The diagnosis and prognosis of venous thromboembolism : variations on a theme Gibson, N.S.

Transcription

1 UvA-DARE (Digital Academic Repository) The diagnosis and prognosis of venous thromboembolism : variations on a theme Gibson, N.S. Link to publication Citation for published version (APA): Gibson, N. S. (2008). The diagnosis and prognosis of venous thromboembolism : variations on a theme General rights It is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), other than for strictly personal, individual use, unless the work is under an open content license (like Creative Commons). Disclaimer/Complaints regulations If you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Ask the Library: or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. You will be contacted as soon as possible. UvA-DARE is a service provided by the library of the University of Amsterdam ( Download date: 20 Sep 2018

2 Safetyandsensitivityoftwoultrasound strategiesinpatientswithclinically suspecteddeepvenousthrombosis; aprospectivemanagementstudy NADINES.GIBSON,SEBASTIANM.SCHELLONG,DAHLIAY.ELKHEIR, JANBEYER,ALEXS.GALLUS,SIMONMCRAE,ROGERE.G.SCHUTGENS, FRANCOPIOVELLA,VICTORE.A.GERDES,HARRYR.BÜLLER SUBMITTED

3 ABSTRACT 106 Background Thediagnosticworkupofpatientswithsuspecteddeepvenousthrombosis(DVT) hasimprovedsignificantlywiththeintroductionofclinicaldecisionrulesandd dimer testing in the last decade. However, it remains unclear whether a single completeultrasound,thatcandetectcalfveinthrombosis,isassafeasabaseline rapidultrasound,repeatedafteroneweekwhennegative,thatexaminestheveins inthegroinandtheknee.therefore,wecomparedthesafetyandfeasibilityoftwo diagnostic ultrasound strategies with a rapid and a complete compression ultrasound(cus). Methods Consecutive patients with suspected DVT underwent clinical probability assessment.inpatientswithanunlikelyclinicalprobabilityandanormalddimer testresultdvtwasconsideredexcluded.allotherswererandomizedtoundergo eitherarapidcus,repeatedifnecessary,orasinglecompletecusexamination. Anticoagulant treatment was withheld in patients in whom DVT was excluded and they were followed for three months to assess the incidence of venous thromboembolism. Results A total of 1002 patients were included. A clinical decision rule indicating DVT unlikelyandanormalddimertestresultoccurredin481patients(48%),witha venous thromboembolism incidence of 0.4% (95% confidence interval (CI) %)duringfollowup.DVTwasconfirmedin59ofthe257patients(23%)that underwentrapidcusandin99ofthe264patients(38%)thatunderwentcomplete CUS.Venousthromboembolismduringfollowupoccurredinfourpatients(2.0%; 95%CI0.65.1%)intherapidCUSarmandin2patients(1.2%;95%CI0.24.3%)in thecompletecusarm. Conclusion Adiagnosticstrategywithaclinicaldecisionrule,aDdimertestand,ifindicated, anultrasoundexaminationissafeandefficient.boththerapidandthecomplete ultrasound test are comparable and efficient strategies with differing pro s and con s.

