diagnosis and management of acute deep vein thrombosis: a ... · 15department of cardiology, athens...

Diagnosis and management of acute deep vein

thrombosis a joint consensus document from the

European society of cardiology working groups of

aorta and peripheral circulation and pulmonary

circulation and right ventricular function

Lucia Mazzolai1 Victor Aboyans2 Walter Ageno3 Giancarlo Agnelli4

Adriano Alatri1 Rupert Bauersachs56 Marjolein PA Brekelmans7 Harry R Buller7

Antoine Elias8 Dominique Farge9 Stavros Konstantinides610 Gualtiero Palareti11

Paolo Prandoni12 Marc Righini13 Adam Torbicki14 Charalambos Vlachopoulos15

and Marianne Brodmann16

1Division of Angiology Heart and Vessel Department Lausanne University Hospital Ch du Mont-Paisible 18 1011 Lausanne Switzerland 2Department of CardiologyDupuytren University Hospital and Inserm 1098 Tropical Neuroepidemiology School of Medicine 2 avenue martin Luther-King 87042 Limoges cedex France 3Department ofClinical and Experimental Medicine University of Insubria Via Ravasi 2 21100 Varese Italy 4Internal and Cardiovascular Medicine - Stroke Unit University of Perugia S Andreadelle Fratte 06156 Perugia Italy 5Department of Vascular Medicine Klinikum Darmstadt GmbH Grafenstraszlige 9 64283 Darmstadt Germany 6Center for Thrombosis andHemostasis University Medical Center Mainz Langenbeckstr 1 55131 Mainz Germany 7Department of Vascular Medicine Academic Medical Center Meibergdreef 9 1105 AZAmsterdam The Netherlands 8Cardiology and Vascular Medicine Toulon Hospital Centre 54 Rue Henri Sainte-Claire Deville 83100 Toulon France 9Assistance Publique-Hopitaux de Paris Saint-Louis Hospital Internal Medicine and Vascular Disease Unit and Groupe Francophone on Thrombosis and Cancer Paris 7 Diderot University SorbonneParis Cite 1 Avenue Claude Vellefaux 75010 Paris France 10Department of Cardiology Democritus University of Thrace Greece 11Cardiovascular Diseases University ofBologna Via Albertoni 15 40138 Bologna Italy 12Department of Cardiovascular Sciences Vascular Medicine Unit University of Padua Via Nicolo Giustiniani 2 35121 PaduaItaly 13Division of Angiology and Hemostasis Department of Medical Specialties Geneva University Hospital Rue Gabrielle Perret-Gentil 4 1205 Geneva Switzerland14Department of Pulmonary Circulation and Thromboembolic Diseases Medical Center for Postgraduate Education ul Plocka 26 01-138 Warszawa Otwock Poland15Department of Cardiology Athens Medical School Profiti elia 24 14575 Athens Greece and 16Division of Angiology Medical University Graz Graz Austria

Received 18 July 2016 revised 4 November 2016 editorial decision 30 December 2016 accepted 9 January 2017

Introduction

Venous thromboembolism (VTE) incidence increases sharply withage (Figure 1) and appears steady over the last 25 years despite pre-ventive strategies1 Women are more often affected at younger agesthis ratio reverses in the elderly2 Incidence is similar in Blacks butlower in Asians3 Almost two-thirds of VTE cases are isolated deepvein thromboses (DVTs) and 80 are proximal4

Recent European population studies reported DVT incidence of70ndash140 cases100000 person-year5

Deep vein thrombosis are mostly secondary to predisposing fac-tors common with pulmonary embolism (PE) (webtable 1)6 Distal(below knee) DVTs are more frequently related to transient situ-ations while proximal ones to chronic conditions7 In 25ndash50 of firstDVT episodes no predisposing factor is identified

In patients with DVT without PE short-term mortality ratesof 2ndash5 were reported more frequent in proximal than distal

DVT7 Recurrence risk is high especially within first 6months8

Early- and mid-term complications include thrombosis extensionand PE and DVT recurrence (see Supplementary material onlineonly section)

Long-term complications include post-thrombotic syn-drome (PTS) defined as chronic venous symptoms andorsigns secondary to DVT It represents the most frequentchronic DVT complication occurring in 30ndash50 of patientswithin 2 years after proximal DVT9 In 5ndash10 of cases PTS issevere9 Previous ipsilateral DVT proximal location (ilio-fem-oral gt popliteal) and residual veins obstruction are most sig-nificant PTS risk factors Obesity and poor INR control duringthe first 3-months treatment are additional independent riskfactors10

Villalta score is used for PTS diagnosis and treatment evaluation(Table 1)11

The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology

Corresponding author Tel thorn41 21 3140750 Fax thorn 41 21 3140761 Email luciamazzolaichuvch

Published on behalf of the European Society of Cardiology All rights reserved VC The Author 2017 For permissions please email journalspermissionsoupcom

European Heart Journal (2017) 0 1ndash13 CURRENT OPINIONdoi101093eurheartjehx003

Diagnosis

Deep vein thrombosis withoutpulmonary embolism symptomsClinical signs and symptoms are highly variable and unspecific but re-main the cornerstone of diagnostic strategy Symptoms include painswelling increased skin veins visibility erythema and cyanosis accom-panied by unexplained fever

Probability assessment and D-dimertestingPre-test probability assessment is the first step in the diagnostic algo-rithm of DVT suspicion (Figure 2) Sensitivity and specificity of clinicalsymptoms are low when considered individually however theircombination using prediction rules allows pre-test clinical probabil-ity classification into two- (DVT unlikely or likely) or three-categories(low- intermediate- or high-clinical probability) corresponding toincreasing disease prevalence1213 Wells score has been widely vali-dated and can be applied both to out- and inpatients (Table 2) Theexpertsrsquo panel favours the modified two-level pre-test probability asit is more straightforward14

Normal D-dimers render DVT unlikely15 however D-dimers havelow specificity Quantitative ELISA or ELISA-derived assays (gt95sensitivity) allow ruling out DVT in patients with DVT lsquounlikelyrsquoNegative ELISA D-dimer can exclude DVT without further testing in30 of patients16 with 3-month thromboembolic risk lt1 withouttreatment13 Quantitative latex-derived and whole-blood agglutin-ation assay have lower sensitivity (85ndash90)17 In patients with lsquolikelyrsquoDVT D-Dimer testing is not necessary imaging is requiredTherapeutic anticoagulation should be initiated if not contraindi-cated in patients with DVT lsquolikelyrsquo until imaging

Imaging

Venous ultrasound (VUS) is the first line DVT imaging modality(other imaging see Supplementary material online only section) It isbased on B-mode combined or not with color-Doppler US andpower imaging techniques DVT diagnostic criteria are cross-sectional vein incompressibility direct thrombus imaging with veinenlargement and abnormal spectral and color-Doppler flow VUScan be performed by examining popliteal and common femoral veinsonly [2-point2-region compression venous ultrasonography (CUS)or limited CUS] or by extended imaging of inferior vena cava iliac

Figure 1 Venous thromboembolism incidence according to age group

Table 1 Villalta score11

Symptoms and

Clinical signs

None Mild Moderate Severe

Symptoms

Pain 0 points 1 points 2 points 3 points

Cramps 0 points 1 points 2 points 3 points

Haeviness 0 points 1 points 2 points 3 points

Paresthesia 0 points 1 points 2 points 3 points

Pruritus 0 points 1 points 2 points 3 points

Clinical signs

Pretibial edema 0 points 1 points 2 points 3 points

Skin induration 0 points 1 points 2 points 3 points

Hyperpigmentation 0 points 1 points 2 points 3 points

Redness 0 points 1 points 2 points 3 points

Venous ectasia 0 points 1 points 2 points 3 points

Pain on calf

compression

0 points 1 points 2 points 3 points

Venous ulcer Absent Present

Points are summed into a total score (range 0ndash33) Post Thrombotic syndrome(PTS) is defined by a total score of gt_5 or the presence of a venous ulcer PTS isclassified as mild if Villalta score is 5ndash9 moderate if 10ndash14 and severe if gt_15 orvenous ulcer is present

2 L Mazzolai et al

and femoral veins and calf veins (whole-leg VUS or complete VUS)There are controversies as to whether explore symptomatic legonly or both1819

In clinically suspected DVT VUS provides overall sensitivity of942 for proximal and 635 for isolated distal DVT with an overallspecificity of 93820 Combination with color-Doppler US increasessensitivity but lowers specificity20 When DVT is suspected (withoutPE symptoms) anticoagulation may be safely withheld in patientswith a single normal complete VUS Same is true for limited CUS pro-vided it can be repeated and integrated within a diagnostic strategyincluding clinical probability and D-dimer assessment21 Overall 3-month VTE incidence rate after negative complete VUS is 05722

but both methods are reported to be equivalent in randomized tri-als2324 Complete VUS may be helpful to explain patientrsquos complaintby providing up to 42 alternative diagnosis25 Point-of care US per-formed by emergency physicians using limited CUS has shown goodperformance (961 sensitivity 968 specificity)26 and may be usefulif vascular laboratories are not available 247 provided its integrationin a validated diagnostic strategy27

In patients with clinically suspected recurrent DVT comparison oftest results with baseline imaging at discontinuation of anticoagulationcan safely rule out diagnosis of recurrence28 A 2- or 4-mm29ndash31 in-crease in vein diameter between two measurements at the commonfemoral and popliteal veins after full compression is the most vali-dated US criterion

Deep vein thrombosis with pulmonaryembolism symptomsDiagnostic approach is described in corresponding 2014 EuropeanSociety of Cardiology (ESC) Guidelines6 Proximal DVT confirmationin a normotensive patient with suspected PE essentially confirms VTEand justifies anticoagulation as after formal PE diagnosis In unstable pa-tients with right ventricular overload but no possibility to confirm PECUS showing proximal DVT facilitates initiation of reperfusion ther-apy CUS diagnostic yield is high in the presence of clinical DVTsigns32 Among unselected PE patients proximal DVT at CUS is foundin 17 patients33 Proximal DVT has high specificity and may justifytreatment even if pulmonary CT is negative6 While negative CUS can-not exclude PE it can justify withholding anticoagulation in patientswith non-diagnostic ventilationperfusion scan and PE-unlikely163435

In symptomatic patients with isolated sub-segmental PE or inciden-tal asymptomatic PE concomitant DVT justifies anticoagulation3637

Deep vein thrombosis imaging may also be useful if secondarily a pa-tient is suspected of VTE recurrence with DVT signs Moreoverpresence of concomitant DVT has been suggested as an independent30-days death risk factor following PE38

Consensus statement diagnosisbull Clinical prediction rule (two-level modified Wells score) is recom-

mended to stratify patients with suspected lower limb DVT

Figure 2 Proposed deep vein thrombosis diagnostic and management algorithm AC anticoagulation DOAC direct oral anticoagulant

Diagnosis and management of acute DVT 3

bull ELISA D-dimer measurement is recommended in lsquounlikelyrsquo clinicalprobability patients to exclude DVT

bull Venous US is recommended as first line imaging method for DVTdiagnosis

bull Venous CT scan should be reserved to selected patients onlybull Venous US should be proposed also in case of confirmed PE for

initial reference venous imaging useful in case of DVT recurrencesuspicion or further stratification in selected patients

bull Venous US may be considered for further stratification in selectedpatients with concomitant suspected PE

Initial (first 5ndash21 days) and long-term (first 3ndash6 months) phasemanagement

Deep vein thrombosis withoutpulmonary embolismAnticoagulation in non-cancer patients

Deep vein thrombosis treatment consists of three phases (Figure 3)39

Initial treatment (5ndash21 days following diagnosis) during this period pa-tients receive either parenteral therapy and are transited to vitamin K an-tagonists (VKA) or use high-dose direct oral anticoagulants (DOACs)Long-term treatment (following 3ndash6 months) patients are treated withVKA or DOACs39 Initial and long-term treatments are mandatory forall DVT patients Decision of extended treatment (beyond first 3ndash6months) is based on benefitrisk balance of continued anticoagulation

In patients with severe renal failure (creatinine clearance lt30 mLmin) unstable renal function or high bleeding risk iv unfractionatedheparin (UFH) may be preferable (short half-life and protamine sul-fate reversibility) Less solid is the evidence in favor of UFH in obese(BMI gt40 kgm2) and underweight patients (lt50 kg) Main disadvan-tage of UFH is its inter-individual dose variability requiring laboratorymonitoring and dose adjustment Additionally UFH is associatedwith high risk of heparin-induced thrombocytopenia For these rea-sons low-molecular weight heparin (LMWH) is the parenteral treat-ment of choice LMWHs are at least as effective as UFH and probablysafer40 Fondaparinux can also be used as parenteral agent41 BothLMWH and fondaparinux do not have specific antidote

Recently DOACs have emerged as valid options for DVT treat-ment39 Dabigatran and edoxaban were studied following initial 7ndash9days treatment with a parenteral agent Apixaban and rivaroxabanwere evaluated by the lsquosingle drug approachrsquo (Figure 3)

DOACs have longer elimination half-lives than UFH or LMWHand may accumulate in patients with suboptimal renal (creatinine

Initial treatment(first 5-21 days)

Long term treatment

(first 3-6 months)

Extended treatment

(following initial 3-6 months)

Apixaban 10 mg bid for 7 days Apixaban 5mg bid Apixaban 25mg bid beyond 6 months

Dabigatran 150 mg bid preceded by LMWH for 5-10 days

Edoxaban 60 mg od (30mg od if ClCreat lt50-30mlmin or concomitant potent P-P inhibitors) preceded by LMWH for 5-10 days

Rivaroxaban 15 mg od for 21 days Rivaroxaban 20mg od

VKA to achieve INR 2-3 preceded by LMWH for 5-10 days

Figure 3 Deep vein thrombosis treatment phases ClCreat creatinine clearance LMWH low molecular weight heparin P-P inhibitors protonpump inhibitors VKA vitamin K antantagonist

