Venøs tromboembolisme (VTE) -Daignostki · 3 Availability of the D-dimer testAvailability of the D-dimer test Several D-dimer tests are commercially available The tests differ as

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Venøs tromboembolisme (VTE)- Diagnostik -

Venøs tromboembolisme (VTE)- Diagnostik -

Jørn Dalsgaard NielsenKøbenhavns Amts Trombosecenter &

KoagulationslaboratoriumAmtssygehuset i Gentofte

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- Problemer -- Problemer -

Klinisk undersøgelse

Visualisering af okkluderede karDVT

• Venografi• (Farve-Doppler) - ultralydscanning

PE• Perfusions/ventilationsscintigrafi• Spiral CT-scanning• Pulmonal angiografi

Biokemiske metoderD-dimér (fibrinfragment)

Trombens alder er vanskelig at vurdere

Crusvenetromboser overses ofte

Oftest ikke-diagnostisk resultat

Vanskelig, invasiv undersøgelse

Lav positiv, prædiktiv værdi.

Kan ikke anvendesved postoper. VTE

Ringe prædiktiv værdi

Kan ikke udelukke mindre embolier

Metoder til påvisning af VTE

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Availability of the D-dimer testAvailability of the D-dimer test

Several D-dimer tests are commercially availableThe tests differ as regards:

Monoclonal antibodies used• Sensitivity/affinity, specificity

Analytical method• ELISA, latex/erythrocyte visual agglutination,

nephelometric methods, immunofiltrationSpeed

• POCT ⇒ Rapid lab-tests ⇒ ELISA

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The D-dimer family

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Diagnostic use of D-dimer in suspected VTEMeta-analysis

Diagnostic use of D-dimer in suspected VTEMeta-analysis

A. Landorph & JD Nielsen, 1997

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Værdien af D-dimer bestemt med Nycocard D-dimer assay

Værdien af D-dimer bestemt med Nycocard D-dimer assay

54 konsekutive patienter mistænkt for VTE

Retrospektiv undersøgelse

NPV 64%, PPV 86%

”The diagnostic value of the Nycocard assay appears to be very limited for the diagnosis of DVT and PE”

Hein-Rasmusen et al. Thromb Res 2000;100:287-92

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Strategi ved VTE-diagnostikStrategi ved VTE-diagnostik

Klinisk us.

Billed-diag. us.

D-dimer

Evt. videre us.VT

E u

delu

kket

VT

E påvist

Klinisk us.

D-dimer

Billed-diag. us.

Evt. videre us.VT

E u

delu

kket

VT

E påvist

Klinisk us.

Billed-diag. us. D-dimer

Evt. videre us.VT

E u

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VT

E påvist

2 3

1

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KOMBINERET BRUG AF FARVE-DOPPLER ULTRALYD OG D-DIMER TIL PÅVISNING AF DVT

Ved klinisk mistanke om DVT bør venografi udføres, hvis CUS er negativ og D-dimer test er positiv.

Follow-up: 1 DVT 7 DVT

DVT påvist hos: 0,2% 8,0%

Bernardi et al. BMJ, 1998

946 patienter med mistænkt DVT

CUS pos: 260 CUS neg: 686

D-dimer neg: 598 D-dimer pos: 88

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Syg Rask SumAbnorm a b a+bNormal c d c+dSum a+c b+d a+b+c+d

PRÆVAL: Andelen af SYGE patienter i forhold til samtlige patienterSENS: Andelen af SYGE patienter med ABNORM test i forhold til samtlige SYGE patienterSPEC: Andelen af RASKE patienter med NORMAL test i forhold til samtlige RASKE patienterPPV: Andelen af SYGE patienter med ABNORM test i forhold til alle med ABNORM test NPV: Andelen af RASKE patienter med NORMAL test i forhold til alle med NORMAL test

Diagnostisk anvendelse af D-dimer ved mistanke om VTEStatistisk analyse


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11





12





13





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NPV: 272/280 = 97%

95% CI: 95-99%

Variansen af den negative prædiktive værdi af en test afhænger af patientantallet i den undersøgte gruppe