4 Safetyandsensitivityoftwoultrasoundstrategies INTRODUCTION The diagnosis of deep venous thrombosis (DVT) remains a challenge, since this common disease is only present in 20% of those with a clinical suspicion 1. If left untreated,thereisaconsiderableriskofpulmonaryembolism 2.Therefore,arapidand efficient confirmation or exclusion of the disease is essential. Traditionally, the diagnostic approach consists of serial ultrasonography, which has proved to be accurateandsafeinlargeseriesofconsecutivepatients 3,4.However,theintroduction of clinical decision rules to assess clinical probability and Ddimer testing has had important implications for the diagnostic workup. The combination of an unlikely clinicalprobabilityfordvtwithanormalddimertest,whichmaybepresentin30 to50%ofpatients,hasbeenshowntoeffectivelyruleoutdvtwithouttheneedfor additional testing 1. Therefore, imaging with ultrasonography could be restricted to only those patients with a likely clinical probability or an abnormal Ddimer test result. Becauseimaginglimitedtoatwopoint rapid ultrasoundexaminationofthegroin andpoplitealfossacannotdetectcalfveinthrombosis,itmustberepeatedafterone week if the initial examination is normal, in order to detect potential extension of distalvenousthrombosistotheproximalveins.thisstrategyisofteninconvenientfor patients because of the extra visit and, although the detection rate of venous thrombosisoneweekafteraninitiallynegativeresultislessthan2% 5,therehavebeen rarefatalcomplicationsbeforethesecondexaminationcouldbeperformed 6. Recent studies have shown that a single complete ultrasound examination, with evaluation of the entire venous system from the groin to the distal part of the leg, effectivelydetectsthrombosisincalfaswellasproximalveins,andthatanticoagulant therapycanbesafelywithheldwhentheresultisnormal 711.However,theprocedure requires a certain expertise, is relatively time consuming, and the diagnosis of thrombosislimitedtooneormoreofthecalfveinsraisesthequestionofhowtotreat thesethrombi. Therehavebeennodirectcomparisonsbetweenextendedultrasoundexaminationof proximal and distal veins at baseline by means of a single complete compression ultrasound(completecus),andabaselinerapidcompressionultrasound(rapidcus) examination, repeated when negative; in particular in the group of patients with either a likely clinical probability for DVT or an abnormal Ddimer test result. We, therefore, studied a large sample of consecutive patients with clinically suspected DVT. Patients with an unlikely clinical probability and a normal Ddimer test were CHAPTER 8 107

5 considered not to have thedisease andwere followed up for three months without anticoagulanttherapy.allotherpatientswererandomizedtohaveeitherarapidcus examinationwitharepeattestafteroneweekifnormal,orasinglecompletecus.we compared these diagnostic approaches for their feasibility, prevalence of confirmed DVT,andsafetyinrulingoutDVT(asmeasuredbythethromboemboliceventrate afterthreemonthsfollowup).wealsoassessedthetreatmentdecisionsinthosewith documentedthrombosis. METHODS 108 Study patients This study was performed in five teaching hospitals between September 2002 and December 2007 in Germany, Australia and the Netherlands. Consecutive patients with a first episode of clinically suspected DVT were eligible for inclusion. Patients were excluded if they had a previous episode of venous thromboembolism, had symptomsofpulmonaryembolism,werepregnant,receivedfulldoselowmolecular weightheparinformorethan24hours,hadalifeexpectancyoflessthan3months, hadsymptomslastinglongerthan4weeks,hadongoinganticoagulanttreatmentfor other reasons, were geographically inaccessible for followup, had anticipated low compliance,orifwritteninformedconsentcouldnotbeobtained.thisstudyprotocol wasapprovedbytheinstitutionalreviewboardsofallparticipatingcenters. Diagnostic algorithm Atreferral,allincludedpatientsunderwentclinicalprobabilityassessment,according to the clinical score described by Wells and others 12. This clinical model stratifies patientswithsuspecteddvtintotwogroupswitheitheranunlikelyprobability(2 points) or a likely probability (> 2 points) for DVT. We have chosen a cutoff of 2 insteadof1toincreasetheproportionofpatientsinwhomdvtcanbeexcluded.to maintain the safety, only patients with a first suspected episode of DVT were included.ddimertestingwasperformedonlyinthepatientswithanunlikelyclinical probability for DVT. A fully automated quantitative immunoturbidimetric DDimer assay (Tinaquant, Roche Diagnostics, Mannheim, Germany) was used 13. A Ddimer testresultoflessthan0.5mg/lfibrinogenequivalentunits(feu)wasconsideredtobe normal. In case of an unlikely clinical probability and a normal Ddimer test, DVT was considered to be excluded, no anticoagulants were prescribed and patients were