Table 2 The Wells score1213

Clinical variable Points

Active cancer (treatment ongoing or within previous 6

months or palliative)

thorn1

Paralysis paresis or recent plaster immobilization of

the lower extremities

thorn1

Recently bedridden for 3 days or more or major sur-

gery within the previous 12 weeks requiring general

or regional anesthesia

thorn1

Localized tenderness along the distribution of the deep

venous system

thorn1

Entire leg swelling thorn1

Calf swelling at least 3 cm larger than that on the

asymptomatic leg (measured 10 cm below the tibial

tuberosity)

thorn1

Pitting edema confined to the symptomatic leg thorn1

Collateral superficial veins (non varicose) thorn1

Previously documented DVT thorn1

Alternative diagnosis at least as likely as DVT -2

Three-level Wells score

Low lt1

Intermediate 1ndash2

High gt2

Two-level Wells score

Unlikely lt_1

Likely gt_2

4 L Mazzolai et al

clearance lt30 mLmin) or hepatic function (Child-Pugh class B or C)Patients with poor renal andor hepatic function pregnancylactationthrombocytopenia were excluded from Phase III studies Patientswith active cancer were scarcely represented (3ndash8 of entire studypopulation)

DOACs are at least as effective as and probably safer than paren-teral drugVKA treatment42 A meta-analysis (27023 patients)showed similar VTE recurrence rates in patients receiving DOACsor conventional therapy (20 vs 22 RR 090) Major bleeding (RR061) fatal bleeding (RR 036) intracranial bleeding (RR 037) andclinically relevant non-major bleeding (RR 073) were significantlylower in DOACs-treated patients42 DOACs reversal agents arebeing investigated Idarucizumab (Dabigatran reversal agent) is cur-rently available for clinical use4344

Thrombolysisthrombectomy

Early clot removal may prevent at least partly PTS developement45

Catheter-directed thrombolysis (CDT) is more efficient than sys-temic lysis mainly due to less bleeding as thrombolytic agent is directlyadministered within the clot Three major randomized controlled trialscompared different CDT modalities on top of anticoagulation andcompression with a control group (anticoagulation and compressiononly) The CAVENT trial included 209 patients with first-time acuteDVT (iliac common femoral andor upper femoral vein)46 AdjuvantCDT was associated with a 26 RR PTS reduction over 2 years (411vs 556 P = 004) compared with anticoagulation alone46 Amount ofresidual post-CDT thrombus correlated with venous patency rates at24-months (P = 004) Persistence of venous patency at 6 and 24months correlated with PTS freedom (P lt 0001) A 32 of patientshad major bleed but there were no intracranial bleeds or deathsOverall trial found no differences in long-term (2 years) quality of lifebetween patients with- or without CDT Results have been confirmedafter 5 years follow-up47

Mechanical thrombus removal alone is not successful and needsadjuvant thrombolytic therapy In PEARL I and II studies only 5 ofpatients were treated without thrombolytics48

Up to 83 of patients treated by any catheter-based therapy needadjunctive angioplasty and stenting49 Primary acute DVT stenting isnot recommended due to lack of data

Vena cava filter

Vena cava filter may be used when anticoagulation is absolutely con-traindicated in patients with newly diagnosed proximal DVT Onemajor complication is filter thrombosis Therefore anticoagulationshould be started as soon as contraindications resolve50 and retriev-able filter rapidly removed Filter placement in addition to anticoagu-lation does not improve survival5152 except in patients withhemodynamically unstable PE or after thrombolytic therapy53

Increased DVT recurrence has been shown with permanent51 butnot with retrievable filters52

Compression

Goal of compression is to relieve venous symptoms and eventuallyprevent PTS54

Elastic compression stockings efficacy has been challenged by theSOX trial55 A total of 806 patients with proximal DVT have been

randomized to either 30ndash40 mmHg or placebo (lt5 mmHg) stock-ings Cumulative 2 years PTS incidence was similar (526 vs 523HR= 10) No difference in PTS severity or quality-of-life was observ-ed55 However compliance definition (stockings wearing for gt_3 daysweek) was significantly lower than in previous studies (56vs90)56 Although role of stockings in PTS prevention may be un-certain their use remains a reasonable option for controlling symp-toms of acute proximal DVT57

Compression associated with early mobilization and walking exer-cise has shown significant efficacy in venous symptom relieve in pa-tients with acute DVT58 Caution should be used in patients withsevere peripheral artery disease

Home vs in-hospital management

Most patients with DVT may be treated on a home basis (seeSupplementary material online only section)

Deep vein thrombosis with pulmonaryembolismManagement of patients with acute PE is described in the 2014 ESCguideline6 (summary in the see Supplementary material online onlysection)

Isolated distal deep vein thrombosisWhether isolated distal DVT should be treated with anticoagulationis still debated A recent trial randomized patients with a first isolateddistal DVT to LMWH or placebo for 42 days59 Rate of symptomaticproximal DVT or PE at 42 days was not different between LMWHand placebo (33 vs 54) major or clinically relevant non-majorbleeding occurred more frequently in the LMWH group (5 vs 0P = 003) These data seem to support that not all isolated distal DVTshould receive full-dose anticoagulation

Approach is to anticoagulate full-dose for at least 3 months as forproximal DVTs patients at high-risk VTE (Table 3)60 Shorter LMWHtreatment (4ndash6 weeks) even at lower doses or ultrasound surveil-lance could be effective and safe in low-risk patients (Table 3)61 Nodata are available on DOACs All patients with acute isolated distalDVT should be recommended to wear elastic stockings6263 Follow-up VUS is recommended to monitor thrombosis progressionevolu-tion both in the presence or absence of anticoagulation

Incidence of recurrent VTE appears to be similar to that of patientswith proximal DVT6465

Consensus statement initial and long-term

managementbull Patients with proximal DVT should be anticoagulated for at least

3-monthsbull Patients with isolated distal DVT at high-risk of recurrence should

be anticoagulated as for proximal DVT for those at low risk ofrecurrence shorter treatment (4ndash6 weeks) even at lower anti-coagulant doses or ultrasound surveillance may be considered

bull In the absence of contraindications DOACs should be preferredas first-line anticoagulant therapy in non-cancer patients with prox-imal DVT

bull Adjuvant CDT may be considered in selected patients with ilio-common femoral DVT symptoms lt14 days and life expectancygt1 year if performed in experienced centres


bull Primary acute DVT stenting or mechanical thrombus removalalone are not recommended

bull Vena cava filters may be considered if anticoagulation is contraindi-cated their use in addition to anticoagulation is notrecommended

bull Compression therapy associated with early mobilization and walk-ing exercise should be considered to relieve acute venoussymptoms

Extended phase management(beyond first 3ndash6 months)

Duration of anticoagulationOnce anticoagulation is stopped risk of VTE recurrence over yearsafter a first episode is consistently around 3066 Risk is more thandoubled in patients with unprovoked (annual rate gt70) vs those with(transient) provoked VTE67 and among the latter in medical ratherthan surgical patients68 Patients with a first symptomatic unprovokedDVT are at higher risk of recurrence than those with a first unpro-voked PE69 Factors related to DVT recurrence are listed in Table 4

For proximal DVT andor PE 3-months anticoagulation is the bestoption if transient and reversible risk factors were present70 In allother patients prolonging anticoagulation protects from recurrence(70ndash90) but exposes to risk of unpredictable bleeding complica-tions Decision to discontinue or not anticoagulation should there-fore be individually tailored and balanced against bleeding risk takingalso into account patientsrsquo preferences Three clinical prediction ruleshave been derived and prospectively validated to detect low-recurrence risk patients (Table 4)71 A number of bleeding scoreswere evaluated none showed sufficient predictive accuracy or hadsufficient validation to be recommended in routine clinicalpractice7273

Table 3 Conditions or risk factors for complicationsafter a first isolated distal DVT

High-risk conditions Low-risk conditions

Previous VTE events Isolated distal DVT second-

ary to surgery or other

transient risk factors (plas-

ters immobilization

trauma long trip etc)

provided complete

mobilization is achieved

Males Isolated distal DVT occurring

during contraceptive or

replacement hormonal

therapy (provided therapy

has been interrupted)

Age gt50 years

Cancer

Unprovoked isolated distal DVT

Secondary isolated distal DVT with

persistently hampered mobilization

Isolated distal DVT involving the

popliteal trifurcation

Isolated distal DVT involving gt1 calf vein

Isolated distal DVT present in both legs

Presence of predisposing diseases

(eg inflammatory bowel diseases)

Known thrombophilic alterations

Axial vs Muscular isolated distal DVT

Table 4 Risk of recurrence after a first episode of unprovoked VTE

Risk factors for DVTrecurrence

Proximal DVT location Male sex Persistence of residual vein thrombosis at ultrasound

Obesity Non-zero blood group High D-dimer values

Old age Early PTS development Role of inherited thrombophilia is controversial

Clinical prediction rules assessing risk of recurrent VTE after first episode of unprovoked VTE71

Score Vienna prediction model DASH score HERDOO-2

Parameters bull D-dimer level at 3 weeks

and 3 9 15 24 months after

stopping anticoagulationbull Male sexbull VTE location (Distal DVT

Proximal DVT PE)

bull Abnormal D-dimer 3ndash5 weeks after

stopping anticoagulationbull Male sexbull Agelt50 yearsbull VTE not associated with

oestrogen-progestatif therapy

in women

bull Abnormal D-dimer before

stopping anticoagulationbull Post thrombotic symptoms

(hyperpigmentation edema

and redness)bull Age gt_65 yearsbull BMI gt_30

Validation study Yes Yes Yes

Commentaries Different nomograms are available

to calculate risk of VTE recurrence

at different time

Patients with low score (lt_1) have

an annual

recurrence rate of 31

It is applicable in women only

Women with low score (lt_1)

have an annual recurrence rate of 13

6 L Mazzolai et al

Continuing indefinite anticoagulation with the same drug adminis-

tered during the first months is the best option for patients with mul-tiple VTE episodes or strong VTE familial history those with majorthrombophilia or longstanding medical diseases at high thromboticrisk70 Indefinite anticoagulation can also be considered in patientswith first episode of unprovoked VTE especially in those with severepresentation provided they are at low bleeding risk70 Finally discon-tinuing anticoagulation in non-cancer patients with repeatedly nega-tive D-dimer (before drug interruption 15 30 60 and 90 daysfollowing interruption) has proved to be safe in patients with unpro-voked proximal DVT provided veins are recanalized or remained sta-ble for 1 year74 However using moderately sensitive D-dimer assayduring and 30 days after stopping anticoagulation these results werenot confirmed in men and in women with VTE not associated withoestrogen treatment75 Similarly when measurements were re-peated using a quantitative assay D-dimer testing failed to identifysubgroups with very low recurrence rate76

AntithromboticsVitamin K antagonists

Four randomized studies evaluated VKA [target international normal-ized ratio (INR) 20ndash30] for VTE extended treatment in patientscompleting 3-months anticoagulation77ndash80 Recurrent VTE occurredless in the VKA groups (combined OR 007)81 Bleeding was signifi-cantly higher81

The ELATE study82 randomized patients to conventional intensity(INR 20ndash30) or low-intensity (INR 15ndash1ndash9) Recurrence rate was07 vs 19100 patient-years respectively (HR 28) with no differencein major bleeding Yet the low-intensity VKA therapy should bediscouraged

Direct oral anticoagulants

Dabigatran (150 mg bid) was as effective as warfarin and more ef-fective than placebo in preventing recurrent VTE (Table 5) Risk ofmajor bleeding was reduced compared with warfarin83

With Rivaroxaban (20 mg od) risk of VTE recurrence was lowercompared with placebo (HR 019) while bleeding risk was notincreased (Table 5)84

VTE recurrence occurred significantly less in standard and lowerdose apixaban (5 and 25 mg bid) vs placebo (Table 5) Bleeding didnot differ between groups85

Recurrence rates with Edoxaban 60 mg were similar to thewarfarin-treated group (post hoc analysis) (Table 5)86 Major bleedingwas lower in the edoxaban group

Data from Phase IV studies are scarce but results from XALIA areconsistent with observations of rivaroxaban and warfarin87

Aspirin

Two studies investigated aspirin 100 mg vs placebo in patients withidiopathic VTE who completed initial anticoagulation treatment8889

Pooled HR for VTE recurrence was 068 and 147 for bleeding90

Other

Recent evaluation of Sulodexide vs placebo in patients with unpro-voked VTE who completed standard course of anticoagulation

showed a HR for VTE recurrence of 049 (P = 002)91 No majorbleeding episodes were observed

Venous occlusion recanalizationEndovascular techniques are available for selected patients withPTS57 Case series and prospective cohort trials suggest that at leastsome subgroups of PTS patients (CEAP classes 4ndash6 Figure 4) maybenefit from addition of endovascular therapy into overall manage-ment strategy

In patients with moderate-to-severe PTS and iliac vein obstructionendovascular stent placement may be used to restore vein patencyIn preliminary studies stent placement in chronically occluded iliacveins contributed to ulcers healing PTS symptoms relief and reducedobstructive venous sequel92

No randomized controlled trials are available the largest seriesfound patients with moderate-to-severe PTS to have reduced pain(P lt 00001) severe pain (from 41 to 11) and severe swelling(from 36 to 18) increased ulcer healing (68) and reduced ven-ous pressure following recanalization with stent placement92

Claudication improvement better outflow fraction and calf pumpfunction was also observed93

In selected infrequent cases surgical vein bypass may be an optionto relieve venous hypertension

Follow-upPatients with DVT should be followed to avoid risk of recurrence aswell as DVT and anticoagulation-related complicationsDevelopment of renal failure changes in body weight or pregnancythat may require anticoagulation adjustment should be monitoredCompliance as well as benefitrisk balance should be assessed regu-larly VUS prior to anticoagulation discontinuation is useful in deter-mining baseline residual vein thrombosis

Consensus statement extended managementbull Decision to discontinue or not anticoagulation should be individu-

ally tailored balancing risk of recurrence against bleeding risk tak-ing into account patientsrsquo preferences and compliance

bull In the absence of contraindications DOACs should be preferredas first line anticoagulant therapy in non-cancer patients

bull When VKAs are proposed they should be administered at con-ventional intensity regimen (INR 2ndash3)

bull Aspirin may be considered for extended treatment if anticoagula-tion is contraindicated

bull Endovascular recanalization may be considered in patients withchronic venous occlusion class CEAP 4ndash6

bull Regular (at least yearly) assessment of compliance and benefitriskbalance should be performed in patients on extended treatment

bull Prior to anticoagulation discontinuation venous US should be per-formed to establish a baseline comparative exam in case ofrecurrence

