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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 Chest

Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Grade 1 recommendations are strongandindicate that thebenefits do or do not outweighrisks,burden, andcosts.Grade 2 suggests that individualpatient values may lead to different choices (for a full understanding of the grading, see Grades ofRecommendation chapter).Among thekey recommendations in this chapter arethe 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 the

international 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 thepatients 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). DVTmay be considered forthrombus removal,generallyusing 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; 133:454S545S)

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;MPFFmicronized 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;

VKAvitamin K antagonist; VTEvenous thromboembolism

SupplementANTITHROMBOTICAND THROMBOLYTIC THERAPY 8THED: ACCP GUIDELINES

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

2008 American College of Chest Physiciansby guest on September 12, 2011chestjournal.chestpubs.orgDownloaded from
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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 18

U/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 corresponds

to 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 nonweight-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 underlying

venous 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), Henderson

General 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 Womens 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



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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 in

addition 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 continuing

such 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-




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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 or

Sulodexide 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 by

continuous 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




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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 nonweight-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 with

LMWH, 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 patients with 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 theclinicians assessment of PE severity, progno-sis, and risk of bleeding. For the majority of

patients 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 bleeding

risk, 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 IVCfilter(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




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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 the

dose 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 to

3.0 (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 vein

thrombosis (ie, where the affected venous segment isshort in length or further from the saphenofemoral junction) 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).




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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, Staged

Approach 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 evidence

of 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 determine

the 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).

This 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,thetreatmentof patients with

acute 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 forthestudies considered in each sectionof the recommendations that follow.

1.0 Initial Treatment of Acute DVT of the

Leg

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 40

years 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 studies24 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




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Table 1Question 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


1.14 Initial treatment of

acute DVT of the leg

Immobilization vs active mobilization Recurrent DVT and PE, total

mortality, QOL, and PTS

RCTs and cohort

studies2.1 Long-term treatment of

acute DVT of the legComparison of different durations of VKA therapy Recurrent DVT and PE, major

bleeding, total mortality,QOL, and PTS

RCTs

2.2 Long-term treatment ofacute DVT of the leg

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

2.5 Long-term treatment of

acute DVT of the leg

New antithrombotic agents (eg, ximelagatran,

idraparinux) vs no treatment or otheranticoagulants

Recurrent DVT and PE, major

bleeding, total mortality,QOL, and PTS

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




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Table 1Continued

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

4.2 Initial treatment of

acute PE

New antithrombotic agent (eg, ximelagatran,

idraparinux) compared to no treatment orconventional therapy

Recurrent DVT and PE, major

bleeding, total mortality,QOL, and CTPH

RCTs and cohort

studies


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 or

regimens 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

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



Catheter extraction, surgical thrombectomy,transluminal angioplasty, stent placement, staged

approach of lysis followed by interventional orsurgical procedure, SVC filter insertion, comparedwith no interventions

Recurrent DVT and PE, majorbleeding, total mortality, and

PTS of the arm


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




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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 UFH

administered 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 to

10 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 compared with 10 mg. Observational studies8,12 have shownthat lower VKA maintenance doses are required inolder patients, women, and those with impaired

nutrition 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 intermittent

IV 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 in

clinical 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.1821 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




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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 nonweight-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 studies2844 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.4547 The most recent such analysis included17 studies28 44,48 in which UFH was administered IV(3,614 patients) and 3 older studies4850 in which UFH was 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 sixstudies28,39,5154 (the same total daily dose of LMWHhas not always been compared within studies). Ametaanalysis55 of five of these studies39,5154 that hadunconfounded comparisons between once- and twice-daily administration found no difference in recurrent




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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 in

the outpatient group.Dalteparin and tinzaparin, each administered once

daily, 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.4547

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 monitoring

with 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 Galilei

study,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 patients 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 with

an 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 if

50 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-term

Treatment 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 reduce

acute 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.6371 Randomized trials,72,73 patient regis-tries,74,75 and studies of other designs7681 support thatsuccessful thrombus removal, using a variety of tech-niques, can improve patient outcomes (see follow-ing).79,8183 It is also possible that thrombus removal




