no treatment, each other, or different durations or regimens of the same agent.§Symptomatic relief, resolution of phlebitis.




have evaluated systemic anticoagulants for the treat-ment of infusion thrombophlebitis.

Recommendation

7.1.1. For patients with symptomatic infusionthrombophlebitis as a complication of IV infusion,we suggest oral diclofenac or another nonsteroi-dal antiinflammatory drug (NSAID) [Grade 2B],topical diclofenac gel (Grade 2B), or heparin gel(Grade 2B) until resolution of symptoms or for upto 2 weeks. We recommend against the use ofsystemic anticoagulation (Grade 1C).

7.2 Treatment of SVT

SVT has been less well studied than DVT but isestimated to occur more often.331,332 It commonlyaffects the lower limbs, often involves a varicosevein, is associated with chronic venous insufficiency,malignancy, thrombophilia, pregnancy or exogenousestrogens, obesity, sclerotherapy and a history ofVTE, or it may be unprovoked.331–333

Although traditionally considered a benign dis-ease, a number of studies331,332 indicate that theconsequences of SVT may be more serious and haveled to trials of more aggressive treatment with thegoals of reducing symptoms, extension, recurrence,and progression to VTE (Table 18). The treatment ofsuperficial vein thrombosis has been the subject of arecent Cochrane Collaboration systematic review.334

Short-Duration Heparin, LMWH, and NSAIDs

In a placebo-controlled trial,335 462 patients withSVT were randomly allocated to receive 8 to 12 daysof enoxaparin in two dosages (40 mg and 1.5 mg/kgSC daily, tenoxicam 20 mg po daily, or placebo).During the treatment period and at 3-month follow-up, rates of SVT extension or recurrence were 29.5%and 33.0%, respectively, in the placebo group, sig-nificantly higher than that of the other three treat-ment groups (enoxaparin 40 mg, 8.3% and 14.5%;enoxaparin 1.5 mg/kg, 5.7% and 15.1%; tenoxicam,13.1% and 15.2%). Rates of DVT tended to be lowerin the treatment groups vs the placebo group duringthe initial treatment period, but this trend was lost by3 months, predominantly due to the occurrence ofVTE in the treatment groups during the first 3 weeksafter treatment was stopped, suggesting that theinitial duration of therapy was inadequate.

In an open-label randomized trial336 of 117 pa-tients, 6-day courses of calcium nadroparin adminis-tered SC daily at doses of 6,150 anti-Xa IU or 31.5anti-Xa IU/kg were superior to naproxen (500 mgonce daily) for relief of symptoms and signs of SVT,

but there was no difference in rates of SVT extensionat the end of treatment or at 8 weeks.

Longer Courses of Heparin or LMWH

A blinded randomized trial337 compared a 30-daycourse of low- vs high-dose SC nadroparin in 164patients with SVT. During 3 months of follow-up,there were five cases of SVT extension in the low-dose group (all occurred on treatment), comparedwith two cases in the high-dose group (one occurredon treatment). There were two symptomatic DVTsin the low-dose group vs three DVTs (two symptom-atic) and one symptomatic PE (occurred on treat-ment) in the high-dose group. Lack of a controlgroup precludes assessment of whether either of thetreatments was more effective than no treatment; forexample, the rate of VTE at 3 months in the highdose group (4.8%) was similar to the 3-month rate ofVTE in the placebo group (4.5%) of the previouslydescribed STENOX trial.335

Sixty patients with acute thrombosis of the greatsaphenous vein were randomized to receive a 4-weekcourse of SC UFH in moderately high unmonitoreddoses (12,500 IU bid for 1 week, followed by 10,000 IUbid) or prophylactic doses (5,000 IU bid).338 At 6months, 6 patients (20%) in the low-dose heparingroup had VTE (three symptomatic events), of whichfour episodes occurred during treatment, comparedwith 1 patient (3.3%) in the high-dose heparin group, whohad symptomatic DVT after treatment was completed.

One trial339 found that warfarin was superior tocontrol and had similar effectiveness to low-doseUFH and LMWH with regard to rate of SVTextension at 3 months; however, no information wasprovided on dose or duration of anticoagulants. Anumber of other small trials have compared topi-cal340 or alternate anticoagulants (eg, dermatan sul-fate)341 for variable time periods to treat SVT (Table18). No trials have evaluated the role of fondaparinuxin the management of SVT.

Surgical vs Medical Therapy

A nonblinded randomized trial339 with six treatmentarms that included approximately 70 patients per groupshowed that compression alone or in addition to flushligation of the saphenous vein were inferior to completevein stripping or treatment with UFH, LMWH, orwarfarin (doses and durations of treatment were notspecified) for the end point of SVT extension at 3months. A second trial342 compared saphenofemoralligation, performed under local anesthesia, with enox-aparin 1 mg/kg bid for 1 week, and then daily for 3weeks. During 6-month follow-up, VTE occurred intwo patients (6.7%) in the surgery group (both PE) vsnone in the enoxaparin group, while SVT occurred in




one patient (3.3%) in the surgery group and threepatients (10%) in the enoxaparin group. Two patients inthe surgical group had wound infections, and the costof surgical treatment was more than three times higherthat of medical treatment. Finally, a review of sixstudies (includes a study339 described above, and fivesmall case series) comparing surgical therapy to antico-agulation for SVT showed similar rates of SVT progres-sion but higher rates of VTE and complications withsurgical therapy.343

Recommendation

7.2.1. For patients with spontaneous superficialvein thrombosis, we suggest prophylactic orintermediate doses of LMWH (Grade 2B) orintermediate doses of UFH (Grade 2B) for atleast 4 weeks. We suggest that as an alternativeto 4 weeks of LMWH or UFH, VKA (target INR,2.5; range, 2.0 to 3.0) can be overlapped with 5days of UFH and LMWH and continued for 4weeks (Grade 2C). We suggest that oral NSAIDsshould not be used in addition to anticoagula-tion (Grade 2B). We recommend medical treat-ment with anticoagulants over surgical treat-ment (Grade 1B).

Remark: It is likely that less extensive superficialvein thrombosis (ie, where the affected venous seg-ment is short in length or further from the saphe-nofemoral junction) does not require treatment withanticoagulants. It is reasonable to use oral or topicalNSAIDs for symptom control in such cases.

8.0 Acute UEDVT

Although most episodes of DVT occur in the lowerlimbs, it is estimated that 1 to 4% of cases involve theupper extremities. UEDVT can be classified into twoetiologic groups: primary (includes unprovoked with orwithout thrombophilia, effort related, and thoracicoutlet syndrome) and secondary (provoked by centralvenous catheters, pacemakers, or cancer); secondaryUEDVT accounts for 75 to 80% of all cases.344–346

UEDVT may involve the subclavian, axillary or bra-chial veins. Clinical manifestations include edema, di-lated collateral veins over the arm, neck, or chest, andlimb pain or discoloration. The disease may lead tocomplications, including pulmonary embolism (esti-mated to occur in up to one third of patients346),recurrent UEDVT (a prospective study347 reportedcumulative incidence rates of 2.0%, 4.2% and 7.7%after 1, 2, and 5 years, respectively) and PTS of thearm.347,348 The treatment of patients with acuteUEDVT may be divided into the initial treatmentphase (with anticoagulants, thrombolytic therapy, cath-eter/surgical techniques, or filter placement) and long-

term treatment (or secondary prophylaxis) with antico-agulants to prevent recurrent VTE.

8.1 IV UFH or LMWH for the Initial Treatment ofUEDVT

It is generally accepted that, as for patients withlower-limb DVT, patients with UEDVT requiretreatment with anticoagulants to prevent throm-bus extension and PE (Table 19). To date, noRCTs have evaluated UFH, LMWH, or otheranticoagulants for the initial treatment of UEDVT.Several small prospective cohort studies have re-ported low rates of recurrent DVT, PE, and majorbleeds using treatment regimens for UEDVT sim-ilar to those for patients with lower-limb DVT(Table 19). In a prospective two-center cohortstudy,349 46 outpatients with UEDVT were treatedwith SC LMWH followed by warfarin. At 3months, there was one recurrence, one majorbleed, and no episodes of PE. In 36 inpatients withUEDVT, LMWH twice daily for up to 7 daysfollowed by warfarin for an average of 5 months(target INR, 2.0 to 2.5) led to significant earlysymptom relief and no recurrent DVT or PE at 1year.350 Rates of VTE recurrence were similarlylow in a cohort of 53 patients who received UFHor LMWH for the initial treatment of UEDVTfollowed by warfarin for 3 months,347 and in 74cancer patients with central venous catheter-asso-ciated UEDVT, in whom treatment with LMWHfor 5 to 7 days followed by warfarin for 3 monthsappeared to prevent catheter failure and was notassociated with any recurrent VTE351 (Table 19).

Recommendation

8.1.1. For patients with acute UEDVT, werecommend initial treatment with therapeuticdoses of LMWH, UFH, or fondaparinux asdescribed for leg DVT (see Section 1) [Grade1C].

8.2 Thrombolytic Therapy for the Initial Treatmentof UEDVT

No randomized controlled studies have evalu-ated the efficacy and safety of thrombolytic ther-apy compared with standard anticoagulation forthe initial treatment of patients with UEDVT(Table 20). A number of retrospective and smallprospective studies92,352–358 that included 6 to 118patients have evaluated streptokinase, urokinase,or rT-PA administered with varying doses, meth-ods of administration (IV, catheter directed), andinfusion durations. Three of these studies352,356,357

included control groups that received anticoagula-




Tab

le18

—Su

perf

icia

lV

ein

Thr

omb

osis

Tre

atm

ent:

Cli

nica

lD

escr

ipti

onan

dR

esu

lts

(Sec

tion

7.2)

*

Aut

hor/

yrT

ype

ofSt

udy†

Part

icip

ants

Inte

rven

tion‡

Out

com

es§

Fol

low

-up

Res

ults

STE

NO

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Gro

up33

5 /20

03

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leng

th)

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wer

extr

emity

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xapa

rin

at40

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dSC

Eno

xapa

rin

at1.

5m

g/kg

/dSC

Ten

oxic

amat

20m

g/d

po

Plac

ebo

once

daily

All

adm

inis

tere

dfo

r8–

12d

All

patie

nts

pres

crib

edel

astic

band

ages

orco

mpr

essi

onst

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for

atle

ast

15d

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trea

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ound

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ebo:

4/11

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);PE

,0

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rin,4

0m

g:1/

110

(0.9

%);

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;RR

,0.2

5(9

5%C

I,0.

03–2

.24)

Eno

xapa

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1.5

mg/

kg:1

/106

(0.9

%);

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;RR

,0.2

6(9

5%C

I,0.

03–2

.33)

Ten

oxic

am:2

/99

(2.0

%);

PE,1

;RR

,0.5

7(9

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11–3

.02)

p�

not

signi

fican

tfo

ral

lcom

paris

ons

ofac

tive

trea

tmen

tvs

plac

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;rec

urre

nce/

exte

nsio

nda

y12

:Pl

aceb

o:33

/112

(29.

5%)

Eno

xapa

rinat

40m

g:9/

110

(8.3

%)

RR

,0.2

8(9

5%C

I,0.

14–0

.55)

Eno

xapa

rinat

1.5

mg/

kg:6

/106

(5.7

%)

RR

,0.1

9(9

5%C

I,0.

08–0

.44)

Ten

oxic

am:1

3/99

(13.

1%)

RR

,0.4

5(9

5%C

I,0.

25–0

.80)

VT

Eat

3m

o:Pl

aceb

o:5/

112

(4.5

%);

PE,0

Eno

xapa

rinat

40m

g:6/

110

(5.7

%)

PE,2

;RR

,1.2

2(9

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I,0.

