1. Suspected pulmonary embolism in primary care: Referral for all?
Update on better disease diagnosis
Suspected pulmonary embolism in primary care: Referral for all?
Dr Geert-Jan Geersing
Utrecht, The Netherlands

2. Today’s presentation Background Venous Thromboembolism
Diagnosing Pulmonary Embolism
Use of a CDR and D-dimer testing
Age-adjusted cut-offs for D-dimer testing
Selective D-dimer testing based on CDR-score
Prognostic models in Pulmonary Embolism
Short-term mortality
Risk of recurrent disease and treatment duration
Risks for overdiagnosis in Pulmonary Embolism

3. Background venous thromboembolism

4. It’s serious!

5. Missing VTE
BMJ 1949

6. Missing VTE today?
Archives of Internal Medicine 2008

7. VTE disease of the elderly

8. Diagnosing PE, the easy part.

9. Risk of PE after a negative CT-scan
R. Quiroz et.al. JAMA 2005

10. Refer all patients?
At least you don’t miss a case of potentially fatal pulmonary embolism!

11. Overutilization of healthcare?
The diagnostic yield of referring all patients for imaging is very low; may be even as low as 5-10%!
Diagnostic yield has even decreased over recent years…
Solution: development of clinical decision rules

12. Clinical Decision Rule by Wells

13. Additional D-dimer testing; introduced in the ’90s
D-dimer degradation product of fibrin
High sensitivity but low specificity > Used to rule-out DVT

14. Combination of CDR and D-dimer testing
W. Lucassen and G.J. Geersing Ann Int Med 2011

15. Combination of CDR and D-dimer testing
Combination of a low score on the clinical decision rule and a negative D-dimer test safely excludes PE in about 1 in every 3 patients.
W. Lucassen and G.J. Geersing Ann Int Med 2011

16. How does this work in Primary Care?

17. Diagnostic validation study Patients suspected of acute PE
The AMUSE-2 study
Diagnostic validation study
Patients suspected of acute PE
All patients referred for reference standard, including 3 months of follow-up
Point-of-care D-dimer test applied

18. Point of Care (p.o.c.) D-dimer test: Simplify®*+ -
Op dit moment moeten de meeste patiënten voor een d-dimeertest nog naar een laboratorium. De daar gebruikte d-dimeertesten (meestal VIDAS of TINAQUANT) hebben een hoge sensitiviteit (96%) voor DVT bij een afkappunt van 0.5mg/l (500ng/ml).
De laatste jaren zijn ‘point-of-care’ testen (‘vingerprik’) op de markt gekomen, waardoor het uitsluiten van DVT volledig binnen het bereik van de eerste lijn komt. De oudste ‘point-of-care’ test (Simpli-Red) kende een relatief lage sensitiviteit (87%) en een grote interbeoordelaarsvariabiliteit en bovendien werden hoge eisen gesteld aan opslag en transport. Dit maakte deze test moeilijk bruikbaar in de huisartspraktijk.
Een nieuwe generatie testen heeft een veel betere interbeoordelaarsbetrouwbaarheid en een hoge sensitiviteit (96%). De specificiteit is echter tamelijk gering (46%).
Cini M, Legnani C, Cavallaroni K, Bettini F, Palareti G. A new rapid bedside
assay for D-dimer measurement (Simplify D-dimer) in the diagnostic work-up for
deep vein thrombosis. J Thromb Haemost 2003; 1:
Neale D, Tovey C, Vali A, et al. Evaluation of the Simplify D-dimer assay as a
screening test for the diagnosis of deep vein thrombosis in an emergency
department. Emerg Med J 2004; 21:
van der Velde EF, Wichers IM, Toll DB, van Weert HC, Buller HR. Feasibility
and accuracy of a rapid 'point-of-care' D-dimer test performed with a capillary
blood sample. J Thromb Haemost 2007;5(6):
* Clearview Simplify®, Inverness Medical, Bedford, UK

19. Patients suspected of PE
Excluded patients N = 64
VKA or LMWH use N = 28
Pregnant N = 15
Age < 18 years N = 3
Unable to follow-up N = 18
Study patients
N = 598
LOW RISK
HIGH RISK
Wells score <2
N = 237
Wells score ≤ 4
N = 422
Wells score > 4
N = 176
Reference:
Spiral CT N = 70
V/Q scan N = 11
US N = 5
3 m f-up only N = 151
Reference:
Spiral CT N = 131
V/Q scan N = 14
DSA N = 3
US N = 9
3 m f-up only N = 265
Reference:
Spiral CT N = 101
V/Q scan N = 7
DSA N = 2
US N = 9
3 m f-up only N = 57
POC DD negative:
N = 168
POC DD positive:
N = 69
POC DD negative:
N = 272
POC DD positive:
N = 150
VTE positive N=2
Failure rate = 1.2 %
Efficiency = 28 %
VTE positive N=5
VTE positive N=4
Failure rate = 1.5 %
Efficiency = 45 %
VTE positive N=17
VTE positive N=52
Hence, confirmed VTE in around 1 in 3 patients