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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% having venous claudication when treated with anticoagulanttherapy alone.8487

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 2Comparison 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, 0.17.5)

1/72 (1.4)

0/74;RR, 3.1 (95%CI, 0.17.5)

3/72 (4.2)

0/74RR, 7.2 (95%CI, 0.4137)

Population: femoralDVT in 81% andpopliteal or moredistal DVT in

19%Primary outcome

was 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, 0.114.5)

3/35

0/33RR, 6.6 (95%CI, 0.3123)

1/35

0/33RR, 2.8 (95%CI, 0.167)

Population:DVT (proportionof proximal anddistal not reported)

Primary outcome was

repeat venographyPrandoni 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, 0.52.2)

5/360 (1.4)

7/360 (1.9)RR, 0.7 (95%CI, 0.22.2)

12/360 (3.3)

12/360 (3.3)RR, 1.0; 95%CI, 0.52.2)

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

Kearon et al25/2006 (FIDO)

UFH at 333 U/kg SCfollowed by 250 U/kg SC

bid (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, 0.52.3)

6/348 (1.7)

12/352 (3.4)RR, 0.5 (95%CI, 0.21.3)

18/348 (5.2)

22/352 (6.3)RR, 0.8 (95%CI, 0.41.5)

Population:proximal DVT

in 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.




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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 studies72,75,76,78,81,89102 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 intravascular

stenting, 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 in

this 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 as pharmacomechanical 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, pharmacomechanical

thrombolysis 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 underlying

venous 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 trials81,103120 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 differed with 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).




16/95
http://chestjournal.chestpubs.org/


17/95


18/95


19/95

Table3Continued

Author/yr

TypeofStudy

Participants

Interventions

Outco

mes

Follow-up

Results

Kimetal95/2006

Retrospective

study

37patients(45limbs)with

acute(14d)

iliofemoralDVT

CDT:6.705.9millionUofurokinase

(mean)infuse

dformeanof56.5

27.4hin

26limbs(23patients)

CDTpluspharmacomechanical:lytictreatment

performedas

describedinCDTgroupplus

AngioJetthro

mbectomydevice

Clotlysis,

bleedin

g,PE,

treatme

nt

duration,cost,

recurrentDVT

32mo

Completelysis:

CDT:21/26

(81%)

CDTplusPMT:16/21(84%)

Majorbleeding:

CDT:2/26(

7%)

CDTplusPMT:1/21(5%)

PE:

CDT:1/26(

4%)

CDTplusPMT:1/21(5%)

Treatmentd

uration:

CDT:57h

CDTplusPMT:30h

Cost(drugp

lusdevice):

CDT:$10,127

CDTplusPMT:$5,128

RecurrentD

VT:

CDT:4/16(25%)

CDTplusPM

T:2/13(15%)

Linetal96/2006

Retrospective

study

93patients(98procedures)

withsymptomaticDVT

CDT:46proceduresusingtPA,rt-PA,or

urokinase

PMT:52proceduresusingAngioJetrheolytic

thrombectom

ysystemwithtPA,rt-PA,or

urokinase

Clotlysis,No.of

venograms,

immediate

clinical

improvement,

bleedin

g,

ICU/ho

spital

stay,1-y

r

primary

patency,cost

1yr

Complete/pa

rtiallysis:

CDT:32/46

(70%)/14/46(30%)

CDTplusPM

T:39/52(75%)/13/52(25%)

No.ofvenog

rams:

CDT:2.5

CDTplusPM

T:0.4(p

0.001)

Immediateclinicalimprovement:

CDT:33/46(72%)

CDTplusPM

T:42/52(81%)

Bleeding:

CDT:2/49(4%)

CDTplusPM

T:3/46(7%)

ICUstay:

CDT:2.4d

CDTplusPM

T:0.6d

Hospitalstay:

CDT:8.4d

CDTplusPM

T:2.4d

1-yrprimary

patency:

CDT:64%

CDTplusPM

T:68%

Cost:

CDT:$85,30

1

CDTplusPM

T:$47,742

*ND

notdetermined.Themethodolog

icqualitydescriptionportionofthistablecanbefoundintheonlineversionofthisa

rticleasadatasupplement.