38–3

.89)

Eno

xapa

rinat

1.5

mg/

kg:4

/106

(3.9

%);

PE,0

;RR

,0.8

5;95

%C

I,0.

23–3

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Ten

oxic

am:4

/99

(4.3

%);

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;RR

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1(9

5%C

I,0.

25–3

.28)

p�

not

signi

fican

tfo

ral

lcom

paris

ons

ofac

tive

trea

tmen

tvs

plac

ebo

SVT

;rec

urre

nce/

exte

nsio

nat

3m

o:Pl

aceb

o:37

/112

(33.

0%)

Eno

xapa

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g:16

/110

(14.

5%);

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,0.4

4(9

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I,0.

26–0

.74)

Eno

xapa

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1.5

mg/

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6(1

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);R

R,0

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(95%

CI,

0.27

-0.

77)

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oxic

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,0.4

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27-

0.78

)

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orbl

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Tab

le18

—C

onti

nued

Aut

hor/

yrT

ype

ofSt

udy†

Part

icip

ants

Inte

rven

tion‡

Out

com

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low

-up

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ults

Tito

net

al33

6 /199

4Pa

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mul

ticen

ter

117

patie

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with

ultr

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conf

irm

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low

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trem

ities

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fixed

dose

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150

anti-

Xa

IU/d

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31.5

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g/d

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give

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0.18

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(95%

CI,

0.51

–12.

83)

VT

E:

Hig

hdo

se:4

/83

(4.8

%;3

sym

ptom

atic

even

ts;1

�PE

�oc

curr

edw

hile

rece

ivin

gtr

eatm

ent)

Low

dose

:2/8

1(2

.5%

;bot

hsy

mpt

omat

icD

VT

)R

R,0

.51

(95%

CI,

0.10

–2.7

2)

Rat

eof

impr

ovem

ent

incl

inic

alsy

mpt

oms

and

signs

simila

rbo

thgr

oups

Maj

orbl

eed:

0D

eath

:0




Tab

le18

—C

onti

nued

Aut

hor/

yrT

ype

ofSt

udy†

Part

icip

ants

Inte

rven

tion‡

Out

com

es§

Fol

low

-up

Res

ults

Mar

chio

riet

al33

8 /20

02Pa

ralle

lRC

T,

sing

lece

nter

60pa

tient

sw

ithul

tras

ound

-co

nfir

med

first

acut

eSV

Tof

grea

ter

saph

enou

sve

in

Low

-dos

eU

FH

(5,0

00IU

SCbi

dfo

r4

wk)

Hig

h-do

seU

FH

(12,

500

IUfo

r1

wk,

then

10,0

00IU

for

3w

k)

Use

ofco

ncom

itant

syst

emic

orlo

cal

antii

nfla

mm

ator

ydr

ugs

perm

itted

,but

use

not

desc

ribe

d

VT

E

Ext

ensi

on/r

ecur

renc

eof

thro

mbo

sis

Maj

orbl

eed

Hep

arin

-indu

ced

thro

mbo

cyto

peni

a

Dea

th

6m

oV

TE

duri

ngtr

eatm

ent

peri

od:

Low

dose

:4/3

0(1

3.3%

;3as

ympt

omat

icD

VT

,1PE

)H

igh

dose

:0/3

0(0

%);

RR

,0.1

1(9

5%C

I,0.

01–1

.98;

p�

not

sign

ifica

nt)

Ext

ensi

on/r

ecur

renc

eSV

Tdu

ring

trea

tmen

tpe

riod

Low

dose

:7/3

0(2

3.3%

)H

igh

dose

:3/3

0(1

0%);

RR

,0.4

0(9

5%C

I,0.

11–1

.40;

p�

not

sign

ifica

nt)

Ove

rall

VT

Edu

ring

follo

w-u

ppe

riod

:L

owdo

se:6

/30

(20%

)H

igh

dose

:1/3

0(3

.3%

),R

R,0

.17

(95%

CI,

0.02

–1.3

0;p

�no

tsi

gnifi

cant

)O

vera

llex

tens

ion/

recu

rren

ceSV

Tdu

ring

follo

w-u

ppe

riod

:L

owdo

se:1

1/30

(36.

7%)

Hig

hdo

se:8

/30

(26.

7%)

RR

,0.7

3(9

5%C

I,0.

34–1

.55;

p�

not

sign

ifica

nt)

No

maj

orbl

eed,

hepa

rin-

indu

ced

thro

mbo

cyto

peni

a,or

deat

hin

any

grou

pB

elca

roet

al33

9 /19

99Pa

ralle

lRC

T,

mul

ticen

ter

562

patie

nts

with

ultr

asou

nd-

conf

irm

edSV

Tan

dla

rge

vari

cose

vein

sor

veno

usin

com

pete

nce

Gro

upA

:ela

stic

com

pres

sion

stoc

king

sal

one

Gro

upB

:ela

stic

com

pres

sion

stoc

king

san

dsi

mpl

eflu

shlig

atio

nG

roup

C:e

last

icco

mpr

essi

onst

ocki

ngs

and

com

plet

est

ripp

ing

and

perf

orat

orlig

atio

nG

roup

D:e

last

icco

mpr

essi

onst

ocki

ngs

and

low

-dos

eSC

hepa

rin

Gro

upE

:ela

stic

com

pres

sion

stoc

king

san

dL

MW

HG

roup

F:e

last

icco

mpr

essi

onst

ocki

ngs

and

VK

AD

oses

and

dura

tion

ofan

ticoa

gula

nts

not

spec

ified

Ext

ensi

onof

SVT

at3

mo

Ext

ensi

onof

SVT

at6

mo

New

DV

Tat

3m

o

6m

oE

xten

sion

ofth

rom

bus

at3

mo:

Gro

upA

:32/

78(4

1%)

Gro

upB

:11/

78(1

4.1%

);R

R,0

.34

(95%

CI,

0.19

–0.6

3)G

roup

C:0

/70;

RR

,0.0

2(9

5%C

I,0.

00–0

.27)

Gro

upD

:4/7

1(5

.6%

);R

R,0

.14

(95%

CI,

0.05

–0.3

7)G

roup

E:4

/76

(5.2

%);

RR

,0.1

3(9

5%C

I,0.

05–0

.35)

Gro

upF

:5/7

1(7

.0%

);R

R,0

.17

(95%

CI,

0.07

–0.4

2;p

�0.

05fo

rgr

oups

C,D

,E,a

ndF

vsgr

oups

Aor

B

Ext

ensi

onat

6m

o:G

roup

A:1

3/78

(16.

7%)

Gro

upB

:6/7

8(7

.7%

);R

R,0

.46

(95%

CI,

0.18

–1.1

5)G

roup

C:1

/70

(1.4

%);

RR

,0.0

9(9

5%C

I,0.

01–0

.64)

Gro

upD

:2/7

1(2

.8%

);R

R,0

.17

(95%

CI,

0.04

–0.7

2)G

roup

E:1

/76

(1.3

%);

RR

,0.0

8(95

%C

I,0.

01–0

.59)

Gro

upF

:5/7

1(7

%);

RR

,0.4

2(9

5%C

I,0.

16–1

.13

Pva

lue

not

stat

ed

New

DV

Tat

3m

o:G

roup

A:6

/78

(7.7

%)

Gro

upB

:2/7

8(2

.5%

);R

R,0

.33

(95%

CI,

0.07

–1.6

0)G

roup

C:2

/70

(2.8

%);

RR

.0.3

7(9

5%C

I,0.

08–1

.78)

Gro

upD

:0/7

1(0

%);

RR

,0.0

8(9

5%C

I,0.

0–1.

47)

Gro

upE

:0/7

6(0

%);

RR

,0.0

8(9

5%C

I,0.

0–1.

38)

Gro

upF

:0/7

1(0

%);

RR

,0.0

8(9

5%C

I,0.

0–1.

47)

P�

not

sign

ifica

nt




Tab

le18

—C

onti

nued

Aut

hor/

yrT

ype

ofSt

udy†

Part

icip

ants

Inte

rven

tion‡

Out

com

es§

Fol

low

-up

Res

ults

Loz

ano

and

Alm

azan

342 /

2003

Para

llelR

CT

,si

ngle

cent

er60

patie

nts

with

ultr

asou

nd-

conf

irm

edab

ove-

knee

inte

rnal

saph

enou

sSV

T

Saph

enof

emor

aldi

scon

nect

ion

unde

rlo

cal

anes

thes

iaw

ithsh

ort-

term

use

ofa

com

pres

sion

band

age

Out

patie

nten

oxap

arin

at1

mg/

kgbi

dfo

r1

wk

and

then

once

daily

for

3w

k

No

plac

ebo/

cont

rolg

roup

All

patie

nts

wer

ein

stru

cted

tow

ear

elas

ticco

mpr

essi

onst

ocki

ngs

and

used

acet

amin

ophe

nfo

rpa

in

Rec

urre

nce/

exte

nsio

nof

SVT

VT

E

Com

plic

atio

nsof

surg

ery

Maj

orbl

eed

Dea

th

Cos

ts

6m

oR

ecur

rent

SVT

:Su

rgic

algr

oup:

1/30

(3.3

%)

Eno

xapa

rin

grou

p:3/

30(1

0%)

RR

,3.0

(95%

CI,

0.33

–27.

24)

VT

E:S

urgi

calg

roup

:2/3

0(6

.7%

;bot

hsy

mpt

omat

icPE

)E

noxa

pari

ngr

oup:

0/30

(0%

)R

R,0

.20;

95%

CI,

0.01

–4.0

Wou

ndin

fect

ions

:Su

rgic

algr

oup:

2/30

(6.7

%)

Maj

orbl

eedi

ng:0

Dea

th:0

Cos

tof

trea

tmen

t:Su

rgic

algr

oup:

$1,4

00pe

rpa

tient

;mea

n1.

6d

inho

spita

lE

noxa

pari

ngr

oup:

$300

per

patie

nt;0

din

hosp

ital

Sulli

van

etal

343 /

2001

Syst

emat

icre

view

ofsi

xst

udie

s(in

clud

esB

elca

ro33

9

abov

ean

dfiv

esm

allc

ase

seri

es)

Patie

nts

with

obje

ctiv

ely

conf

irm

edab

ove-

knee

SVT

Lig

atio

nof

grea

ter

saph

enou

sve

inat

saph

enof

emor

alju

nctio

n,w

ithor

with

out

vein

stri

ppin

g(n

�24

6)

Ant

icoa

gula

tion

(IV

hepa

rin

follo

wed

byV

KA

for

6w

k-6

mo;

n�

88)

SVT

prog

ress

ion

DV

T

PE Surg

ical

com

plic

atio

ns

Ble

edin

gco

mpl

icat

ions

Surg

ical

grou

p:4–

6m

o

Med

ical

grou

p:6

dto

14m

o

SVT

prog

ress

ion:

Surg

ical

grou

p:18

/148

(12%

)M

edic

algr

oup:

10/7

1(1

4%)

RR

,0.1

6(9

5%C

I,0.

56–2

.38)

DV

TSu

rgic

algr

oup:

7/20

4(3

.4%

)M

edic

algr

oup:

2/88

(2.2

%)

RR

,0.6

6(9

5%C

I,0.

14–3

.13)

PE Surg

ical

grou

p:2/

98(2

.0%

)M

edic

algr

oup:

0/17

(0%

)R

R,1

.10

(95%

CI,

0.06

–21.

