1. Computed Tomography in the Diagnosis of Pulmonary Embolism Scott M Silvers, MD 1 st Pan American Conference Emergency Medicine Clinical Policies November 6 – 7, 2003

2. Lecture Outline Case Critical Question Literature Search Critical Literature Evaluation Evidence-based Recommendations

3. Case Ms. Smith is an active 39 yo F who presents to the ED with 1 day of pleuritic left anterior chest pain and mild shortness of breath. She denies any cough, leg pain, leg swelling, recent surgery, history of malignancy, or history of DVT / PE in the past. PMH: Hypertension Meds: BCPAll: NKDAFH: None SH: Denies tobacco, alcohol, and drug abuse T=37.6 HR= 115SBP= 120/74 RR=20 SO2=93% RA PE: Normal including heart, lungs, and extremities. Chest X-ray: Normal

4. Case What next?? –Ventilation / Perfusion scan? –Traditional pulmonary arteriography? –Computed Tomography (CT) scan?

5. CT PA in Diagnosing PE Swensen SJ, et al. Outcomes after withholding anticoagulation from patients with suspected acute pulmonary embolism and negative computed tomographic findings: a cohort study. Mayo Clinic Proc. 2002;77:130-138. Baseline Chest CT…Repeat Chest CT

6. Critical Question What is the diagnostic utility of computed tomography in pulmonary embolism (PE)? –Types of CT imaging for PE Single detector pulmonary angiogaphy (PA) Multidetector PA –Combined venography or ultrasound –Negative CT outcome data

7. Literature Search Medline January 1992 – Present Keywords –“Computed tomography,” “CT,” “Pulmonary embolism,” and “PE”  973 papers Limits –Human subjects, clinical trials, meta-analyses  34

8. Literature Search Reviews and clinical policies –2000 – present (references crosschecked)

9. Definitions for Clarity CT-PA = CT with pulmonary angiography Arteriography = Traditional pulmonary angiography

10. What about single-detector CT-PA for detecting PE?

11. Single-Detector CT-PA vs. Arteriography for Detecting PE All patients compared to arteriography 5 studies to date Weaknesses –Small sample size –Large variability of findings –Inclusion of only patients referred for arteriography (sample bias)

12. Single-Detector CT-PA vs. Arteriography for Detecting PE StudyYearNDesign PE % Sens % Spec % Comments Study Grade Remy-Jardin et al 1992 42 Prospective 8610095 Excluded inconclusive CTs 3 Blum et al1994 10 Prospective 70100 Very small sample 3 Goodman et al 1995 20 Prospective 556489 Intermediate VQ only Excluded if + u/s 3 Remy-Jardin et al 1996 75 Prospective 579178 Thoracic radiologists Only those referred for arteriography 2 Drucker et al 1998 47 Prospective 3257 * 89 * Thoracic radiologists Only those referred for arteriography 2 * = Pooled data

13. Single-Detector CT-PA vs. Arteriography for Detecting PE StudyYearNDesign PE % Sens % Spec % Comments Study Grade Remy-Jardin et al 1992 42 Prospective 8610095 Excluded inconclusive CTs 3 Blum et al1994 10 Prospective 70100 Very small sample 3 Goodman et al 1995 20 Prospective 556489 Intermediate VQ only Excluded if + u/s 3 Remy-Jardin et al 1996 75 Prospective 579178 Thoracic radiologists Only those referred for arteriography 2 Drucker et al 1998 47 Prospective 3257 * 89 * Thoracic radiologists Only those referred for arteriography 2 * = Pooled data

14. Single-Detector CT-PA vs. Arteriography for Detecting PE Explanations for Poor Performance –Less resolution than multi-detector CT –Digital monitor technology not available Image scrolling on one screen

15. What about multi-detector CT-PA for detecting PE?

16. Multi-Detector CT-PA for Detecting PE 4 studies to date Higher resolution (less motion artifact) Digital monitors with scrolling images Weaknesses –Studies variable in use of traditional arteriography as “gold standard” –Large variability of findings

17. Multi-Detector CT-PA for Detecting PE StudyYearNDesign PE % Sens % Spec % Comments Study Grade Qanadli et al 2000157 Prospective 399094 Consecutive patients All had CT & arteriography 1 Ost et al (High Risk) 2001103 Prospective 268189 High clinical probability and Low/ intermediate VQ only 21 lost in follow-up 3 Perrier et al 2001299 Prospective 397091 D-dimer > 500  g/L All 3month follow-up 1 Nilsson et al 200290 Prospective 379196 Small sample All had Arteriography 2

18. Multi-Detector CT-PA for Detecting PE StudyYearNDesign PE % Sens % Spec % Comments Study Grade Qanadli et al 2000157 Prospective 399094 Consecutive patients All had CT & arteriography 1 Ost et al (High Risk) 2001103 Prospective 268189 High clinical probability and Low/ intermediate VQ only 21 lost in follow-up 3 Perrier et al 2001299 Prospective 397091 D-dimer > 500  g/L All 3month follow-up 1 Nilsson et al 200290 Prospective 379196 Small sample All had Arteriography 2

19. What about CT-PA with Delayed Venography for Detecting PE?

20. CT Venogram Loud PA et al. Deep venous thrombosis with suspected pulmonary embolism: detection with combined CT venography and pulmonary angiography. Radiology. 2001;219:498-502.