6 Safetyandsensitivityoftwoultrasoundstrategies followedupforthreemonths.allpatientswithalikelyclinicalprobability,andthose withanunlikelyprobabilityandanabnormalddimertestresult,wererandomisedto undergoeitherarapidcusoracompletecusexamination. Rapid CUS In patients randomised to the rapid CUS arm, the ultrasound examination was performedasfollows:thecommonfemoralvein(inthegroin),andthepoplitealvein (inthepoplitealfossa),downtothebranchingofthecalfveins,wereexaminedinthe transverse plane. The diagnosis of thrombosis was based on the lack of compressibility of one or more of these venous segments 14. Patients with abnormal ultrasound results were considered to have DVT and anticoagulant therapy was administered according to local protocols. Patients with a normal ultrasound examinationwerescheduledforarepeatcustestoneweeklater.inpatientswithan abnormalrepeatcusresult,anticoagulanttreatmentwasadministered.thosewitha normal repeat ultrasound result were considered not to have DVT, received no anticoagulanttreatment,andwerefollowedupforthreemonths. Complete CUS Withthisproceduretheentiredeepvenoussystemwasimagedfromthegroindown tothedistalsysteminthecalf.theproximalvenoussystemwasexaminedfirst,with thepatientlyingsupine.thefemoralbifurcation,thegreatsaphenousveinjunction, theprofundafemorisandthefemoralveindowntothedistalpartofthethighwere scannedalongtheirlengthinthetransverseplane.afterthisthepoplitealveintoits trifurcation, the paired posterior tibial veins, the paired peroneal veins, the lesser saphenousveinjunctionandthemuscularveins(gastrocnemialandsolealsinusoids) wereevaluatedwiththepatientinthesittingposition.theonlycriterionacceptedfor a diagnosis of DVT was the finding of one or more noncompressible venous segments 9.ThesepatientswereconsideredtohaveDVTandtreatedaccordingtolocal protocols. Patients with a normal wholeleg CUS examination were not further investigated, receivednoanticoagulanttreatment,andwerefollowedupforthreemonths. For bothultrasoundstrategiesaninconclusiveresultwasdefinedastheinabilityto eitherconfirmorrefutethepresenceofdvt,dueto,forexample,severeoedema,a plastercastoranopenwound.incaseofaninadequateproximalvenoussystem,a venographyhadtobeperformed,andinpatientswithaninadequatedistalvenous CHAPTER 8 109

7 system,arepeatcompletecushadtobeperformedafteroneweek.inadditiontothe assessment of the deep venous system, if clinically indicated, patients were investigated for the presence of superficial vein thrombosis. This was classified separately. All sonographers from the five study centers were specialized in performing ultrasounds of the venous system and were trained in performing the complete CUS by the vascular unit of the University Hospital Carl Gustav Cars in Dresden,Germany. 110 Follow-up Allpatientswithanormaldiagnosticworkupwerefollowedupandcontactedat3 months.inadditionpatientswereinstructedtoimmediatelycontactthestudycentre ifsignsorsymptomsofvenousthromboembolismoccurred.patientspresentingwith clinically suspected thrombosis during followup underwent objective testing to confirmorrefutethedisease 6,14. InthecaseofsuspectedsymptomaticDVTthediagnosiswasruledinbyeitheranew incompressibility on CUS or by an intraluminal filling defect on ascending venography.incaseofsuspectedsymptomaticpulmonaryembolism,thediseasewas confirmedbyahighprobabilityventilationperfusionlungscan,abnormalpulmonary angiography,oranabnormalspiralctscan.allcausesofdeathwereclassifiedbythe adjudication committee using clinical reports and if available, autopsy reports, as causedbypulmonaryembolismornot. Objective This study had four objectives: to compare the two ultrasound techniques for feasibility (i.e. the proportion of inconclusive test results), the prevalence of DVT detected, and safety, as measured by the thromboembolic event rate during three monthsoffollowup.lastly,weassessedthetreatmentdecisionsofphysicians. Analysis InthoseinwhomDVTwasruledoutbyanunlikelyclinicalprobabilityandanormal Ddimertestresult,safetywasexpressedastheincidencerateofnewandconfirmed episodesofvteduring3monthsalongwithits95%confidenceinterval(ci).forthe comparisonbetweenthetwoultrasoundapproaches,theratesofinconclusiveresults,

