Venøs tromboembolisme (VTE) -Diagnostik - Jørn Dalsgaard Nielsen Københavns Amts Trombosecenter & Koagulationslaboratorium Amtssygehuset i Gentofte

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1 Venøs tromboembolisme (VTE) -Diagnostik - Jørn Dalsgaard Nielsen Københavns Amts Trombosecenter & Koagulationslaboratorium Amtssygehuset i Gentofte

2 Metoder til påvisning af VTE Klinisk undersøgelse - Problemer - Visualisering af okkluderede kar DVT PE Venografi (Farve-Doppler) - ultralydscanning Perfusions/ventilationsscintigrafi Spiral CT-scanning Pulmonal angiografi Biokemiske metoder D-dimér (fibrinfragment) Ringe prædiktiv værdi Trombens alder er vanskelig at vurdere Crusvenetromboser overses ofte Oftest ikke-diagnostisk resultat Kan ikke udelukke mindre embolier Vanskelig, invasiv undersøgelse Lav positiv, prædiktiv værdi. Kan ikke anvendes ved postoper. VTE

3 Availability of the D-dimer test Several D-dimer tests are commercially available The tests differ as regards: Monoclonal antibodies used Sensitivity/affinity, specificity Analytical method ELISA, latex/erythrocyte visual agglutination, nephelometric methods, immunofiltration Speed POCT Rapid lab-tests ELISA

4 The D-dimer family

5 Diagnostic use of D-dimer in suspected VTE Meta-analysis 1,00 0,90 0,80 0,70 0,60 0,50 Latex - Biopool Latex - Boehringer Mannheim Latex - Merz-Dade Latex - Ortho Latex - Agen (I) Latex - Dade Latex - Stago Latex - Organon Teknika Latex - Baxter Latex - Sigma Latex - Agen (II) Latex - American Bioproducts Im.filtr. - Nycomed Im.filtr. - Stago Eryt. - Agen ELISA - Behringwerke ELISA - Byk Sangtec Diagnostica ELISA - Organon Teknika ELISA - Agen (II) ELISA - Boehringer Mannheim ELISA - Agen (I) ELISA - Laevosan ELISA - Stago Aut.Latex - Behringwerke Aut.Latex - Boehringer Mannheim Aut. ELISA - BioMérieux A. Landorph & JD Nielsen, 1997 NPV

6 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

7 Strategi ved VTE-diagnostik 1 Klinisk us. VTE udelukket Billed-diag. us. Evt. videre us. D-dimer VTE påvist 2 3 Klinisk us. Klinisk us. VTE udelukket Billed-diag. us. D-dimer Evt. videre us. VTE påvist VTE udelukket D-dimer Billed-diag. us. Evt. videre us. VTE påvist

8 KOMBINERET BRUG AF FARVE-DOPPLER ULTRALYD OG D-DIMER TIL PÅVISNING AF DVT Bernardi et al. BMJ, patienter med mistænkt DVT CUS pos: 260 CUS neg: 686 D-dimer neg: 598 D-dimer pos: 88 Follow-up: 1 DVT 7 DVT DVT påvist hos: 0,2% 8,0% Ved klinisk mistanke om DVT bør venografi udføres, hvis CUS er negativ og D-dimer test er positiv.

9 Diagnostisk anvendelse af D-dimer ved mistanke om VTE Statistisk analyse Syg Rask Sum Abnorm a b a+b Normal c d c+d Sum a+c b+d a+b+c+d PRÆVAL: Andelen af SYGE patienter i forhold til samtlige patienter SENS: Andelen af SYGE patienter med ABNORM test i forhold til samtlige SYGE patienter SPEC: Andelen af RASKE patienter med NORMAL test i forhold til samtlige RASKE patienter PPV: 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

14 Diagnostisk anvendelse af D-dimer ved mistanke om VTE Statistisk analyse D-dimer DVT Rask Sum Høj Normal Sum NPV: 272/280 = 97% 95% CI: 95-99% D-dimer DVT Rask Sum Høj Normal Sum NPV: 5/5 = 100% 95% CI: 0,6-1,0 Variansen af den negative prædiktive værdi af en test afhænger af patientantallet i den undersøgte gruppe

15 Diagnostisk anvendelse af D-dimer ved mistanke om VTE Statistisk analyse Syg Rask Sum Abnorm Normal Sum Sensitivitet: 450/500 = 90% Specificitet: 450/500 = 90% Prævalens: 500/1000 = 50% PPV: 450/500 = 90% NPV: 450/500 = 90% Syg Rask Sum Abnorm Normal Sum Sensitivitet: 90/100 = 90% Specificitet: 810/900 = 90% Prævalens: 100/1000 = 10% PPV: 90/180 = 50% NPV: 810/820 = 99% Den negative prædiktive værdi af en test afhænger af prævalensen af sygdom i den undersøgte gruppe