21. CT Pulmonary Angiogram with Delayed Venography for Detecting PE Typical Study Methodology –Consecutive patients with concern for PE –PE = Positive CT PA OR Positive CT venogram –Evaluate benefit of added CT venography Conclusions –CT venography diagnoses an additional 13 – 27% more pulmonary embolism than CT PA alone

22. CT Pulmonary Angiogram with Delayed Venography for Detecting PE StudyYearNDesign CT PA or Venogram ( # PE) Venogram And CT PA Comments Study Grade Loud et al 200071 Prospective 26 (37%)7 (27%) Venogram vs u/s 2 Coche et al 200065 Prospective 25 (38%)3 (12%) Small sample 2 Cham et al 2000541 Prospective 107 (20 %)16 (15%) Venogram vs u/s 1 Loud et al 2001650 Prospective 116 (18%)31 (27%) Venogram vs u/s 1 Au et al 200150 Prospective 14 (28%)2 (14%) Small sample 2 Walsh et al 200296 Prospective 39 (41%)5 (13%) Small sample 2 + + -

23. CT Pulmonary Angiogram with Delayed Venography for Detecting PE StudyYearNDesign CT PA or Venogram ( # PE) Venogram And CT PA Comments Study Grade Loud et al 200071 Prospective 26 (37%)7 (27%) Venogram vs u/s 2 Coche et al 200065 Prospective 25 (38%)3 (12%) Small sample 2 Cham et al 2000541 Prospective 107 (20 %)16 (15%) Venogram vs u/s 1 Loud et al 2001650 Prospective 116 (18%)31 (27%) Venogram vs u/s 1 Au et al 200150 Prospective 14 (28%)2 (14%) Small sample 2 Walsh et al 200296 Prospective 39 (41%)5 (13%) Small sample 2 + + -

24. Is CT venography comparable to lower extremity ultrasound? Yes.

25. Sensitivity of CT Delayed Venography for Detecting DVT StudyYearN Positive CT Venogram SENSITIVITY: CT Venography vs. Bilateral Lower Extremity Ultrasound Study Grade Loud et al19997119 100 % *2 Garg et al2000687100 %2 Cham et al200054145100 %1 Coche et al20016516100 %2 Loud et al200165089 97 % *1 Au et al2001508100 %2 * = CT Venography detected DVT that bilateral lower extremity ultrasound missed

26. Outcome Studies?

27. Outcome Studies of CT-PA alone for Detecting PE 6 studies to date All with significant weaknesses –Excluded patients with other positive testing (Selection Bias) D-dimer Lower extremity ultrasound –Adequacy of follow-up period (3 mos – 1 yr) –Lose patients in follow-up

28. Outcome Studies of CT-PA Alone for Detecting PE StudyYearNDesignCommentsGrade Ost et al 2001103Prospective 6 month follow up 23 (32%) patients with negative CT died 2 had autopsies (both negative) 3 Perrier et al2001299Prospective 3 month follow up Excluded abnormal d-dimers (38%) 3 Goodman et al 20001,015Prospective 3 month follow up 20% lost to follow up 3 Gottsäter et al2001215 Retrospective Cohort 3 month follow up 16 died. 6 autopsies - 3 (50%) proven PEs 3 Swensen et al2002993 Retrospective cohort 3 month follow up 118 (12%) died, 34 autopsies – 3 (9%) PEs 17 pts excluded for positive LE ultrasound 3 Tillie-Leblond et al 200246Prospective 3 months, 6 months, and 1 year follow up 3 (6.5%) PE during follow up (all fatal) Excluded if other positive imaging for clot 3

29. Outcome Studies of CT PA with Delayed Venography for Detecting PE None

30. Outcome Studies of CT PA with Bilateral Lower Extremity Ultrasound for Detecting PE 2 studies to date

31. Outcome After a Negative CT PA with Bilateral Lower Extremity Ultrasound Van Strijen et al (2003; “ANTELOPE” Study Group) Van Strijen et al. Ann Int Med. 2003;138:307-315. Prospective, Single-detector CT 510 Consecutive in/outpatients clinically suspected to have PE 246 with negative CT PA & bilateral lower extremity ultrasound 3 month follow up (100% capture) –3 patients returned with symptoms concerning for PE –CT PA positive in 1 (0.4% {95% CI 0.0 – 2.2%}) Weaknesses –Followed for only 3 months Study Grade = 2

32. Outcome After a Negative CT PA with Bilateral Lower Extremity Ultrasound Musset et al (2002) Musset et al. Lancet. 2002;360:1914 -1920. Prospective, multi-detector CT 1,041 consecutive in/outpatients suspected of having PE 527 Low and intermediate risk patients had negative studies 507 were not anticoagulated (others e.g. ACS) 3 month follow up (99% capture) –9 (1.8 %) developed PE  Of 76 “high risk” patients, 5 (5.3%) had PE Weaknesses –Followed for only 3 months Study Grade = 2

33. Evidenced-based Recommendations For CT scanning in PE Level A Recommendations None specified

34. Evidenced-based Recommendations For CT scanning in PE Level B Recommendations Low and intermediate risk patients for pulmonary embolism may be presumed not to have pulmonary embolism following a negative CT pulmonary angiogram and bilateral lower extremity ultrasound. Low and intermediate risk patients for pulmonary embolism with a negative CT pulmonary angiogram and negative CT venography of the abdomen and lower extremities may be presumed not to have pulmonary embolism.