Special situations

Upper extremities deep vein thrombosisUpper extremities DVT (UEDVT) accounts for 10 of all DVTs withan annual incidence of 04ndash1010000 persons9495 Incidence risesbecause of increasing use of central venous catheters cardiac


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8 L Mazzolai et al

pacemakers and defibrillators9495 Complications are similaralthough less frequent to those of lower limb DVT9495 About 20ndash30 of UEDVT are primary comprising those caused by anatomicabnormalities or following sustained physical efforts96 SecondaryDVT include venous catheter- and devices-related complicationscancer pregnancy and recent armshoulder surgery or trauma Mostcommon clinical presentation includes pain swelling and skin discol-oration A clinical decision score has been proposed (Table 6)97

D-Dimer showed good negative predictive value in symptomaticDVT9899 VUS is the first choice exam for diagnosis100

A diagnostic algorithm using Constans score D-dimer and VUS wasproposed99 Contrast- CT- and MR-venography are not recom-mended for diagnosis but limited to unresolved selected cases95

Anticoagulation is similar to that of lower limb DVT Thrombolysis isnot routinely recommended but limited to selected severe cases Aprognostic score identifying low-risk DVT patients who could be safelytreated at home has been proposed but not yet externally validated101

Deep vein thrombosis at unusual sitesCerebral vein thrombosis

Most common cerebral vein thrombosis (CVT) presentation includessevere headaches seizures focal neurological deficits and altered

consciousness102103 For the diagnosis and treatment refer to theSupplementary material online only section

Splanchnic vein thrombosis

Splanchnic vein thrombosis may present as sudden onset of abdom-inal pain with or without other non-specific abdominal symp-toms104105 Upper gastrointestinal bleeding or abrupt ascitesworsening may occur in cirrhotic patients lower gastrointestinalbleeding or acute abdomen may occur in patients with mesentericvein thrombosis104 For the diagnosis and treatment refer to theSupplementary material online only section

Deep vein thrombosis and cancerCancer patients show four- to seven-fold increased VTE risk (secondcause of death) Incidental VTE is increasingly diagnosed and associ-ated with worse overall survival VTE risk varies from cancer diagno-sis through treatment with annual incidence rate of 05ndash20according to cancer site and type metastasis status treatment (sur-gery chemotherapy) use of central venous catheters hospitalizationand patient-related factor Risk-assessment models may help stratifyindividual VTE risk and tailor adequate therapy (Table 6)106ndash108

Cancer-related VTE is at high risk of recurrence and bleeding dur-ing treatment risk of death increases up to eight-fold following acuteVTE compared with non-cancer patients LMWH is recommendedfor initial treatment (similar efficacy and higher safety than UFH)Fondaparinux in patients with history of heparin-induced thrombo-cytopenia and UFH in case of renal failure are valid alternatives Venacava filter and thrombolysis should only be considered on a case-by-case basis For long-term treatment superiority of LMWH overshort-term heparin followed by VKA is well documented LMWHused during at least 3 and up to 6 months when compared with VKAsignificantly reduced VTE recurrence with similar safety profile After

Table 6 Constans and Khorana clinical decisionscore97106

Risk

score

Constans score item

Central venous catheter or pacemaker thread 1

Localized pain 1

Unilateral edema 1

Other diagnosis at least as plausible -1

Khorana score patient characteristic

Site of cancer

Very high risk (stomach pancreas) 2

High risk (lung lymphoma gynecologic bladder testicular) 1

Pre-chemotherapy platelet count 350 109L or more 1

Hemoglobin level lt10 gdL or use of red cell growth factors 1

Pre-chemotherapy leukocyte count gt11 109L 1

BMI gt_35 kgm2 1

Constans score Score lt_1 = Upper extremity DVT unlikelyScore gt_2 = Upper extremity DVT likelyKhorana score Score gt_ 3= high risk Score 1ndash2= intermediate risk Score 0= lowrisk

Figure 4 Chronic venous disorders clinical classification (CEAP)


6 months termination or continuation of anticoagulation should beindividually evaluated benefitndashrisk ratio tolerability patientsrsquo prefer-ence and cancer activity109

In symptomatic catheter-related thrombosis anticoagulation is recom-mended for at least 3-months LMWHs are suggested although VKAscan also be used (no direct comparison available) Central-vein-catheter can be maintained in place if it is functional non-infectedand there is good thrombosis resolution Optimal anticoagulationduration has not been determined however 3-months durationseems acceptable in analogy with upper extremity DVT (UEDVT)109

For VTE recurrence under proper anticoagulation (INR antiXa withintherapeutical range) 3 options are recommended (i) switch fromVKA to LMWH in patients treated with VKA (ii) increase weight-adjusted dose of LMWH by 20ndash25 (iii) vena cava filter use althoughno specific results are available for cancer patients

No direct comparison of DOACs with LMWH is currently avail-able Nevertheless data from recent large VTE trials showed non-inferiority in terms of efficacy and safety of DOACs compared withAVK in cancer patients included in the studies110

Deep vein thrombosis in pregnancyVTE remains the leading cause of maternal mortality in industrializedworld111 VTE risk factors are listed in Table 7 Validity of DVT clinicalprediction rules in pregnancy has not yet been tested prospectively112

The LEFt clinical score was proposed112 Although D-dimers increaseduring pregnancy normal values exclude VTE with likelihood similar tonon-pregnant women6 VUS is the primary imaging test113114 Unlesscontraindicated anticoagulation should be initiated until objective test-ing114115 If VUS is negative but clinical suspicion high testing should berepeated116117 Rarely CT or MRI venography may be considered

Treatment is based on heparin anticoagulation (no placenta cross-ing and not significantly found in breast milk)6 LMWHs are safe inpregnancy118ndash120 anti-Xa monitoring and dose adaptation cannot berecommended routinely but may be considered in women at ex-tremes of body-weight or renal disease6 Whether initial full doseanticoagulation can be reduced to intermediate dose for secondaryprevention during ongoing pregnancy remains unclear119 Dose re-duction should be considered for women at high risk of bleedingosteoporosis or low VTE recurrence risk115 Evidence is insufficientto recommend od or bid LMWH but bid may be more suitableperinatally to avoid high anti-Xa levels at time of deliveryAnticoagulation should be continued for at least 6 weeks postnatallyand until at least a total of 3 months treatment116

Consensus statement DVT management in special

situationsbull In case of UEDVT suspicion venous US is the first choice imaging

testbull Treatment of UEDVT is similar to that of lower limb DVT with

regard to anticoagulationbull LMWH are recommended for acute treatment of CVTbull LMWH are recommended for acute treatment of splanchnic vein

thrombosisbull LMWH are recommended for initial and long-term treatment in

cancer patientsbull In cancer patients after 6 months decision of continuation and if

so the mode of anticoagulation should be based on individualevaluation of the benefit-risk ratio tolerability patientsrsquo preferenceand cancer activity

bull During pregnancy venous US is recommended as first line DVTimaging test

bull During pregnancy LMWH is recommended for initial and long-term treatment

bull Anticoagulant treatment should be continued for at least 6 weeksafter delivery with a total of 3-months treatment

Supplementary material

Supplementary material is available at European Heart Journal online

Conflict of interest none declared

References1 Silverstein MD Heit JA Mohr DN Petterson TM Orsquofallon WM Melton LJ III

Trends in the incidence of deep vein thrombosis and pulmonary embolism a25-year population-based study Arch Intern Med 1998158585ndash593

2 Heit JA The epidemiology of venous thromboembolism in the communityArterioscler Thromb Vasc Biol 200828370ndash372

3 White RH Zhou H Romano PS Incidence of idiopathic deep venous throm-bosis and secondary thromboembolism among ethnic groups in California AnnIntern Med 1998128737ndash740

4 White RH The epidemiology of venous thromboembolism Circulation2003107(23 Suppl 1)I4ndashI8

5 Raskob GE Angchaisuksiri P Blanco AN Buller H Gallus A Hunt BJ HylekEM Kakkar A Konstantinides SV McCumber M Ozaki Y Wendelboe A WeitzJI Day ISCfWT Thrombosis a major contributor to global disease burdenArterioscler Thromb Vasc Biol 2014342363ndash2371

6 Konstantinides SV Torbicki A Agnelli G Danchin N Fitzmaurice D Galie NGibbs JS Huisman MV Humbert M Kucher N Lang I Lankeit M Lekakis JMaack C Mayer E Meneveau N Perrier A Pruszczyk P Rasmussen LHSchindler TH Svitil P Vonk Noordegraaf A Zamorano JL Zompatori M TaskForce for the D Management of Acute Pulmonary Embolism of the EuropeanSociety of Cardiology 2014 ESC guidelines on the diagnosis and managementof acute pulmonary embolism Eur Heart J 2014353033ndash3069

7 Galanaud JP Kahn SR Khau Van Kien A Laroche JP Quere I [Epidemiology and man-agement of isolated distal deep venous thrombosis] La Revue De Medecine InterneFondee Par La Societe Nationale Francaise De Medecine Interne 201233678ndash685

8 Mearns ES Coleman CI Patel D Saulsberry WJ Corman A Li D HernandezAV Kohn CG Index clinical manifestation of venous thromboembolism pre-dicts early recurrence type and frequency a meta-analysis of randomized con-trolled trials J Thromb Haemost 2015131043ndash1052

9 Prandoni P Kahn SR Post-thrombotic syndrome prevalence prognosticationand need for progress Br J Haematol 2009145286ndash295

10 Baldwin MJ Moore HM Rudarakanchana N Gohel M Davies AH Post-throm-botic syndrome a clinical review J Thromb Haemost 201311795ndash805

11 Soosainathan A Moore HM Gohel MS Davies AH Scoring systems for thepost-thrombotic syndrome J Vasc Surg 201357254ndash261

12 Wells PS Hirsh J Anderson DR Lensing AW Foster G Kearon C Weitz JDrsquoovidio R Cogo A Prandoni P Accuracy of clinical assessment of deep-veinthrombosis Lancet 19953451326ndash1330

13 Wells PS Anderson DR Rodger M Forgie M Kearon C Dreyer J Kovacs GMitchell M Lewandowski B Kovacs MJ Evaluation of D-dimer in the diagnosisof suspected deep-vein thrombosis N Engl J Med 20033491227ndash1235

Table 7 VTE risk factors during pregnancy

Prior VTE Preterm delivery

Smoking Pre-eclampsia

Varicosis Caesarean section (specifically in the

emergency situation)

Hyperemesis Postpartum infection or hemorrhage

severe thrombophilia Transfusion

assisted reproductive

technology

Immobilization

BMI gt30 kgm2 Systemic lupus erythematosus

10 L Mazzolai et al

14 Geersing GJ Zuithoff NP Kearon C Anderson DR Ten Cate-Hoek AJ Elf JL

Bates SM Hoes AW Kraaijenhagen RA Oudega R Schutgens RE Stevens SMWoller SC Wells PS Moons KG Exclusion of deep vein thrombosis using theWells rule in clinically important subgroups individual patient data meta-ana-lysis BMJ 2014348g1340

15 Righini M Perrier A De Moerloose P Bounameaux H D-Dimer for venousthromboembolism diagnosis 20 years later J Thromb Haemost200861059ndash1071

16 Perrier A Desmarais S Miron MJ de Moerloose P Lepage R Slosman DDidier D Unger PF Patenaude JV Bounameaux H Non-invasive diagnosis ofvenous thromboembolism in outpatients Lancet 1999353190ndash195

17 Di Nisio M Sohne M Kamphuisen PW Buller HR D-Dimer test in cancer pa-tients with suspected acute pulmonary embolism J Thromb Haemost200531239ndash1242

18 Le Gal G Robert-Ebadi H Carrier M Kearon C Bounameaux H Righini M Is ituseful to also image the asymptomatic leg in patients with suspected deep veinthrombosis J Thromb Haemost 201513563ndash566

19 Galanaud JP Sevestre MA Genty C Pernod G Quere I Bosson JL Is it usefulto also image the asymptomatic leg in patients with suspected deep vein throm-bosis Comment J Thromb Haemost 2015132127ndash2130

20 Goodacre S Sampson F Thomas S van Beek E Sutton A Systematic reviewand meta-analysis of the diagnostic accuracy of ultrasonography for deep veinthrombosis BMC Med Imaging 200556

21 Ageno W Camporese G Riva N Iotti M Bucherini E Righini M KamphuisenPW Verhamme P Douketis JD Tonello C Prandoni P Analysis of an algorithmincorporating limited and whole-leg assessment of the deep venous system insymptomatic outpatients with suspected deep-vein thrombosis (PALLADIO) aprospective multicentre cohort study Lancet Haematol 20152e474ndashe480

22 Johnson SA Stevens SM Woller SC Lake E Donadini M Cheng J Labarere JDouketis JD Risk of deep vein thrombosis following a single negative whole-legcompression ultrasound a systematic review and meta-analysis JAMA2010303438ndash445

23 Bernardi E Camporese G Buller HR Siragusa S Imberti D Berchio AGhirarduzzi A Verlato F Anastasio R Prati C Piccioli A Pesavento R Bova CMaltempi P Zanatta N Cogo A Cappelli R Bucherini E Cuppini S Noventa FPrandoni P Serial 2-point ultrasonography plus D-dimer vs whole-leg color-coded Doppler ultrasonography for diagnosing suspected symptomatic deepvein thrombosis a randomized controlled trial JAMA 20083001653ndash1659

24 Gibson NS Schellong SM Kheir DY Beyer-Westendorf J Gallus AS McRae SSchutgens RE Piovella F Gerdes VE Buller HR Safety and sensitivity of twoultrasound strategies in patients with clinically suspected deep venous throm-bosis a prospective management study J Thromb Haemost 200972035ndash2041

25 Elias A Mallard L Elias M Alquier C Guidolin F Gauthier B Viard A MahouinP Vinel A Boccalon H A single complete ultrasound investigation of the ven-ous network for the diagnostic management of patients with a clinically sus-pected first episode of deep venous thrombosis of the lower limbs ThrombHaemost 200389221ndash227

26 Pomero F Dentali F Borretta V Bonzini M Melchio R Douketis JD FenoglioLM Accuracy of emergency physician-performed ultrasonography in the diag-nosis of deep-vein thrombosis a systematic review and meta-analysis ThrombHaemost 2013109137ndash145