8 Safetyandsensitivityoftwoultrasoundstrategies Table 1. Baseline characteristics of the study population (1002 patients). Characteristics n (%) Age in years, mean (range) 58 (18-99) Female gender 607 (61) Complaints in days, median (IQR) 7 (3-13) Outpatient 940 (94) Malignancy 61 (6) Major surgery < 4 weeks 46 (5) Hormone therapy 100 (10) Long haul flight 49 (5) Known trombophilia 7 (1) the prevalence of DVT detected, and the 3 month event rate were calculated along withtheir95%ciandcomparedwithfisher sexacttest(spssinc.,cary,nc,version andCIA,version1.0). RESULTS Study patients During the study period a total of 1258 consecutive patients with a first episode of clinically suspected DVT was screened, of whom 225 (18%) were excluded for the following reasons: previous venous thromboembolism (n = 85), symptoms lasting more than 4 weeks (n = 59), more than 24 hours of therapeuticdose low molecular weightheparin(n=31),ongoinganticoagulanttreatmentforotherreasons(n=12), anticipatedlowcompliance(n=11),pregnancy(n=9),geographicinaccessibilityfor followup (n = 9), concurrent symptoms of pulmonary embolism (n = 8) and life expectancy less than 3 months (n = 1). In addition, 31 patients refused informed consent.thebaselineclinicalcharacteristicsoftheremaining1002studypatientsare shownintable1. CHAPTER Diagnostic algorithm Figure1detailstheresults ofthediagnosticalgorithmappliedinthisstudy.ofthe 1002 patients enrolled, 749 (75%) had an unlikely clinical probability for DVT and underwentddimertesting.in481patients(48%ofallstudypatients),theddimer testresultwasnormalanddvtwasconsideredtobeexcluded.the521patientswith alikelyclinicalprobability(n=253)oranabnormalddimerconcentration(n=268)

9 Clinically suspected DVT (n = 1258) Study patients (n = 1002) Excluded (n = 225) No consent (n = 31) Clinical decision rule (n = 1002) Low DVT probability (n = 749) High DVT probability (n = 253) D-dimer normal (n = 481) D-dimer abnormal (n = 268) DVT excluded (n = 481) Randomization CUS (n = 521) Rapid CUS (n = 257) Complete CUS (n = 264) 112 Figure 1. Diagnostic flow chart of consecutive patients with the clinical suspicion of DVT. wererandomizedtoundergoeitherrapidcusorcompletecus.thebaselineclinical characteristics including age, gender, duration of symptoms and risk factors were comparableinthetwostudygroups(datanotshown). Unlikely clinical probability and normal D-dimer level Of the 481 patients with an unlikely clinical probability for DVT and a normal D dimerlevelwhowerenottreatedwithanticoagulanttherapy,15returnedduringthe threemonthfollowupperiodwithasuspicionofvenousthromboembolism.in13of thesepatientsthediagnosiswasruledoutandintwoadeepvenousthrombosiswas confirmedbyobjectivetesting.therefore,theincidenceofvenousthromboembolism inthisgroupwas0.4%(95%ci %).oneofthe481patientsdied(0.2%),butnot asaresultoffatalpulmonaryembolism.