98)

Surg

ical

com

plic

atio

ns:6

/78

(7.7

%;h

emat

oma,

sero

ma,

infe

ctio

n)

Ble

edin

gco

mpl

icat

ions

:0/1

7(0

%)




Tab

le18

—C

onti

nued

Aut

hor/

yrT

ype

ofSt

udy†

Part

icip

ants

Inte

rven

tion‡

Out

com

es§

Fol

low

-up

Res

ults

Gor

skie

tal

340 /

2005

Para

llelR

CT

,m

ultic

ente

r46

patie

nts

with

ultr

asou

nd-

conf

irm

edSV

T

Top

ical

lipos

omal

hepa

rin

spra

yge

l(fo

ursp

rays

of45

8IU

tid)

Eno

xapa

rin

at40

mg

SCqd

Tre

atm

ent

for

7–14

d

Pain

byV

AS

(0–1

0sc

ale)

Are

aof

eryt

hem

a

Subj

ectiv

eef

ficac

yas

sess

men

tby

inve

stig

ator

and

patie

nt

Dup

lex

asse

ssm

ent

for

thro

mbu

sre

gres

sion

day

21

DV

T

Adv

erse

even

ts

Dea

th

21d

Dat

aex

trap

olat

edfr

omgr

aphs

and

figur

esin

pape

rby

revi

ewer

Pain

byV

AS

day

21T

opic

alhe

pari

n,0

LM

WH

,0Im

prov

emen

tno

ted

atea

chtim

epo

int;

nopa

inat

21d,

nosi

gnifi

cant

diff

eren

cebe

twee

ngr

oups

Are

aof

eryt

hem

a:Im

prov

emen

tno

ted

atea

chtim

epo

int;

noer

ythe

ma

at21

d,no

sign

ifica

ntdi

ffer

ence

betw

een

grou

psSu

bjec

tive

effic

acy

asse

ssed

Maj

ority

ofpa

tient

s(�

75%

)re

port

edgo

odor

very

good

trea

tmen

tef

ficac

y;no

sign

igic

ant

diff

eren

cebe

twee

ngr

oups

Thr

ombu

sre

gres

sion

Top

ical

hepa

rin:

10/2

1(4

7.6%

)L

MW

H:9

/23

(39.

1%)

RR

,0.8

2(9

5%C

I,0.

42–1

.62)

DV

TT

opic

alhe

pari

n:3/

21(1

4.3%

)L

MW

Hhe

pari

n:1/

23(4

.3%

)R

R,0

.30

(95%

CI,

0.03

–2.7

0)

Adv

erse

even

tsA

llerg

icre

actio

nin

one

patie

ntin

enox

apar

ingr

oup

Dea

th:0

And

reoz

ziet

al34

1 /199

6Pa

ralle

lRC

T,

mul

ticen

ter

56pa

tient

sw

ithSV

Tof

the

low

erlim

bs

Gro

upA

:der

mat

ansu

lfate

at10

0m

gSQ

qdG

roup

B:d

erm

atan

sulfa

teat

100

mg

SQbi

dG

roup

C:d

erm

atan

sulfa

teat

200

mg

IMqd

Tre

atm

ent

for

30d

Pain

Incr

ease

infu

nctio

nal

abili

ty

Loc

aled

ema

30d

Dat

aex

trap

olat

edfr

omgr

aphs

and

figur

esin

pape

rby

revi

ewer

Res

olut

ion

ofpa

in,d

ay30

:G

roup

A:4

7%G

roup

B:8

3%G

roup

C:7

9%(p

valu

eno

tst

ated

)In

crea

sein

abili

tyto

perf

orm

norm

alda

ilyac

tiviti

es:d

ay30

Gro

upA

:44%

Gro

upB

:67%

Gro

upC

:84%

(p�

0.05

;gro

ups

Ban

dC

vsgr

oup

A)

Loc

aled

ema:

day

30:

Prog

ress

ive

impr

ovem

ent

inal

lthr

eegr

oups

;no

sign

ifica

ntdi

ffer

ence

sbe

twee

ngr

oups

*The

met

hodo

logi

cqu

ality

desc

ript

ion

port

ion

ofth

ista

ble

can

befo

und

inth

eon

line

vers

ion

ofth

isar

ticle

asa

data

supp

lem

ent.

†Stu

dyde

sign

:RC

T,c

ohor

t2.

‡Dru

gs:V

KA

,UF

H,L

MW

H,N

SAID

s,as

piri

n,to

pica

ltre

atm

ents

,sur

gery

vspl

aceb

o,no

trea

tmen

t,ea

chot

her

ordi

ffer

ent

dura

tions

orre

gim

ens

ofth

esa

me

agen

t.§O

utco

mes

:ext

ensi

onof

thro

mbu

s,sy

mpt

omat

icre

lief,

DV

Tan

dPE

,maj

orbl

eedi

ng,s

urgi

calc

ompl

icat

ions

,dea

th.




tion alone. In some studies, a few patients addi-tionally had venous angioplasty354 or surgical de-compression352,354,357 (Table 20).

In the largest of the studies,357 118 consecutivepatients with UEDVT were assessed retrospec-tively. At a median of 40 months of follow-up,venous patency on ultrasound was noted in 65% ofpatients who had been treated with IV urokinasecompared with 20% of patients treated with stan-dard anticoagulants; however, the rates of recur-rent VTE were similar in the two groups and thelysis group had a 15.2% rate of bleeding, com-pared with no bleeds in the anticoagulant group, adifference that was highly statistically significant.In the largest of the prospective studies,353 among35 patients with primary UEDVT treated withCDT followed by warfarin for a mean of 5 months,the rate of ipsilateral UEDVT recurrence at 54months of follow-up was substantial at 23%.

To summarize the heterogeneous, low-to-mod-erate quality data available, some studies352,356,357

report good-to-excellent success of thrombolytictherapy in terms of early and late venous patency.However, for important clinical end points such asPE, recurrent VTE, bleeding, and PTS, it is notknown if initial thrombolytic therapy is, on bal-ance, superior or inferior to anticoagulant therapy,or whether one thrombolytic approach is better orworse than another, as no prospective, controlledcomparisons have been performed.

Recommendations

8.2.1. For most patients with acute UEDVT, werecommend against the routine use of systemicor catheter-directed thrombolytic therapy(Grade 1C).8.2.2. In selected patients with acute UEDVT(eg, those with a low risk of bleeding andsevere symptoms of recent onset), we suggestthat CDT may be used for initial treatment ifappropriate expertise and resources are avail-able (Grade 2C).

8.3 Catheter Extraction, Surgical Thrombectomy,Transluminal Angioplasty, Stent Placement, StagedApproach of Lysis Followed by Interventional orSurgical Procedure, SVC Filter Insertion, for theInitial Treatment of UEDVT.

A number of reviews359,360 have advocatedstaged, multidisciplinary approaches to the man-agement of primary UEDVT that involve throm-bolysis and angioplasty or stent placement, fol-lowed by early or late surgical decompression ofthe thoracic outlet. However, data on the efficacy

and safety of these approaches are limited andderived from small, uncontrolled, prospec-tive361–363 or retrospective364 –372 case series, mostsingle-center (Table 21). In studies where resultswere reported separately for surgical and nonsur-gical approaches, surgery with or without lysistended to achieved higher late rates of vein pa-tency and lower rates of PTS than lysis alone.361,367

Among studies that only reported results for sur-gical treatment, rates of PTS ranged from 15 to50%,366,368,370,373 which are similar to rates reportedafter medical therapy alone.347,348 Most studies did notprovide data on surgical complications; however, onesmall prospective study362 reported a 26% rate ofserious postoperative complications.

SVC filters have been used in small series ofpatients with contraindications to or failure ofanticoagulant therapy.363,364 In a prospectivestudy363 of 41 patients with UEDVT who had SVCfilters placed, the rates of PE and PTS duringlong-term follow-up were 2.4% and 0%, respec-tively. In a retrospective series364 of 72 patientswith SVC filters, there were no episodes of PE orSVC thrombosis during long-term follow-up.

Recommendations

8.3.1. For most patients with acute UEDVT, werecommend against the routine use of catheterextraction, surgical thrombectomy, translumi-nal angioplasty, stent placement, staged ap-proach of lysis followed by interventional orsurgical procedure, or SVC filter placement(Grade 1C).8.3.2. In selected patients with acute UEDVT(eg, those with primary UEDVT and failure ofanticoagulant or thrombolytic treatment whohave severe persistent symptoms), we suggestthat catheter extraction, surgical thrombec-tomy, transluminal angioplasty, or a staged ap-proach of lysis followed by a vascular interven-tional or surgical procedure may be used ifappropriate expertise and resources are avail-able (all Grade 2C).8.3.3. In selected patients with acute UEDVT (eg,those in whom anticoagulant treatment is contra-indicated and there is clear evidence of DVTprogression or clinically significant PE), we sug-gest placement of an SVC filter (Grade 2C).

8.4 Anticoagulants for the Long-term Treatment ofUEDVT

There are no randomized studies of duration orintensity of long-term anticoagulation for the preven-tion of recurrent VTE in patients with UEDVT (Table




22). There is general agreement that, as for patientswith lower-extremity DVT, patients with symptomaticacute DVT of the upper extremity require long-termtreatment with anticoagulants following initialtreatment, and that a similar process as for lower-extremity DVT should be used to determine theoptimal duration of anticoagulation.374 –377 How-ever, there is little evidence to support indefiniteanticoagulant therapy for a first unprovokedUEDVT.

In prospective cohort studies346,349–351,378 of thetreatment of UEDVT, patients received VKA (targetINR, 2.5; range, 2.0 to 3.0) for periods of 3 to 6 monthsor longer. Similar regimens were reported in retrospec-tive studies.373,379–383 Rates of recurrent VTE, bleed-ing, PTS, and death reported during long-term fol-low-up in these studies are shown in Table 22. No dataare available regarding the long-term use of LMWHmonotherapy or newer anticoagulants, such asfondaparinux, for the long-term treatment of UEDVT.

Table 19—Initial Treatment of Acute UEDVT With IV UFH or LMWH: Clinical Description and Results (Section 8.1)*

Author/yr Type of Study† Participants Intervention‡ Outcomes§ Follow-up Results

Savage et al349/1999

Prospective cohort,two center

46 outpatientswith UEDVT(includes 16patients withcentral venouscatheter)

Dalteparin daily for5–7 d (200 IU/kg)and VKA withtarget INR of2.0–3.0

Duration of VKA notprovided

Symptomaticrecurrence/extension of DVT

PEMajor bleedDeath

3 mo Recurrence/extensionDVT: 1/46 (2%)

PE: 0/46Major bleed: 1/46 (2%;

on VKA)Death: 7/46 (15%; none

from PE or bleed)

Karabay et al350/2003

Prospective cohort,single center

36 inpatientswith UEDVT(includes 13with centralvenous catheter)

Nadroparin SC bid,86 aXa IU/kg forup to 7 d, thenVKA (started onday 3; target INR,2–2.5) for meanof 4.7 mo

Symptom reliefLysis of thrombus

on ultrasoundRecurrent DVTPEDeath

1 yr Significant symptomrelief: day 7: 32/36(89%)

Lysis: day 10� 35%: 16/36 (45%)� 35%: 17/36 (47%)none: 3/36 (8%)

Recurrent DVT: 0/36PE: 0/36Death: 9/36 (25%);

none due toPE or bleed

Prandoni et al229/2004

Prospective cohort,number ofcenters notstated

53 patients withfirst UEDVT(included 6 withcentral venouscatheter)

Therapeutic doseheparin (81%received UFH,19% receivedLMWH) thenVKA (median,3 mo)

Recurrent VTEDeath

Median,48 mo

Results not presentedaccording to initialtreatment withUFH vs LMWH

Recurrent VTE: 3/53(5.7%; 2 arm, 1 leg);cumulative incidence1 yr, 2 yr, and 5 yr:2.0%, 4.2%, 7.7%

Death: 11/53 (20.8%);due to cancer, PE,congestive heartfailure (numbersnot provided)

Kovacs et al351/2007

Prospective cohort,multicenter

74 cancer patientswith confirmedUEDVT (allhad centralvenous catheter)

Dalteparin daily for5–7 d (200 IU/kg)and VKA toachieve targetINR of 2.0–3.0

Recurrent VTEPEMajor bleedDeathCatheter failure due

to DVT or inabilityto infuse

3 mo Recurrent VTE: 0/74PE: 0/74Major bleed: 3/74 (4%)Death: 7/74 (6 cancer,

1 major bleed)Catheter failure due to

DVT or inability toinfuse: 0/74

*The methodologic quality description portion of this table can be found in the online version of this article as a data supplement.†Prospective cohort studies.‡Drugs: IV UFH or LMWH followed by oral anticoagulants.§Recurrent DVT and PE, major bleeding, total mortality, early symptom relief.




