prospective evaluation of innovance d-dimer in the exclusion of venous thromboembolism [vte]. robert...

Prospective evaluation of Innovance D-dimer in the

exclusion of venous thromboembolism [VTE].

Robert Gosselin, CLSRobert Gosselin, CLSDepartment of Clinical Pathology and Laboratory MedicineDepartment of Clinical Pathology and Laboratory Medicine

University of California, Davis Health SystemUniversity of California, Davis Health SystemSacramento, CA Sacramento, CA

• D-dimerD-dimer– Indicates clot formationIndicates clot formation– Indicates clot degradationIndicates clot degradation

• D-dimer test commonly used for D-dimer test commonly used for exclusion:exclusion:– Pulmonary embolismPulmonary embolism– Deep vein thrombosisDeep vein thrombosis– Consumptive coagulopathyConsumptive coagulopathy– Aortic dissectionAortic dissection

• Innovance D-dimer and Stratus CS Innovance D-dimer and Stratus CS

D-dimer new test from Siemen D-dimer new test from Siemen HealthcareHealthcare

• Prospective study in the US to validate Prospective study in the US to validate cut-off for excluding PE and DVTcut-off for excluding PE and DVT

• 3 sites in US3 sites in US– Duke UniversityDuke University– Cleveland ClinicCleveland Clinic– UC DavisUC Davis

• Total enrollment all sitesTotal enrollment all sites– 550 PE550 PE– 480 DVT480 DVT

• Inclusion criteriaInclusion criteria– First clinically suspected PE and/or DVTFirst clinically suspected PE and/or DVT– Objective testingObjective testing

• Diagnostic algorithmsDiagnostic algorithms• Radiographic studiesRadiographic studies

– Capable of giving informed consentCapable of giving informed consent– Agree to 3 month follow-up for patients Agree to 3 month follow-up for patients

with negative imaging studies.with negative imaging studies.

• Exclusion criteriaExclusion criteria– Under 18 years of ageUnder 18 years of age– PregnantPregnant– Previous Hx of PE or DVTPrevious Hx of PE or DVT– Resolved symptoms >72 hours before Resolved symptoms >72 hours before

presenting to EDpresenting to ED– Oral anticoagulationOral anticoagulation– 3 month f/u not available3 month f/u not available– InpatientInpatient– PrisonersPrisoners

Active cancerActive cancer +1+1

Paralysis, paresis, recent casting of legParalysis, paresis, recent casting of leg +1+1

Bedridden (>3 days) or major (>12 weeks)Bedridden (>3 days) or major (>12 weeks) +1+1

Entire leg swollenEntire leg swollen +1+1

Calf swelling (>3cm) compared to other legCalf swelling (>3cm) compared to other leg +1+1

Pitting edema greater in symptomatic legPitting edema greater in symptomatic leg +1+1

Collateral nonvaricose superficial veinsCollateral nonvaricose superficial veins +1+1

Localized tenderness along deep venous systemLocalized tenderness along deep venous system +1+1

Previously documented DVTPreviously documented DVT +1+1

Alternative Dx as or more likely than DVTAlternative Dx as or more likely than DVT -2-2

Score:Score: DVT unlikely <2DVT unlikely <2 DVT likely DVT likely >>22

Clinical Probability for DVTClinical Probability for DVT

Wells PS, et al Lancet 1997; 350:1795-98; N Engl J Med 2003;349: 1227-35Wells PS, et al Lancet 1997; 350:1795-98; N Engl J Med 2003;349: 1227-35

Clinical signs and symptoms of DVTClinical signs and symptoms of DVT +3+3Heart rate >100/minHeart rate >100/min +1.5+1.5Hemoptysis Hemoptysis +1+1Active cancerActive cancer +1+1Bedridden (>3 days) or major (>12 weeks)Bedridden (>3 days) or major (>12 weeks)

+1.5+1.5Previously history of DVT or PEPreviously history of DVT or PE +1.5+1.5PE most likely diagnosisPE most likely diagnosis +3+3

Clinical Probability for PEClinical Probability for PE

Score:Score: Low <2Low <2 Moderate 2-6Moderate 2-6 High >6High >6

Wells PS, et al Thromb Haemost 2000; 83:416-20.Wells PS, et al Thromb Haemost 2000; 83:416-20.