10 Safetyandsensitivityoftwoultrasoundstrategies Table 2. Localization of the thrombi in the patients with DVT. Baseline RCUS* Proximal DVT Distal DVT Repeat RCUS Femoral bifurcation Femoral vein NP NP 16 Popliteal vein Trifurcation Paired calf veins NP NP 11 Calf muscle veins NP NP 27 Total *RCUS: rapid compression ultrasound **CCUS: complete compression ultrasound NP: not performed. CCUS** Rapid CUS Atotalof257patientswasallocatedtotherapidCUSstrategy.Thebaselinetestwas inconclusivein3patients:intwoofthemthecusexaminationwasrepeated,andin thethirdpatientavenogramwasobtained,whichwasnormal.therapidcusafter oneweekwasnotobtainedin26patients,butallwerefollowedup. DVTwasconfirmedin59patients,aprevalenceof23%(95%CI1828%).Ofthese59 patients,dvtwasdetectedatbaselinein56pts(95%).thelocalizationofthrombiin these patients is detailed in Table 2. In 5 patients the thrombus was present in the trifurcation.inadditionin7patients(3%)anisolatedsuperficialveinthrombosiswas diagnosed. Followup was performed in all 198 patients (77%) where a repeat ultrasound examination, or a normal venogram in one patient, did not reveal thrombosis. Fourteenofthese198patients,returnedwithasuspicionofVTEduringfollowup.In tenpatientsthediagnosiswasrefutedandfourhadvenousthromboembolicdisease confirmedbyobjectivetesting(incidenceofvenousthromboembolism2.0%;95%ci: %). Two of the four patients had symptomatic DVT in the same leg and two hadpulmonaryembolism.fourpatientsdiedduringfollowup;innoneofthemwas fatalpulmonaryembolismthecauseofdeath. All 59 patients with thrombosis were initially treated with (low molecular weight) heparinfollowedbyavitaminkantagonistforatleastthreemonths. CHAPTER Complete CUS Atotalof264patientsunderwentacompleteCUSexamination. In13patients(5%)

11 114 the complete CUS examination was inconclusive; eight of these had a repeat test performed one week later, whereas the remaining five patients did not return for repeat testing, but all were followed up. DVT was confirmed in 99 patients, for an overallprevalenceof38%(95%ci:3243%).thelocalizationofthrombiinthisgroup is shown in Table 2. Distal thrombosis in either the paired calf veins or the muscle veins was observed in 39 of the 99 patients (39%). One of the paired calf veins thrombosis was detected in the eight patients that underwent a repeat ultrasound. Additionally, in ten patients (4%) an isolated superficial vein thrombosis was diagnosed. DVT was considered to be excluded in 165 patients (63%) with a normal complete CUSresult,ofwhomthreereturnedduringfollowup withthesuspicionofvenous thromboembolism.intwoofthesepatientsthediagnosiswasrefutedandonepatient hadadvtconfirmedbyobjectivetesting.oneofthe5patientsinwhomthebaseline completecuswasinconclusive,andwhodidnotreturnforarepeattest,diedatday 60 of the followup period and fatal pulmonary embolism was proven by autopsy. Therefore,therewere2venousthromboemboliceventsduringthefollowupperiod, anincidenceof1.2%(95%ci:0.24.3%). All61patientswithproximalDVTwereinitiallytreatedwith(lowmolecularweight) heparinfollowedbyavitaminkantagonistforatleastthreemonths. Asimilarregimenwasprescribedtotheelevenpatientswiththrombosisinthepaired calfveins.treatmentinpatientswithmuscleveinthrombosisdiffered:18receiveda therapeutic dosage of LMWH for only 1012 days, 2 patients were given a prophylactic dosage of LMWH for ten days, 2 patients received a vitamin K antagonistforatleastthreemonthsafteraninitialcourseoflmwh,2patientswere nottreated,andin3patientsthetreatmentwasunknown. Net clinical benefit OutcomesofthetwodiagnosticapproachesaresummarizedinTable3.Inconclusive resultswereobtainedin1.2%and4.9%withtherapidandcompletecusstrategies, respectively(p=0.012).almost80%ofthoseundergoingrapidcusexaminationhad toreturnforrepeattestingwithadocumentedthrombosisin3patients(i.e.1.5%ofall those undergoing repeat testing). Repeat complete CUS examination was necessary duetoinconclusivefindingsinapproximatelyonepertwentypatients.