Tab

le20

—In

itia

lT

reat

men

tof

Acu

teU

ED

VT

Wit

hT

hrom

bol

ytic

The

rapy

:C

lini

cal

Des

crip

tion

and

Res

ult

s(S

ecti

on8.

2)*

Aut

hor/

yrT

ype

ofSt

udy†

Part

icip

ants

Inte

rven

tion‡

Out

com

es§

Fol

low

-up

Res

ults

Abu

Rah

ma

etal

352 /

1996

Ret

rosp

ectiv

eca

sese

ries

,sin

gle

cent

er

19pa

tient

sw

ithU

ED

VT

(13

prim

ary,

6ce

ntra

lve

nous

cath

eter

rela

ted)

Adj

uste

dIV

hepa

rin

then

VK

Afo

r3–

12m

o(n

�9)

Uro

kina

seat

4,50

0U

/kg

load

,th

en4,

500

U/k

g/h

for

24–4

8h

orst

rept

okin

ase

250,

000U

then

100,

000U

/hfo

r48

hpl

usIV

hepa

rin

plus

VK

A(n

�10

)T

hree

patie

nts

also

had

first

rib

rese

ctio

n

Ble

edw

ithin

itial

trea

tmen

tV

ein

pate

ncy

onul

tras

ound

atfin

alfo

llow

-up

Clin

ical

reso

lutio

nat

final

follo

w-u

p

Mea

n,36

mo

Ble

ed:0

/19

Vei

npa

tent

:A

ntic

oagu

latio

ngr

oup:

2/9

(22.

2%)

Lys

isgr

oup:

8/10

(80%

)p

�0.

018

Com

plet

ecl

inic

alre

solu

tion:

Ant

icoa

gula

tion

grou

p:2/

9(2

2.2%

)L

ysis

grou

p:8/

10(8

0%)

Pegi

set

al35

5 /199

7Pr

ospe

ctiv

eca

sese

ries

,sin

gle

cent

er

6pa

tient

sw

ithef

fort

-in

duce

dU

ED

VT

and

thor

acic

outle

tsy

ndro

me

Cat

hete

r-di

rect

edur

okin

ase

infu

sion

(2,5

00U

/kg

bolu

s,th

en2,

500

U/k

g/h)

and

hepa

rin

(100

U/k

gq1

2h)

duri

nga

mea

nof

64h

Imm

edia

tecl

otly

sis

(com

plet

e,pa

rtia

l,or

noly

sis)

Ble

edA

ble

tore

sum

eno

rmal

leve

lof

activ

ity

31m

o(m

ean)

Com

plet

ely

sis:

3/6

(50%

)Pa

rtia

llys

is:2

/6(3

3%)

No

lysi

s:1/

6(1

7%)

Ble

ed:0

/6A

ble

tore

sum

eus

uala

ctiv

ity:

5/6

(83%

)Pa

tient

with

noly

sis

was

the

one

not

able

tore

sum

eac

tivity

Schi

ndle

ret

al35

8 /19

99R

etro

spec

tive

case

seri

es,s

ingl

ece

nter

18ca

ncer

patie

nts

unde

rgoi

ngre

gion

alth

rom

boly

sis

for

cent

ral

veno

usca

thet

er-r

elat

edU

ED

VT

duri

nghi

gh-

dose

chem

othe

rapy

Uro

kina

seIV

infu

sion

ata

dose

of75

,000

–150

,000

U/h

for

24–9

6h,

then

adju

sted

IVhe

pari

nfo

r5–

7d

and

VK

A(t

arge

tIN

R,

2–3)

for

atle

ast

3m

o

VT

Ere

curr

ence

Ble

eddu

ring

lysi

sU

nspe

cifie

dV

TE

recu

rren

ce(a

llU

ED

VT

):4/

18(2

2.2%

)�d

ay13

,16,

48,5

4�,

allw

ithsu

bthe

rape

utic

INR

Ble

ed:4

/18

(22.

2%)

min

or;

1/18

(5.6

%)

maj

or

Petr

akis

etal

356 /

2000

Ret

rosp

ectiv

eca

sese

ries

,sin

gle

cent

er

20pa

tient

sw

ith1°

(n�

11)

and

2°(n

�9)

UE

DVT

Ant

icoa

gula

ntth

erap

y(a

djus

ted

IVhe

pari

nfo

r7

d,V

KA

toac

hiev

epr

othr

ombi

ntim

e1.

5–2

�co

ntro

lfor

6–12

mo;

n�

11)

Thr

ombo

lysi

s(u

roki

nase

at4,

500

U/k

glo

adin

gdo

se,t

hen

4,50

0U

/kg/

h,or

stre

ptok

inas

eat

250,

000

Ulo

ad,t

hen

100,

00U

/hfo

r24

–48

h,fo

llow

edby

IVhe

pari

nfo

r7

dan

dV

KA

for

3m

o(n

�9)

Vei

npa

tenc

yat

follo

w-u

pC

linic

alim

prov

emen

tin

sym

ptom

s

Ant

icoa

gula

tion

grou

p:82

mo

(mea

n)L

ysis

grou

p:52

mo

(mea

n)

Ven

ous

pate

ncy:

antic

oagu

latio

n:1/

11(9

%)

Lys

is:5

/9(5

6%)

�p�

0.04

0�C

linic

alim

prov

emen

t:an

ticoa

gula

tion:

4/11

(36%

)L

ysis

:8/9

(89%

)�p

�0.

028�

Hor

neet

al92

/200

0Pr

ospe

ctiv

eco

hort

,si

ngle

cent

er18

patie

nts

with

axill

ary

orsu

bcla

vian

DV

TC

athe

ter-

dire

cted

rt-P

A(2

mg/

cmof

thro

mbu

sto

max

imum

of20

mg)

,the

nV

KA

for

3m

o

Imm

edia

tepa

tenc

yE

stab

lishm

ent

ofan

tegr

ade

flow

Ble

edin

gev

ents

6m

oIm

med

iate

pate

ncy:

10/1

8(5

6%);

ante

grad

eflo

w:1

1/18

(61%

);bl

eeds

(all

min

or):

5/18

(28%

)

Lok

anat

han

etal

354 /

2001

Ret

rosp

ectiv

eca

sese

ries

,sin

gle

cent

er

28pa

tient

sw

ithfir

step

isod

eof

prim

ary

UE

DV

T(0

cent

ra;

veno

usca

thet

ers)

Uro

kina

sebo

lus

(ran

ge,1

0,00

0-1,

000,

000

U)

plus

cont

inuo

usin

fusi

on(5

0,00

0–24

0,00

0U

/h),

follo

wed

byIV

hepa

rin

then

VK

Afo

r3

mo

12pa

tient

sha

dan

giop

last

y;2

patie

nts

had

thor

acic

outle

tde

com

pres

sion

VT

Ere

curr

ence

PE Ble

edPT

Ssy

mpt

oms

2.9

yr(m

ean)

VT

Ere

curr

ence

:3/2

1(1

4%)

PE:1

/21

(5%

)B

leed

:0PT

S:no

ne:6

/21

(29%

)M

ild:1

3/21

(62%

)M

oder

ate:

2/21

(10%

)




Tab

le20

—C

onti

nued

Aut

hor/

yrT

ype

ofSt

udy†

Part

icip

ants

Inte

rven

tion‡

Out

com

es§

Fol

low

-up

Res

ults

Sabe

tiet

al35

7 /200

2R

etro

spec

tive

coho

rtst

udy,

sing

lece

nter

118

cons

ecut

ive

inpa

tient

sw

ithU

ED

VT

Adj

uste

dIV

hepa

rin

orL

MW

H10

0IU

/kg

bid

plus

oral

VK

Afo

r6

mo

(IN

R,2

–3)

�n�

62�

Uro

kina

seat

150,

00IU

/hfo

r24

hpl

usor

alV

KA

for

6m

o(I

NR

,2–

3)�n

�33

�3

patie

nts

also

had

first

rib

rese

ctio

n

Vei

npa

tenc

yon

ultr

asou

nd(a

sses

sed

in83

patie

nts)

Rec

urre

ntV

TE

Ble

edPT

S

Med

ian,

40m

oV

enou

spa

tenc

yra

te:

signi

fican

tlyhi

gher

inly

sisgr

oup

than

antic

oagu

latio

ngr

oup

(p�

0.01

log

rank

test

);da

tano

tpro

vide

dR

ecur

rent

VT

E:

Ant

icoa

gula

tion

grou

p:5/

62L

ysis

grou

p:2/

33,

p�

0.9

Maj

orbl

eed:

Ant

icoa

gula

tion

grou

p:0/

62;

Lys

isgr

oup:

5/33

p�

0.00

01PT

S:A

ntic

oagu

latio

ngr

oup:

6/62

;L

ysis

grou

p:3/

33p

�0.

3L

eeet

al35

3 /200

6Pr

ospe

ctiv

eca

sese

ries

,sin

gle

cent

er

35pa

tient

sw

ithpr

imar

yU

ED

VT

who

had

com

plet

ere

solu

tion

ofac

ute

sym

ptom

sw

ithC

DT

(n�

29)

orIV

hepa

rin

(n�

6)

Ora

lVK

Afo

rm

ean

of5.

2m

oR

ecur

rent

DV

T54

mo

Ipsil

ater

alre

curr

entD

VT:

8/35

(23%

)

*The

met

hodo

logi

cqu

ality

desc

ript

ion

port

ion

ofth

ista

ble

can

befo

und

inth

eon

line

vers

ion

ofth

isar

ticle

asa

data

supp

lem

ent.

†Ret

rosp

ectiv

ean

dpr

ospe

ctiv

eco

hort

stud

ies.

‡Dru

gs:t

hrom

boly

ticth

erap

y,co

mpa

red

with

diff

eren

tty

pes

ofly

ticth

erap

yor

with

antic

oagu

lant

s.§O

utco

mes

:Rec

urre

ntD

VT

and

PE,v

ein

pate

ncy,

maj

orbl

eedi

ng,t

otal

mor

talit

y,an

dPT

Sof

the

arm

.




Tab

le21

—In

itia

lT

reat

men

tof

Acu

teU

ED

VT

Wit

hC

athe

ter

Ext

ract

ion,

Surg

ical

Thr

omb

ecto

my,

Tra

nslu

min

alA

ngio

plas

ty,

Sten

tP

lace

men

t,St

aged

App

roac

hto

Lys

isF

ollo

wed

by

Inte

rven

tion

orSu

rgic

alP

roce

dure

,or

SVC

Fil

ter

Inse

rtio

n:C

lini

cal

Des

crip

tion

and

Res

ult

s(S

ecti

on8.