27 Lewiss RE Kaban NL Saul T Point-of-care ultrasound for a deep venousthrombosis Glob Heart 20138329ndash333

28 Hamadah A Alwasaidi T Leg G Carrier M Wells PS Scarvelis D Gonsalves CForgie M Kovacs MJ Rodger MA Baseline imaging after therapy for unpro-voked venous thromboembolism a randomized controlled comparison of base-line imaging for diagnosis of suspected recurrence J Thromb Haemost201192406ndash2410

29 Prandoni P Cogo A Bernardi E Villalta S Polistena P Simioni P Noventa FBenedetti L Girolami A A simple ultrasound approach for detection of recur-rent proximal-vein thrombosis Circulation 1993881730ndash1735

30 Prandoni P Lensing AW Bernardi E Villalta S Bagatella P Girolami A Thediagnostic value of compression ultrasonography in patients with suspected re-current deep vein thrombosis Thromb Haemost 200288402ndash406

31 Le Gal G Kovacs MJ Carrier M Do K Kahn SR Wells PS Anderson DAChagnon I Solymoss S Crowther M Righini M Perrier A White RH Vickars LRodger M Validation of a diagnostic approach to exclude recurrent venousthromboembolism J Thromb Haemost 20097752ndash759

32 Pollack CV Schreiber D Goldhaber SZ Slattery D Fanikos J Orsquoneil BJThompson JR Hiestand B Briese BA Pendleton RC Miller CD Kline JAClinical characteristics management and outcomes of patients diagnosed withacute pulmonary embolism in the emergency department initial report ofEMPEROR (Multicenter Emergency Medicine Pulmonary Embolism in the RealWorld Registry) J Am Coll Cardiol 201157700ndash706

33 Da Costa Rodrigues J Alzuphar S Combescure C Le Gal G Perrier ADiagnostic characteristics of lower limb venous compression ultrasonography

in suspected pulmonary embolism a meta-analysis J Thromb Haemost2016141765ndash1772

34 Wells PS Ginsberg JS Anderson DR Kearon C Gent M Turpie AG BormanisJ Weitz J Chamberlain M Bowie D Barnes D Hirsh J Use of a clinical modelfor safe management of patients with suspected pulmonary embolism AnnIntern Med 1998129997ndash1005

35 Anderson DR Kahn SR Rodger MA Kovacs MJ Morris T Hirsch A Lang EStiell I Kovacs G Dreyer J Dennie C Cartier Y Barnes D Burton E PleasanceS Skedgel C Orsquorouke K Wells PS Computed tomographic pulmonary angiog-raphy vs ventilation-perfusion lung scanning in patients with suspected pulmon-ary embolism a randomized controlled trial JAMA 20072982743ndash2753

36 Carrier M Righini M Wells PS Perrier A Anderson DR Rodger MA PleasanceS Le Gal G Subsegmental pulmonary embolism diagnosed by computed tom-ography incidence and clinical implications A systematic review and meta-analysis of the management outcome studies J Thromb Haemost201081716ndash1722

37 Dentali F Ageno W Becattini C Galli L Gianni M Riva N Imberti D SquizzatoA Venco A Agnelli G Prevalence and clinical history of incidental asymptom-atic pulmonary embolism a meta-analysis Thromb Res 2010125518ndash522

38 Becattini C Cohen AT Agnelli G Howard L Castejon B Trujillo-Santos JMonreal M Perrier A Yusen RD Jimenez D Risk stratification of patients withacute symptomatic pulmonary embolism based on presence or absence oflower extremity DVT systematic review and meta-analysis Chest2016149192ndash200

39 Becattini C Agnelli G Treatment of venous thromboembolism with new anti-coagulant agents J Am Coll Cardiol 2016671941ndash1955

40 Erkens PM Prins MH Fixed dose subcutaneous low molecular weight heparinsversus adjusted dose unfractionated heparin for venous thromboembolismCochrane Database Syst Rev 20109Cd001100

41 Buller HR Davidson BL Decousus H Gallus A Gent M Piovella F Prins MHRaskob G van den Berg-Segers AE Cariou R Leeuwenkamp O Lensing AWSubcutaneous fondaparinux versus intravenous unfractionated heparin in theinitial treatment of pulmonary embolism N Engl J Med 20033491695ndash1702

42 van Es N Coppens M Schulman S Middeldorp S Buller HR Direct oral anti-coagulants compared with vitamin K antagonists for acute venous thrombo-embolism evidence from phase 3 trials Blood 20141241968ndash1975

43 Pollack CV Jr Reilly PA Eikelboom J Glund S Verhamme P Bernstein RADubiel R Huisman MV Hylek EM Kamphuisen PW Kreuzer J Levy JH SellkeFW Stangier J Steiner T Wang B Kam CW Weitz JI Idarucizumab forDabigatran reversal N Engl J Med 2015373511ndash520

44 Siegal DM Curnutte JT Connolly SJ Lu G Conley PB Wiens BL Mathur VSCastillo J Bronson MD Leeds JM Mar FA Gold A Crowther MA AndexanetAlfa for the reversal of factor Xa inhibitor activity N Engl J Med20153732413ndash2424

45 Alesh I Kayali F Stein PD Catheter-directed thrombolysis (intrathrombus in-jection) in treatment of deep venous thrombosis a systematic review CatheterCardiovasc Interv 200770143ndash148

46 Enden T Haig Y Klow NE Slagsvold CE Sandvik L Ghanima W Hafsahl GHolme PA Holmen LO Njaastad AM Sandbaek G Sandset PM CaVen TSGLong-term outcome after additional catheter-directed thrombolysis versusstandard treatment for acute iliofemoral deep vein thrombosis (the CaVenTstudy) a randomised controlled trial Lancet 201237931ndash38

47 Haig Y Enden T Grotta O Klow NE Slagsvold CE Ghanima W Sandvik LHafsahl G Holme PA Holmen LO Njaaastad AM Sandbaek G Sandset PMPost-thrombotic syndrome after catheter-directed thrombolysis for deep veinthrombosis (CaVenT) 5-year follow-up results of an open-label randomisedcontrolled trial Lancet Haematol 20163e64ndashe71

48 Garcia MJ Lookstein R Malhotra R Amin A Blitz LR Leung DA Simoni EJSoukas PA Endovascular management of deep vein thrombosis with rheolyticthrombectomy final report of the prospective multicenter PEARL (peripheraluse of angiojet rheolytic thrombectomy with a variety of catheter lengths)registry J Vasc Interv Radiol 201526777ndash785 Quiz 786

49 Engelberger RP Spirk D Willenberg T Alatri A Do DD Baumgartner IKucher N Ultrasound-assisted versus conventional catheter-directed thromb-olysis for acute iliofemoral deep vein thrombosis Circ Cardiovasc Interv 20158

50 Ray CE Jr Prochazka A The need for anticoagulation following inferior venacava filter placement systematic review Cardiovasc Interv Radiol200831316ndash324

51 PREPIC Study Group Eight-year follow-up of patients with permanent venacava filters in the prevention of pulmonary embolism the PREPIC (Preventiondu Risque drsquoEmbolie Pulmonaire par Interruption Cave) randomized studyCirculation 2005112416ndash422

52 Mismetti P Laporte S Pellerin O Ennezat PV Couturaud F Elias A Falvo NMeneveau N Quere I Roy PM Sanchez O Schmidt J Seinturier C SevestreMA Beregi JP Tardy B Lacroix P Presles E Leizorovicz A Decousus H BarralFG Meyer G Effect of a retrievable inferior vena cava filter plus anticoagulation


vs anticoagulation alone on risk of recurrent pulmonary embolism a random-ized clinical trial JAMA 20153131627ndash1635

53 Stein PD Matta F Keyes DC Willyerd GL Impact of vena cava filters on in-hospital case fatality rate from pulmonary embolism Am J Med2012125478ndash484

54 Kearon C Akl EA Comerota AJ Prandoni P Bounameaux H Goldhaber SZNelson ME Wells PS Gould MK Dentali F Crowther M Kahn SR AmericanCollege of Chest Physicians Antithrombotic therapy for VTE disease antith-rombotic therapy and prevention of thrombosis 9th ed American Collegeof Chest Physicians Evidence-Based Clinical Practice Guidelines Chest2012141(2 Suppl)e419Sndashe494S

55 Kahn SR Shapiro S Wells PS Rodger MA Kovacs MJ Anderson DR TagalakisV Houweling AH Ducruet T Holcroft C Johri M Solymoss S Miron MJ YeoE Smith R Schulman S Kassis J Kearon C Chagnon I Wong T Demers CHanmiah R Kaatz S Selby R Rathbun S Desmarais S Opatrny L Ortel TLGinsberg JS Compression stockings to prevent post-thrombotic syndrome arandomised placebo-controlled trial Lancet 2014383880ndash888

56 Brandjes DP Buller HR Heijboer H Huisman MV de Rijk M Jagt H ten CateJW Randomised trial of effect of compression stockings in patients with symp-tomatic proximal-vein thrombosis Lancet 1997349759ndash762

57 Kahn SR Comerota AJ Cushman M Evans NS Ginsberg JS Goldenberg NAGupta DK Prandoni P Vedantham S Walsh ME Weitz JI American HeartAssociation Council on Peripheral Vascular Disease CoCC Council on CStroke N The postthrombotic syndrome evidence-based prevention diagnosisand treatment strategies a scientific statement from the American HeartAssociation Circulation 20141301636ndash1661

58 Partsch H Blattler W Compression and walking versus bed rest in the treat-ment of proximal deep venous thrombosis with low molecular weight heparinJ Vasc Surg 200032861ndash869

59 Righini M Galanaud JP Guenneguez H Brisot D Diard A Faisse P BarrelierMT Desnos CH Jurus C Pichot O Martin M Mazzolai L Choquenet CAccassat S Carrier M Gal GL Mermillod B Laroche JP Bounameaux HPerrier A Kahn S Quere I Anticoagulant therapy for symptomatic distal deepvein thrombosis The cactus randomized placebocontrolled trial J ThrombHaemost 20151350

60 Palareti G How I treat isolated distal deep vein thrombosis (IDDVT) Blood20141231802ndash1809

61 Parisi R Visona A Camporese G Verlato F Lessiani G Antignani PL PalaretiG Isolated distal deep vein thrombosis efficacy and safety of a protocol oftreatment Treatment of Isolated Calf Thrombosis (TICT) Study Int Angiol20092868ndash72

62 Schwarz T Buschmann L Beyer J Halbritter K Rastan A Schellong S Therapyof isolated calf muscle vein thrombosis a randomized controlled study J VascSurg 2010521246ndash1250

63 Palareti G Cosmi B Lessiani G Rodorigo G Guazzaloca G Brusi C Valdre LConti E Sartori M Legnani C Evolution of untreated calf deep-vein thrombosisin high risk symptomatic outpatients the blind prospective CALTHRO studyThromb Haemost 20101041063ndash1070

64 Galanaud JP Sevestre MA Genty C Kahn SR Pernod G Rolland C Diard ADupas S Jurus C Diamand JM Quere I Bosson JL Incidence and predictors ofvenous thromboembolism recurrence after a first isolated distal deep veinthrombosis J Thromb Haemost 201412436ndash443

65 Sartori M Migliaccio L Favaretto E Palareti G Cosmi B Two years outcome ofisolated distal deep vein thrombosis Thromb Res 201413436ndash40

66 Boutitie F Pinede L Schulman S Agnelli G Raskob G Julian J Hirsh J KearonC Influence of preceding length of anticoagulant treatment and initial presenta-tion of venous thromboembolism on risk of recurrence after stopping treat-ment analysis of individual participantsrsquo data from seven trials BMJ2011342d3036

67 Prandoni P Noventa F Ghirarduzzi A Pengo V Bernardi E Pesavento R IottiM Tormene D Simioni P Pagnan A The risk of recurrent venous thrombo-embolism after discontinuing anticoagulation in patients with acute proximaldeep vein thrombosis or pulmonary embolism A prospective cohort study in1626 patients Haematologica 200792199ndash205

68 Baglin T Luddington R Brown K Baglin C Incidence of recurrent venousthromboembolism in relation to clinical and thrombophilic risk factors pro-spective cohort study Lancet 2003362523ndash526

69 Kovacs MJ Kahn SR Wells PS Anderson DA Chagnon IGLEG Solymoss SCrowther M Perrier A Ramsay T Betancourt MT White RH Vickars LRodger MA Patients with a first symptomatic unprovoked deep vein thrombosisare at higher risk of recurrent venous thromboembolism than patients with a firstunprovoked pulmonary embolism J Thromb Haemost 201081926ndash1932

70 Kearon C Akl EA Ornelas J Blaivas A Jimenez D Bounameaux H Huisman MKing CS Morris TA Sood N Stevens SM Vintch JR Wells P Woller SCMoores L Antithrombotic therapy for VTE disease CHEST guideline and ex-pert panel report Chest 2016149315ndash352

71 Kyrle PA Eichinger S Clinical scores to predict recurrence risk of venousthromboembolism Thromb Haemost 20121081061ndash1064

72 Loewen P Dahri K Risk of bleeding with oral anticoagulants an updated sys-tematic review and performance analysis of clinical prediction rules AnnHematol 2011901191ndash1200

73 Burgess S Crown N Louzada ML Dresser G Kim RB Lazo-Langner A Clinicalperformance of bleeding risk scores for predicting major and clinically relevantnon-major bleeding events in patients receiving warfarin J Thromb Haemost2013111647ndash1654

74 Palareti G Cosmi B Legnani C Antonucci ED Micheli V Ghirarduzzi A PoliD Testa S Tosetto A Pengo V Prandoni P DULCIS (D-dimer andULtrasonography in Combination Italian Study) Investigators D-dimer to guidethe duration of anticoagulation in patients with venous thromboembolism amanagement study Blood 2014124196ndash203

75 Kearon C Spencer FA Orsquokeeffe D Parpia S Schulman S Baglin T Stevens SMKaatz S Bauer KA Douketis JD Lentz SR Kessler CM Moll S Connors JMGinsberg JS Spadafora L Julian JA D-dimer testing to select patients with a firstunprovoked venous thromboembolism who can stop anticoagulant therapy acohort study Ann Intern Med 201516227ndash34

76 Kearon C Parpia S Spencer FA Baglin T Stevens SM Bauer KA Lentz SRKessler CM Douketis JD Moll S Kaatz S Schulman S Connors JM Ginsberg JSSpadafora L Liaw P Weitz JI Julian JA D-dimer levels and recurrence in pa-tients with unprovoked VTE and a negative qualitative D-dimer test after treat-ment Thromb Res 2016146119ndash125