20. Patients suspected of PE
Excluded patients N = 64
VKA or LMWH use N = 28
Pregnant N = 15
Age < 18 years N = 3
Unable to follow-up N = 18
Study patients
N = 598
LOW RISK
HIGH RISK
Wells score <2
N = 237
Wells score ≤ 4
N = 422
Wells score > 4
N = 176
Reference:
Spiral CT N = 70
V/Q scan N = 11
US N = 5
3 m f-up only N = 151
Reference:
Spiral CT N = 131
V/Q scan N = 14
DSA N = 3
US N = 9
3 m f-up only N = 265
Reference:
Spiral CT N = 101
V/Q scan N = 7
DSA N = 2
US N = 9
3 m f-up only N = 57
POC DD negative:
N = 168
POC DD negative:
N = 272
POC DD positive:
N = 150
VTE positive N=2
Failure rate = 1.2 %
Efficiency = 28 %
VTE positive N=4
Failure rate = 1.5 %
Efficiency = 45 %
VTE positive N=17
VTE positive N=52
Hence, confirmed VTE in around 1 in 3 patients

21. Patients suspected of PE
Excluded patients N = 64
VKA or LMWH use N = 28
Pregnant N = 15
Age < 18 years N = 3
Unable to follow-up N = 18
Study patients
N = 598
LOW RISK
HIGH RISK
Wells score <2
N = 237
Wells score ≤ 4
N = 422
Wells score > 4
N = 176
Using either a low score on the Wells score is both safe and efficient in primary care for ruling-out acute PE.
Reference:
Spiral CT N = 70
V/Q scan N = 11
US N = 5
3 m f-up only N = 151
Reference:
Spiral CT N = 131
V/Q scan N = 14
DSA N = 3
US N = 9
3 m f-up only N = 265
Reference:
Spiral CT N = 101
V/Q scan N = 7
DSA N = 2
US N = 9
3 m f-up only N = 57
POC DD negative:
N = 168
POC DD positive:
N = 69
POC DD negative:
N = 272
VTE positive N=2
Failure rate = 1.2 %
Efficiency = 28 %
VTE positive N=5
VTE positive N=4
Failure rate = 1.5 %
Efficiency = 45 %
VTE positive N=52
Hence, confirmed VTE in around 1 in 3 patients

22. Age-adjusted D-dimer levels
Threshold for D-dimer = (AGE x 10) IF AGE > 50 years
R. Douma et.al. BMJ 2010

23. Age-adjusted D-dimer levels

24. Age-adjusted D-dimer levels

25. Age-adjusted D-dimer levels
H. Schouten et.al. BMJ 2013

26. Age-adjusted D-dimer levels
H. Schouten et.al. BMJ 2013

27. Selective D-dimer testing based on CDR
L. Linkins et.al. Ann Int Med 2013

28. Selective D-dimer testing based on CDR
Selective testing: Failure rate 0.5%
Efficiency 49%
Uniform testing: Failure rate 0.5%
Efficiency 41%
However….
Alarmingly low prevalence (7.1%)
Not yet validated for use in primary care
L. Linkins et.al. Ann Int Med 2013

29. Summary so far … Pulmonary embolism is an easy diagnosis to miss.
Referral for all is not really an option, given the relatively low prevalence of confirmed cases in the suspected population and iatrogenic effects of CT-scanning.
Clinical decision rules in combination with D-dimer testing can exclude PE in about half of the suspected cases, missing less than 2% of cases.
Recently, this rule-out approach has also been validated for use in primary care.
New insights are emerging on the optimal threshold for D-dimer testing, including an age-adjusted cut-off or selective testing depending on the CDR score.

30. Prognosis of pulmonary embolism
Short-term prognosis: acute mortality >> primarily related to the need for hospital admission.
Long-term prognosis: recurrence risk >> primarily related to the treatment duration.
G.J. Geersing et.al. CMAJ 2012

31. Short-term prognosis.
PESI score groups I and II considered low-risk and candidates for home-treatment.

32. Short-term prognosis.
D. Aujesky et.al. Lancet 2011

33. Short-term prognosis.
D. Aujesky et.al. Lancet 2011

34. Home treatment of Pulmonary Embolism.

35. Long-term prognosis.
> 10% recurrent events 2 years after stopping treatment!!
Recurrence risk highest during the first 6 months after stopping treatment.
F. Boutitie et.al. BMJ 2011

36. Prolong study.
G. Palareti et.al. NEJM 2006

37. Prolong study.
Risk of recurrence is moren than 5 times higher if D-dimer levels are high after treatment is ended!
G. Palareti et.al. NEJM 2006

38. Overdiagnosis of pulmonary embolism?
R. Soylemes Wiener et.al. Arch Int Med 2011

39. Diagnosing PE, maybe not the easy part?!