12 Safetyandsensitivityoftwoultrasoundstrategies Table 3. The net clinical benefit of the rapid and the complete CUS examination. Rapid CUS Complete CUS p-value Number of patients Inconclusive tests 3 (1.2%) 13 (4.9%) Number of repeated test needed 199 (77%) 13 (4.9%) <0.001 Prevalence 23% 38% <0.001 VTE during FU 2.0% (95% CI: ) 1.2% (95% CI: ) 0.69 The prevalence of venous thrombosis detected was 23% (95% CI 1828%) and 38% (95% CI 3243%) after rapid CUS and complete CUS examination, respectively (p < 0.001). Finally,duringfollowuptheincidenceofvenousthromboembolismwas2.0%witha rapid CUS and 1.2% with a complete CUS examination (p=0.69, absolute difference 0.8%;95%CI1.83.4%). DISCUSSION CHAPTER 8 The first part of the present study confirms it is safe and efficient to accept that an unlikely clinical probability plus a normal Ddimer result excludes DVT. This combinationwaspresentinapproximately50%ofourstudypatients;thisobservation isnotnewandisinfullagreementwithpreviousstudies 1. The second major objective of our study was to compare the clinical validity of the two ultrasound strategies. Both strategies appeared to be equally safe in excluding DVT(the3monthVTErateswere2.0%and1.2%forrapidCUSandcompleteCUS, respectively), and both have a comparable high feasibility, although there were slightly more inconclusive tests with the complete CUS examination (3 versus 13 patients,respectively). The prevalence of DVT was 23% and 38% (p < 0.001) for rapid CUS and complete CUS, respectively, due to the extra calf thrombi detected by the complete CUS examination.therefore,applyingtherapidcusstrategyimpliesthat4in5patients needtoreturnforrepeattesting,whereasthetestcanbeperformedin3to5minutes bytechniciansinaroutinesetting.thecompletecuscanbeusedasasingletestbut takes 8 to 10 minutes and requires more experience from the technician 9. Given the uncertaintyabouttheoptimaltherapeuticapproachtothrombosisconfinedtothecalf veins, another aspect of the complete CUS strategy is that it puts the attending 115

13 116 physicianinatherapeuticdilemmaforoneofeveryeightpatientsinvestigated. We therefore conclude that both diagnostic strategies are equally valid, and that a preferencemainlydependsonthebalanceofavailableexpertiseandfacilitiesonone handandwillingnessforrepeatedtestingandpossibleextraanticoagulanttreatment ontheotherhand. The rates of VTE during 3 months of followup observed in the present study in patients with normal ultrasound examination results (1.2 to 2.0%) are somewhat higherthaninpublishedstudies 15.Thisisexplainedbythefactthatweincludedonly patientswithalikelyclinicalprobability oranabnormalddimerresultinthecus technique comparison. These patients are more likely to have comorbid conditions predisposingthemtoahigherriskofvte.incontrast,previousstudieswitheither rapidcusorcompletecusincludedallcomers. Some methodological aspects require comment. While the comparison of the ultrasoundstrategieswasrandomized,thedesignwasopenandthesamplesizewas modest.eventhoughthetechniciansandphysiciansknewwhichultrasoundtestwas performed,theywerewelltrainedinbothtechniquesandfollowedastrictimaging protocol.therefore,biascannotberuledoutbutislikelytobeminimal.noneofthe participatingcentershadanexplicitpreferenceforeithertechnique. Bothstudygroupsincludedapproximately250patients.Althoughthegroupsarenot verylarge,theoverall3monthincidencesandtheir95%ciarefullycomparableand itisunlikelythatalargedifferencewasmissed.because94%ofourstudypopulation consistedofoutpatients,ourconclusionsapplymainlytothisgroup.furthermore,the study was conducted in 5 centers around the world, with no major differences regardingoutcomesinthevarioussettings,therebysupportingtheexternalvalidityof theresults.finally,decisionsabouttreatmentwerelefttothediscretionofthetreating physician, and were not dictated by the protocol. Since this study was designed to comparediagnosticstrategiesandbecausethegroupof38patientswastoosmallto quantifytheriskofbleedingassociatedwiththeanticoagulanttreatmentgiven,there wasnoformalfollowupofthetreatedpatients.therefore,sincethereisnouniversal consensusaboutthetreatmentofdistalthrombosis,theneedfor arandomisedtrial that assesses the usefulness of anticoagulant treatment in symptomatic distal deep venousthrombosispersists.