77 Schulman S Granqvist S Holmstrom M Carlsson A Lindmarker P Nicol PEklund SG Nordlander S Larfars G Leijd B Linder O Loogna E The durationof oral anticoagulant therapy after a second episode of venous thromboembol-ism The Duration of Anticoagulation Trial Study Group N Engl J Med1997336393ndash398

78 Kearon C Gent M Hirsh J Weitz J Kovacs MJ Anderson DR Turpie AGGreen D Ginsberg JS Wells P MacKinnon B Julian JA A comparison of threemonths of anticoagulation with extended anticoagulation for a first episode ofidiopathic venous thromboembolism N Engl J Med 1999340901ndash907

79 Agnelli G Prandoni P Santamaria MG Bagatella P Iorio A Bazzan M Moia MGuazzaloca G Bertoldi A Tomasi C Scannapieco G Ageno W WarfarinOptimal Duration Italian Trial Investigators Three months versus one year oforal anticoagulant therapy for idiopathic deep venous thrombosis N Engl J Med2001345165ndash169

80 Agnelli G Prandoni P Becattini C Silingardi M Taliani MR Miccio M Imberti DPoggio R Ageno W Pogliani E Porro F Zonzin P Warfarin Optimal DurationItalian Trial Investigators Extended oral anticoagulant therapy after a first epi-sode of pulmonary embolism Ann Intern Med 200313919ndash25

81 Castellucci LA Cameron C Le Gal G Rodger MA Coyle D Wells PS CliffordT Gandara E Wells G Carrier M Efficacy and safety outcomes of oral anti-coagulants and antiplatelet drugs in the secondary prevention of venousthromboembolism systematic review and network meta-analysis BMJ2013347f5133

82 Kearon C Ginsberg JS Kovacs MJ Anderson DR Wells P Julian JA MacKinnonB Weitz JI Crowther MA Dolan S Turpie AG Geerts W Solymoss S vanNguyen P Demers C Kahn SR Kassis J Rodger M Hambleton J Gent MExtended Low-Intensity Anticoagulation For Thrombo-Embolism I Comparisonof low-intensity warfarin therapy with conventional-intensity warfarin therapyfor long-term prevention of recurrent venous thromboembolism N Engl J Med2003349631ndash639

83 Schulman S Kearon C Kakkar AK Schellong S Eriksson H Baanstra D KvammeAM Friedman J Mismetti P Goldhaber SZ RE-MEDY Trials Investigators RE-SONATE Trials Investigators Extended use of dabigatran warfarin or placebo invenous thromboembolism N Engl J Med 2013368709ndash718

84 Bauersachs R Berkowitz SD Brenner B Buller HR Decousus H Gallus ASLensing AW Misselwitz F Prins MH Raskob GE Segers A Verhamme P WellsP Agnelli G Bounameaux H Cohen A Davidson BL Piovella F Schellong SThe EINSTEIN Investigators Oral rivaroxaban for symptomatic venousthromboembolism N Engl J Med 20103632499ndash2510

85 Agnelli G Buller HR Cohen A Curto M Gallus AS Johnson M Porcari ARaskob GE Weitz JI AMPLIFY-EXT Investigators Apixaban for extended treat-ment of venous thromboembolism N Engl J Med 2013368699ndash708

86 Raskob G Ageno W Cohen AT Brekelmans MP Grosso MA Segers A MeyerG Verhamme P Wells PS Lin M Winters SM Weitz JI Buller HR Extendedduration of anticoagulation with edoxaban in patients with venous thrombo-embolism a post-hoc analysis of the Hokusai-VTE study Lancet Haematol20163e228ndashe236

87 Ageno W Mantovani LG Haas S Kreutz R Monje D Schneider J van EickelsM Gebel M Zell E Turpie AG Safety and effectiveness of oral rivaroxaban ver-sus standard anticoagulation for the treatment of symptomatic deep-veinthrombosis (XALIA) an international prospective non-interventional studyLancet Haematol 20163e12ndashe21

12 L Mazzolai et al

88 Becattini C Agnelli G Schenone A Eichinger S Bucherini E Silingardi MBianchi M Moia M Ageno W Vandelli MR Grandone E Prandoni PWARFASA Investigators Aspirin for preventing the recurrence of venousthromboembolism N Engl J Med 20123661959ndash1967

89 Brighton TA Eikelboom JW Mann K Mister R Gallus A Ockelford P Gibbs HHague W Xavier D Diaz R Kirby A Simes J Investigators A Low-dose aspirinfor preventing recurrent venous thromboembolism N Engl J Med20123671979ndash1987

90 Simes J Becattini C Agnelli G Eikelboom JW Kirby AC Mister R Prandoni PBrighton TA Investigators IS Aspirin for the prevention of recurrent venousthromboembolism the INSPIRE collaboration Circulation 20141301062ndash1071

91 Andreozzi GM Bignamini AA Davi G Palareti G Matuska J Holy MPawlaczyk-Gabriel K Dzupina A Sokurenko GY Didenko YP Andrei LDLessiani G Visona A Sulodexide for the prevention of recurrent venousthromboembolism the sulodexide in secondary prevention of recurrent deepvein thrombosis (SURVET) study a multicenter randomized double-blind pla-cebo-controlled trial Circulation 20151321891ndash1897

92 Neglen P Hollis KC Olivier J Raju S Stenting of the venous outflow in chronicvenous disease long-term stent-related outcome clinical and hemodynamic re-sult J Vasc Surg 200746979ndash990

93 Delis KT Bjarnason H Wennberg PW Rooke TW Gloviczki P Successful iliacvein and inferior vena cava stenting ameliorates venous claudication and im-proves venous outflow calf muscle pump function and clinical status in post-thrombotic syndrome Ann Surg 2007245130ndash139

94 Kucher N Clinical practice Deep-vein thrombosis of the upper extremities NEngl J Med 2011364861ndash869

95 Grant JD Stevens SM Woller SC Lee EW Kee ST Liu DM Lohan DG ElliottCG Diagnosis and management of upper extremity deep-vein thrombosis inadults Thromb Haemost 20121081097ndash1108

96 Thompson JF Winterborn RJ Bays S White H Kinsella DC Watkinson AF Venousthoracic outlet compression and the Paget-Schroetter syndrome a review and rec-ommendations for management Cardiovasc Interv Radiol 201134903ndash910

97 Constans J Salmi LR Sevestre-Pietri MA Perusat S Nguon M Degeilh MLabarere J Gattolliat O Boulon C Laroche JP Le Roux P Pichot O Quere IConri C Bosson JL A clinical prediction score for upper extremity deep ven-ous thrombosis Thromb Haemost 200899202ndash207

98 Sartori M Migliaccio L Favaretto E Cini M Legnani C Palareti G Cosmi B D-dimer for the diagnosis of upper extremity deep and superficial venous throm-bosis Thromb Res 2015135673ndash678

99 Kleinjan A Di Nisio M Beyer-Westendorf J Camporese G Cosmi BGhirarduzzi A Kamphuisen PW Otten HM Porreca E Aggarwal A BrodmannM Guglielmi MD Iotti M Kaasjager K Kamvissi V Lerede T Marschang PMeijer K Palareti G Rickles FR Righini M Rutjes AW Tonello C Verhamme PWerth S van Wissen S Buller HR Safety and feasibility of a diagnostic algo-rithm combining clinical probability d-dimer testing and ultrasonography forsuspected upper extremity deep venous thrombosis a prospective manage-ment study Ann Int Med 2014160451ndash457

100 Di Nisio M Van Sluis GL Bossuyt PM Buller HR Porreca E Rutjes AWAccuracy of diagnostic tests for clinically suspected upper extremity deep veinthrombosis a systematic review J Thromb Haemost 20108684ndash692

101 Rosa-Salazar V Trujillo-Santos J Diaz Peromingo JA Apollonio A Sanz O MalyR Munoz-Rodriguez FJ Serrano JC Soler S Monreal M Investigators R A prog-nostic score to identify low-risk outpatients with acute deep vein thrombosis inthe upper extremity J Thromb Haemost 2015131274ndash1278

102 Ferro JM Canhao P Stam J Bousser MG Barinagarrementeria F Investigators IPrognosis of cerebral vein and dural sinus thrombosis results of theInternational Study on Cerebral Vein and Dural Sinus Thrombosis (ISCVT)Stroke 200435664ndash670

103 Wasay M Bakshi R Bobustuc G Kojan S Sheikh Z Dai A Cheema Z Cerebralvenous thrombosis analysis of a multicenter cohort from the United StatesJ Stroke Cerebrovasc Dis 20081749ndash54

104 Thatipelli MR McBane RD Hodge DO Wysokinski WE Survival and recur-rence in patients with splanchnic vein thromboses Clin Gastroenterol Hepatol20108200ndash205

105 Ageno W Riva N Schulman S Bang SM Sartori MT Grandone E Beyer-Westendorf J Barillari GD Minno MN Dentali F IRSVT study groupAntithrombotic treatment of splanchnic vein thrombosis results of an interna-tional registry Semin Thromb Hemost 20144099ndash105

106 Khorana AA Kuderer NM Culakova E Lyman GH Francis CW Developmentand validation of a predictive model for chemotherapy-associated thrombosisBlood 20081114902ndash4907

107 Pabinger I Thaler J Ay C Biomarkers for prediction of venous thromboembol-ism in cancer Blood 20131222011ndash2018

108 Khorana AA Dalal M Lin J Connolly GC Incidence and predictors of venousthromboembolism (VTE) among ambulatory high-risk cancer patients undergo-ing chemotherapy in the United States Cancer 2013119648ndash655

109 Farge D Bounameaux H Brenner B Cajfinger F Debourdeau P Khorana AAPabinger I Solymoss S Douketis J Kakkar A International clinical practiceguidelines including guidance for direct oral anticoagulants in the treatment andprophylaxis of venous thromboembolism in patients with cancer Lancet Oncol201617e452ndashe466

110 Vedovati MC Germini F Agnelli G Becattini C Direct oral anticoagulants inpatients with VTE and cancer a systematic review and meta-analysis Chest2015147475ndash483

111 Nelson-Piercy C MacCallum P Mackillop L Reducing the risk of thrombosisand embolism during pregnancy and the puerperium (Green-top guideline no37a) R Coll Obstetr Gynaecol 20151ndash40

112 Le Moigne E Genty C Meunier J Arnoult AC Righini M Bressollette L BossonJL Le Gal G Validation of the LEFt score a newly proposed diagnostic tool fordeep vein thrombosis in pregnant women Thromb Res 2014134664ndash667

113 Le Gal G Prins AM Righini M Bohec C Lacut K Germain P Vergos JCKaczmarek R Guias B Collet M Bressollette L Oger E Mottier D Diagnosticvalue of a negative single complete compression ultrasound of the lower limbsto exclude the diagnosis of deep venous thrombosis in pregnant or postpartumwomen a retrospective hospital-based study Thromb Res 2006118691ndash697

114 Le Gal G Kercret G Ben Yahmed K Bressollette L Robert-Ebadi H Riberdy LLouis P Delluc A Labalette ML Baba-Ahmed M Bounameaux H Mottier DRighini M Diagnostic value of single complete compression ultrasonography inpregnant and postpartum women with suspected deep vein thrombosis pro-spective study BMJ 2012344e2635

115 Bates SM Greer IA Middeldorp S Veenstra DL Prabulos AM Vandvik POVTE thrombophilia antithrombotic therapy and pregnancy antithrombotictherapy and prevention of thrombosis 9th ed American College of ChestPhysicians Evidence-Based Clinical Practice Guidelines Chest 2012141(2Suppl)e691Sndashe736S

116 Thomsen A Greer I Thromboembolic disease in pregnancy and the puerper-ium acute management (Green-top guideline no 37b) R Coll Obstetr Gynaecol20151ndash32

117 Chan WS Spencer FA Lee AY Chunilal S Douketis JD Rodger M Ginsberg JSSafety of withholding anticoagulation in pregnant women with suspected deepvein thrombosis following negative serial compression ultrasound and iliac veinimaging CMAJ 2013185E194ndashE200

118 Romualdi E Dentali F Rancan E Squizzato A Steidl L Middeldorp S Ageno WAnticoagulant therapy for venous thromboembolism during pregnancy a sys-tematic review and a meta-analysis of the literature J Thromb Haemost201311270ndash281

119 Bauersachs RM Treatment of venous thromboembolism during pregnancyThromb Res 2009123(Suppl 2)S45ndashS50

120 Bauersachs RM Dudenhausen J Faridi A Fischer T Fung S Geisen UHarenberg J Herchenhan E Keller F Kemkes-Matthes B Schinzel H SpannaglM Thaler CJ Risk stratification and heparin prophylaxis to prevent venousthromboembolism in pregnant women Thromb Haemost 2007981237ndash1245


ehx003-T1

ehx003-TF1

ehx003-TF2

ehx003-TF3

Diagnosis

Deep vein thrombosis withoutpulmonary embolism symptomsClinical signs and symptoms are highly variable and unspecific but re-main the cornerstone of diagnostic strategy Symptoms include painswelling increased skin veins visibility erythema and cyanosis accom-panied by unexplained fever

Probability assessment and D-dimertestingPre-test probability assessment is the first step in the diagnostic algo-rithm of DVT suspicion (Figure 2) Sensitivity and specificity of clinicalsymptoms are low when considered individually however theircombination using prediction rules allows pre-test clinical probabil-ity classification into two- (DVT unlikely or likely) or three-categories(low- intermediate- or high-clinical probability) corresponding toincreasing disease prevalence1213 Wells score has been widely vali-dated and can be applied both to out- and inpatients (Table 2) Theexpertsrsquo panel favours the modified two-level pre-test probability asit is more straightforward14

Normal D-dimers render DVT unlikely15 however D-dimers havelow specificity Quantitative ELISA or ELISA-derived assays (gt95sensitivity) allow ruling out DVT in patients with DVT lsquounlikelyrsquoNegative ELISA D-dimer can exclude DVT without further testing in30 of patients16 with 3-month thromboembolic risk lt1 withouttreatment13 Quantitative latex-derived and whole-blood agglutin-ation assay have lower sensitivity (85ndash90)17 In patients with lsquolikelyrsquoDVT D-Dimer testing is not necessary imaging is requiredTherapeutic anticoagulation should be initiated if not contraindi-cated in patients with DVT lsquolikelyrsquo until imaging