D-dimer DVT Rask SumHøj 62 56 118Normal 8 272 280Sum 70 328 398

D-dimer DVT Rask SumHøj 5 2 7Normal 0 5 5Sum 5 7 12

NPV: 5/5 = 100%

95% CI: 0,6-1,0



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Syg Rask SumAbnorm 450 50 500Normal 50 450 500Sum 500 500 1000

Syg Rask SumAbnorm 90 90 180Normal 10 810 820Sum 100 900 1000

Sensitivitet: 450/500 = 90%Specificitet: 450/500 = 90%

Sensitivitet: 90/100 = 90%Specificitet: 810/900 = 90%

Prævalens: 500/1000 = 50%

Prævalens: 100/1000 = 10%

PPV: 450/500 = 90%NPV: 450/500 = 90%

PPV: 90/180 = 50%NPV: 810/820 = 99%

Den negative prædiktive værdi af en test afhænger af prævalensen af sygdom i den undersøgte gruppe



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Den negative prædiktive værdi af en test afhænger af prævalensen af sygdom i den undersøgte gruppe

Specificitet x (1 – Prævalens)

Specificitet x (1 – Prævalens) + (1 – Sensitivitet) x PrævalensNPV =



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Anvendelse af D-dimer ved mistanke om venøs tromboembolisk sygdomForslag til kravsspecifikation

Anvendelse af D-dimer ved mistanke om venøs tromboembolisk sygdomForslag til kravsspecifikation

• Hurtigmetode

• Observatøruafhængig metode foretrækkes

• NPV ≥95% ved prævalens på 30%, specielt hvis testen tænkes anvendt ved visitation til bileddiagnostisk undersøgelse

• Negativ test hos relevant antal patienter

• Testen kombineres med kvantitativ klinisk vurdering af patienten for at opnå en passende lav prætest sandsynlighed for VTE

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DVT: Symptoms and Signs DVT: Symptoms and Signs

Symptoms are neither sensitive nor specific

for DVT

Leg (or arm) pain, tenderness or swellingSensation of muscle crampingRisk factors usually present Homans’ signMay be acute or develop over days or longer

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Acute DVT: The Differential DiagnosisAcute DVT: The Differential Diagnosis

DVT

Postphlebitic syndrome

Cellulitis

Trauma/hematoma

Muscle cramp

Baker’s cyst

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Klinisk vurdering af patienter mistænkt for DVTKlinisk vurdering af patienter mistænkt for DVT

Aktiv cancerParese eller nylig gipsbandagering af UENyligt sengeliggende >3 dage og/eller større operation inden for 4 ugerØmhed langs dybe venerHævet femur + crusCrusomfang af det syge ben målt 10 cm under tub. tibiae >3 cm større end det raske benVTE hos ≥2 personer i nærmeste familie

Major pointTraume mod det syge ben inden for 60 dageDeklivt ødem kun i det syge benDilatation af ikke-varikøse, overfladiske vener kun i det syge benHospitalisering inden for de sidste 6 månederErytem

Minor point

Høj sandsynlighed for DVT ≥3 major point + ingen alternativ diagnose≥2 major + ≥2 minor point + ingen alternativ diagnose

Lav sandsynlighed for DVT 1 major + ≤2 minor point + har alternativ diagnose1 major + ≤1 minor point + ingen alternativ diagnose0 major + ≤ 3 minor point + har alternativ diagnose0 major + ≤ 2 minor point + ingen alternativ diagnose

Moderat sandsynlighed for DVT Alle andre kombinationer

Wells et al. Lancet 1995; 345: 1326-30

DVT påvistes hos:

85 %

5 %

33 %

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Aktiv cancer(behandling inden for de sidste 6 mdr) 1

Parese eller nylig gipsbandagering af UE 1

Nyligt sengeliggende >3 dage og/eller større operation inden for 12 uger 1

Ømhed langs dybe vener 1

Hævet femur + crus 1

Crusomfang >3 cm større på det syge ben, målt 10 cm under tub. tibiae 1

Deklivt ødem kun i det syge ben 1

Dilatation af ikke-varikøse, overfladiske vener kun i det syge ben 1

Alternativ diagnose mere, eller lige så sandsynlig som DVT -2

Beregn sum:

Anamnese og klinisk undersøgelse Score

Anderson et al. J Emergency Med 2000; 19: 225-30

≥31-2

0

point = HØJ risiko: I denne gruppe vil ca. 50% have DVT

point = MODERAT risiko: I denne gruppe vil ca. 14% have DVT

point = LAV risiko: I denne gruppe vil ca. 3% have DVT

Risiko-vurdering:

Klinisk vurdering af patienter mistænkt for DVTKlinisk vurdering af patienter mistænkt for DVT

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Værdien af perfusions/ventilations lungescintigrafi ved mistanke om PEVærdien af perfusions/ventilations

lungescintigrafi ved mistanke om PE

Angiografiverificeret PE:

hos 86% med segmental V/Q-mismatch

hos 21-40% med subsegmental V/Q-mismatch

hos 0% uden V/Q-mismatch

Hull et al. Chest 1985; 88: 819-28

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Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED)

Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED)

251 af 755 ptt. (33%) havde angiografisk verificeret PEVentilation/perfusionsscintigrafi:

Høj sandsynlighed: 116 ptt. (15%)• af disse havde 102 (88%) PE.

Mod. sandsynlighed: 322 ptt. (43%)• af disse havde 105 (33%) PE.

Lav sandsynlighed: 131 ptt. (17%)• af disse havde 15 (12%) PE.

Normal undersøgelse: 186 ptt. (24%)• af disse havde 7 (4%) PE.

JAMA 1990; 263; 2753-9

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Klinisk vurdering af sandsynligheden for lungeemboli Klinisk vurdering af sandsynligheden for lungeemboli

Analyse omfattende 1093 patienter

Diagnostik:V/Q-lungeskintigrafi

Ultralyd-us. Af UE

D-dimer

Pulmonal angiografi ved usikker diagnose

Wicki et al. Arch Intern Med 2001;161:92-97

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Multivariate prædiktorerAlder (3 klasser)

Tidligere VTE

Nylig kirurgi

Puls >100

PaCO2 (3 klasser)

PaO2 (5 klasser)

Rtg. af thorax (3 klasser)

Total score: 0 - 16



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Sandsynlighed PE%

Lav 10

Intermediær 38

Høj 81

PE%9

3366

Empirisk



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V/Q scan N% Incidence

thromboembolism(3 months)

95 %confidence

limitsProcedure

Anticoagulants

Pos. serial IPGAnticoagulants

Neg. serial IPGNo treatment

No treatment

High probability

Non-diagnostic

Normal

66

7

371

315

7

0

2,7

1

2,5-16,8

0

1,3-4,9

0,2-2,8

Hull et al. Arch Intern Med 1989;149:2549-55

When can treatment be withheld in patients withsuspected pulmonary embolism?

When can treatment be withheld in patients withsuspected pulmonary embolism?

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When can treatment be withheld in patients with suspected pulmonary embolism?

When can treatment be withheld in patients with suspected pulmonary embolism?

Kruit et al. J Intern Med 1991;230:333-9

62 PE suspects with abnormal V/Q scans but normal venograms were followed up for 3 months without anticoagulants.One patient developed DVT. None had PE during follow up.

Conclusion: No DVT - No treatment

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DVT: Objective Imaging StudiesDVT: Objective Imaging Studies

Phlebography Gold standardCompression US Most common

US, ultrasound

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DVT: Compression USDVT: Compression US

Most common imaging test for suspected DVTSensitive for proximal (thigh), not calf DVTSensitive in symptomatic patients (≥95%)Operator dependentSensitivity only 30–60% if asymptomaticThus, not good screening test

Tapson VF et al. Am J Respir Crit Care Med 1999;160:1043–66.

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DVT: Objective Imaging StudiesDVT: Objective Imaging Studies

Colour-Doppler/US Improvement of USIPG Low specificitySpiral CT Evolving, promisingMRI Evolving, promising

US, ultrasoundIPG, impedance plethysmographyMRI, magnetic resonance imaging

Phlebography Gold standardCompression US Most common

MRI for Suspected DVT*MRI for Suspected DVT*

Sensitivity Specificity Reference (%) (%) test

Evans, 1993† 95 97 VenographySpritzer, 1990 97 95 VenographyCarpenter, 1993 100 96 VenographyEvans, 1996 100 100 Serial US

*Clinical trials with n ≥50. †Sensitivity for calf = 87%

Tapson VF et al. Am J Respir Crit Care Med 1999;160:1043–66.

