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New PIOPED Recommendations for the Diagnosis of Pulmonary Embolism
The American Journal of Medicine (2006) 119, 1001-1002
COMMENTARY
New PIOPED Recommendations for the Diagnosis of Pulmonary Embolism When pulmonary embolism (PE) is suspected, the diagnosis must be confirmed or excluded by further testing because PE is only present in about one third of those in whom it is suspected.1 Before the introduction of pulmonary angiography, the only way to confirm or exclude the diagnosis of pulmonary embolism during life was to perform pulmonary embolectomy. The development of pulmonary angiography with injection into the pulmonary artery in the 1960s2-4 permitted an accurate diagnosis of pulmonary embolism, and pulmonary angiography became the gold standard for the diagnosis of PE. Pulmonary angiography has the disadvantage of being an expensive invasive procedure with potential complications. In addition, it requires special equipment and expertise that it is not available in all hospitals. The introduction of ventilation and perfusion scanning (V/Q scans) in the 1960s and the early 1970s offered distinct advantages over pulmonary angiography.5,6 It is a noninvasive procedure with minimal complications. V/Q scans soon became available in most hospitals and became the most frequently used test to confirm the diagnosis of PE, largely replacing pulmonary angiography. However, the sensitivity and specificity of V/Q scans was uncertain until the Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED) investigators published their landmark study in 1990.1 There were 750 patients with suspected PE who underwent V/Q scans and pulmonary angiography in a multicenter investigation. PE was confirmed by pulmonary angiography in 88% of patients with high-probability V/Q scans, defined as 2 or more large segmental (or the equivalent number of moderate size perfusion defects where 2 moderates ⫽ 1 large) perfusion defects without corresponding ventilation or roentgenographic abnormalities. However, only 41% of patients with documented PE had a high probability scan. In patients with normal or near normal scans, angiography and clinical follow-up indicated that the incidence of PE was 8% or less.1 These findings of the PIOPED study indicated that a high probability scan is sufficient evidence to treat for PE and that therapy can be safely withheld in patients with a normal or near normal scan. Unfortunately, only 16% of the patients with suspected PE had high probability scans and only 0002-9343/$ -see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.amjmed.2006.06.034
8% had normal or near normal scans. Nearly one half (44%) had intermediate probability scans that neither confirmed nor excluded PE. The incidence of PE in patients with intermediate probability scans was 33%.1 Three different approaches have helped to determine if therapy is indicated or if it can safely be withheld in patients with low or intermediate-probability lung scans. Most agree that if venous ultrasound is positive for deep vein thrombosis (DVT), therapy is indicated and if it shows no evidence of DVT in a patient with a low or intermediateprobability V/Q scan, anticoagulant therapy can safely be withheld. Multiple studies have shown that the vast majority of patients with venous thromboembolism have elevated Ddimer by the quantitative enzyme-linked immunosorbent assay (ELISA).7,8 Thus, if the D-dimer is negative in a patient with an intermediate or low-probability lung scan, therapy for PE can safely be withheld. Several algorithms to assess the clinical probability of pulmonary embolism have been reported and validated.9,10 These assessments rate the clinical probability of PE as being low, moderate or high. Prospective studies utilizing these assessments have shown that the incidence of PE is approximately 10% when the clinical probability is low, 30% with moderate probability, and 60% to 70% when the clinical probability is high. When the clinical probability is low and the D-dimer is negative, therapy can safely be withheld in patients with low or intermediate probability lung scans of PE.9 Contrast computed tomographic pulmonary angiography (CTA) was introduced in the 1990s.11,12 As was the case with V/Q scans, CTA became widely accepted, largely replacing V/Q scans as a diagnostic test for PE, even though the sensitivity and specificity of CTA had not been conclusively determined. The PIOPED investigators recently reported the results of another landmark study (PIOPED II) of the diagnosis of PE.13 In a prospective multicenter study, they investigated the use of multidetector spiral CTA alone and combined with imaging of the pelvic and thigh veins (CTA/CTV) for the diagnosis of PE. A composite reference test including lung scans, digital subtraction angiography, and venous