Imaging

Venous ultrasound (VUS) is the first line DVT imaging modality(other imaging see Supplementary material online only section) It isbased on B-mode combined or not with color-Doppler US andpower imaging techniques DVT diagnostic criteria are cross-sectional vein incompressibility direct thrombus imaging with veinenlargement and abnormal spectral and color-Doppler flow VUScan be performed by examining popliteal and common femoral veinsonly [2-point2-region compression venous ultrasonography (CUS)or limited CUS] or by extended imaging of inferior vena cava iliac

Figure 1 Venous thromboembolism incidence according to age group

Table 1 Villalta score11

Symptoms and

Clinical signs

None Mild Moderate Severe

Symptoms

Pain 0 points 1 points 2 points 3 points

Cramps 0 points 1 points 2 points 3 points

Haeviness 0 points 1 points 2 points 3 points

Paresthesia 0 points 1 points 2 points 3 points

Pruritus 0 points 1 points 2 points 3 points

Clinical signs

Pretibial edema 0 points 1 points 2 points 3 points

Skin induration 0 points 1 points 2 points 3 points

Hyperpigmentation 0 points 1 points 2 points 3 points

Redness 0 points 1 points 2 points 3 points

Venous ectasia 0 points 1 points 2 points 3 points

Pain on calf

compression

0 points 1 points 2 points 3 points

Venous ulcer Absent Present

Points are summed into a total score (range 0ndash33) Post Thrombotic syndrome(PTS) is defined by a total score of gt_5 or the presence of a venous ulcer PTS isclassified as mild if Villalta score is 5ndash9 moderate if 10ndash14 and severe if gt_15 orvenous ulcer is present

2 L Mazzolai et al

























Long term treatment

(first 3-6 months)

Extended treatment












thorn1



thorn1




thorn1


venous system

thorn1




tuberosity)

thorn1






Low lt1


High gt2


Unlikely lt_1

Likely gt_2

4 L Mazzolai et al








Vena cava filter



Compression





























ters immobilization


provided complete







Age gt50 years

Cancer






















Proximal DVT PE)




in women








at different time


an annual





6 L Mazzolai et al












Aspirin



Other

















Special situations



Tab

le5

Exte

nd

ed

seco

nd

ary

pre

ven

tio

no

fV

TE

co

mp

ari

son

ofre

sult

sfr

om

Ph

ase

III

tria

lsw

ith

dir

ect

ora

lan

tico

agu

lan

ts

Dir

ect

ora

lan

tico

agu

-

lan

ttr

ial

Desi

gn

nT

reatm

en

t

regim

en

Recu

rren

tV

TE

or

VT

E-r

ela

ted

death

(o

fp

op

u-

lati

on

H

R)

Majo

rb

leed

ing

(o

fp

op

ula

tio

n

HR

)

Intr

acra

nia

lh

em

-

orr

hage

(o

f

po

pu

lati

on

H

R)

Gast

roin

test

inal

ble

ed

ing

(o

f

po

pu

lati

on

H

R)

Death

fro

man

y

cau

se(

ofp

op

u-

lati

on

H

R)

Dab

igat

ran

RE-

MED

Y7

RE-

SON

AT

E83

Ran

dom

ized

dou

ble-

blin

dR

ando

miz

edd

oubl

e-bl

ind

2866

1343

Dab

igat

ran

150

mg

bid

vs

war

fari

n(IN

R2

0ndash3

0)D

abig

atra

n15

0m

gb

idv

spl

aceb

o

Dab

igat

ran

150

mg

vs

war

fari

n1

8vs

13

HR

144

95

CI

078

ndash26

4P

=0

01no

n-in

feri

ority

Rec

urre

ntor

fata

lV

TE

orun

expl

aine

dde

ath

Dab

igat

ran

150

mg

vs

plac

ebo

04

vs5

6H

R0

089

5C

I0

02ndash0

25

Plt

000

1fo

rsu

perio

rity

Dab

igat

ran

150

mg

vs

war

fari

n0

9vs

18

HR

052

95

CI

027

ndash10

2P

=0

06D

abig

atra

n15

0m

gvs

pl

aceb

o0

3vs

0N

oH

Rre

port

edP

=1

0

Dab

igat

ran

150

mg

vs

war

fari

n0

1vs

03

No

HR

repo

rted

No

intr

acra

nial

hem

-or

rhag

esob

serv

ed

Dab

igat

ran

150

mg

vs

war

fari

n0

3vs

06

No

HR

repo

rted

Dab

igat

ran

150

mg

vs

plac

ebo

03

vs0

No

HR

repo

rted

Dab

igat

ran

150

mg

vs

war

fari

n1

2vs

13

HR

090

95

CI

047

ndash17

2P

=0

74D

abig

atra

n15

0m

gvs

pl

aceb

o0

vs0

3N

oH

Rre

port

ed

Riv

arox

aban

EIN

STEI

N-E

xten

tion8

4R

ando

miz

edd

oubl

e-bl

ind

1197

Riv

arox

aban

20m

god

vsp

lace

boR

ecur

rent

VT

ER

ivar

oxab

an20

mg

vs

plac

ebo

13

vs7

1H

R0

189

5C

I0

09ndash0

39

Plt

000

1

Riv

arox

aban

20m

gvs

pl

aceb

o0

7vs

0N

oH

Rre

port

edP

=0

11

No

intr

acra

nial

hem

-or

rhag

esob

serv

edR

ivar

oxab

an20

mg

vs

plac

ebo

05

vs0

No

HR

repo

rted

Riv

arox

aban

20m

gvs

pl

aceb

o0

2vs

03

No

HR

repo

rted

Api

xaba

nA

MPL

IFY

-Ext

ensi

on85

Ran

dom

ized

dou

ble-

blin

d24

86A

pixa

ban

5m

gb

id

orap

ixab

an2

5m

gb

idv

spl

aceb

o

Api

xaba

n5

mg

vsp

la-

cebo

17

vs8

8R

R0

209

5C

I01

1ndash0

34A

pixa

ban

25

mg

vs

plac

ebo

17

vs8

8R

R0

199

5C

I01

1ndash0

33

Api

xaba

n5

mg

vsp

la-

cebo

01

vs0

5R

R0

259

5C

I00

3ndash2

24A

pixa

ban

25

mg

vs

plac

ebo

02

vs0

5R

R0

499

5C

I00

9ndash2

64

No

intr

acra

nial

hem

-or

rhag

esob

serv

ed

No

intr

acra

nial

hem

-or

rhag

esob

serv

ed

Api

xaba

n5

mg

vsp

la-

cebo

01

vs0

3N

oR

Rre

port

ed

No

gast

roin

test

inal

blee

dsob

serv

ed

Api

xaba

n5

mg

vsp

la-

cebo

05

vs1

7N

oR

Rre

port

ed

Api

xaba

n2

5m

gvs

pl

aceb

o0

5vs

17

No

RR

repo

rted

Edox

aban

Hok

usai

-VT

Epo

stho

c86

Ran

dom

ized

dou

ble

blin

d72

27Ed

oxab

an60

mg

qd(o

rdo

sere

duce

d30

mg)

vsw

arfa

rin

Edox

aban

vsw

arfa

rin

18

vs1

9H

R0

979

5C

I0

69ndash1

37)

Edox

aban

vsw

arfa

rin

03

vs0

7H

R0

459

5C

I0

22ndash0

92)

Edox

aban

vsw

arfa

rin

lt0

1vs

02

HR

016

95

CI

002

ndash13

6)

Not

asse

ssed

Not

asse

ssed

Dat

afr

omco

mpa

rativ

ePh

ase

IVst

udie

sR

ivar

oxab

anX

ALI

A87

Pros

pect

ive

non-

inte

rven

tiona

l51

42R

ivar

oxab

an15

mg

bid

for

3w

eeks

follo

wed

by20

mg

qdvs

hep

arin

vita

-m

inK

anta

goni

st

Riv

arox

aban

vshe

p-ar

inV

KA

14

vs2

3H

R0

919

5C

I0

54ndash1

54

P=

072

Riv

arox

aban

vshe

p-ar

inV

KA

08

vs2

1H

R0

779

5C

I0

40ndash1

50

P=

044

Not

asse

ssed

Not

asse

ssed

Riv

arox

aban

vshe

p-ar

inV

KA

04

vs3

4H

R0

5195

C

I02

4ndash1

07P

=0

07

8 L Mazzolai et al













Risk

score

Constans score item


Localized pain 1

Unilateral edema 1



Site of cancer






BMI gt_35 kgm2 1














































technology

Immobilization


10 L Mazzolai et al















































































12 L Mazzolai et al



































ehx003-T1

ehx003-TF1

ehx003-TF2

ehx003-TF3

























Long term treatment

(first 3-6 months)

Extended treatment












thorn1



thorn1




thorn1


venous system

thorn1




tuberosity)

thorn1






Low lt1


High gt2


Unlikely lt_1

Likely gt_2

4 L Mazzolai et al








Vena cava filter



Compression





























ters immobilization


provided complete







Age gt50 years

Cancer






















Proximal DVT PE)




in women








at different time


an annual





6 L Mazzolai et al












Aspirin



Other

















Special situations



Tab

le5

Exte

nd

ed

seco

nd

ary

pre

ven

tio

no

fV

TE

co

mp

ari

son

ofre

sult

sfr

om

Ph

ase

III

tria

lsw

ith

dir

ect

ora

lan

tico

agu

lan

ts

Dir

ect

ora

lan

tico

agu

-

lan

ttr

ial

Desi

gn

nT

reatm

en

t

regim

en

Recu

rren

tV

TE

or

VT

E-r

ela

ted

death

(o

fp

op

u-

lati

on

H

R)

Majo

rb

leed

ing

(o

fp

op

ula

tio

n

HR

)

Intr

acra

nia

lh

em

-

orr

hage

(o

f

po

pu

lati

on

H

R)

Gast

roin

test

inal

ble

ed

ing

(o

f

po

pu

lati

on

H

R)

Death

fro

man

y

cau

se(

ofp

op

u-

lati

on

H

R)

Dab

igat

ran

RE-

MED

Y7

RE-

SON

AT

E83

Ran

dom

ized

dou

ble-

blin

dR

ando

miz

edd

oubl

e-bl

ind

2866

1343

Dab

igat

ran

150

mg

bid

vs

war

fari

n(IN

R2

0ndash3

0)D

abig

atra

n15

0m

gb

idv

spl

aceb

o

Dab

igat

ran

150

mg

vs

war

fari

n1

8vs

13

HR

144

95

CI

078

ndash26

4P

=0

01no

n-in

feri

ority

Rec

urre

ntor

fata

lV

TE

orun

expl

aine

dde

ath

Dab

igat

ran

150

mg

vs

plac

ebo

04

vs5

6H

R0

089

5C

I0

02ndash0

25

Plt

000

1fo

rsu

perio

rity

Dab

igat

ran

150

mg

vs

war

fari

n0

9vs

18

HR

052

95

CI

027

ndash10

2P

=0

06D

abig

atra

n15

0m

gvs

pl

aceb

o0

3vs

0N

oH

Rre

port

edP

=1

0

Dab

igat

ran

150

mg

vs

war

fari

n0

1vs

03

No

HR

repo

rted

No

intr

acra

nial

hem

-or

rhag

esob

serv

ed

Dab

igat

ran

150

mg

vs

war

fari

n0

3vs

06

No

HR

repo

rted

Dab

igat

ran

150

mg

vs

plac

ebo

03

vs0

No

HR

repo

rted

Dab

igat

ran

150

mg

vs

war

fari

n1

2vs

13

HR

090

95

CI

047

ndash17

2P

=0

74D

abig

atra

n15

0m

gvs

pl

aceb

o0

vs0

3N

oH

Rre

port

ed

Riv

arox

aban

EIN

STEI

N-E

xten

tion8

4R

ando

miz

edd

oubl

e-bl

ind

1197

Riv

arox

aban

20m

god

vsp

lace

boR

ecur

rent

VT

ER

ivar

oxab

an20

mg

vs

plac

ebo

13

vs7

1H

R0

189

5C

I0

09ndash0

39

Plt

000

1

Riv

arox

aban

20m

gvs

pl

aceb

o0

7vs

0N

oH

Rre

port

edP

=0

11

No

intr

acra

nial

hem

-or

rhag

esob

serv

edR

ivar

oxab

an20

mg

vs

plac

ebo

05

vs0

No

HR

repo

rted

Riv

arox

aban

20m

gvs

pl

aceb

o0

2vs

03

No

HR

repo

rted

Api

xaba

nA

MPL

IFY

-Ext

ensi

on85

Ran

dom

ized

dou

ble-

blin

d24

86A

pixa

ban

5m

gb

id

orap

ixab

an2

5m

gb

idv

spl

aceb

o

Api

xaba

n5

mg

vsp

la-

cebo

17

vs8

8R

R0

209

5C

I01

1ndash0

34A

pixa

ban

25

mg

vs

plac

ebo

17

vs8

8R

R0

199

5C

I01

1ndash0

33

Api

xaba

n5

mg

vsp

la-

cebo

01

vs0

5R

R0

259

5C

I00

3ndash2

24A

pixa

ban

25

mg

vs

plac

ebo

02

vs0

5R

R0

499

5C

I00

9ndash2

64

No

intr

acra

nial

hem

-or

rhag

esob

serv

ed

No

intr

acra

nial

hem

-or

rhag

esob

serv

ed

Api

xaba

n5

mg

vsp

la-

cebo

01

vs0

3N

oR

Rre

port

ed

No

gast

roin

test

inal

blee

dsob

serv

ed

Api

xaba

n5

mg

vsp

la-

cebo

05

vs1

7N

oR

Rre

port

ed

Api

xaba

n2

5m

gvs

pl

aceb

o0

5vs

17

No

RR

repo

rted

Edox

aban

Hok

usai

-VT

Epo

stho

c86

Ran

dom

ized

dou

ble

blin

d72

27Ed

oxab

an60

mg

qd(o

rdo

sere

duce

d30

mg)

vsw

arfa

rin

Edox

aban

vsw

arfa

rin

18

vs1

9H

R0

979

5C

I0

69ndash1

37)