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*In patients with no previous cardiopulmonary disease

Stein PD et al. Chest 1991;100:598–603.

PE: Symptoms*PE: Symptoms*

Dyspnea 73%Pleuritic CP 66%Cough 37%Leg swelling 28%Leg pain 26%Hemoptysis 13%

Palpitations 10%Syncope <10%Wheezing 9%‘Anginal’ CP 4%Sudden death ?

CP, chest pain

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PE: Signs*PE: Signs*

Tachycardia 70%Tachypnea 30%Crackles 51%Loud P2 23%Diaphoresis 11%Hypotension 8%

Fever 7%Wheezing 5%RV lift 4%Homans’ sign 4%Pleural rub 3%Cyanosis 1%

Stein PD et al. Chest 1991;100:598–603.

*In patients with no previous cardiopulmonary disease

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Arterial blood gassesArterial blood gasses

p02 usually low (but may be normal)pC02 usually low (but may be normal or increased)

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The Chest RadiographThe Chest Radiograph

Usually abnormal, but nonspecificNormal chest X ray with significant, otherwise unexplained symptoms/hypoxemia suggests PE

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ECGECG

Tachycardia most useful, but nonspecificS1 Q3 T3 pattern is not specific for PERight heart strain may occur with larger PE (nonspecific)ECG most useful in suggesting other disease (MI, pericarditis, etc.)

38Nonspecific!!

S1

Q3 T3S1 Q3 T3 pattern may be present

in PE but is not diagnostic!!

PE Diagnosis: the ECGPE Diagnosis: the ECG

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”Massiv” lungeemboli”Massiv” lungeemboli

Lungeemboli med kredsløbssvigt

• Højresidigt hjertesvigtEkkocardiografi viser akut dilatation af højre ventrikel (typisk: hø. > ve. ventrikel) og tricuspidalinsufficiensBelastningen kan føre til højresidigt myokardieinfarkt og pludselig død

• Venstresidigt hjertesvigtBlodtryksfald til <90 mm Hg ledsaget af takykardi med hjerteaktion typisk >100/minEvt. synkope eller længerevarende bevidtløshed ⇒ død.

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Problems with the V/Q Scan (1)Problems with the V/Q Scan (1)

In PIOPEDOnly 41% of patients with PE had high-probability scansIn patients with COPD, 5% high-probability, 5% normal, 90% inconclusive In patients with any cardiopulmonary disease, 77% of V/Q scans were inconclusive

PIOPED Investigators. JAMA 1990;263:2753–9.

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Problems with the V/Q Scan (2)Problems with the V/Q Scan (2)

Actual emboli not visualizedInterobserver variation in interpretation Inaccurate for subsegmental PEIn most cases, the V/Q scan isnondiagnosticExpensive because usually nondiagnosticNot diagnostic for other entities

Spiral CT Scan StudiesSpiral CT Scan Studies

Sensitivity Specificity(%) (%)

Remy-Jardin, 1992 100 96Remy-Jardin, 1996 91 78van Rossum, 1996 95 97Goodman, 1995* 86 92Sostman, 1996 73 97Mayo, 1997† 87 95Drucker, 1998‡ 60/53 81/97Perrier,2001 70 91*For main, lobar, segmental emboli (63% and 89% for all including peripheral).†Prospective outcome study (3 months).‡The two values refer to readings of the same film set at two different institutions.

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Potential Diagnoses or Findings by Chest CT ScanPotential Diagnoses or Findings by Chest CT Scan

PEPulmonary infarctionChronic PEPneumoniaLung nodules or massesPleural effusionPleural massesPneumothoraxEmphysemaLymphadenopathyEsophageal disease

Cardiac abnormalitiesAortic dissection SVC syndromeOther vascular diseaseRib fracturesBony abnormalitiesDiaphragmatic diseaseAbdominal diseaseInterstitial lung diseaseTracheal abnormalitiesBronchiectasisOther airway disease

SVC, superior vena cava

Garg K et al. Am J Roentgenol 1999;172:1627–31.