16 Diagnostisk anvendelse af D-dimer ved mistanke om VTE Statistisk analyse NPV = Specificitet x (1 Prævalens) Specificitet x (1 Prævalens) + (1 Sensitivitet) x Prævalens Den negative prædiktive værdi af en test afhænger af prævalensen af sygdom i den undersøgte gruppe

17 Anvendelse af D-dimer ved mistanke om venøs tromboembolisk sygdom Forslag 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

18 DVT: Symptoms and Signs Leg (or arm) pain, tenderness or swelling Sensation of muscle cramping Risk factors usually present Homans sign May be acute or develop over days or longer Symptoms are neither sensitive nor specific for DVT

19 Acute DVT: The Differential Diagnosis DVT Postphlebitic syndrome Cellulitis Trauma/hematoma Muscle cramp Baker s cyst

20 Klinisk vurdering af patienter mistænkt for DVT Major point Aktiv cancer Parese eller nylig gipsbandagering af UE Nyligt sengeliggende >3 dage og/eller større operation inden for 4 uger Ømhed langs dybe vener Hævet femur + crus Crusomfang af det syge ben målt 10 cm under tub. tibiae >3 cm større end det raske ben VTE hos 2 personer i nærmeste familie Høj sandsynlighed for DVT Lav sandsynlighed for DVT Moderat sandsynlighed for DVT Minor point Traume mod det syge ben inden for 60 dage Deklivt ødem kun i det syge ben Dilatation af ikke-varikøse, overfladiske vener kun i det syge ben Hospitalisering inden for de sidste 6 måneder Erytem 3 major point + ingen alternativ diagnose 2 major + 2 minor point 85 + ingen % alternativ diagnose 1 major + 2 minor point + har alternativ diagnose 5 % 1 major + 1 minor point + ingen alternativ diagnose 0 major + 3 minor point + har alternativ diagnose 0 major + 2 minor point + ingen alternativ diagnose Alle andre kombinationer DVT påvistes hos: 33 % Wells et al. Lancet 1995; 345:

21 Klinisk vurdering af patienter mistænkt for DVT Anamnese og klinisk undersøgelse Score 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: Risikovurdering: 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 Anderson et al. J Emergency Med 2000; 19:

22 Værdien af perfusions/ventilations lungescintigrafi ved mistanke om PE Angiografiverificeret PE: hos 86% med segmental V/Qmismatch hos 21-40% med subsegmental V/Qmismatch hos 0% uden V/Q-mismatch Hull et al. Chest 1985; 88:

23 Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED) 251 af 755 ptt. (33%) havde angiografisk verificeret PE Ventilation/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;

24 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

25 Klinisk vurdering af sandsynligheden for lungeemboli Multivariate prædiktorer Alder (3 klasser) Tidligere VTE Nylig kirurgi Puls >100 PaCO 2 (3 klasser) PaO 2 (5 klasser) Rtg. af thorax (3 klasser) Total score: 0-16 Wicki et al. Arch Intern Med 2001;161:92-97

26 Klinisk vurdering af sandsynligheden for lungeemboli Sandsynlighed PE% Lav 10 Intermediær 38 Høj 81 Empirisk PE% Wicki et al. Arch Intern Med 2001;161:92-97

27 When can treatment be withheld in patients with suspected pulmonary embolism? V/Q scan N Procedure % Incidence thromboembolism (3 months) 95 % confidence limits High probability 66 Anticoagulants 7 2,5-16,8 Non-diagnostic Pos. serial IPG Anticoagulants Neg. serial IPG No treatment 0 2,7 0 1,3-4,9 Normal 315 No treatment 1 0,2-2,8 Hull et al. Arch Intern Med 1989;149:

28 When can treatment be withheld in patients with suspected pulmonary embolism? 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 Kruit et al. J Intern Med 1991;230:333-9

29 DVT: Objective Imaging Studies Phlebography Compression US Gold standard Most common US, ultrasound

30 DVT: Compression US Most common imaging test for suspected DVT Sensitive for proximal (thigh), not calf DVT Sensitive in symptomatic patients ( 95%) Operator dependent Sensitivity only 30 60% if asymptomatic Thus, not good screening test Tapson VF et al. Am J Respir Crit Care Med 1999;160:

31 DVT: Objective Imaging Studies Phlebography Compression US Colour-Doppler/US IPG Spiral CT MRI Gold standard Most common Improvement of US Low specificity Evolving, promising Evolving, promising US, ultrasound IPG, impedance plethysmography MRI, magnetic resonance imaging

32 MRI for Suspected DVT* Sensitivity Specificity Reference (%) (%) test Evans, Venography Spritzer, Venography Carpenter, Venography Evans, Serial US *Clinical trials with n 50. Sensitivity for calf = 87% Tapson VF et al. Am J Respir Crit Care Med 1999;160:

33 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? *In patients with no previous cardiopulmonary disease CP, chest pain Stein PD et al. Chest 1991;100:

34 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% *In patients with no previous cardiopulmonary disease Stein PD et al. Chest 1991;100:

35 Arterial blood gasses p0 2 usually low (but may be normal) pc0 2 usually low (but may be normal or increased)

36 The Chest Radiograph Usually abnormal, but nonspecific Normal chest X ray with significant, otherwise unexplained symptoms/hypoxemia suggests PE

37 ECG Tachycardia most useful, but nonspecific S1 Q3 T3 pattern is not specific for PE Right heart strain may occur with larger PE (nonspecific) ECG most useful in suggesting other disease (MI, pericarditis, etc.)

