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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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Theimportanceofclinicalprobability
assessmentininterpretinganormal
Ddimerinpatientswithsuspected
pulmonaryembolism
NADINES.GIBSON,MAAIKESÖHNE,VICTORE.A.GERDES,
MATHILDENIJKEUTER,HARRYR.BÜLLER
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A
BSTRACT
Background
ThemeasurementoftheDdimerconcentrationtestisawidelyappliedtestinthe diagnosticworkupofpatientswithsuspectedpulmonaryembolism.Theobjective of this study was to investigate how often the Ddimer test fails when clinical probabilityisnottakenintoaccount.
Methods
Weuseddatacollectedin1722consecutivepatientswithclinicallysuspectedPEto analyzethethreemonthsvenousthromboembolism(VTE)rateinallpatientswith a normal Ddimer concentration and separately for patients with a normal D dimer with an unlikely or likely clinical probability for pulmonary embolism, as assessedbytheWellsclinicaldecisionrule.
Results
The3monthVTErateinallpatientswithanormalDdimerconcentration(N=563) was2.3%(95%CI:1.43.9%).Inthepatientswithanunlikelyprobability(N=477) VTE was confirmed in 1.1% of the patients with a normal Ddimer (95% CI: 0.4 2.4%).Inthosewithalikelyclinicalprobability(N=86)VTEwasconfirmedin9.3% of the patients with a normal Ddimer (95% CI: 4.817.3%). The difference of the VTE incidence between the unlikely and the likely probability categories was significant(p<0.001).
Conclusion
Our findings indicate that it is of utmost importance to first examine the patient andassesstheclinicalprobabilityafterwhichtheDdimerresultcanbetakeninto account, in order to prevent that physicians will be influenced by a normal D dimertestresultwhentheyevaluatetheclinicalprobability.Patientswithalikely clinical probability should undergo further testing, regardless the Ddimer outcome.
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I
NTRODUCTION
In the last decade Ddimer testing has gained widespread popularity for excluding pulmonary embolism and deep venous thrombosis, mainly as a result of its noninvasive character and high negative predictive value. A necessity for the appropriate implementation in clinical practice however is that the Ddimer test is usedincombinationwithaclinicalpretestprobabilityassessment,sincebothdiseases canbesafely excludedincaseofan unlikelyclinicalprobabilitytesttogetherwitha
normal Ddimer13. In patients with a likely clinical probability a normal Ddimer
result can not be used to exclude pulmonary embolism, and additional imaging
testingisnecessary1.
Althoughthisstrategyisrecommendedinseveralguidelines,indailyclinicalpractice
physiciansareofteninfluencedbyanormalDdimer46.Duetologisticadvantagesina
hectic emergency room setting the Ddimer test result is often available before a physicianexaminesthepatient.Asaconsequence,thephysicianmightbeinfluenced andtendedtodecidethattheclinicalprobabilityforvenousthromboembolism(VTE) islow.AnevenbiggerriskariseswhentheDdimerisusedasthestandalonetestin managementdecisions.
Based on the data collected in a large diagnostic management study in consecutive patients with suspected pulmonary embolism we assessed firstly the negative predictive value of a normal Ddimer used as a stand alone test and secondly, the negative predictive value of a normal Ddimer in patients with an unlikely as comparedtothosewithalikelyclinicalprobabilityforpulmonaryembolism.Finally, we studied the clinical characteristics of those patients with a false normal Ddimer test.
M
ETHODS
Data were obtained from a prospective diagnostic management study that included 3306 patients with clinically suspected pulmonary embolism enrolled between November2002andAugust2004in12hospitalsintheNetherlands2.Theinstitutional review boards of all participating hospitals approved the study protocol. Exclusion criteria were patients receiving (low molecular weight) heparin for more than 24 hours, younger than 18 years of age, pregnancy, a known hypersensitivity for iodinated contrast fluid, a life expectancy of less than three months, if there was
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Table 1. Clinical decision rule according to Wells et al.7,8.