3)*

Aut

hor/

yrT

ype

ofSt

udy†

Part

icip

ants

Inte

rven

tion‡

Out

com

es§

Fol

low

-up

Res

ults

Mac

hled

er36

1 /19

93Pr

ospe

ctiv

eca

sese

ries

,sin

gle

cent

er

50pa

tient

sw

ithpr

imar

yU

ED

VT

Stag

edm

ultid

isci

plin

ary

appr

oach

Syst

emic

orca

thet

er-d

irec

ted

lysi

sw

ithur

okin

ase

orst

rept

okin

ase,

follo

wed

byIV

hepa

rin

and

VK

Afo

r3

mo,

with

subs

eque

ntsu

rgic

altr

eatm

ent

(tra

nsax

illar

yfir

stri

bre

sect

ion)

inca

ses

whe

rean

unde

rlyi

ngco

mpr

essi

veab

norm

ality

ofve

inre

mai

ned

orob

stru

ctio

nof

veno

usco

llate

rals

with

arm

abdu

ctio

nw

aspr

esen

t35

patie

nts

(70%

)un

derw

ent

tran

saxi

llary

first

rib

rese

ctio

n

Ble

edPT

Ssy

mpt

oms

3.1

yr(m

ean)

Ble

ed:1

/50

(occ

urre

don

VK

A)

PTS

sym

ptom

s:In

thos

ew

hoha

dsu

rger

y:N

one:

25/3

5(7

2%)

Min

imal

:5/3

5(1

4%)

Pers

iste

nt:5

/35

(14%

)

Inth

ose

who

did

not

have

surg

ery:

Non

e:6/

15(4

0%)

Min

imal

:4/1

5(2

7%)

Pers

iste

nt:5

/15

(33%

)M

alcy

nski

etal

367 /1

993

Ret

rosp

ectiv

eca

sese

ries

,sin

gle

cent

er

12pa

tient

sw

ithpr

imar

yU

ED

VT

Stag

edm

ultid

isci

plin

ary

appr

oach

Cat

hete

r-di

rect

edly

sis

(uro

kina

seor

stre

ptok

inas

e),

then

IVhe

pari

npl

usV

KA

(3–6

mo)

�n�

9�Su

rgic

alde

com

pres

sion

(fir

stri

bre

sect

ion

orsc

alen

ecto

my;

n�

8;5

ofth

ese

also

trea

ted

with

lysi

s)

Ble

edV

ein

pate

ncy

PTS

Mea

n,3

yrB

leed

:1/1

2(8

.3%

)�m

inor

�V

ein

pate

ncy:

Lys

is:(

25%

)L

ysis

plus

surg

ery:

5/5

(100

%)

Surg

ery

alon

e:3/

3(1

00%

)

PTS:

Lys

isal

one:

3/4

(75%

)L

ysis

plus

surg

ery:

0/5

(0%

)Su

rger

yal

one:

0/3

(0%

)Sa

nder

san

dC

oope

r369 /

1995

Ret

rosp

ectiv

e,si

ngle

cent

er12

patie

nts

with

acut

eor

chro

nic

UE

DV

Tor

nont

hrom

botic

subc

lavi

anve

inob

stru

ctio

n

Var

ious

surg

ical

inte

rven

tions

incl

udin

gfir

stri

bre

sect

ion,

thro

mbe

ctom

y,ve

nous

bypa

ss,v

ein

patc

han

giop

last

y,th

rom

boly

sis

All

patie

nts

rece

ived

VK

Afo

r3–

6m

o

PTS

(pai

n,sw

ellin

g)26

mo

(mea

n)PT

S:6/

12(5

0%)

Mei

eret

al36

8 /19

96R

etro

spec

tive,

sing

lece

nter

11pa

tient

sw

ithpr

imar

yU

ED

VT

Thr

ombo

lysi

sw

ithca

thet

er-d

irec

ted

urok

inas

e(2

50,0

00–5

00,0

00U

bolu

s)fo

llow

edby

infu

sion

of60

,000

–180

,000

U/h

(n�

11),

veno

usst

ent

(Wal

lste

nt)

plac

emen

tin

som

epa

tient

s(n

�8)

;all

had

IVhe

pari

nan

dV

KA

for

3m

o;fiv

epa

tient

ssu

bseq

uent

lyha

dfir

stri

bre

sect

ion

Rec

urre

ntV

TE

Sten

tco

mpl

icat

ions

PTS

sym

ptom

s

12m

oR

ecur

rent

arm

DV

Ton

veno

gram

at8–

12w

k:2/

11(1

8%)

Sten

tfr

actu

re:2

/11

(18%

)PT

S:3/

11(2

7%)

Shee

ran

etal

370 /

1997

Ret

rosp

ectiv

eca

sese

ries

,sin

gle

cent

er

14pa

tient

sw

ithpr

imar

yU

ED

VT

Stag

edm

ultid

isci

plin

ary

appr

oach

Cat

hete

r-di

rect

edur

okin

ase

(240

/000

U/h

for

4h

then

120,

000

U/h

,fol

low

edby

IVhe

pari

nan

dV

KA

for

3m

o(p

roth

rom

bin

time

1.5–

2�

cont

rol)

Mos

tpa

tient

sal

soun

derw

ent

tran

slum

inal

angi

opla

sty

(n�

5)an

dfir

stri

bre

sect

ion

(n�

8)

Ble

edPT

S24

mo

Ble

ed:0

PTS:

2/14

(14.

3%)




Tab

le21

—C

onti

nued

Aut

hor/

yrT

ype

ofSt

udy†

Part

icip

ants

Inte

rven

tion‡

Out

com

es§

Fol

low

-up

Res

ults

Lee

etal

366 /

1998

Ret

rosp

ectiv

eca

sese

ries

,sin

gle

cent

er

11pa

tient

sw

ithU

ED

VT

from

thor

acic

inle

tob

stru

ctiv

edi

seas

e

Cat

hete

r-di

rect

edly

sis

(uro

kina

se)

follo

wed

byad

just

edIV

hepa

rin

with

in5

dof

lysi

s,su

rgic

alde

com

pres

sion

,ven

ous

bypa

ssor

angi

opla

sty,

follo

wed

byV

KA

for

3–6

mo

PTS

(res

idua

lsy

mpt

oms,

limite

dfu

nctio

n)

24m

o(m

ean)

PTS:

2/11

(18.

2%)

Yilm

azet

al37

2 /20

00R

etro

spec

tive

case

seri

es,s

ingl

ece

nter

24pa

tient

sw

ithsp

onta

neou

sef

fort

thro

mbo

sis

ofth

esu

bcla

vian

vein

Stag

edm

ultid

isci

plin

ary

appr

oach

Stre

ptok

inas

eat

10,0

00U

load

ing

dose

then

10,0

00U

/hun

tilcl

otly

sis

then

UF

H(2

0,00

0U

/h)

follo

wed

byV

KA

for

3m

o6–

12w

ksla

ter,

19pa

tient

sha

dfir

stri

bre

sect

ion

Imm

edia

teou

tcom

es(n

�24

)C

lot;

lysi

sPE B

leed

Lon

g-te

rmsy

mpt

oms

(n�

13)

40m

o(m

ean)

Clo

tly

sis:

23/2

4(9

5.8%

)PE

:1/2

4(4

%)

Ble

ed(m

inor

):4/

24(1

6.7%

)Pe

rsis

tent

sym

ptom

:2/1

3(1

5%)

�all

refu

sed

rib

rese

ctio

n�

Feu

gier

etal

365 /

2001

Ret

rosp

ectiv

eca

sese

ries

,sin

gle

cent

er

10at

hlet

esw

ithex

ertio

nalU

ED

VT

Stag

edm

ultid

isci

plin

ary

appr

oach

Cat

hete

r-di

rect

edur

okin

ase

(2,5

00IU

/kg/

h)fo

r24

–72

h,fo

llow

edby

hepa

rin

and

VK

A(n

�6)

,LM

WH

and

VK

Aal

one

(n�

4);d

urat

ion

ofV

KA

not

prov

ided

All

patie

nts

subs

eque

ntly

had

surg

ical

trea

tmen

t9

d–9

mo

late

r

Pain

Abi

lity

tore

sum

esp

orts

activ

ities

Ede

ma

Dea

th

45m

o(m

ean)

Pain

:0/1

0(0

%)

Res

umpt

ion

ofac

tiviti

es:1

0/10

(100

%;w

ithin

mea

nof

71d)

Ede

ma:

3/10

(30%

)D

eath

:0/1

0(0

%)

�res

ults

not

prov

ided

byin

itial

trea

tmen

tgr

oup�

Urs

chel

and

Pate

l371 /2

003

Ret

rosp

ectiv

eca

sese

ries

406

patie

nts

with

prim

ary

UE

DV

T,

incl

udin

g22

refe

rred

for

sten

tth

rom

bosi

s

Cat

hete

r-di

rect

edly

sis

(uro

kina

seat

4,40

0U

/kg

bolu

sth

en4,

400

U/h

ortP

Aat

2m

g/h

for

8h,

then

1m

g/h

until

clot

lysi

s,fo

llow

edby

IVhe

pari

n,th

enfir

stri

bre

sect

ion)

PE Dea

thSy

mpt

oms

ofPT

S

Sten

tgr

oup:

3.5

yr;

Surg

ery

grou

p:7

yr

PE:0

Dea

th:0

PTS:

Initi

alst

ent

grou

p:5/

22(2

3%)

Surg

ery-

only

grou

p:4/

384

(1%

)Sc

hnei

der

etal

362 /2

004

Pros

pect

ive,

two-

cent

erst

udy

23pa

tient

sw

ithac

ute

subc

lavi

anve

inth

rom

bosi

s

Thr

ombo

lysi

s(n

�21

)fo

llow

edby

imm

edia

tede

com

pres

sion

surg

ery

(n�

7)or

dela

yed

surg

ical

deco

mpr

essi

onaf

ter

VK

Afo

r0.

5–7

mo

(n�

14);

antic

oagu

latio

nal

one

(n�

2)T

rans

lum

inal

angi

opla

sty

also

perf

orm

edin

16pa

tient

s

Surg

ical

com

plic

atio

nsSu

bcla

vian

vein

pate

ncy

atfo

llow

-up

Res

idua

lpai

nan

dsw

ellin

gD

eath

Mea

n,10

mo

Surg

ical

com

plic

atio

ns:

Wou

ndhe

mat

oma

requ

irin

gop

erat

ive

expl

orat

ion:

3(1

3%)

Phre

nic

nerv

edy

sfun

ctio

n:1

(4%

);Po

stop

erat

ive

subc

lavi

anre

thro

mbo

sis:

2(8

%)

Subc

lavi

anve

inpa

tenc

yat

follo

w-u

p:22

/23

(96%

)R

esid

ualp

ain

and

swel

ling:

1/23

(4%

)D

eath

:0/2

3




Recommendations

8.4.1. For patients with acute UEDVT, we rec-ommend treatment with a VKA for > 3 months(Grade 1C).

Remark: A similar process as for lower-extremityDVT (see Section 2) should be used to determinethe optimal duration of anticoagulation.8.4.2. For most patients with UEDVT in associ-ation with an indwelling central venous cathe-ter, we suggest that the catheter not be re-moved if it is functional and there is an ongoingneed for the catheter (Grade 2C).8.4.3. For patients who have UEDVT in associ-ation with an indwelling central venous cathe-ter that is removed, we do not recommend thatthe duration of long-term anticoagulant treat-ment be shortened to < 3 months (Grade 2C).

8.5 Prevention of PTS of the Arm

PTS of the arm occurs in 15 to 25% of patientsafter treated UEDVT.347,348 Upper-extremity PTS isa potentially disabling condition that adversely affectQOL, particularly if the dominant arm is involved.384

To date, no controlled studies have evaluated theeffectiveness of elastic bandages, compressionsleeves, or venoactive drugs to prevent PTS afterUEDVT.

Recommendation

8.5.1. For patients at risk for PTS after UEDVT,we do not suggest routine use of elastic com-pression or venoactive medications (Grade 2C).