1002
The American Journal of Medicine, Vol 119, No 12, December 2006
ultrasound, was used to confirm or exclude the diagnosis of PE.13 They reported that the sensitivity of CTA was 83% and the specificity was 96%. The sensitivity of CTA/CTV was 90% and specificity was 95%. This important study demonstrated that the sensitivity and specificity of CTA and CTA/CTV in the diagnosis of PE exceeds that of lung scans. In this issue of The American Journal of Medicine, the PIOPED investigators present their recommendations for diagnostic pathways for the diagnosis of PE and recommendations for treatment based on the findings in PIOPED I and PIOPED II, and other relevant investigations.14 Once PE has been suspected, they recommend assessment of the clinical probability of PE utilizing one of the clinical algorithms9,10 and measurement of D-dimer (ELISA). If the clinical probability is low or moderate and the D-dimer is negative, PE is excluded. If PE is not excluded by these 2 tests, CTA/CTV is recommended by most of the PIOPED investigators. In pregnant women or in women in the child-bearing age, some prefer V/Q scans to CTA/CTV because of concerns for radiation exposure. The recommended treatment decisions are based on the clinical probability of PE and the findings by CTA/CTV. In patients with a low clinical probability, no treatment is recommended if the CTA/CTV is negative. In patients with a moderate clinical probability and negative CTA/CTV, they recommend no treatment or the option of further testing. In patients with a high clinical probability who have a negative CTA/CTV, they recommend further testing.14 Because CTA evidence of PE in segmental or sub-segmental arteries was found to have lower positive predictive values for PE than main or lobar PE in PIOPED II, they recommend further testing if PE is limited to segmental or sub-segmental arteries in patients with a low clinical probability of PE. In patients with a moderate or high probability of PE who have a positive CTA/CTV, therapy is recommended if the emboli are located in segmental, sub-segmental, lobar, or main pulmonary arteries. These recommendations from the PIOPED investigators14 will have a major impact on the diagnosis and treatment of pulmonary embolism. Now that PIOPED I has clarified the role of V/Q scans and PIOPED II has clarified the role of CTA, the PIOPED investigators are currently conducting the PIOPED III trial to assess the specificity and sensitivity of gadolinium-
enhanced magnetic resonance angiography in the diagnosis of PE. James E. Dalen, MD, MPH Professor Emeritus University of Arizona Tucson
References 1. The PIOPED Investigators. Value of the ventilation/perfusion scan in acute pulmonary embolism: results of the prospective investigation of pulmonary embolism diagnosis (PIOPED). JAMA. 1990;263:27532759. 2. Williams JR, Wilcox C, Andrews GJ, et al. Angiography in pulmonary embolism. JAMA. 1963;184:473-476. 3. Sasahara AA, Stein M, Simon M, et al. Pulmonary angiography in the diagnosis of thromboembolic disease. N Engl J Med. 1964;270:10751081. 4. Stein PD, O’Conner JF, Dalen JE, et al. The angiographic diagnosis of acute pulmonary embolism: evaluation of criteria. Am Heart J. 1967; 73:730-741. 5. Wagner HN, Sabiston DC, McAfee JG, et al. Diagnosis of massive pulmonary embolism in man by radioisotope scanning. N Engl J Med. 1964;271:377-384. 6. Fred HL, Burdine JA, Gonzalez DA, et al. Arteriographic assessment of lung scanning in the diagnosis of pulmonary thromboembolism. N Engl J Med. 1966;275:1025-1032. 7. Heaton DC, Billings JD, Hickton CM. Assessment of d-dimer assays for the diagnosis of deep vein thrombosis. J Lab Clin Med. 1987;110: 588-591. 8. Bounameaux H, Schneider PA, Reber G, et al. Measurement of plasma d-dimer for diagnosis of deep venous thrombosis. Am J Clin Pathol. 1989;91:82-85. 9. Wells PS, Anderson DR, Rodger M, et al. 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. Ann Intern Med. 2001;135:98-107. 10. Wicki J, Perneger TV, Junod AF, et al. Assessing clinical probability of pulmonary embolism in the emergency ward. A simple score. Arch Intern Med. 2001;161:92-97. 11. Remy-Jardin M, Remy J, Wattine L, et al. Central pulmonary thromboembolism: diagnosis with spiral volumetric CT with the singlebreath-hold technique; comparison with pulmonary angiography. Radiology. 1992;185:381-387. 12. Teigen CL, Maus TP, Sheedy PF, et al. Pulmonary embolism: diagnosis with electron beam CT. Radiology. 1993;188:839-845. 13. Stein PD, Fowler SE, Goodman LR, et al. Multidetector computed tomography for acute pulmonary embolism. N Engl J Med. 2006;354: 2317-2327. 14. Stein PD, Woodard PK, Weg JG, et al. Diagnostic pathways in acute pulmonary embolism: recommendations of the PIOPED II investigators. Am J Med. 2006;119:1048-1055.