Points
1. Clinical signs and symptoms of DVT 3
2. Tachycardia (heart rate > 100/min) 1.5 3. Immobilization or surgery in the previous four weeks 1.5
4. Previous DVT/PE 1.5
5. Hemoptysis 1
6. Malignancy (on treatment, treated in the last six months or palliative) 1 7. An alternative diagnosis is less likely than PE 3 Clinical probability of PE unlikely 4 points, clinical probability of PE likely > 4 points. DVT: deep venous thrombosis
PE: pulmonary embolism
geographicinabilityforfollowuporifnoinformedconsentwasobtained.
The main results have been published previously2. Briefly, the primary findings indicated that the diagnostic management strategy, using a clinical decision rule (CDR),aDdimertestandaspiralCTiseffectiveandsafeintheworkupofpatients withclinicallysuspectedpulmonaryembolism.
At presentation all patients underwent clinical probability assessment with the
dichotomous CDR according to Wells and colleagues (Table 1)7,8. Pulmonary
embolism was considered unlikely if the CDR score wasd4andlikelyifthescore was above 4. In those with an unlikely clinical probability a Ddimer test was performed (Tinaquant, Roche Diagnostica, Mannheim, Germany or Vidas Ddimer, Biomerieux, Marcy L’Etoile, France) and was defined as normal if the concentration wasd0.5mg/l.ThecombinationofpulmonaryembolismunlikelyandanormalD dimer result was considered to rule out pulmonary embolism and anticoagulant treatment was withheld. In all other patients in whom pulmonary embolism was consideredlikelyorinpatientswithanabnormalDdimertestaspiralCTscanwas performed.
In seven of the twelve participating hospitals a Ddimer assay was performed in all patients and the data obtained from these patients form the basis for the present analysis.
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Followup was performed in all patients, which consisted of a hospital visit or a telephoneinterviewatthreemonthsandtheinstructiontocontactthestudycentreor theirgeneralpractitionerincaseofcomplaintssuggestiveofVTE,eitherdeepvenous thrombosis or pulmonary embolism. In case of clinically suspected deep venous thrombosisorpulmonaryembolisminthefollowupperiod,compressionultrasound for suspected deep venous thrombosis and ventilationperfusion scintigraphy or spiralCTforsuspectedpulmonaryembolismwererequiredtoconfirmorrefutethe diagnosis. In case of death, information was obtained from the general practitioner, from the hospital records or from autopsy. The three month VTE failure rate was defined as either pulmonary embolism at baseline or symptomatic, objectively confirmedVTEinthethreemonthfollowup.Alloutcomeswereblindlyassessedby anindependentadjudicationcommittee.
ForthisanalysiswecomparedthethreemonthsVTErateinpatientswithanormalD dimer concentration used as a stand alone test to rule out pulmonary embolism for thetotalstudygroup,aswellasseparatelyforpatientswithanunlikelyandforthose withalikelyclinicalprobabilityforpulmonaryembolism. Finally,weassessedspecificclinicalcharacteristicssuchasage,anticoagulantusage, theusedDdimerassay,theDdimerlevelandthelocalizationofthethrombiinthe patientswithanormalDdimerandalikelyclinicalprobability,but withconfirmed VTE.Wecomparedthesetothecharacteristicsofthetotalstudypopulation.
R
ESULTS
Patients
Of the 1825 consecutive patients from the seven hospitals eligible for inclusion, 103 (5.6%) were excluded because of predefined criteria or due to the inability to obtain informedconsent.TheclinicalprobabilityassessmentwiththeCDRofWellsetal.was completed in all 1722 subjects, whereas Ddimer results were available in 1632 of
thesepatients(95%)7.In477patients(28%)withaunlikelyCDRscoreandanormalD
dimer,spiralCTcouldbewithheldandPEwasconsideredtoberuledout.Themean age of the study population was 54 years (range 20100) and 78% were outpatients (Table 2). The prevalence of pulmonary embolism at baseline in these 1632 patients was22%.
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Table 2. Baseline characteristics of the study population (n=1722).