8.6 Treatment of PTS of the Arm

Symptoms of PTS of the arm include swelling,heaviness, and limb fatigue with exertion.347,384 Nocontrolled studies have evaluated the effectiveness ofelastic bandages, compression sleeves (as are usedfor lymphedema), or venoactive drugs to treat PTSafter UEDVT. Anecdotal evidence suggests thatpatients with persistent arm swelling and pain mayderive symptomatic relief from elastic bandages orcompression sleeves. As these are unlikely to causeharm, they could be tried.

Recommendation

8.6.1. In patients with UEDVT who have persis-tent edema and pain, we suggest elastic ban-dages or elastic compression sleeves to reducesymptoms of PTS of the upper extremity (Grade2C).

Tab

le21

—C

onti

nued

Aut

hor/

yrT

ype

ofSt

udy†

Part

icip

ants

Inte

rven

tion‡

Out

com

es§

Fol

low

-up

Res

ults

Spen

ceet

al36

3 /19

99Pr

ospe

ctiv

eco

hort

,si

ngle

cent

er41

patie

nts

with

UE

DV

Tw

ithfa

ilure

ofor

cont

rain

dica

tion

toan

ticoa

gula

tion

(cen

tral

veno

usca

thet

erin

36pa

tient

s)

Plac

emen

tof

Gre

enfie

ld(3

3pa

tient

s),S

imon

nitin

ol(5

patie

nts)

,Ven

aT

ech

(2pa

tient

s),o

rB

ird’

sN

est

(1pa

tient

)fil

ters

PE PTS

Dea

th

Med

ian,

12w

kPE

:1/4

1(2

.4%

)at

44m

oin

apa

tient

with

acut

ele

gD

VT

;PT

S:0/

41D

eath

(sur

viva

lana

lysi

s):5

9%at

12m

o(n

one

due

toPE

)

Asc

her

etal

364 /

2000

Ret

rosp

ectiv

eca

sese

ries

,sin

gle

cent

er

72pa

tient

sw

ithU

ED

VT

(20

with

cent

ralv

enou

sca

thet

er)

inw

hom

antic

oagu

latio

nw

asco

ntra

indi

cate

d(n

�67

)or

had

faile

d(n

�5)

.

Gre

enfie

ldSV

Cfil

ter

PE SVC

thro

mbo

sis

Filt

er;c

ompl

icat

ions

Dea

th

Mea

n,7.

8m

oPE

:0SV

Cth

rom

bosi

s:0

Com

plic

atio

ns:o

nefil

ter

inco

rrec

tlydi

scha

rged

into

inno

min

ate

vein

Dea

th:3

8/72

(53%

;non

edu

eto

VT

Ecl

inic

ally

;no

auto

psie

s)

*The

met

hodo

logi

cqu

ality

desc

ript

ion

port

ion

ofth

ista

ble

can

befo

und

inth

eon

line

vers

ion

ofth

isar

ticle

asa

data

supp

lem

ent.

†Ret

rosp

ectiv

ean

dpr

ospe

ctiv

eco

hort

stud

ies.

‡Cat

hete

rex

trac

tion,

surg

ical

thro

mbe

ctom

y,tr

ansl

umin

alan

giop

last

y,st

ent

plac

emen

t,st

aged

appr

oach

ofly

sis

follo

wed

byin

terv

entio

nalo

rsu

rgic

alpr

oced

ure,

SVC

filte

r.§R

ecur

rent

DV

Tan

dPE

,maj

orbl

eedi

ng,o

pera

tive

com

plic

atio

ns,t

otal

mor

talit

y,an

dPT

Sof

the

arm

.




Tab

le22

—L

ong-

term

Tre

atm

ent

ofA

cute

UE

DV

T:

Cli

nica

lD

escr

ipti

onan

dR

esu

lts

(Sec

tion

8.4)

*

Aut

hor/

yrT

ype

ofSt

udy†

Part

icip

ants

Inte

rven

tion‡

Out

com

es§

Fol

low

-up

Res

ults

Lin

dbla

det

al38

2 /19

88R

etro

spec

tive

case

seri

es,m

ultic

ente

r12

0pa

tient

sw

ithco

nfir

med

UE

DV

T(in

clud

es29

with

cent

ralv

enou

sca

thet

er)

Hep

arin

then

VK

A(n

�59

),he

pari

nal

one

(n�

32),

notr

eatm

ent

(n�

5),V

KA

(n�

5),s

trep

toki

nase

(n�

5),o

rot

her

(n�

4)D

rug,

dose

s,du

ratio

nof

antic

oagu

latio

nno

tpr

ovid

ed

PE PTS

8yr

(mea

n)PE

:4/1

20(3

%;3

fata

l)PT

Spa

inor

disc

omfo

rt:

Mild

:29/

120

(24%

)M

oder

ate:

5/12

0(4

%)

Seve

re:0

(Res

ults

not

prov

ided

bytr

eatm

ent

grou

p)B

urih

anet

al37

9 /19

93R

etro

spec

tive

case

seri

es,s

ingl

ece

nter

52pa

tient

sw

ithco

nfir

med

UE

DV

T(in

clud

es15

with

cent

ralv

enou

sca

thet

er)

IVhe

pari

nth

enV

KA

(n�

43),

SChe

pari

n(n

�7)

,ven

ous

thro

mbe

ctom

y(n

�1)

,or

SVC

-rig

htat

rial

bypa

ss(n

�1)

Dru

gdo

ses

not

prov

ided

;dur

atio

nof

antic

oagu

latio

n,6

mo

PE Dea

thPT

S

6m

oPE

:2/5

2(4

%)

Dea

th:9

/52

(17%

)PT

S:Sy

mpt

omfr

ee:2

1/52

(40%

)M

inim

aled

ema:

11/5

2(2

1%)

Sym

ptom

atic

edem

a:7/

52(1

3%)

�Res

ults

not

prov

ided

bytr

eatm

ent

grou

p�H

ingo

rani

etal

380 /

1997

Ret

rosp

ectiv

eco

hort

stud

y,si

ngle

cent

er17

0pa

tient

sw

ithU

ED

VT

(97

with

cent

ralv

enou

sca

thet

er)

Adj

uste

dIV

hepa

rin

then

VK

Afo

r3–

6m

o(t

arge

tIN

R,2

–3;n

�87

)SV

Cfil

ter

(n�

23)

Thr

ombo

lysi

spl

usop

erat

ive

deco

mpr

essi

onof

thor

acic

outle

tsy

ndro

me

(n�

2)N

oan

ticoa

gula

ntth

erap

y(n

�58

)

Rec

urre

ntV

TE

Dea

thPT

S(s

igni

fican

tsw

ellin

g)

Mea

n,13

mo

Rec

urre

ntV

TE

:2/1

70(1

.2%

)D

eath

;1-

mo

mor

talit

y:25

/170

(15%

)3-

mo

mor

talit

y:58

/170

(34%

)�N

ode

aths

from

PE�

PTS:

7(4

%)

�Res

ults

not

prov

ided

bytr

eatm

ent

grou

p�M

arie

etal

373 /

1998

Ret

rosp

ectiv

eca

sese

ries

,sin

gle

cent

er49

patie

nts

with

conf

irm

edU

ED

VT

(incl

udes

3w

ithce

ntra

lven

ous

cath

eter

)

Hep

arin

ther

apy

(LM

WH

,n�

36;U

FH

,n

�11

);V

KA

(n�

44),

surg

ical

thro

mbe

ctom

ypl

usve

nous

ligat

ion

(n�

1)D

urat

ion

ofV

KA

,3–6

mo

Sym

ptom

atic

VT

E;

recu

rren

cePE PT

S(r

esid

uall

imb

edem

a,pa

inor

heav

ines

s);m

ajor

blee

d

6m

oV

TE

recu

rren

ce:1

/49

(2.2

%)

PE:6

/49

(12.

2%)

PTS:

19/4

9(3

8.8%

)M

ajor

blee

d:0

(Res

ults

not

prov

ided

bytr

eatm

ent

grou

p)

Sava

geet

al34

9 /19

99Pr

ospe

ctiv

eco

hort

,tw

oce

nter

46ou

tpat

ient

sw

ithco

nfir

med

UE

DV

T(in

clud

es16

with

cent

ral

veno

usca

thet

er)

Dal

tepa

rin

daily

for

5–7

d(2

00IU

/kg)

and

VK

Ato

achi

eve

targ

etIN

Rof

2.0–

3.0

for

3m

oD

urat

ion

ofV

KA

not

prov

ided

Sym

ptom

atic

recu

rren

ce/e

xten

sion

ofD

VT

PE Maj

orbl

eed

Dea

th

3m

oR

ecur

renc

e/ex

tens

ion:

1/46

(2%

)PE

:0M

ajor

blee

d:1/

46(2

%;o

nV

KA

)D

eath

:7/4

6(1

5%;n

one

from

PEor

blee

d)




Tab

le22

—C

onti

nued

Aut

hor

Typ

eof

Stud

y†Pa

rtic

ipan

tsIn

terv

entio

n‡O

utco

mes

§F

ollo

w-u

pR

esul

ts

Mar

inel

laet

al38

3 /20

00R

etro

spec

tive

case

seri

es,s

ingl

ece

nter

90pa

tient

sw

ithco

nfir

med

UE

DV

T(in

clud

es65

with

cent

ralv

enou

sca

thet

er)

Hep

arin

(n�

65),

VK

A(n

�53

),ca

thet

erre

mov

al(in

39/6

5pa

tient

sw

ithce

ntra

lve

nous

cath

eter

)D

rug

dose

s,du

ratio

nof

antic

oagu

latio

nno

tpr

ovid

ed

Dea

thN

otsp

ecifi

edD

eath

:11/

90(1

2%)

�Res

ults

not

prov

ided

bytr

eatm

ent

grou

p�

Mas

sour

eet

al39

2 /20

00R

etro

spec

tive

case

seri

es,s

ingl

ece

nter

40pa

tient

sw

ithco

nfir

med

UE

DV

T(2

2w

ithce

ntra

lve

nous

cath

eter

)

LM

WH

(n�

27),

UF

H(n

�13

),ca

thet

er-

dire

cted

lysi

s(n

�4)

,VK

A(n

�26

;m

ean

dura

tion

not

spec

ified

)

PE Maj

orbl

eed

PTS

Dea

th

9m

o(m

ean)

PE:2

/40

(5%

)M

ajor

blee

d:2/

40(5

%)

PTS:

14/4

0(3

5%;s

ever

ein

2/40

�5%

�)D

eath

:16/

40(4

0%)

Hin

gora

niet

al38

1 /20

01R

etro

spec

tive

char

tre

view

,sin

gle

cent

er

165

patie

nts

with

conf

irm

edU

ED

VT

:144

with

UE

DV

Tal

one

(incl

udes

90w

ithce

ntra

lven

ous

cath

eter

),an

d21

with

both

UE

DV

Tan

dlo

wer

-ex

trem

ityD

VT

(incl

udes

14w

ithce

ntra

lven

ous

cath

eter

)

UE

DV

Tal

one:

syst

emic

antic

oagu

latio

n(n

�94

),no

antic

oagu

latio

n(n

�31

),SV

Cfil

ter

(n�

16),

aspi

rin

(n�

3)U

ED

VT

and

low

er-e

xtre

mity

DV

T:s

yste

mic

antic

oagu

latio

n(n

�17

);SV

Cpl

usIV

Cfil

ter

(n�

2);n

oan

ticoa

gula

tion

(n�

1),

aspi

rin

(n�

1)D

rug

dose

s,du

ratio

nof

antic

oagu

latio

nno

tpr

ovid

ed

PEat

time

ofU

ED

VT

diag

nosi

sD

eath

with

in2

mo

ofU

ED

VT

diag

nosi

s

2m

oPE

attim

eof

UE

DV

Tdi

agno

sis:

UE

DV

Tal

one:

16/1

44(1

1%)

UE

DV

Tpl

uslo

wer

-ext

rem

ityD

VT

:2/2

1(9

.5%

;p�

0.59

)A

ll-ca

use

deat

hw

ithin

2m

oof

diag

nosi

s:U

ED

VT

alon

e:38

/144

(26%

)U

ED

VT

plus

low

er-e

xtre

mity

DV

T:1

1/21

(52%

)��

0.02

�D

eath

from

PEno

tre

port

ed(R

esul

tsno

tpr

ovid

edby

trea

tmen

tgr

oup)

Kar

abay

etal

350 /

2003

Pros

pect

ive

coho

rt,

sing

lece

nter

36in

patie

nts

with

conf

irm

edU

ED

VT

(incl

udes

13w

ithce

ntra

lven

ous

cath

eter

)

Nad

ropa

rin

SCbi

d,86

aXa

IU/k

gfo

rup

to7

d,th

enV

KA

(sta

rted

onda

y3;

targ

etIN

R,2

–2.5

)fo

rm

ean

of4.