38 PE Diagnosis: the ECG S1 Q3 T3 S1 Q3 T3 pattern may be present in PE but is not diagnostic!! Nonspecific!!

39 Massiv lungeemboli Lungeemboli med kredsløbssvigt Højresidigt hjertesvigt Ekkocardiografi viser akut dilatation af højre ventrikel (typisk: hø. > ve. ventrikel) og tricuspidalinsufficiens Belastningen kan føre til højresidigt myokardieinfarkt og pludselig død Venstresidigt hjertesvigt Blodtryksfald til <90 mm Hg ledsaget af takykardi med hjerteaktion typisk >100/min Evt. synkope eller længerevarende bevidtløshed død.

40 Problems with the V/Q Scan (1) In PIOPED Only 41% of patients with PE had high-probability scans In 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:

41 Problems with the V/Q Scan (2) Actual emboli not visualized Interobserver variation in interpretation Inaccurate for subsegmental PE In most cases, the V/Q scan is nondiagnostic Expensive because usually nondiagnostic Not diagnostic for other entities

42 Spiral CT Scan Studies Sensitivity Specificity (%) (%) Remy-Jardin, Remy-Jardin, van Rossum, Goodman, 1995* Sostman, Mayo, Drucker, /53 81/97 Perrier, *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.

43 Potential Diagnoses or Findings by Chest CT Scan PE Pulmonary infarction Chronic PE Pneumonia Lung nodules or masses Pleural effusion Pleural masses Pneumothorax Emphysema Lymphadenopathy Esophageal disease Cardiac abnormalities Aortic dissection SVC syndrome Other vascular disease Rib fractures Bony abnormalities Diaphragmatic disease Abdominal disease Interstitial lung disease Tracheal abnormalities Bronchiectasis Other airway disease SVC, superior vena cava

44 Alternative Diagnoses or Significant Findings New diagnoses made by spiral CT scan: 31 (40%) New diagnosis Emphysema 6 6 Aspiration pneumonia 4 2 Pulmonary edema 2 5 Interstitial lung disease 4 4 Lung cancer 4 1 Esophageal cancer 2 1 Hypersensitivity pneumonitis 2 0 Bronchiolitis obliterans 2 0 Invasive aspergillosis 1 0 Drug toxicity 1 0 Previously known Garg K et al. Am J Roentgenol 1999;172:

45 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

46 A Simple Clinical Model and D-dimer to Assess Pre-test Probability Points Clinical DVT (objective swelling, tenderness) 3.0 Heart rate >100 bpm 1.5 Immobilization 3 days or surgery in the previous 4 weeks 1.5 Previous DVT/PE 1.5 Hemoptysis 1.0 Malignancy 1.0 PE as likely, or more likely, than alternative disease 3.0 Clinical model applied to 946 patients Probability: <2 = low, 2 6 = intermediate, >6 = high Wells PS et al. Ann Intern Med 2001;135:

47 Clinical Factors Suggesting the Probability of PE Of 437 patients with low clinical probability and negative SimpliRED D-dimer assay, only 1 had PE Wells PS et al. Ann Intern Med 2001;135:

48 Excluding Pulmonary Embolism at the Bedside Without Diagnostic Imaging Conclusion Managing patients with suspected PE on the basis of pre-test probability and D-dimer testing is safe and decreases the need for diagnostic imaging Wells PS et al. Ann Intern Med 2001;135:

49 Simplification of the Diagnostic Management 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 %), which is fully comparable to the present standard diagnostic approach Kraaijenhagen RA et al. Arch Intern Med 2002;162:

50 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 PE The chest radiograph and ABG may offer useful clues to the presence of PE, but are not diagnostic The diagnosis of VTE requires objective testing US is very sensitive for symptomatic DVT; less so for asymptomatic DVT

51 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 diagnoses D-dimer testing, when used carefully, can reduce the need for diagnostic testing in suspected acute DVT Pretest probability estimates, particularly combined with D-dimer testing, appear useful

52 Udredning ved klinisk mistanke om venøs tromboembolisk sygdom (VTE) Klinisk mistanke om VTE Lav-moderat Høj Normal D-dimer Høj D-dimer V/Q-scint v. PE-symp. Duplexscan. v. DVT-symp. Ingen beh. Billeddiag. us. Diagnostisk Ikke-diag. Normal DVT Normal Behandling Us. for DVT Ingen beh. Behandling D-dimer Pos. Neg. Høj Normal Behandling Ingen beh. Flebografi Ingen beh. DVT Normal Behandling Ingen beh.