Edox

aban

vsw

arfa

rin

03

vs0

7H

R0

459

5C

I0

22ndash0

92)

Edox

aban

vsw

arfa

rin

lt0

1vs

02

HR

016

95

CI

002

ndash13

6)

Not

asse

ssed

Not

asse

ssed

Dat

afr

omco

mpa

rativ

ePh

ase

IVst

udie

sR

ivar

oxab

anX

ALI

A87

Pros

pect

ive

non-

inte

rven

tiona

l51

42R

ivar

oxab

an15

mg

bid

for

3w

eeks

follo

wed

by20

mg

qdvs

hep

arin

vita

-m

inK

anta

goni

st

Riv

arox

aban

vshe

p-ar

inV

KA

14

vs2

3H

R0

919

5C

I0

54ndash1

54

P=

072

Riv

arox

aban

vshe

p-ar

inV

KA

08

vs2

1H

R0

779

5C

I0

40ndash1

50

P=

044

Not

asse

ssed

Not

asse

ssed

Riv

arox

aban

vshe

p-ar

inV

KA

04

vs3

4H

R0

5195

C

I02

4ndash1

07P

=0

07

8 L Mazzolai et al













Risk

score

Constans score item


Localized pain 1

Unilateral edema 1



Site of cancer






BMI gt_35 kgm2 1














































technology

Immobilization


10 L Mazzolai et al















































































12 L Mazzolai et al



































ehx003-T1

ehx003-TF1

ehx003-TF2

ehx003-TF3








Vena cava filter



Compression





























ters immobilization


provided complete







Age gt50 years

Cancer






















Proximal DVT PE)




in women








at different time


an annual





6 L Mazzolai et al












Aspirin



Other

















Special situations



Tab

le5

Exte

nd

ed

seco

nd

ary

pre

ven

tio

no

fV

TE

co

mp

ari

son

ofre

sult

sfr

om

Ph

ase

III

tria

lsw

ith

dir

ect

ora

lan

tico

agu

lan

ts

Dir

ect

ora

lan

tico

agu

-

lan

ttr

ial

Desi

gn

nT

reatm

en

t

regim

en

Recu

rren

tV

TE

or

VT

E-r

ela

ted

death

(o

fp

op

u-

lati

on

H

R)

Majo

rb

leed

ing

(o

fp

op

ula

tio

n

HR

)

Intr

acra

nia

lh

em

-

orr

hage

(o

f

po

pu

lati

on

H

R)

Gast

roin

test

inal

ble

ed

ing

(o

f

po

pu

lati

on

H

R)

Death

fro

man

y

cau

se(

ofp

op

u-

lati

on

H

R)

Dab

igat

ran

RE-

MED

Y7

RE-

SON

AT

E83

Ran

dom

ized

dou

ble-

blin

dR

ando

miz

edd

oubl

e-bl

ind

2866

1343

Dab

igat

ran

150

mg

bid

vs

war

fari

n(IN

R2

0ndash3

0)D

abig

atra

n15

0m

gb

idv

spl

aceb

o

Dab

igat

ran

150

mg

vs

war

fari

n1

8vs

13

HR

144

95

CI

078

ndash26

4P

=0

01no

n-in

feri

ority

Rec

urre

ntor

fata

lV

TE

orun

expl

aine

dde

ath

Dab

igat

ran

150

mg

vs

plac

ebo

04

vs5

6H

R0

089

5C

I0

02ndash0

25

Plt

000

1fo

rsu

perio

rity

Dab

igat

ran

150

mg

vs

war

fari

n0

9vs

18

HR

052

95

CI

027

ndash10

2P

=0

06D

abig

atra

n15

0m

gvs

pl

aceb

o0

3vs

0N

oH

Rre

port

edP

=1

0

Dab

igat

ran

150

mg

vs

war

fari

n0

1vs

03

No

HR

repo

rted

No

intr

acra

nial

hem

-or

rhag

esob

serv

ed

Dab

igat

ran

150

mg

vs

war

fari

n0

3vs

06

No

HR

repo

rted

Dab

igat

ran

150

mg

vs

plac

ebo

03

vs0

No

HR

repo

rted

Dab

igat

ran

150

mg

vs

war

fari

n1

2vs

13

HR

090

95

CI

047

ndash17

2P

=0

74D

abig

atra

n15

0m

gvs

pl

aceb

o0

vs0

3N

oH

Rre

port

ed

Riv

arox

aban

EIN

STEI

N-E

xten

tion8

4R

ando

miz

edd

oubl

e-bl

ind

1197

Riv

arox

aban

20m

god

vsp

lace

boR

ecur

rent

VT

ER

ivar

oxab

an20

mg

vs

plac

ebo

13

vs7

1H

R0

189

5C

I0

09ndash0

39

Plt

000

1

Riv

arox

aban

20m

gvs

pl

aceb

o0

7vs

0N

oH

Rre

port

edP

=0

11

No

intr

acra

nial

hem

-or

rhag

esob

serv

edR

ivar

oxab

an20

mg

vs

plac

ebo

05

vs0

No

HR

repo

rted

Riv

arox

aban

20m

gvs

pl

aceb

o0

2vs

03

No

HR

repo

rted

Api

xaba

nA

MPL

IFY

-Ext

ensi

on85

Ran

dom

ized

dou

ble-

blin

d24

86A

pixa

ban

5m

gb

id

orap

ixab

an2

5m

gb

idv

spl

aceb

o

Api

xaba

n5

mg

vsp

la-

cebo

17

vs8

8R

R0

209

5C

I01

1ndash0

34A

pixa

ban

25

mg

vs

plac

ebo

17

vs8

8R

R0

199

5C

I01

1ndash0

33

Api

xaba

n5

mg

vsp

la-

cebo

01

vs0

5R

R0

259

5C

I00

3ndash2

24A

pixa

ban

25

mg

vs

plac

ebo

02

vs0

5R

R0

499

5C

I00

9ndash2

64

No

intr

acra

nial

hem

-or

rhag

esob

serv

ed

No

intr

acra

nial

hem

-or

rhag

esob

serv

ed

Api

xaba

n5

mg

vsp

la-

cebo

01

vs0

3N

oR

Rre

port

ed

No

gast

roin

test

inal

blee

dsob

serv

ed

Api

xaba

n5

mg

vsp

la-

cebo

05

vs1

7N

oR

Rre

port

ed

Api

xaba

n2

5m

gvs

pl

aceb

o0

5vs

17

No

RR

repo

rted

Edox

aban

Hok

usai

-VT

Epo

stho

c86

Ran

dom

ized

dou

ble

blin

d72

27Ed

oxab

an60

mg

qd(o

rdo

sere

duce

d30

mg)

vsw

arfa

rin

Edox

aban

vsw

arfa

rin

18

vs1

9H

R0

979

5C

I0

69ndash1

37)

Edox

aban

vsw

arfa

rin

03

vs0

7H

R0

459

5C

I0

22ndash0

92)

Edox

aban

vsw

arfa

rin

lt0

1vs

02

HR

016

95

CI

002

ndash13

6)

Not

asse

ssed

Not

asse

ssed

Dat

afr

omco

mpa

rativ

ePh

ase

IVst

udie

sR

ivar

oxab

anX

ALI

A87

Pros

pect

ive

non-

inte

rven

tiona

l51

42R

ivar

oxab

an15

mg

bid

for

3w

eeks

follo

wed

by20

mg

qdvs

hep

arin

vita

-m

inK

anta

goni

st

Riv

arox

aban

vshe

p-ar

inV

KA

14

vs2

3H

R0

919

5C

I0

54ndash1

54

P=

072

Riv

arox

aban

vshe

p-ar

inV

KA

08

vs2

1H

R0

779

5C

I0

40ndash1

50

P=

044

Not

asse

ssed

Not

asse

ssed

Riv

arox

aban

vshe

p-ar

inV

KA

04

vs3

4H

R0

5195

C

I02

4ndash1

07P

=0

07

8 L Mazzolai et al













Risk

score

Constans score item


Localized pain 1

Unilateral edema 1



Site of cancer






BMI gt_35 kgm2 1














































technology

Immobilization


10 L Mazzolai et al















































































12 L Mazzolai et al



































ehx003-T1

ehx003-TF1

ehx003-TF2

ehx003-TF3












ters immobilization


provided complete







Age gt50 years

Cancer






















Proximal DVT PE)




in women








at different time


an annual





6 L Mazzolai et al












Aspirin



Other

















Special situations



Tab

le5

Exte

nd

ed

seco

nd

ary

pre

ven

tio

no

fV

TE

co

mp

ari

son

ofre

sult

sfr

om

Ph

ase

III

tria

lsw

ith

dir

ect

ora

lan

tico

agu

lan

ts

Dir

ect

ora

lan

tico

agu

-

lan

ttr

ial

Desi

gn

nT

reatm

en

t

regim

en

Recu

rren

tV

TE

or

VT

E-r

ela

ted

death

(o

fp

op

u-

lati

on

H

R)

Majo

rb

leed

ing

(o

fp

op

ula

tio

n

HR

)

Intr

acra

nia

lh

em

-

orr

hage

(o

f

po

pu

lati

on

H

R)

Gast

roin

test

inal

ble

ed

ing

(o

f

po

pu

lati

on

H

R)

Death

fro

man

y

cau

se(

ofp

op

u-

lati

on

H

R)

Dab

igat

ran

RE-

MED

Y7

RE-

SON

AT

E83

Ran

dom

ized

dou

ble-

blin

dR

ando

miz

edd

oubl

e-bl

ind

2866

1343

Dab

igat

ran

150

mg

bid

vs

war

fari

n(IN

R2

0ndash3

0)D

abig

atra

n15

0m

gb

idv

spl

aceb

o

Dab

igat

ran

150

mg

vs

war

fari

n1

8vs

13

HR

144

95

CI

078

ndash26

4P

=0

01no

n-in

feri

ority

Rec

urre

ntor

fata

lV

TE

orun

expl

aine

dde

ath

Dab

igat

ran

150

mg

vs

plac

ebo

04

vs5

6H

R0

089

5C

I0

02ndash0

25

Plt

000

1fo

rsu

perio

rity

Dab

igat

ran

150

mg

vs

war

fari

n0

9vs

18

HR

052

95

CI

027

ndash10

2P

=0

06D

abig

atra

n15

0m

gvs

pl

aceb

o0

3vs

0N

oH

Rre

port

edP

=1

0

Dab

igat

ran

150

mg

vs

war

fari

n0

1vs

03

No

HR

repo

rted

No

intr

acra

nial

hem

-or

rhag

esob

serv

ed

Dab

igat

ran

150

mg

vs

war

fari

n0

3vs

06

No

HR

repo

rted

Dab

igat

ran

150

mg

vs

plac

ebo

03

vs0

No

HR

repo

rted

Dab

igat

ran

150

mg

vs

war

fari

n1

2vs

13

HR

090

95

CI

047

ndash17

2P

=0

74D

abig

atra

n15

0m

gvs

pl

aceb

o0

vs0

3N

oH

Rre

port

ed

Riv

arox

aban

EIN

STEI

N-E

xten

tion8

4R

ando

miz

edd

oubl

e-bl

ind

1197

Riv

arox

aban

20m

god

vsp

lace

boR

ecur

rent

VT

ER

ivar

oxab

an20

mg

vs

plac

ebo

13

vs7

1H

R0

189

5C

I0

09ndash0

39

Plt

000

1

Riv

arox

aban

20m

gvs

pl

aceb

o0

7vs

0N

oH

Rre

port

edP

=0

11

No

intr

acra

nial

hem

-or

rhag

esob

serv

edR

ivar

oxab

an20

mg

vs

plac

ebo

05

vs0

No

HR

repo

rted

Riv

arox

aban

20m

gvs

pl

aceb

o0

2vs

03

No

HR

repo

rted

Api

xaba

nA

MPL

IFY

-Ext

ensi

on85

Ran

dom

ized

dou

ble-

blin

d24

86A

pixa

ban

5m

gb

id

orap

ixab

an2

5m

gb

idv

spl

aceb

o

Api

xaba

n5

mg

vsp

la-

cebo

17

vs8

8R

R0

209

5C

I01

1ndash0

34A

pixa

ban

25

mg

vs

plac

ebo

17

vs8

8R

R0

199

5C

I01

1ndash0

33

Api

xaba

n5

mg

vsp

la-

cebo

01

vs0

5R

R0

259

5C

I00

3ndash2

24A

pixa

ban

25

mg

vs

plac

ebo

02

vs0

5R

R0

499

5C

I00

9ndash2

64

No

intr

acra

nial

hem

-or

rhag

esob

serv

ed

No

intr

acra

nial

hem

-or

rhag

esob

serv

ed

Api

xaba

n5

mg

vsp

la-

cebo

01

vs0

3N

oR

Rre

port

ed

No

gast

roin

test

inal

blee

dsob

serv

ed

Api

xaba

n5

mg

vsp

la-

cebo

05

vs1

7N

oR

Rre

port

ed

Api

xaba

n2

5m

gvs

pl

aceb

o0

5vs

17

No

RR

repo

rted

Edox

aban

Hok

usai

-VT

Epo

stho

c86

Ran

dom

ized

dou

ble

blin

d72

27Ed

oxab

an60

mg

qd(o

rdo

sere

duce

d30

mg)

vsw

arfa

rin

Edox

aban

vsw

arfa

rin

18

vs1

9H

R0

979

5C

I0

69ndash1

37)

Edox

aban

vsw

arfa

rin

03

vs0

7H

R0

459

5C

I0

22ndash0

92)

Edox

aban

vsw

arfa

rin

lt0

1vs

02

HR

016

95

CI

002

ndash13

6)

