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The diagnosis and prognosis of venous thromboembolism : variations on a
theme
Gibson, N.S.
Publication date
2008
Link to publication
Citation for published version (APA):
Gibson, N. S. (2008). The diagnosis and prognosis of venous thromboembolism : variations
on a theme.
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Safetyandsensitivityoftwoultrasound
strategiesinpatientswithclinically
suspecteddeepvenousthrombosis;
aprospectivemanagementstudy
NADINES.GIBSON,SEBASTIANM.SCHELLONG,DAHLIAY.ELKHEIR, JANBEYER,ALEXS.GALLUS,SIMONMCRAE,ROGERE.G.SCHUTGENS,
FRANCOPIOVELLA,VICTORE.A.GERDES,HARRYR.BÜLLER
SUBMITTED
106
A
BSTRACT
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 unlikely and a normal Ddimer test result occurred in 481 patients (48%), with a venous thromboembolism incidence of 0.4% (95% confidence interval (CI) 0.05 1.5%)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, an ultrasound examination is safe and efficient. Both the rapid and the complete ultrasound test are comparable and efficient strategies with differing pro’s and con’s.107
C
HAPTER
8
I
NTRODUCTION
The diagnosis of deep venous thrombosis (DVT) remains a challenge, since this
common disease is only present in 20% of those with a clinical suspicion1. If left
untreated,thereisaconsiderableriskofpulmonaryembolism2.Therefore,arapidand
efficient confirmation or exclusion of the disease is essential. Traditionally, the diagnostic approach consists of serial ultrasonography, which has proved to be
accurateandsafeinlargeseriesofconsecutivepatients3,4.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 testing1. Therefore, imaging with ultrasonography could be restricted to
only those patients with a likely clinical probability or an abnormal Ddimer test result.
Because imaging limited to a two point ‘rapid’ ultrasound examination of the groin and popliteal fossa cannot detect calf vein thrombosis, it must be repeated after one 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
rarefatalcomplicationsbeforethesecondexaminationcouldbeperformed6.
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
therapycanbesafelywithheldwhentheresultisnormal711.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
108
considered not to have the disease and were followed up for three months without anticoagulanttherapy.AllotherpatientswererandomizedtohaveeitherarapidCUS examinationwitharepeattestafteroneweekifnormal,orasinglecompleteCUS.We compared these diagnostic approaches for their feasibility, prevalence of confirmed DVT, and safety in ruling out DVT (as measured by the thromboembolic event rate afterthreemonthsfollowup).Wealsoassessedthetreatmentdecisionsinthosewith documentedthrombosis.
M
ETHODS
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 weightheparinfor morethan24hours, hadalifeexpectancyoflessthan3 months, 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 others12. 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 used13. 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
109 C HAPTER 8 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 segments14. 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 venoussegments9.ThesepatientswereconsideredtohaveDVTandtreatedaccordingtolocal
protocols.
Patients with a normal wholeleg CUS examination were not further investigated, receivednoanticoagulanttreatment,andwerefollowedupforthreemonths.
For both ultrasound strategies an inconclusive result was defined as the inability to either confirm or refute the presence of DVT, due to, for example, severe oedema, a plaster cast or an open wound. In case of an inadequate proximal venous system, a venography had to be performed, and in patients with an inadequate distal venous
110
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.
Follow-up
Allpatientswithanormal diagnosticworkupwerefollowedup andcontactedat3 months.Inadditionpatientswereinstructedtoimmediatelycontactthestudycentre ifsignsorsymptomsofvenousthromboembolismoccurred.Patientspresentingwith clinically suspected thrombosis during followup underwent objective testing to
confirmorrefutethedisease6,14.
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,111
C
HAPTER
8
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 14.0.2andCIA,version1.0).
R
ESULTS
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 weight heparin (n = 31), ongoing anticoagulant treatment for other reasons (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.