Characteristics n (%)
Age in years, mean (range) 54 (20-100)
Female gender 960 (56)
Complaints in days, median (IQR) 2 (1-7)
Anticoagulant therapy 237 (14)
Heart failure 156 (9)
COPD 168 (10)
Malignancy 273 (16)
History of venous thromboembolism 244 (14)
Outpatients 1339 (78)
Pulmonary embolism at baseline 378 (22)
Safety of a normal D-dimer
AnormalDdimerresultwaspresentin563ofthe1632studypatients(34%).Ofthese, 13 patients were objectively diagnosed to have pulmonary embolism, either at baseline or during the three months of followup. None of these patients had deep venous thrombosis during the three months followup. Therefore, the 3 month VTE rateinallpatientswithanormalDdimerconcentrationwas2.3%(95%CI:1.43.9%; Table3).
The frequency of a normal Ddimer test result in those patients with an unlikely clinical probability for pulmonary embolism was 45% (n=1060). In the likely clinical probabilitygroupthisfrequencywas15.2%(n=566;differenceinfrequencyp<0.001). In patients with an unlikely probability VTE was confirmed in 5 of the 477 patients with a normal Ddimer (1.1%; 95% CI: 0.42.4%; Table 3). Two of these patients, in whomtheprotocolwasviolated,hadpulmonaryembolismdiagnosedatbaseline(by spiral CT requested by the treating physician, outside of the protocol) and in the remainingpatientsVTEoccurredduringthefollowupperiod.
Inthepatientswithalikelyclinicalprobabilitypulmonaryembolismwasconfirmed in 8 of the 86 patients with a normal Ddimer (9.3%; 95% CI: 4.817.3%; Table 3). Of thesesevenwerefoundatbaselineandoneduringthethreemonthfollowupperiod. The difference of the VTE incidence between the unlikely and the likely probability categorieswassignificant(p<0.001).
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Table 3. Three-month VTE failure rate per strategy to exclude pulmonary embolism
Strategy to exclude pulmonary embolism n Failures 3-month VTE rate; % (95%CI)
Normal D-dimer 563 13 2.3% (1.4-3.9)
Normal D-dimer in patients with an
unlikely clinical probability 477 5 1.1% (0.4-2.4) Normal D-dimer in patients with a
likely clinical probability 86 8 9.3% (4.8-17.3)
Table 4. Main characteristics of the failures when D-dimer is used as a stand alone test in
patients with a likely clinical probability for pulmonary embolism. Gender Age In/out
patient LMWH Compl (days) CDR score D-dimer D-dimer assay CT result Localization embolus
Male 63 Out No 2 5 0.40 Tinaquant PE Subsegmental Female 28 Out Yes 1 6 0.30 Tinaquant PE Segmental Male 46 Out No 4 5.5 0.45 VIDAS CT normal* NDA
Female 46 In Yes 1 4.5 0.41 VIDAS PE Subsegmental Male 65 In No 1 5.5 0.50 VIDAS PE Segmental Male 42 Out No 1 4.5 0.18 VIDAS PE Central Female 54 Out Yes 7 7.5 0.44 Tinaquant PE Subsegmental Female 71 Out No 7 4.5 0.37 Tinaquant PE NDA
LMWH: low molecular weight heparin CDR: clinical decision rule
NDA: no data available.
* This patient had PE diagnosed during the first month of follow-up.
False negative D-dimer
Table 4 details the clinical characteristics of the eight patients with a likely clinical probabilityandanormalDdimerwhoturnedouttohavepulmonaryembolism.The meanageofthesepatientswas52(range2871)versus54(range20100)inthetotal studycohort. Threeofthe8patients(38%;95%CI:1469)hadreceivedoneor more injections of LMWH versus 237/1722 (14%; 95% CI: 1216) in the total study population.
FalsenegativeDdimertestresultswereobservedwithbothTinaquantandVidasD dimerassays(4patientseach).
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(95% CI: 356) versus 28% (95% CI: 2333) for central emboli, 33% (95% CI: 1070) versus48%(95%CI:4354)forsegmentalemboliand50%(1981)versus24%(1929) forsubsegmentalemboli,respectively.
ThemedianDdimerresultforthe8patientswas0.41mg/l(IQR0.320.45)versus0.30 mg/l (IQR 0.200.40) for all patients with a normal Ddimer and likely clinical probability.