7m

o

Sym

ptom

relie

f;ly

sis

ofth

rom

bus

onul

tras

ound

Rec

urre

ntD

VT

PE Dea

thPT

S

1yr

Sign

ifica

ntsy

mpt

omre

lief,

day

7:32

/36

(89%

)L

ysis

,day

10:

�35

%:1

6/36

(45%

)�

35%

:17/

36;(4

7%)

Non

e:3/

36(8

%)

Rec

urre

ntD

VT

:0PE

:0D

eath

:9/3

6(2

5%),

none

due

toPE

orbl

eed

PTS:

0M

artin

elli

etal

378 /

2004

Cas

e-co

ntro

lstu

dyw

ithpr

ospe

ctiv

efo

llow

-up

ofca

ses,

sing

lece

nter

98pa

tient

sw

ithpr

imar

yU

ED

VT

(non

ew

ithce

ntra

lven

ous

cath

eter

)

VK

Afo

rm

ean

6m

o(n

�77

),he

pari

nSQ

(n�

14),

oran

tipla

tele

tag

ents

(n�

7)fo

r�

3m

o

Rec

urre

ntV

TE

afte

ran

ticoa

gula

nts

stop

ped

Med

ian,

5.1

yrR

ecur

rent

VT

E:1

2/98

(12%

)ov

eral

l(a

llU

ED

VT

)A

nnua

linc

iden

ceof

recu

rren

tV

TE

:2.

4%(9

5%C

I,1.

2–4.

0%R

esul

tsno

tpr

ovid

edby

trea

tmen

tgr

oup)




Tab

le22

—C

onti

nued

Aut

hor

Typ

eof

Stud

y†Pa

rtic

ipan

tsIn

terv

entio

n‡O

utco

mes

§F

ollo

w-u

pR

esul

ts

Pran

doni

etal

347 /

2004

Pros

pect

ive

coho

rt,

num

ber

ofce

nter

sno

tst

ated

53pa

tient

sw

ithco

nfir

med

first

UE

DV

T(in

clud

ed6

with

cent

ralv

enou

sca

thet

er)

The

rape

utic

dose

hepa

rin

(81%

rece

ived

UF

H,1

9%re

ceiv

edL

MW

H)

then

VK

A(m

edia

n,3

mo)

Rec

urre

ntV

TE

Dea

thPT

S

Med

ian,

48m

oR

esul

tsno

tpr

esen

ted

acco

rdin

gto

initi

altr

eatm

ent

with

UF

Hvs

LM

WH

;R

ecur

rent

VT

E:3

/53

(5.7

%;2

arm

,1le

g);c

umul

ativ

ein

cide

nce

at1

yr,2

yr,a

nd5

yr:2

.0%

,4.2

%,7

.7%

Dea

th:1

1/53

(20.

8%);

due

toca

ncer

,PE

,con

gest

ive

hear

tfa

ilure

(bre

akdo

wn

not

prov

ided

)PT

S:13

/53

24.5

%);

2-yr

cum

ulat

ive

inci

denc

e:27

.3%

Kah

net

al38

4 /200

5R

etro

spec

tive

coho

rt,

sing

lece

nter

24pa

tient

sw

ithco

nfir

med

UE

DV

T(in

clud

es11

with

cent

ralv

enou

sca

thet

er)

Hep

arin

(med

ian

of9

d,th

enV

KA

(med

ian,

5m

o;n

�23

),L

MW

Hm

onot

hera

py(n

�1)

PTS

Med

ian,

13m

oPT

S:11

/24

(46%

)

Pers

son

etal

393 /

2006

Ret

rosp

ectiv

eca

sese

ries

,sin

gle

cent

er31

patie

nts

with

conf

irm

edpr

imar

yU

ED

VT

(non

ew

ithce

ntra

lven

ous

cath

eter

)

LM

WH

follo

wed

byV

KA

for

3–6

mo

Rec

urre

ntV

TE

PTS

5yr

Rec

urre

ntV

TE

:0PT

S:9/

31(2

9%;n

one

seve

re)

Kov

acs

etal

351 /

2007

Pros

pect

ive

coho

rt,

mul

ticen

ter

74ca

ncer

patie

nts

with

conf

irm

edU

ED

VT

(all

had

cent

ralv

enou

sca

thet

er)

Dal

tepa

rin

(200

IU/k

g)da

ilyfo

r5–

7d

and

VK

Ato

achi

eve

targ

etIN

Rof

2.0–

3.0

Rec

urre

ntV

TE

PE Maj

orbl

eed

Dea

thC

athe

ter

failu

redu

eto

DV

Tor

inab

ility

toin

fuse

3m

oR

ecur

rent

VT

E:0

PE:0

Maj

orbl

eed:

3(4

%)

Dea

th:7

(6ca

ncer

,1m

ajor

blee

d)C

athe

ter

failu

redu

eto

DV

Tor

inab

ility

toin

fuse

:0

*The

met

hodo

logi

cqu

ality

desc

ript

ion

port

ion

ofth

ista

ble

can

befo

und

inth

eon

line

vers

ion

ofth

isar

ticle

asa

data

supp

lem

ent.

†Ret

rosp

ectiv

ean

dpr

ospe

ctiv

eco

hort

stud

ies

(incl

udes

stud

ies

inT

able

8.1)

.‡V

KA

,UF

H,L

MW

Hvs

plac

ebo,

cont

rol,

orea

chot

her.

§Rec

urre

ntD

VT

and

PE,m

ajor

blee

ding

,tot

alm

orta

lity,

and

PTS

ofth

ear

m.




App

end

ix:S

um

mar

y

Tab

le23

—St

rept

okin

ase

Plu

sH

epar

invs

Con

trol

(Hep

arin

)

Qua

lity

Ass

essm

ent

Sum

mar

yof

Fin

ding

s

No.

ofPa

tient

s/T

otal

Patie

nts

(%)

Eff

ect

Qua

lity

Stud

ies,

No.

Des

ign

Lim

itatio

nsC

onsi

sten

cyD

irec

tnes

sPr

ecis

ion

Rep

ortin

gB

ias

Stre

ngth

ofA

ssoc

iatio

nSt

rept

okin

ase

Plus

Hep

arin

Con

trol

(Hep

arin

)

RR

(95%

CI)

orW

eigh

ted

Mea

nD

iffer

ence

Eve

nts

Prev

ente

dpe

r1,

000

Tre

ated

Rec

urre

ntD

VT

and

PE4*

RC

TSo

me

limita

tions

†N

oim

port

ant

inco

nsis

tenc

yN

o dire

ctne

ssSo

me

impr

ecis

ion‡

No re

port

ing

bias

No

stro

ngas

soci

atio

n‡1/

44(2

.27)

7/43

(16.

2%)

0.25

(0.0

6–1.

15)§

Not si

gnifi

cant

Mod

erat

e

Maj

orbl

eedi

ng4*

RC

TSo

me

limita

tions

No

impo

rtan

tin

cons

iste

ncy

No di

rect

ness

Som

eim

prec

isio

n‡N

o repo

rtin

gbi

as

No

stro

ngas

soci

atio

n8/

44(1

8.18

)7/

43(1

6.2)

1.07

6(0

.43–

2.72

)�N

ot sign

ifica

ntM

oder

ate

Tot

alm

orta

lity

4*R

CT

Som

elim

itatio

nsN

oim

port

ant

inco

nsis

tenc

yN

o dire

ctne

ssSo

me

impr

ecis

ion‡

No re

port

ing

bias

No

stro

ngas

soci

atio

n2/

44(4

.55)

4/43

(9.3

0)0.

46(0

.09–

2.29

)¶N

ot sign

ifica

ntM

oder

ate

*Inc

lude

sT

ibbu

ttD

,197

4;L

yB

,197

8;D

otte

rC

,197

9;an

dJe

rjes

-San

chez

C.1

995.

†See

met

hods

tabl

e.‡9

5%C

Iin

clud

esno

effe

cts.

§Bas

edon

met

aana

lysi

sof

thre

est

udie

s:T

ibbu

ttD

,197

4re

port

sno

case

sof

DV

Tin

eith

erth

etr

eatm

ent(

0of

11pa

tient

s)or

cont

rolg

roup

(0of

12pa

tient

s)an

dw

asno

tinc

lude

din

the

met

aana

lysi

s.�B

ased

onm

etaa

naly

sis

ofth

ree

stud

ies:

Jerj

es-S

anch

ezC

,199

5re

port

sno

case

sof

maj

orbl

eedi

ngin

eith

erth

etr

eatm

ent

(0of

4pa

tient

s)or

cont

rolg

roup

(0of

4pa

tient

s)an

dw

asno

tin

clud

edin

the

met

aana

lysi

s¶B

ased

onm

etaa

naly

sis

ofth

ree

stud

ies:

Tib

butt

D,1

974

and

Jerj

es-S

anch

ezC

,199

5re

port

node

aths

inei

ther

the

trea

tmen

tor

cont

rolg

roup

and

wer

eex

clud

edfr

omth

em

etaa

naly

sis.




Tab

le24

—U

roki

nase

vsC

ontr

ol(H

epar

in)

Qua

lity

Ass

essm

ent

Sum

mar

yof

Fin

ding

s

No.

ofPa

tient

s/T

otal

(%)

Eff

ect

Qua

lity

No.

ofSt

udie

sD

esig

nL

imita

tions

Con

sist

ency

Dir

ectn

ess

Prec

isio

nR

epor

ting

Bia

sSt

reng

thof

Ass

ocia

tion

Uro

kina

seC

ontr

ol(H

epar

in)

RR

(95%

CI)

orW

eigh

ted

Mea

nD

iffer

ence

Eve

nts

Prev

ente

dpe

r1,

000

Tre

ated

Rec

urre

ntD

VT

and

PE2*

RC

TSo

me

limita

tions

†N

oim

port

ant

inco

nsis

tenc

yN

opr

oble

ms

Som

eim

prec

isio

n‡N

o repo

rtin

gbi

as

No

stro

ngas

soci

atio

n12

/98

(12.

24)

15/8

8(1

7.05

)0.

76(0

.38–

1.52

)§N

ot sign

ifica

ntM

oder

ate

Maj

orbl

eedi

ng2*

RC

TSo

me

limita

tions

No

impo

rtan

tin

cons

iste

ncy

No

prob

lem

sN

opr

oble

ms

No re

port

ing

bias

No

stro

ngas

soci

atio

n37

/92

(40.

22)

21/8

8(2

3.86

)1.