35. Evidenced-based Recommendations For CT scanning in PE Level C Recommendations CT with pulmonary angiogram alone may be considered as an alternative diagnostic test to ventilation-perfusion imaging and traditional arteriography in the initial evaluation of a patient with possible pulmonary embolism. Consider further screening after a negative CT pulmonary angiogram alone among patients with possible pulmonary embolism.

36. Key References Swensen SJ, et al. Outcomes after withholding anticoagulation from patients with suspected acute pulmonary embolism and negative computed tomographic findings: a cohort study. Mayo Clinic Proc. 2002;77:130-138. Remy-Jardin M, et al. Central pulmonary thromboembolism: diagnosis with spiral volumetric CT with the single-breath-hold technique--comparison with pulmonary angiography. Radiology. 1992 Nov;185(2):381-7. Blum AG, et al. Spiral-computed tomography versus pulmonary angiography in the diagnosis of acute massive pulmonary embolism. Am J Cardiol. 1994 Jul 1;74(1):96-8. Goodman et al. Detection of pulmonary embolism in patients with unresolved clinical and scintigraphic diagnosis: helical CT versus angiography. Am J Roentgenol. 1995;164:1369-1374. Remy-Jardin M, et al. Diagnosis of pulmonary embolism with spiral CT: comparison with pulmonary angiography and scintigraphy. Radiology. 1996;200(3):699-706. Drucker N, et al. Acute pulmonary embolism: assessment of helical CT for diagnosis. Radiology. 1998;209:235-241. Qanadli SD, et al. Pulmonary embolism detection: prospective evaluation of dual-section helical CT versus selective pulmonary arteriography in 157 patients. Radiology. 2000;217:447-455.

37. Key References Ost D, et al. The negative predictive value of spiral computed tomography for the diagnosis of pulmonary embolism in patients with nondiagnostic ventilation- perfusion scans. Am J Med. 2001;110:16-21. Perrier A, et al. Performance of helical computed tomography in unselected outpatients with suspected pulmonary embolism. Ann Int Med. 2001;135:88-97. Nilsson T, et al. A comparison of spiral computed tomography and latex agglutination d-dimer assay in acute pulmonary embolism using pulmonary arteriography as gold standard. Scand Cardiovasc J. 2002;36(6):373-7. Loud PA, et al. Deep venous thrombosis with suspected pulmonary embolism: detection with combined CT venography and pulmonary angiography. Radiology. 2001;219:498-502. Loud PA, et al. Combined CT venography and pulmonary angiography in suspected thromboembolic disease: diagnostic accuracy for deep venous evaluation. Am J Roentgenol. 2000;174:61-65. Cham MD, et al. Deep venous thrombosis: detection by using indirect CT venography. Radiology. 2000;216:744-751. Coche EE, et al. Using dual-detector helical CT angiography to detect deep venous thrombosis in patients with suspicion of pulmonary embolism: diagnostic value and additional findings. Amer J Roentgenol. 2001;176:1035-1039. Au V WK, et al. Computed tomography pulmonary angiography with pelvic venography in the evaluation of thrombo-embolic disease. Australasian Radiology. 2001;45:141-145.

38. Key References Walsh G, and Redmond S. Does addition of CT pelvic venography to CT pulmonary angiography protocols contribute to the diagnosis of thromboembolic disease? Clinical Radiology. 2002;57:462-465. Garg K, et al. Thromboembolic disease: comparison of combined CT pulmonary angiography and venography with bilateral leg sonography in 70 patients. Amer J Roentgenol. 2000;175:997-1001. Goodman LR, et al. Subsequent pulmonary embolism: risk after a negative helical CT pulmonary angiogram – prospective comparison with scintigraphy. Radiology. 2000;215:535-542. Gottsäter A, et al. Clinically suspected pulmonary embolism: is it safe to withhold anticoagulation after a negative spiral CT? Eur Radiol. 2001;11:65-72. Tillie-Lebond I, et al. Risk of pulmonary embolism after a negative spiral CT angiogram in patients with pulmonary disease: 1-year clinical follow-up study. Radiology. 2002;223:461-467. Musset et al. Diagnostic strategy for patients with suspected pulmonary embolism: a prospective multicentre outcome study. Lancet. 2002;360:1914 -1920. Van Strijen et al. Single-detector helical computed tomography as the primary diagnostic test in suspected pulmonary embolism: A multicenter clinical management study of 510 patients. Ann Int Med. 2003;138:307-315

40. The End