Clinical characteristics of the five patients with an unlikely clinical probability for pulmonaryembolismandafalsenegativeDdimerwereasfollows(Table3).Twoof them had received one or more injections of LMWH, and the median Ddimer was 0.45mg/l(IQR0.160.49).InthetwopatientsinwhomaspiralCTwasperformedat baseline,onehadsegmentallocalizedemboli,andonehadacentralembolus.
D
ISCUSSION
This study convincingly illustrates that relying on Ddimer testing alone carries an unacceptableriskifclinicalprobabilityisnottakenintoaccount.Theapriorichance of having pulmonary embolism in consecutive patients with signs and symptoms
suggestiveforthisdiseaseis2025%2,911.Ourdatashowthatinpatientswithanormal
DdimerindependentoftheclinicalprobabilitythethreemonthVTEriskis2.3%with anupperlevelofthe95%confidenceintervalofalmost4%,whereasinpatientswitha likely clinical probability despite a normal Ddimer approximately 1 in10 will still havepulmonaryembolism.Incontrastandinagreementwithnumerouspublications inpatientswithanunlikelyclinicalprobabilityandanormalDdimertheriskofVTE ifuntreatedisaround1%.Hence,cliniciansneedtorealizethattheyshouldignorea normalDdimerwhentheclinicalprobabilityisconsideredtobelikely.Thefindings of this work support current guidelines and recommendations on the diagnostic
approachtopatientswithsuspectedvenousthromboembolism46.
It is difficultto identify indicators that could predict which patients are at risk for a falsenegativeDdimer.Infact,afewpreviouslysuggestedreasonsforfalsenegative Ddimerssuchassmallsizedemboli,symptomsexistinglongerthanseveraldaysand pretreatmentwithanticoagulanttherapy,wereonlyapossibleexplanationinfourof
theeightpatients1214.ThespiralCTscanshowedmajorembolisminthreeoftheeight
patients of whom even one was a centrally localized embolus. The complaints of all eightpatientsdidnotexistlongerthan7daysandfinallyitshouldbenotedthatfive oftheeightpatientshadaDdimerbetween0.40and0.50,whichindicatesthatnotall
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failures had highnormal Ddimer results. Taken together it is unlikely that one can predicttheriskofafalsenegativeDdimer.
Some methodological aspects of our study require comment. First we studied consecutivepatientswithbaselineclinicalcharacteristicssimilartorecentstudies,and hence we believe that our observations are relevant for similar settings that investigatepatientswithsuspectedpulmonaryembolism.Second,althoughthisstudy had a reasonable sample size of 1722 patients, our conclusions about a normal D dimerandalikelyclinicalprobabilityonlyinvolve86patients.Thereforeitshouldbe notedthattheobservedfrequencyofthethreemonthVTEfailurerateinthispatient groupwas9.3%withaconfidenceintervalof4.317.3%.Howeverthelowerboundary of the confidence interval is generally considered to be clinically unacceptable for a
strategytoruleoutpulmonaryembolism15.AthirdaspectofourstudyisthattheD
dimer test results were not available in 5% of the 1722. However, since the clinical characteristics of these 90 missing patients (data not shown) did not differ from the studypopulationwebelievethatthisdoesnotconstituteabias.Finally,althoughitis conceivablethatthesubjectiveelement‘alternativediagnosisislesslikelythanPE’of theCDRscoremaybeinfluencedbyanormalDdimerresult,especiallywhenused byrelativelyinexperiencedphysicians,thiscouldnotbeinvestigatedduetothestudy design7. Inconclusion,ourfindingsindicatethatitisofutmostimportancetofirstexaminethe patientandassesstheclinicalprobabilityafterwhichtheDdimerresultcanbetaken intoaccount.This,topreventthatphysicianswillbeinfluencedbyanormalDdimer testresultwhentheyevaluatetheclinicalprobability.Inpatientswithalikelyclinical pretestprobabilityofdisease,DDimertestingshouldnotbeperformed.Iftestinghas alreadybeenperformed,theresultsshouldbeignoreduntilfurtherdiagnostictesting hasbeenobtained.
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