Compression USCompression US

PositivePositive NegativeNegative Low probLow prob

Serial CUS Serial CUS (5-8 days)(5-8 days) Mod or High ProbMod or High Prob

DVT PositiveDVT Positive

Positive VTEPositive VTE

DVT NegativeDVT Negative

Negative VTENegative VTE

3 month f/u3 month f/uPositivePositive NegativeNegative

DVT DVT

AlgorithmAlgorithm

Spiral CT or AngiogramSpiral CT or Angiogram

PositivePositive NegativeNegative

PE PositivePE Positive

Positive VTEPositive VTE

PE NegativePE Negative

Negative VTENegative VTE

3 month f/u3 month f/u

PE PE

AlgorithmAlgorithm

• After informed consentAfter informed consent– Blood collectedBlood collected

• 3.2% sodium citrate3.2% sodium citrate• Lithium heparin (Stratus only)Lithium heparin (Stratus only)

– If testing within 4 hours of collectionIf testing within 4 hours of collection• Whole blood heparin on StratusWhole blood heparin on Stratus• Plasma testing on other analyzersPlasma testing on other analyzers

– If testing not completed within 4 hours of If testing not completed within 4 hours of collectioncollection• Samples processed and refrigeratedSamples processed and refrigerated• Testing completed within 24 hours of collectionTesting completed within 24 hours of collection

Testing performed on:Testing performed on:

Sysmex analyzersSysmex analyzers

CA560CA560

CA1500CA1500

CA7000CA7000

BCSBCS

StratusStratus (heparin and citrate testing)(heparin and citrate testing)

[Delayed testing---CS2000i][Delayed testing---CS2000i]

• As of May 11, 2009As of May 11, 2009– 381 patients enrolled381 patients enrolled– 353 with demographics complete353 with demographics complete– 284 with 3 mo f/u284 with 3 mo f/u

• 2 withdrawn2 withdrawn– One patient declined participation after testing One patient declined participation after testing

completed [1 month later]completed [1 month later]– One patient had imaging studies canceled after One patient had imaging studies canceled after

enrollmentenrollment

• 4 pending 3 month f/u4 pending 3 month f/u• 8 patients expired8 patients expired

– 0/8 with normal D-dimer levels0/8 with normal D-dimer levels

37% males [91/248]37% males [91/248]

Median age 51.5 years [range 19-81 years]Median age 51.5 years [range 19-81 years]

Patients with PE studies Patients with PE studies • Probability scoresProbability scores

– Low probability 62% [154/248]Low probability 62% [154/248]– Moderate probability 33% [82/248] Moderate probability 33% [82/248] – High probability 3% [7/248]High probability 3% [7/248]– No score performed 2% [5/248]No score performed 2% [5/248]

Patients with DVT studiesPatients with DVT studies• Probability scores Probability scores

– Unlikely 64.4% [94/146]Unlikely 64.4% [94/146]– Likely 30.8% [45/146]Likely 30.8% [45/146]– No score performed 4.7% [7/146]No score performed 4.7% [7/146]

• Of the 353 patients with demographics:Of the 353 patients with demographics:– 70.2% [248/353] tested for PE70.2% [248/353] tested for PE

• 238 with spiral CT238 with spiral CT• 12 with V/Q scan12 with V/Q scan• 25 with PE [10.5%]25 with PE [10.5%]

– 41.4% [146/353] CUS for DVT41.4% [146/353] CUS for DVT• 13 with DVT [9.6%]13 with DVT [9.6%]

