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

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

Background venous thromboembolism

It’s serious!

Missing VTE BMJ 1949

Missing VTE today? Archives of Internal Medicine 2008

VTE disease of the elderly

Diagnosing PE, the easy part.

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

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

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

Clinical Decision Rule by Wells

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

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

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

How does this work in Primary Care?

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

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: 2681-3. 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: 663-6. 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):1327-30 * Clearview Simplify®, Inverness Medical, Bedford, UK

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

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

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

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

Age-adjusted D-dimer levels

Age-adjusted D-dimer levels

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

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

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

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

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.

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

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

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

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

Home treatment of Pulmonary Embolism.

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

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

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

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

Diagnosing PE, maybe not the easy part?!