20/95

Table

4SystemicThrombolyticTherapyforAcuteDVT:ClinicalDescriptionandResults(Section1.9)*

Author/yr

TypeofStudy

Participants

Interventions

Outcomes

Follow-up

Results

Browseetal105/

1968

RCT,singlecenter

10patientswith

lower-extremity

DVTconfirmed

byphlebography

Lysis:600,000Uof

streptokinaseplus

100mgofhydrocortisoneforfirst

hour,thencontin

uedevery6hfor

3d(n

5)

Anticoagulation:4-to6-hdosesof

5,000Uheparinfor48hfollowed

bywarfarin(n

5)

Clotlysis,PE,

bleeding

710d

Thrombolysis:

Completeclotlysis:3/5(60%)

Partiallysis:1/5(20%)

Nolysis:1(20%)

PE:0

Bleeding:0

Anticoagulation:

Completeclotlysis:0/5

Partiallysis:0/5

Nolysis:5/5(100%)

PE:0

Bleeding:0

Robertsonetal113/

1968

RCT,singlecenter

16patientswith

DVT

Thrombolysis:200,0

00Uof

streptokinaseover90min,then

100,000Uasmaintenancedosefor

22.5h;500mgofheparin

administeredover24h,plus

prednisone(n

8)

Anticoagulation:heparinplus

prednisone(n

8)

Clotlysis,bleeding

7d

Thrombolysis:

Significantlysis:5/8(63%)


Nolysis:1/8(12%)

Bleeding:Major:

2/8(25%)

Minor:2/8(25%)

Anticoagulation:



Nolysis:5/8(63%)

Bleeding:Major:

1/8(12%)

Minor:1/8(12%)

Kakkaretal109/

1969

RCT,singlecenter

30patientswith

DVTof

4d

Thrombolysis:streptokinaseat500,000

UIVover30min

,900,000Uevery

6hfor5d(n

10)

Arvin:arvinloading

dose80UIVover

6h,80Uover15min,40to80U

every6hfor5d

(n

10)

Anticoagulation:heparinat10,000U

IVover5min,th

en10,00015,000

Uevery6hfor5

d(n

10)

Clotlysis,PE,

bleeding,death

612mo

Thrombolysis:



Nolysis:2/9(22%)

PE:0

Bleeding:4/10(4

0%)

Death:2/9(22%)

1patientexclud

edfromtreatment

Arvin:

Completelysis:1

/10(10%)

Partiallysis:3/10

(30%)

Nolysis:6/10(60%)

PE:0

Bleeding:0

Death:0

Anticoagulation:



Nolysis:5/9(55%)

PE:1/10

Death:2/9(22%)

Bleeding:2/9(22

%)

note:1patientexcludedfromtreatment




21/95

Table4Continued

Author/yr

TypeofStudy

Participants

Interventions

Outcomes

Follow-up

Results

Tsapogasetal117/

1973

RCT,singlecenter

34patientswith

DVTof

5d

Thrombolysis:titratedinitialdoseof

streptokinaseIV,

thenstreptokinase

at100,000U/hm

aintainedand

adjustedupto72

h;IVheparinfor

1wk612hafterstreptokinase

(n

19)

Anticoagulation:heparinIVinto

affectedlimb,7,0

00Ubolusthen

1,500U/hadjuste

d;continuedfor

7d(n

15)

Clotlysis,PE,

bleeding

7d

Thrombolysis:

Complete/partial

lysis:10/19(53%)

Nolysis:9/19(47%)

PE:0

Bleeding:minor:

3(16%)

Anticoagulation:

Complete/partial

lysis:1/15(7%)

Nolysis:14/15(93%)

PE:1/15(7%)

Bleeding:0

Duckertetal106/

1975

Prospectivestudy

134patientswith

acuteor

subacuteDVT

Thrombolysis:initialdoseof

streptokinasecalc

ulatedaccording

totoleranceinjec

tedover1530

min;maintenancedoseat30mL/h

wastwothirdsof

firstdose(n

92)