37 patients evaluated for PE and DVT37 patients evaluated for PE and DVT– 30 with CT and CUS30 with CT and CUS– 6 with VQ and CUS6 with VQ and CUS– 1 with CUS, CT and VQ1 with CUS, CT and VQ– 3 patients with both DVT and PE3 patients with both DVT and PE

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LowLow ModMod HighHigh UnlikelyUnlikely LikelyLikely

PE ProbabilityPE Probability DVT ProbabilityDVT Probability

BCS CA1500 CA7000 CA560 SCS-H SCS-C

Neg VTE <0.5 mg/L 110 101 119 115 118 138

>0.5 mg/L 247 256 238 240 236 218

Pos VTE <0.5 mg/L 1 1 2 2 1 1

>0.5 mg/L 36 36 35 34 35 36

Data for all patients enrolledData for all patients enrolled

SCS-H Heparin sample on StratusSCS-H Heparin sample on Stratus SCS-C Citrate sample on StratusSCS-C Citrate sample on Stratus


Sens 97.3% 97.3% 94.6% 94.4% 97.2% 97.3%

Spec 30.8% 28.3% 33.3% 32.4% 33.3% 38.8%

NPV 99.1% 99.0% 98.3% 98.3% 99.2% 99.3%

PPV 12.7% 12.3% 12.8% 12.4% 12.9% 14.2%


Innovance D-dimer in all VTEInnovance D-dimer in all VTE


Neg PE <0.5 mg/L 79 69 84 81 86 93

>0.5 mg/L 144 154 139 142 135 129

Pos PE <0.5 mg/L 1 1 2 2 1 1

>0.5 mg/L 24 24 23 23 23 24

Patients evaluated for PE Patients evaluated for PE N=248N=248


Innovance D-dimer in PE Innovance D-dimer in PE


Sens 96.0% 96.0% 92.0% 92.0% 95.8% 96.0%

Spec 35.4% 30.9% 37.7% 36.3% 38.9% 41.9%

NPV 98.8% 98.6% 97.7% 97.6% 98.9% 98.9%

PPV 14.3% 13.5% 14.2% 13.9% 14.6% 15.7%



Neg DVT <0.5 mg/L 31 32 35 34 32 45

>0.5 mg/L 103 102 99 98 101 89

Pos DVT <0.5 mg/L 0 0 0 0 0 0

>0.5 mg/L 12 12 12 11 12 12

Patients evaluated for DVT Patients evaluated for DVT N=146N=146



Sens 100.0% 100.0% 100.0% 100.0% 100.0% 100.0%

Spec 23.1% 23.9% 26.1% 25.8% 24.1% 33.6%

NPV 100.0% 100.0% 100.0% 100.0% 100.0% 100.0%

PPV 10.4% 10.5% 10.8% 10.1% 10.6% 11.9%

Innovance D-dimer in DVT Innovance D-dimer in DVT


• SummarySummary– Poor positive predictive value of D-dimer Poor positive predictive value of D-dimer

with VTEwith VTE– Acceptable negative predictive value for Acceptable negative predictive value for

Innovance D-dimer in excluding VTE in Innovance D-dimer in excluding VTE in outpatientsoutpatients

– Need more data for PE sensitivity Need more data for PE sensitivity – WeaknessWeakness

• Few positive samples in subset analysisFew positive samples in subset analysis

• Fellow collaborators at UC Davis Fellow collaborators at UC Davis – Edward Panacek, MD, MPHEdward Panacek, MD, MPH– Abhi Gorhi, MS, CCRPAbhi Gorhi, MS, CCRP– Shari Nichols, CCRPShari Nichols, CCRP– Allyson Sage, RNAllyson Sage, RN– Leslie Freeman, CLSLeslie Freeman, CLS– Andrea Picazo, CCRPAndrea Picazo, CCRP

prospective evaluation of innovance d-dimer in the exclusion of venous thromboembolism [vte]. robert...

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