COMMENTARY
New PIOPED Recommendations for the Diagnosis of Pulmonary Embolism When pulmonary embolism (PE) is suspected, the diagnosis must be confirmed or excluded by further testing because PE is only present in about one third of those in whom it is suspected.1 Before the introduction of pulmonary angiography, the only way to confirm or exclude the diagnosis of pulmonary embolism during life was to perform pulmonary embolectomy. The development of pulmonary angiography with injection into the pulmonary artery in the 1960s2-4 permitted an accurate diagnosis of pulmonary embolism, and pulmonary angiography became the gold standard for the diagnosis of PE. Pulmonary angiography has the disadvantage of being an expensive invasive procedure with potential complications. In addition, it requires special equipment and expertise that it is not available in all hospitals. The introduction of ventilation and perfusion scanning (V/Q scans) in the 1960s and the early 1970s offered distinct advantages over pulmonary angiography.5,6 It is a noninvasive procedure with minimal complications. V/Q scans soon became available in most hospitals and became the most frequently used test to confirm the diagnosis of PE, largely replacing pulmonary angiography. However, the sensitivity and specificity of V/Q scans was uncertain until the Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED) investigators published their landmark study in 1990.1 There were 750 patients with suspected PE who underwent V/Q scans and pulmonary angiography in a multicenter investigation. PE was confirmed by pulmonary angiography in 88% of patients with high-probability V/Q scans, defined as 2 or more large segmental (or the equivalent number of moderate size perfusion defects where 2 moderates ⫽ 1 large) perfusion defects without corresponding ventilation or roentgenographic abnormalities. However, only 41% of patients with documented PE had a high probability scan. In patients with normal or near normal scans, angiography and clinical follow-up indicated that the incidence of PE was 8% or less.1 These findings of the PIOPED study indicated that a high probability scan is sufficient evidence to treat for PE and that therapy can be safely withheld in patients with a normal or near normal scan. Unfortunately, only 16% of the patients with suspected PE had high probability scans and only 0002-9343/$ -see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.amjmed.2006.06.034
8% had normal or near normal scans. Nearly one half (44%) had intermediate probability scans that neither confirmed nor excluded PE. The incidence of PE in patients with intermediate probability scans was 33%.1 Three different approaches have helped to determine if therapy is indicated or if it can safely be withheld in patients with low or intermediate-probability lung scans. Most agree that if venous ultrasound is positive for deep vein thrombosis (DVT), therapy is indicated and if it shows no evidence of DVT in a patient with a low or intermediateprobability V/Q scan, anticoagulant therapy can safely be withheld. Multiple studies have shown that the vast majority of patients with venous thromboembolism have elevated Ddimer by the quantitative enzyme-linked immunosorbent assay (ELISA).7,8 Thus, if the D-dimer is negative in a patient with an intermediate or low-probability lung scan, therapy for PE can safely be withheld. Several algorithms to assess the clinical probability of pulmonary embolism have been reported and validated.9,10 These assessments rate the clinical probability of PE as being low, moderate or high. Prospective studies utilizing these assessments have shown that the incidence of PE is approximately 10% when the clinical probability is low, 30% with moderate probability, and 60% to 70% when the clinical probability is high. When the clinical probability is low and the D-dimer is negative, therapy can safely be withheld in patients with low or intermediate probability lung scans of PE.9 Contrast computed tomographic pulmonary angiography (CTA) was introduced in the 1990s.11,12 As was the case with V/Q scans, CTA became widely accepted, largely replacing V/Q scans as a diagnostic test for PE, even though the sensitivity and specificity of CTA had not been conclusively determined. The PIOPED investigators recently reported the results of another landmark study (PIOPED II) of the diagnosis of PE.13 In a prospective multicenter study, they investigated the use of multidetector spiral CTA alone and combined with imaging of the pelvic and thigh veins (CTA/CTV) for the diagnosis of PE. A composite reference test including lung scans, digital subtraction angiography, and venous