Not

asse

ssed

Not

asse

ssed

Dat

afr

omco

mpa

rativ

ePh

ase

IVst

udie

sR

ivar

oxab

anX

ALI

A87

Pros

pect

ive

non-

inte

rven

tiona

l51

42R

ivar

oxab

an15

mg

bid

for

3w

eeks

follo

wed

by20

mg

qdvs

hep

arin

vita

-m

inK

anta

goni

st

Riv

arox

aban

vshe

p-ar

inV

KA

14

vs2

3H

R0

919

5C

I0

54ndash1

54

P=

072

Riv

arox

aban

vshe

p-ar

inV

KA

08

vs2

1H

R0

779

5C

I0

40ndash1

50

P=

044

Not

asse

ssed

Not

asse

ssed

Riv

arox

aban

vshe

p-ar

inV

KA

04

vs3

4H

R0

5195

C

I02

4ndash1

07P

=0

07

8 L Mazzolai et al













Risk

score

Constans score item


Localized pain 1

Unilateral edema 1



Site of cancer






BMI gt_35 kgm2 1














































technology

Immobilization


10 L Mazzolai et al















































































12 L Mazzolai et al



































ehx003-T1

ehx003-TF1

ehx003-TF2

ehx003-TF3












Aspirin



Other

















Special situations



Tab

le5

Exte

nd

ed

seco

nd

ary

pre

ven

tio

no

fV

TE

co

mp

ari

son

ofre

sult

sfr

om

Ph

ase

III

tria

lsw

ith

dir

ect

ora

lan

tico

agu

lan

ts

Dir

ect

ora

lan

tico

agu

-

lan

ttr

ial

Desi

gn

nT

reatm

en

t

regim

en

Recu

rren

tV

TE

or

VT

E-r

ela

ted

death

(o

fp

op

u-

lati

on

H

R)

Majo

rb

leed

ing

(o

fp

op

ula

tio

n

HR

)

Intr

acra

nia

lh

em

-

orr

hage

(o

f

po

pu

lati

on

H

R)

Gast

roin

test

inal

ble

ed

ing

(o

f

po

pu

lati

on

H

R)

Death

fro

man

y

cau

se(

ofp

op

u-

lati

on

H

R)

Dab

igat

ran

RE-

MED

Y7

RE-

SON

AT

E83

Ran

dom

ized

dou

ble-

blin

dR

ando

miz

edd

oubl

e-bl

ind

2866

1343

Dab

igat

ran

150

mg

bid

vs

war

fari

n(IN

R2

0ndash3

0)D

abig

atra

n15

0m

gb

idv

spl

aceb

o

Dab

igat

ran

150

mg

vs

war

fari

n1

8vs

13

HR

144

95

CI

078

ndash26

4P

=0

01no

n-in

feri

ority

Rec

urre

ntor

fata

lV

TE

orun

expl

aine

dde

ath

Dab

igat

ran

150

mg

vs

plac

ebo

04

vs5

6H

R0

089

5C

I0

02ndash0

25

Plt

000

1fo

rsu

perio

rity

Dab

igat

ran

150

mg

vs

war

fari

n0

9vs

18

HR

052

95

CI

027

ndash10

2P

=0

06D

abig

atra

n15

0m

gvs

pl

aceb

o0

3vs

0N

oH

Rre

port

edP

=1

0

Dab

igat

ran

150

mg

vs

war

fari

n0

1vs

03

No

HR

repo

rted

No

intr

acra

nial

hem

-or

rhag

esob

serv

ed

Dab

igat

ran

150

mg

vs

war

fari

n0

3vs

06

No

HR

repo

rted

Dab

igat

ran

150

mg

vs

plac

ebo

03

vs0

No

HR

repo

rted

Dab

igat

ran

150

mg

vs

war

fari

n1

2vs

13

HR

090

95

CI

047

ndash17

2P

=0

74D

abig

atra

n15

0m

gvs

pl

aceb

o0

vs0

3N

oH

Rre

port

ed

Riv

arox

aban

EIN

STEI

N-E

xten

tion8

4R

ando

miz

edd

oubl

e-bl

ind

1197

Riv

arox

aban

20m

god

vsp

lace

boR

ecur

rent

VT

ER

ivar

oxab

an20

mg

vs

plac

ebo

13

vs7

1H

R0

189

5C

I0

09ndash0

39

Plt

000

1

Riv

arox

aban

20m

gvs

pl

aceb

o0

7vs

0N

oH

Rre

port

edP

=0

11

No

intr

acra

nial

hem

-or

rhag

esob

serv

edR

ivar

oxab

an20

mg

vs

plac

ebo

05

vs0

No

HR

repo

rted

Riv

arox

aban

20m

gvs

pl

aceb

o0

2vs

03

No

HR

repo

rted

Api

xaba

nA

MPL

IFY

-Ext

ensi

on85

Ran

dom

ized

dou

ble-

blin

d24

86A

pixa

ban

5m

gb

id

orap

ixab

an2

5m

gb

idv

spl

aceb

o

Api

xaba

n5

mg

vsp

la-

cebo

17

vs8

8R

R0

209

5C

I01

1ndash0

34A

pixa

ban

25

mg

vs

plac

ebo

17

vs8

8R

R0

199

5C

I01

1ndash0

33

Api

xaba

n5

mg

vsp

la-

cebo

01

vs0

5R

R0

259

5C

I00

3ndash2

24A

pixa

ban

25

mg

vs

plac

ebo

02

vs0

5R

R0

499

5C

I00

9ndash2

64

No

intr

acra

nial

hem

-or

rhag

esob

serv

ed

No

intr

acra

nial

hem

-or

rhag

esob

serv

ed

Api

xaba

n5

mg

vsp

la-

cebo

01

vs0

3N

oR

Rre

port

ed

No

gast

roin

test

inal

blee

dsob

serv

ed

Api

xaba

n5

mg

vsp

la-

cebo

05

vs1

7N

oR

Rre

port

ed

Api

xaba

n2

5m

gvs

pl

aceb

o0

5vs

17

No

RR

repo

rted

Edox

aban

Hok

usai

-VT

Epo

stho

c86

Ran

dom

ized

dou

ble

blin

d72

27Ed

oxab

an60

mg

qd(o

rdo

sere

duce

d30

mg)

vsw

arfa

rin

Edox

aban

vsw

arfa

rin

18

vs1

9H

R0

979

5C

I0

69ndash1

37)

Edox

aban

vsw

arfa

rin

03

vs0

7H

R0

459

5C

I0

22ndash0

92)

Edox

aban

vsw

arfa

rin

lt0

1vs

02

HR

016

95

CI

002

ndash13

6)

Not

asse

ssed

Not

asse

ssed

Dat

afr

omco

mpa

rativ

ePh

ase

IVst

udie

sR

ivar

oxab

anX

ALI

A87

Pros

pect

ive

non-

inte

rven

tiona

l51

42R

ivar

oxab

an15

mg

bid

for

3w

eeks

follo

wed

by20

mg

qdvs

hep

arin

vita

-m

inK

anta

goni

st

Riv

arox

aban

vshe

p-ar

inV

KA

14

vs2

3H

R0

919

5C

I0

54ndash1

54

P=

072

Riv

arox

aban

vshe

p-ar

inV

KA

08

vs2

1H

R0

779

5C

I0

40ndash1

50

P=

044

Not

asse

ssed

Not

asse

ssed

Riv

arox

aban

vshe

p-ar

inV

KA

04

vs3

4H

R0

5195

C

I02

4ndash1

07P

=0

07

8 L Mazzolai et al













Risk

score

Constans score item


Localized pain 1

Unilateral edema 1



Site of cancer






BMI gt_35 kgm2 1














































technology

Immobilization


10 L Mazzolai et al















































































12 L Mazzolai et al



































ehx003-T1

ehx003-TF1

ehx003-TF2

ehx003-TF3

Tab

le5

Exte

nd

ed

seco

nd

ary

pre

ven

tio

no

fV

TE

co

mp

ari

son

ofre

sult

sfr

om

Ph

ase

III

tria

lsw

ith

dir

ect

ora

lan

tico

agu

lan

ts

Dir

ect

ora

lan

tico

agu

-

lan

ttr

ial

Desi

gn

nT

reatm

en

t

regim

en

Recu

rren

tV

TE

or

VT

E-r

ela

ted

death

(o

fp

op

u-

lati

on

H

R)

Majo

rb

leed

ing

(o

fp

op

ula

tio

n

HR

)

Intr

acra

nia

lh

em

-

orr

hage

(o

f

po

pu

lati

on

H

R)

Gast

roin

test

inal

ble

ed

ing

(o

f

po

pu

lati

on

H

R)

Death

fro

man

y

cau

se(

ofp

op

u-

lati

on

H

R)

Dab

igat

ran

RE-

MED

Y7

RE-

SON

AT

E83

Ran

dom

ized

dou

ble-

blin

dR

ando

miz

edd

oubl

e-bl

ind

2866

1343

Dab

igat

ran

150

mg

bid

vs

war

fari

n(IN

R2

0ndash3

0)D

abig

atra

n15

0m

gb

idv

spl

aceb

o

Dab

igat

ran

150

mg

vs

war

fari

n1

8vs

13

HR

144

95

CI

078

ndash26

4P

=0

01no

n-in

feri

ority

Rec

urre

ntor

fata

lV

TE

orun

expl

aine

dde

ath

Dab

igat

ran

150

mg

vs

plac

ebo

04

vs5

6H

R0

089

5C

I0

02ndash0

25

Plt

000

1fo

rsu

perio

rity

Dab

igat

ran

150

mg

vs

war

fari

n0

9vs

18

HR

052

95

CI

027

ndash10

2P

=0

06D

abig

atra

n15

0m

gvs

pl

aceb

o0

3vs

0N

oH

Rre

port

edP

=1

0

Dab

igat

ran

150

mg

vs

war

fari

n0

1vs

03

No

HR

repo

rted

No

intr

acra

nial

hem

-or

rhag

esob

serv

ed

Dab

igat

ran

150

mg

vs

war

fari

n0

3vs

06

No

HR

repo

rted

Dab

igat

ran

150

mg

vs

plac

ebo

03

vs0

No

HR

repo

rted

Dab

igat

ran

150

mg

vs

war

fari

n1

2vs

13

HR

090

95

CI

047

ndash17

2P

=0

74D

abig

atra

n15

0m

gvs

pl

aceb

o0

vs0

3N

oH

Rre

port

ed

Riv

arox

aban

EIN

STEI

N-E

xten

tion8

4R

ando

miz

edd

oubl

e-bl

ind

1197

Riv

arox

aban

20m

god

vsp

lace

boR

ecur

rent

VT

ER

ivar

oxab

an20

mg

vs

plac

ebo

13

vs7

1H

R0

189

5C

I0

09ndash0

39

Plt

000

1

Riv

arox

aban

20m

gvs

pl

aceb

o0

7vs

0N

oH

Rre

port

edP

=0

11

No

intr

acra

nial

hem

-or

rhag

esob

serv

edR

ivar

oxab

an20

mg

vs

plac

ebo

05

vs0

No

HR

repo

rted

Riv

arox

aban

20m

gvs

pl

aceb

o0

2vs

03

No

HR

repo

rted

Api

xaba

nA

MPL

IFY

-Ext

ensi

on85

Ran

dom

ized

dou

ble-

blin

d24

86A

pixa

ban

5m

gb

id

orap

ixab

an2

5m

gb

idv

spl

aceb

o

Api

xaba

n5

mg

vsp

la-

cebo

17

vs8

8R

R0

209

5C

I01

1ndash0

34A

pixa

ban

25

mg

vs

plac

ebo

17

vs8

8R

R0

199

5C

I01

1ndash0

33

Api

xaba

n5

mg

vsp

la-

cebo

01

vs0

5R

R0

259

5C

I00

3ndash2

24A

pixa

ban

25

mg

vs

plac

ebo

02

vs0

5R

R0

499

5C

I00

9ndash2

64

No

intr

acra

nial

hem

-or

rhag

esob

serv

ed

No

intr

acra

nial

hem

-or

rhag

esob

serv

ed

Api

xaba

n5

mg

vsp

la-

cebo

01

vs0

3N

oR

Rre

port

ed

No

gast

roin

test

inal

blee

dsob

serv

ed

Api

xaba

n5

mg

vsp

la-

cebo

05

vs1

7N

oR

Rre

port

ed

Api

xaba

n2

5m

gvs

pl

aceb

o0

5vs

17

No

RR

repo

rted

Edox

aban

Hok

usai

-VT

Epo

stho

c86

Ran

dom

ized

dou

ble

blin

d72

27Ed

oxab

an60

mg

qd(o

rdo

sere

duce

d30

mg)

vsw

arfa

rin

Edox

aban

vsw

arfa

rin

18

vs1

9H

R0

979

5C

I0

69ndash1

37)

Edox

aban

vsw

arfa

rin

03

vs0

7H

R0

459

5C

I0

22ndash0

92)

Edox

aban

vsw

arfa

rin

lt0

1vs

02

HR

016

95

CI

002

ndash13

6)

Not

asse

ssed

Not

asse

ssed

Dat

afr

omco

mpa

rativ

ePh

ase

IVst

udie

sR

ivar

oxab

anX

ALI

A87

Pros

pect

ive

non-

inte

rven

tiona

l51

42R

ivar

oxab

an15

mg

bid

for

3w

eeks

follo

wed

by20

mg

qdvs

hep

arin

vita

-m

inK

anta

goni

st

Riv

arox

aban

vshe

p-ar

inV

KA

14

vs2

3H

R0

919

5C

I0

54ndash1

54

P=

072

Riv

arox

aban

vshe

p-ar

inV

KA

08

vs2

1H

R0

779

5C

I0

40ndash1

50

P=

044

Not

asse

ssed

Not

asse

ssed

Riv

arox

aban

vshe

p-ar

inV

KA

04

vs3

4H

R0

5195

C

I02

4ndash1

07P

=0

07

8 L Mazzolai et al













Risk

score

Constans score item


Localized pain 1

Unilateral edema 1



Site of cancer






BMI gt_35 kgm2 1














































technology

Immobilization


10 L Mazzolai et al















































































12 L Mazzolai et al



































ehx003-T1

ehx003-TF1

ehx003-TF2

ehx003-TF3













Risk

score

Constans score item


Localized pain 1

Unilateral edema 1



Site of cancer






BMI gt_35 kgm2 1














































technology

Immobilization


10 L Mazzolai et al















































































12 L Mazzolai et al



































ehx003-T1

ehx003-TF1

ehx003-TF2

ehx003-TF3











































technology

Immobilization


10 L Mazzolai et al















































































12 L Mazzolai et al



































ehx003-T1

ehx003-TF1

ehx003-TF2

ehx003-TF3















































































12 L Mazzolai et al



































ehx003-T1

ehx003-TF1

ehx003-TF2

ehx003-TF3



































ehx003-T1

ehx003-TF1

ehx003-TF2

ehx003-TF3

diagnosis and management of acute deep vein thrombosis: a ... · 15department of cardiology, athens...

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