Diagnostic algorithm
Figure 1 details the results of the diagnostic algorithm applied in this study. Of the 1002 patients enrolled, 749 (75%) had an unlikely clinical probability for DVT and underwent Ddimer testing. In 481 patients (48% of all study patients), the Ddimer testresultwasnormalandDVTwasconsideredtobeexcluded.The521patientswith alikelyclinicalprobability(n=253)oranabnormalDdimerconcentration(n=268)
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%CI0.051.5%).Oneofthe481patientsdied(0.2%),butnot asaresultoffatalpulmonaryembolism. Clinically suspected DVT (n = 1258) Excluded (n = 225) No consent (n = 31) Study patients (n = 1002)
Clinical decision rule (n = 1002) Low DVT probability (n = 749) DVT excluded (n = 481) D-dimer normal (n = 481) High DVT probability (n = 253) D-dimer abnormal (n = 268) Randomization CUS (n = 521) Rapid CUS (n = 257) Complete CUS (n = 264)
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C
HAPTER
8
Table 2. Localization of the thrombi in the patients with DVT.
Baseline RCUS* Repeat RCUS CCUS** Femoral bifurcation 20 1 19 Femoral vein NP NP 16 Popliteal vein 31 2 18 Proximal DVT Trifurcation 5 0 8
Paired calf veins NP NP 11 Distal DVT
Calf muscle veins NP NP 27
Total 56 3 99
*RCUS: rapid compression ultrasound **CCUS: complete compression ultrasound NP: not performed.
Rapid CUS
Atotalof257patientswasallocatedtotherapidCUSstrategy.Thebaselinetestwas inconclusivein3patients:intwoofthemtheCUSexaminationwasrepeated,andin thethirdpatientavenogramwasobtained,whichwasnormal.Therapid CUSafter 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: 0.65.1%). 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.
Complete CUS
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 CUS result, of whom three returned during followup with the suspicion of venous 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.
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HAPTER
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Table 3. The net clinical benefit of the rapid and the complete CUS examination.
Rapid CUS Complete CUS p-value Number of patients 257 264
Inconclusive tests 3 (1.2%) 13 (4.9%) 0.012 Number of repeated test needed 199 (77%) 13 (4.9%) <0.001 Prevalence 23% 38% <0.001 VTE during FU 2.0% (95% CI: 0.6-5.1) 1.2% (95% CI: 0.2-4.3) 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%).
D
ISCUSSION
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
isnotnewandisinfullagreementwithpreviousstudies1.
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 technician9. Given the
uncertaintyabouttheoptimaltherapeuticapproachtothrombosisconfinedtothecalf veins, another aspect of the complete CUS strategy is that it puts the attending
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
higherthaninpublishedstudies15.Thisisexplainedbythefactthatweincludedonly
patients with a likely clinical probability or an abnormal Ddimer result in the CUS technique comparison. These patients are more likely to have comorbid conditions predisposing them to a higher risk of VTE. In contrast, previous studies with either rapidCUSorcompleteCUSincludedallcomers.
Some methodological aspects require comment. While the comparison of the ultrasoundstrategieswasrandomized,thedesignwasopenandthesamplesizewas modest.Eventhoughthetechniciansandphysiciansknewwhichultrasoundtestwas performed, they were well trained in both techniques and followed a strict imaging 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 consensus about the treatment of distal thrombosis, the need for a randomised trial that assesses the usefulness of anticoagulant treatment in symptomatic distal deep venousthrombosispersists.
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C
HAPTER
8
Inconclusion,adiagnosticstrategywithaclinicaldecisionrule,aDdimertestand,if indicated, an ultrasound examination is safe and efficient. Both the rapid and the complete ultrasound test are comparable and efficient strategies with differing pro’s andcon’s.
A
CKNOWLEDGEMENTS
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 Gurp for performing the ultrasounds with expertise. Furthermore, we would like to thankMartinPrinsforhisexpertstatisticaladvice.Thisstudywassupportedinpart bygrantsfromtheNetherlandsHeartFoundation.
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