New diagnoses made by spiral CT scan: 31 (40%)

Alternative Diagnoses or Significant Findings

Alternative Diagnoses or Significant Findings

New Previously diagnosis known

Emphysema 6 6Aspiration pneumonia 4 2Pulmonary edema 2 5Interstitial lung disease 4 4Lung cancer 4 1Esophageal cancer 2 1Hypersensitivity pneumonitis 2 0Bronchiolitis obliterans 2 0Invasive aspergillosis 1 0Drug toxicity 1 0

Excluding Pulmonary Embolism at the Bedside Without Diagnostic Imaging: Management of

Patients with Suspected Pulmonary Embolism Presenting to the Emergency Department by Using a

Simple Clinical Model and D-dimer

Excluding Pulmonary Embolism at the Bedside Without Diagnostic Imaging: Management of

Patients with Suspected Pulmonary Embolism Presenting to the Emergency Department by Using a

Simple Clinical Model and D-dimer

Wells PS et al. Ann Intern Med 2001;135:98–107

A Simple Clinical Model and D-dimer to Assess Pre-test Probability

A Simple Clinical Model and D-dimer to Assess Pre-test Probability

Points

Clinical DVT (objective swelling, tenderness) 3.0Heart rate >100 bpm 1.5Immobilization ≥3 days

or surgery in the previous 4 weeks 1.5Previous DVT/PE 1.5Hemoptysis 1.0Malignancy 1.0PE as likely, or more likely, than alternative

disease 3.0

Clinical model applied to 946 patientsProbability: <2 = low, 2–6 = intermediate, >6 = high

Wells PS et al. Ann Intern Med 2001;135:98–107.

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Clinical Factors Suggesting the Probability of PEClinical Factors Suggesting the Probability of PE

Of 437 patients with low clinical probability and negative SimpliRED™D-dimer assay, only 1 had PE…


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Excluding Pulmonary Embolism at the Bedside Without Diagnostic Imaging

Excluding Pulmonary Embolism at the Bedside Without Diagnostic Imaging

ConclusionManaging patients with suspected PE on the basis of pre-test probability and D-dimer testing is safe and decreases the need for diagnostic imaging


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Simplification of the DiagnosticManagement of Suspected DVTSimplification of the DiagnosticManagement of Suspected DVT

The need for repeated US can be reduced by about 60% without a decrease in safety by using the SimpliRED™ D-dimer assay. The total rate of DVT identified by this novel strategy was 1.3% (95% CI 0.7–2.0%), which is fully comparable to the present standard diagnostic approach

Kraaijenhagen RA et al. Arch Intern Med 2002;162:907–11.

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Conclusions (1)Conclusions (1)

The presence of compatible symptoms and signs lead to the diagnostic evaluation for DVT or PE. The presence of risk factors may further suggest the need for this evaluation History and physical exam are neither sensitive nor specific for acute DVT or PEThe chest radiograph and ABG may offer useful clues to the presence of PE, but are not diagnosticThe diagnosis of VTE requires objective testingUS is very sensitive for symptomatic DVT; less so for asymptomatic DVT

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Conclusions (2)Conclusions (2)

The spiral CT scan is being used increasingly for suspected acute PE and appears sensitive and specific for PE in segmental or larger vessels. It is also useful in making alternative diagnosesD-dimer testing, when used carefully, can reduce the need for diagnostic testing in suspected acute DVTPretest probability estimates, particularly combined with D-dimer testing, appear useful

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Ingen beh.

Normal D-dimer

Billeddiag. us.

Høj D-dimer

Lav-moderat

Behandling

Diagnostisk

Behandling

Pos.

Ingen beh.

Neg.

Us. for DVT

Ikke-diag.

Ingen beh.

Normal

V/Q-scint v. PE-symp.

Behandling

DVT

Behandling

DVT

Ingen beh.

Normal

Flebografi

Høj

Ingen beh.

Normal

D-dimer

Normal

Duplexscan. v. DVT-symp.

Høj

Klinisk mistanke om VTE

Udredning ved klinisk mistanke om venøstromboembolisk sygdom (VTE)

Documents

Venøs tromboembolisme (VTE) -Daignostki · 3 Availability of the D-dimer testAvailability of the D-dimer test Several D-dimer tests are commercially available The tests differ as