14 Safetyandsensitivityoftwoultrasoundstrategies Inconclusion,adiagnosticstrategywithaclinicaldecisionrule,aDdimertestand,if indicated, an ultrasound examination is safe and efficient. Both the rapid and the completeultrasoundtestarecomparableandefficientstrategieswithdifferingpro s andcon s. ACKNOWLEDGEMENTS We are indebted to Belia Rekké and Jantje Visser for excellent patient care and collaboration and to Marja Pannekoek, Aart Terpstra, Fraukje Kalb and Johan van Gurpforperformingtheultrasoundswithexpertise.Furthermore,wewouldliketo thankmartinprinsforhisexpertstatisticaladvice.thisstudywassupportedinpart bygrantsfromthenetherlandsheartfoundation. CHAPTER 8 117

15 REFERENCELIST Ten Cate-Hoek AJ, Prins MH. Management studies using a combination of D-dimer test result and clinical probability to rule out venous thromboembolism: a systematic review. J Thromb Haemost. 2005;3: Naess IA, Christiansen SC, Romundstad P, Cannegieter SC, Rosendaal FR, Hammerstrom J. Incidence and mortality of venous thrombosis: a population-based study. J Thromb Haemost. 2007;5: Birdwell BG, Raskob GE, Whitsett TL, Durica SS, Comp PC, George JN et al. The clinical validity of normal compression ultrasonography in outpatients suspected of having deep venous thrombosis. Ann Intern Med. 1998;128: Cogo A, Lensing AW, Koopman MM, Piovella F, Siragusa S, Wells PS et al. Compression ultrasonography for diagnostic management of patients with clinically suspected deep vein thrombosis: prospective cohort study. BMJ. 1998;316: Michiels JJ, Gadisseur A, Van Der Planken M, Schroyens W, De Maeseneer M, Hermsen JT et al. A critical appraisal of non-invasive diagnosis and exclusion of deep vein thrombosis and pulmonary embolism in outpatients with suspected deep vein thrombosis or pulmonary embolism: how many tests do we need? Int Angiol. 2005;24: Kraaijenhagen RA, Piovella F, Bernardi E, Verlato F, Beckers EA, Koopman MM et al. Simplification of the diagnostic management of suspected deep vein thrombosis. Arch Intern Med. 2002;162: Cornuz J, Pearson SD, Polak JF. Deep venous thrombosis: complete lower extremity venous US evaluation in patients without known risk factors--outcome study. Radiology. 1999;211: Elias A, Mallard L, Elias M, Alquier C, Guidolin F, Gauthier B et al. A single complete ultrasound investigation of the venous network for the diagnostic management of patients with a clinically suspected first episode of deep venous thrombosis of the lower limbs. Thromb Haemost. 2003;89: Schellong SM, Schwarz T, Halbritter K, Beyer J, Siegert G, Oettler W et al. Complete compression ultrasonography of the leg veins as a single test for the diagnosis of deep vein thrombosis. Thromb Haemost. 2003;89: Stevens SM, Elliott CG, Chan KJ, Egger MJ, Ahmed KM. Withholding anticoagulation after a negative result on duplex ultrasonography for suspected symptomatic deep venous thrombosis. Ann Intern Med. 2004;140: Subramaniam RM, Heath R, Chou T, Cox K, Davis G, Swarbrick M. Deep venous thrombosis: withholding anticoagulation therapy after negative complete lower limb US findings. Radiology. 2005;237: Wells PS, Anderson DR, Bormanis J, Guy F, Mitchell M, Gray L et al. Value of assessment of pretest probability of deep-vein thrombosis in clinical management. Lancet. 1997;350: Schutgens RE, Ackermark P, Haas FJ, Nieuwenhuis HK, Peltenburg HG, Pijlman AH et al. Combination of a normal D-dimer concentration and a non-high pretest clinical probability score is a safe strategy to exclude deep venous thrombosis. Circulation. 2003;107: Lensing AW, Prandoni P, Brandjes D, Huisman PM, Vigo M, Tomasella G et al. Detection of deep-vein thrombosis by real-time B-mode ultrasonography. N Engl J Med. 1989;320: Righini M, Paris S, Le GG, Laroche JP, Perrier A, Bounameaux H. Clinical relevance of distal deep vein thrombosis. Review of literature data. Thromb Haemost. 2006;95:56-64.