Anticoagulation:5,0

00Uheparinfor

initialdosefollow

edby25,000U/24

hinfusion(n4

2)

Clotlysis,PE,

bleeding

Approximately7d

Thrombolysis:


Partiallysis:23/9

2(25%)

Nolysis:30/92(33%)

PE:7(8%)

Bleeding:Major:

58(62%)

Minor:24(26%)

Anticoagulation:


Partiallysis:4/42

(10%)

Nolysis:38/42(90%)

PE:5/42(12%)

Bleeding:Major:

2/42(5%)

Minor:4/42(10%)

Porteretal112/

1975

RCT,singlecenter

50patientswith

DVT

14din

duration

Thrombolysis:streptokinaseIVat

250,000Uover3

0min,then

100,000U/htitratedfor72h;

followedbyIVheparintitratedover

7d(n

23)

Anticoagulation:IV

heparinat150

U/kgloadingdosethentitratedfor

10d(n

26)

Clotlysis,PE,

bleeding,deathdue

totreatment

10d

Thrombolysis:

Completelysis:6

/23(26%)

Partiallysis:15/2

3(65%)

Nolysis:2/23(9%)

PE:0

Bleeding:4/23(1

7%)

Death:1(4%)

Anticoagulation:

Completelysis:1

/26(4%)

Partiallysis:20/2

6(77%)

Nolysis:5/26(19%)

PE:0

Bleeding:1/26(4

%)

Death:0

Marderetal111/

1977

RCT,singlecenter

24patientswith

DVT

Thrombolysis:initiald

oseof250,000Uof

streptokinasefor20min,followedby

100,000U/hfor72

h(n

12)

Anticoagulation:initialIVheparindoseof

150U/kg,followed

bytitratedinfusion

for72h

Cotreatment:100mg

bolus

hydrocortisoneprio

rtotreatment

Clotlysis,deathdue

totreatment

5d

Thrombolysis:


Partiallysis:2/12

(16%)

Nolysis:5/12(42%)

Death:1/12(8%)

Anticoagulation:


Partiallysis:3/12

(25%)

Nolysis:9/12(75%)

Death:0




22/95

Table4Continued

Author/yr

TypeofStudy

Participants

Interventions

Outcomes

Follow-up

Results

Arnesenetal103/

1978

RCT,singlecenter

42patientswith

proximalDVT

of

5d

Thrombolysis:250,000UloadingofIV

streptokinase,then100,000IU/hIV

for7296h(n

21)

Anticoagulation:15,0

00IUIVbolus

heparin,thentotalof30,000IUIV

infusionfor7290

h(n

21)

Clotlysis,PE,

bleeding

21dto6yr

Thrombolysis:


Nolysis:6/21(29%)

PE:1/21(5%)

Bleeding:2/21(9

%)

Anticoagulation:


Nolysis:16/21(76%)

PE:0

Bleeding:2/21(9

%)

Elliotetal107/

1979

RCT,singlecenter

51patientswith

clinicalhistory

ofDVTof

8d

Thrombolysis:loadingdoseof600,000

Uofstreptokinaseinfusedover30

min,followedby

100,000/hfor3d;

heparinfor4dfollowing

streptokinase(n

26)

Anticoagulation:10,000UofIV

heparininitially,followedby10,000

UIVdailyfora6-hinfusionto

maintainclotting

timeof2.5to3

timesnormal,for

7d(n

25)

Immediate:clotlysis,

PE,bleeding

Longterm:symptom

free

Immediate:5d

Long-term:19mo

(mean)

Immediate:

Thrombolysis:


Partiallysis:1/26

(4%)

Nolysis:8/26(31%)

PE:0

Bleeding:2(8%)

Anticoagulation:


Partiallysis:0/25

(0%)

Nolysis:25/25(100%)

PE:0

Bleeding:2/21(9

%)

Long-term

Thrombolysis:

Symptomfree:12/20(60%)

fourdeaths,othercauses,twounavailable

forfollow-up;

Treatment2:

Symptomfree:2/21(9%)

fourdeaths,two

PE,twoothercauses

Watzetal120/

1979

Prospectivestudy

35patientswith

DVT

Thrombolysis:initialdoseof250,000

Uofstreptokinasein30min,

followedbymaintenanceof100,000

U/hforhowlong

?????(n

18)

Anticoagulation:45,000Uofheparin

dailywithwarfarin(n

17)

Clotlysis,PE,

bleeding

12mo

Thrombolysis:



Nolysis:6/18(34%

)

PE:1/18(5%)

Bleeding:minor:3

/18(12%)

Anticoagulation:



Nolysis:11/17(65

%)

PE:1/17(6%)

Bleeding:minor2/17(12%)




23/95

Table4Continued

Author/yr

TypeofStudy

Participants

Interventions

Outcomes

Follow-up

Results

Kiiletal110/

1981

RCT,singlecenter

20patientswith

DVTof

72h

Thrombolysis:urokinaseat200,000U

IVfor24h;after

18h,heparin

loadingdoseof15,000U,then

40,000U/dfor5

d(n

11)

Anticoagulation:heparinat40,000U/d

IVfor6d(n9

)

Clotlysis,PE,

bleeding

2wk

Thrombolysis:

Partiallysis:1/11

(9%)

Nolysis:10/11(91%)

PE:0

Bleeding:3/11(2

7%)

Anticoagulation:


Nolysis:7/8(88%)

PE:0

Bleeding:3/9(33

%)

note:1patientexcludedfromgroup

Arnesenetal104/

1982

Follow-uptoRCTof

Arnesen/1978

(n

48)

35/42patients

fromRCT

Phlebographyandc

linicalexamination

byblindedevalua

tors

Normallegs,PTS

symptoms

6.5yr

Thrombolysis:

Normallegs:13/1

7(77%)

PTS:symptoms(moderate):4/17(24%)

Anticoagulation:

Normallegs:6/18

(33%)

PTSsymptoms(m

oderate):9/18(50%)

Schulmanetal114/

1986

RCT,singlecenter

36patientswith

calfDVTof

7d

Thrombolysis:streptokinaseat50,000

IUIVover15min,then100,000IU

over12hforup

to7d,titrated;

administeredwith5,000IUof

heparinIVover1

2h(n

17)

Anticoagulation:heparinat5,000IU

IVfor15minthen30,000IU/d,

titratedover7d(n

19)

Clotlysis,bleeding,

PE

5yr

Thrombolysis:

Completelysis:7

/17(41%)

Bleeding:3/17(1

8%);

PE:0

Anticoagulation:

Completelysis:2

/19(10%)

Bleeding:1/19(5

%)

PE:0

Verhaegheetal119/

1989

Prospectivecohort

study(studyA)and

multicenterRCT

(studyB)

32patientswith

DVTof

10d

StudyA:

Open-labelstudywith

IVrt-PA100mg

over8h(day1),50mgrt-PAover8h

(day2);10%doseasbolus(n

11)

StudyB:

rt-PAat100mg;IVo

f100mLcontaining

rt-PA100mginfusedover8h(day1),

IVof100mLcontaining50mgofrt-

PAinfusedover8h(day2);10%dose

asbolus(n

8)

rt-P

A50mg:

IVo

f10

0m

Lcontainingrt-

PA50mginfuse

dover

8hon

bothdays

1an

d2;

10%

dose

as

bo

lus

(n

6)

Place

bo:

IVo

f100m

Lcontainingp

lace

bo

infuse

dover

8hon

bothdays

1an

d2

(n

7)

Cotreatment:heparin

at5

,000U

IVbo

lus

thencontinuous

inf

usion

1,0

00U/hfor

upto72h

Clotlysis,bleeding

72h

Note:authorsassignedveinsarelativevalue

reflectingdegreeofthrombosis(maximumof

40U:complete

thrombosis);theunitscores

reflectthereductioninthrombosisafterlysis

StudyA:

Changeinunitsco

re3.2

StudyB:

rt-PA100mg

Changeinunitsco

re24.3

Bleeding:6

rt-PA:50mg

Changeinunitsco

re34.3

Bleeding:3

Placebo:

Changeinunitsco

re2.8

Bleeding:0




24/95

Table4Continued

Author/yr

TypeofStudy

Participants

Interventions

Outcomes

Follow-up

Results

Goldhaberetal108/

1990

RCT,multicenter

64patients(65

randomizations)

withDVTof

14d

rt-PA:rt-PA0.05mg/kg/hIVfor24h,

thenheparin100U

/kgbolus,then

1,000U/h,adjusted

(n

36)

rt-PAplusheparin:rt-PAasingroup1

plusheparinconcomitantly(n

17)

Anticoagulation:heparin100U/kgbolus,

then1,000U/h(n

12)

Clotlysis,bleeding

36h

rt-PA:

Completelysis:2

/32(6%)

Partiallysis:18/3

2(57%)

Nolysis:12/32(38%)

Bleeding:1/32(3

%)

rt-PAplusheparin:

Completelysis:1

/17(6%)

Partiallysis:8/17

(48%)

Nolysis:8/17(48%)

Bleeding:0

Anticoagulation:

Partiallysis:2/11

(18%)

Nolysis:9/11(89%)

Bleeding:0

(note:5of65venogramswerenotanalyzed)

Turpieetal118/

1990

RCT,multicenter

83patientswith

DVTof

7d

Phase1:

Lysisplusheparin:two-chainrt-PA0.5

mg/kgIVfor4h

(n

12)

Placeboplusheparin(n

12)

Phase2:

Lysisplusheparin:one-chainrt-PA

0.5mg/kgIVfor

8handrepeated

in24h(n

29)

Placeboplusheparin(n

30)

Cotreatment:IVheparin5,000U

bolusthen30,000

U/24h,adjusted

for710d

Clotlysis,bleeding

2448h

Phase1:

Lysisplusheparin:

50%lysis:7/12

(58%)

50%lysis:2/12(17%)

Nolysis:3/12(25%)

Bleeding:4/12(3

3%)

Placeboplushep

arin:

50%lysis:2/12(17%)

Nolysis:10/12(83%)

Bleeding:1/12(8

%)

Phase2:

Lysisplusheparin:

50%lysis:6/29

(21%);

50%lysis:7/29(24%)

Nolysis:15/29(52%)

Bleeding:1/29(3

%)

Placeboplushep

arin:

50%lysis:2/30

(7%);

50%lysis:5/30(17%)

Nolysis:23/30(77%)

Bleeding:1/30(3

%)

Schweizeretal115/

1998

RCT,singlecenter

69patientswith

DVTof

7d

rt-PA:20mgIVinto

pedalvein4h/dfor

7d;heparinIVadministered

concomitantly;warfarinday7to12mo

Urokinase:100,000IU

/hIVintopedal

veincontinuously7

d;heparinIV7d;

plasminogenmonitored;warfarinday

712mo

Anticoagulation:heparinIVadjustedfor7

d;.warfarin,day1to12mo

7d:clotlysis,

bleeding

1yr:PTSsymptoms

7dand1yr

rt-PA:

Completelysis:6

/22(27%)

Bleeding:1/22(5

%)

PTSsymptoms:14/22(64%)

Urokinase:

Completelysis:1

1/22(50%)

Bleeding:1/22(5

%)


Anticoagulation:

Completelysis:0

Bleeding:0





25/95

Table4Continued

Author/yr

TypeofStudy

Participants

Interventions

Outcomes

Follow-up

Results

Schweizeretal116/

2000

RCT,multicenter

250patientswith

DVTof

9d

rt-PA:locoregionalrt-PA20mg/dfor4h

viapedalveinfor4

7d;IVheparin

administeredsimultaneouslyat1,000

IU/h;adjusted

Urokinase:locoregion

alurokinase100,000

IU/infusedcontinuously;fibrinogen

andplasminogenm

onitored;IVheparin

administeredconco

mitantly

Systemicstreptokinase:3,000,000U/dfor

6hwithheparinfo

rupto7d;

premedications:hydrocortisoneat100

mg,ranitidineat50mg,clemastineat

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