68(1

.08–

2.59

)§N

ot sign

ifica

ntM

oder

ate

Tot

alm

orta

lity

2*R

CT

Som

elim

itatio

nsN

oim

port

ant

inco

nsis

tenc

yN

opr

oble

ms

Som

eim

prec

isio

nN

o repo

rtin

gbi

as

No

stro

ngas

soci

atio

n6/

92(6

.52)

7/88

(7.9

5)0.

82(0

.29–

2.32

)§N

ot sign

ifica

ntM

oder

ate

*Inc

lude

sU

PET

stud

ygr

oup

1970

;Mar

iniC

1988

.†S

eem

etho

dsta

ble.

‡95%

CI

cont

ains

noef

fect

.§B

ased

onon

est

udy:

Mar

iniC

,198

8w

asex

clud

edbe

caus

eit

repo

rts

noca

ses

inei

ther

trea

tmen

tor

cont

rolg

roup

s.

Tab

le25

—rt

-PA

Plu

sH

epar

invs

Con

trol

(Hep

arin

)

Qua

lity

Ass

essm

ent

Sum

mar

yof

Fin

ding

s

No

ofPa

tient

sE

ffec

t

Qua

lity

Stud

ies,

No.

Des

ign

Lim

itatio

nsC

onsi

sten

cyD

irec

tnes

sPr

ecis

ion

Rep

ortin

gB

ias

Stre

ngth

ofA

ssoc

iatio

nrt

-PA

Plus

Hep

arin

Con

trol

(Hep

arin

)

RR

(95%

CI)

orW

eigh

ted

Mea

nD

iffer

ence

Eve

nts

Prev

ente

dpe

r1,

000

Tre

ated

Rec

urre

ntD

VT

and

PE1*

RC

TSo

me

limita

tions

†N

oim

port

ant

inco

nsis

tenc

yN

opr

oble

ms

Som

eim

prec

isio

n‡N

o repo

rtin

gbi

as

No

stro

ngas

soci

atio

n0/

465/

55(9

.09)

0.10

8(0

.01–

1.91

)N

otsi

gnifi

cant

Mod

erat

e

Maj

orbl

eedi

ng1*

RC

TSo

me

limita

tions

No

impo

rtan

tin

cons

iste

ncy

No

prob

lem

sSo

me

impr

ecis

ion

No re

port

ing

bias

No

stro

ngas

soci

atio

n3/

46(6

.52)

1/55

(1.8

2)3.

59(0

.39–

33.3

3)N

ot sign

ifica

ntM

oder

ate

Tot

alm

orta

lity

1*R

CT

Som

elim

itatio

nsN

oim

port

ant

inco

nsis

tenc

yN

opr

oble

ms

Som

eim

prec

isio

nN

o repo

rtin

gbi

as

No

stro

ngas

soci

atio

n0/

462/

53(3

.64)

0.24

(0.0

1–4.

84)

Not

sign

ifica

ntM

oder

ate

*Gol

dhab

erS,

1993

.†N

oev

iden

ceof

blin

ding

;see

met

hods

tabl

e.‡9

5%C

Ish

ows

noef

fect

.




Tab

le26

—rt

-PA

Plu

sH

epar

invs

Con

trol

(Hep

arin

Plu

sP

lace

bo)

Qua

lity

Ass

essm

ent

Sum

mar

yof

Fin

ding

s

No.

ofPa

tient

s/T

otal

(%)

Eff

ect

Qua

lity

Stud

ies,

No.

Des

ign

Lim

itatio

nsC

onsi

sten

cyD

irec

tnes

sPr

ecis

ion

Rep

ortin

gB

ias

Stre

ngth

ofA

ssoc

iatio

nrt

-PA

Plus

Hep

arin

Con

trol

(Hep

arin

Plus

Plac

ebo)

RR

(95%

CI)

orW

eigh

ted

Mea

nD

iffer

ence

Eve

nts

Prev

ente

dpe

r1,

000

Tre

ated

Rec

urre

ntD

VT

and

PE1*

RC

TN

ose

riou

slim

itatio

nsN

oim

port

ant

inco

nsis

tenc

yN

o dire

ctne

ssSo

me

impr

ecis

ion†

No re

port

ing

bias

No

stro

ngas

soci

atio

n4/

118

(3.3

9)4/

138

(2.9

)1.

17(0

.30–

4.58

)N

ot sign

ifica

ntM

oder

ate

Maj

orbl

eedi

ng1*

RC

TN

ose

riou

slim

itatio

nsN

oim

port

ant

inco

nsis

tenc

yN

o dire

ctne

ssSo

me

impr

ecis

ion

No re

port

ing

bias

No

stro

ngas

soci

atio

n4/

118

(3.3

9)4/

138

(2.9

0)0.

23(0

.03–

1.97

)N

ot sign

ifica

ntM

oder

ate

Tot

alm

orta

lity

1*R

CT

No

seri

ous

limita

tions

No

impo

rtan

tin

cons

iste

ncy

No di

rect

ness

Som

eim

prec

isio

nN

o repo

rtin

gbi

as

No

stro

ngas

soci

atio

n4/

118

(3.3

9)3/

138

(2.1

7)1.

56(0

.36–

6.83

)N

ot sign

ifica

ntM

oder

ate

*Kon

stan

tinid

esS,

2002

.†9

5%C

Ico

ntai

nsno

effe

ct.

Tab

le27

—rt

-PA

and

Hep

arin

vsC

ontr

ol(H

epar

in)

Qua

lity

Ass

essm

ent

Sum

mar

yof

Fin

ding

s

No.

ofPa

tient

s/T

otal

(%)

Eff

ect

Qua

lity

No.

ofst

udie

sD

esig

nL

imita

tions

Con

sist

ency

Dir

ectn

ess

Prec

isio

nR

epor

ting

Bia

sSt

reng

thof

Ass

ocia

tion

rt-P

APl

usH

epar

inC

ontr

ol(H

epar

in)

RR

(95%

CI)

orW

eigh

ted

Mea

nD

iffer

ence

Eve

nts

Prev

ente

dpe

r1,

000

Tre

ated

Rec

urre

ntD

VT

and

PE1*

RC

TSo

me

limita

tions

†N

oim

port

ant

inco

nsis

tenc

yN

o dire

ctne

ssSo

me

impr

ecis

ion‡

No re

port

ing

bias

No

stro

ngas

soci

atio

n1/

20(5

.00)

0/16

2.43

(0.1

1–55

.89)

Not

sign

ifica

ntM

oder

ate

Maj

orbl

eedi

ng1*

RC

TSo

me

limita

tions

No

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References1 Barritt DW, Jordan SC. Anticoagulant drugs in the treat-

ment of pulmonary embolism: a controlled trial. Lancet1960; 1:1309–1312

2 Alpert JS, Smith R, Carlson J, et al. Mortality in patients treatedfor pulmonary embolism. JAMA 1976; 236:1477–1480

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Tab

le28

—rt

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vsC

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ent

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mar

yof

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No.

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otal

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ies,

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ign

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ias

Stre

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(Pla

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Prev

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ased

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Errata

In the June 2008 supplement, in the article by Hirsh et al,“Executive Summary: American College of Chest PhysiciansEvidence-Based Clinical Practice Guidelines (8th Edition)”(Chest 2008; 133[suppl]:71S–109S), on page 99S, in column one,Recommendation 2.5.2, the text should read “For patients withacute ST-segment elevation myocardial infarction receiving fi-bronolytic therapy who have preserved renal function (� 2.5mg/dL [220 �mol/L] in males and � 2.0 mg/dL [175 �mol/L] infemales), we recommend the use of enoxaparin over UFH,continued up to 8 days (Grade 2A).” The online version has beencorrected, and that version should be used.

In the June 2008 supplement, in the article by Goodman et al,“Acute ST-Segment Elevation Myocardial Infarction: AmericanCollege of Chest Physicians Evidence-Based Clinical PracticeGuidelines (8th Edition)” (Chest 2008; 133[suppl]:708S–775S),on page 710S, in column one, Recommendation 2.5.2 (and onpage 739S column one), the text should read “For patients withacute ST-segment elevation myocardial infarction receiving fi-bronolytic therapy who have preserved renal function (� 2.5mg/dL [220 �mol/L] in males and � 2.0 mg/dL [175 �mol/L] infemales), we recommend the use of enoxaparin over UFH,continued up to 8 days (Grade 2A).” The online version has beencorrected and that version should be used.

In the June 2008 supplement, in the article by Kearon et al,“Antithrombotic Therapy for Venous Thromboemobolic Disease:American College of Chest Physicians Evidence-Based ClinicalPractice Guidelines (8th Edition)” (Chest 2008; 133[suppl]:454S–545S), the conflict of interest disclosures from the authorswere inadvertently left out. They are as follows: Dr. Kearondiscloses that he has received grant monies from the CanadianInstitutes for Health Research and the Heart and Stroke Foun-dation of Canada. He is also on an advisory committee forGlaxoSmithKline and Boehringer Ingelheim. Dr. Agnelli revealsno real or potential conflicts of interest or commitment. Dr.Goldhaber discloses that he has received grant monies fromMitsubishi, Boehringer Ingelheim, Sanofi-Aventis, Eisai, Glaxo-SmithKline, and AstraZeneca. He has also received consultantfees from Sanofi-Aventis, Eisai, Bristol-Myers Squibb, andBoehringer Ingelheim. Dr. Raskob discloses that he has servedon the speaker bureau and advisory committees and has received

consultant fees from Bayer, BMS, Daiichi-Sankyo, Pfizer, Sanofi-Aventis, Takedo and Boehringer Ingelheim. Dr. Comerottadiscloses that he is on the speaker bureaus of Sanofi-Aventis,Bristol-Myers Squibb, and GlaxoSmithKline and serves on anadvisory committee for ConvaTec, and Bacchus Vascular. He isalso a shareholder of LeMaitre Vascular.

In the September 2008 supplement by Tarlo et al, “Diagnosis andManagement of Work-Related Asthma: American College of ChestPhysicians Consensus Statement” (Chest 2008; 134:1S–41S), someof the subheadings are misleading in the print version. The onlineversion has been corrected and should be used. There is no changeto the text, but the level of headings shown on pages 7S–9S, 17S, and31S–32S is more clear in the corrected online edition. Also, on theTable of Contents pages the Endorsements should read “TheCanadian Society of Allergy and Clinical Immunology and TheCanadian Thoracic Society”.

In the July 2008 issue, in the correspondence by BaHammamet al, “Positive Airway Pressure Therapy and Daytime Hypercap-nia in Patients With Sleep-Disordered Breathing” (Chest 2008;134:218–219), the first author’s surname was misspelled. It isBaHammam. It has been corrected in the online edition.

Correction

I have come to realize that I neglected to provide as full apotential conflict of interest statement as I could have in myreview article, “Update on the Management of COPD” (Chest2008; 133:1451–1462). I wish to disclose the following: Bar-tolome R. Celli has been reimbursed by GSK, BI, Pfizer, AZ,Almirall, and Esteve for participating in advisory boards andspoken at different meetings. The division that Dr. Celli headshas been awarded research grants for different medication trialsby the same companies and for the discovery of new biomarkersin COPD, and has received grants for the participation in thedevelopment of biological lung volume reduction surgery fromthe company AERIS. Bartolome R. Celli, MD, FCCP, Pulmo-nary and Critical Care Medicine, Caritas St. Elizabeth’s MedicalCenter, Boston, MA.

CHEST Errata

892 Errata



DOI 10.1378/chest.08-0658 2008;133; 454S-545SChest

Raskob and Anthony J. ComerotaClive Kearon, Susan R. Kahn, Giancarlo Agnelli, Samuel Goldhaber, Gary E.

Practice Guidelines (8th Edition)American College of Chest Physicians Evidence-Based Clinical

:*Antithrombotic Therapy for Venous Thromboembolic Disease

October 14, 2011This information is current as of

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