1002
The American Journal of Medicine, Vol 119, No 12, December 2006
ultrasound, was used to confirm or exclude the diagnosis of PE.13 They reported that the sensitivity of CTA was 83% and the specificity was 96%. The sensitivity of CTA/CTV was 90% and specificity was 95%. This important study demonstrated that the sensitivity and specificity of CTA and CTA/CTV in the diagnosis of PE exceeds that of lung scans. In this issue of The American Journal of Medicine, the PIOPED investigators present their recommendations for diagnostic pathways for the diagnosis of PE and recommendations for treatment based on the findings in PIOPED I and PIOPED II, and other relevant investigations.14 Once PE has been suspected, they recommend assessment of the clinical probability of PE utilizing one of the clinical algorithms9,10 and measurement of D-dimer (ELISA). If the clinical probability is low or moderate and the D-dimer is negative, PE is excluded. If PE is not excluded by these 2 tests, CTA/CTV is recommended by most of the PIOPED investigators. In pregnant women or in women in the child-bearing age, some prefer V/Q scans to CTA/CTV because of concerns for radiation exposure. The recommended treatment decisions are based on the clinical probability of PE and the findings by CTA/CTV. In patients with a low clinical probability, no treatment is recommended if the CTA/CTV is negative. In patients with a moderate clinical probability and negative CTA/CTV, they recommend no treatment or the option of further testing. In patients with a high clinical probability who have a negative CTA/CTV, they recommend further testing.14 Because CTA evidence of PE in segmental or sub-segmental arteries was found to have lower positive predictive values for PE than main or lobar PE in PIOPED II, they recommend further testing if PE is limited to segmental or sub-segmental arteries in patients with a low clinical probability of PE. In patients with a moderate or high probability of PE who have a positive CTA/CTV, therapy is recommended if the emboli are located in segmental, sub-segmental, lobar, or main pulmonary arteries. These recommendations from the PIOPED investigators14 will have a major impact on the diagnosis and treatment of pulmonary embolism. Now that PIOPED I has clarified the role of V/Q scans and PIOPED II has clarified the role of CTA, the PIOPED investigators are currently conducting the PIOPED III trial to assess the specificity and sensitivity of gadolinium-
enhanced magnetic resonance angiography in the diagnosis of PE. James E. Dalen, MD, MPH Professor Emeritus University of Arizona Tucson
References 1. The PIOPED Investigators. Value of the ventilation/perfusion scan in acute pulmonary embolism: results of the prospective investigation of pulmonary embolism diagnosis (PIOPED). JAMA. 1990;263:27532759. 2. Williams JR, Wilcox C, Andrews GJ, et al. Angiography in pulmonary embolism. JAMA. 1963;184:473-476. 3. Sasahara AA, Stein M, Simon M, et al. Pulmonary angiography in the diagnosis of thromboembolic disease. N Engl J Med. 1964;270:10751081. 4. Stein PD, O’Conner JF, Dalen JE, et al. The angiographic diagnosis of acute pulmonary embolism: evaluation of criteria. Am Heart J. 1967; 73:730-741. 5. Wagner HN, Sabiston DC, McAfee JG, et al. Diagnosis of massive pulmonary embolism in man by radioisotope scanning. N Engl J Med. 1964;271:377-384. 6. Fred HL, Burdine JA, Gonzalez DA, et al. Arteriographic assessment of lung scanning in the diagnosis of pulmonary thromboembolism. N Engl J Med. 1966;275:1025-1032. 7. Heaton DC, Billings JD, Hickton CM. Assessment of d-dimer assays for the diagnosis of deep vein thrombosis. J Lab Clin Med. 1987;110: 588-591. 8. Bounameaux H, Schneider PA, Reber G, et al. Measurement of plasma d-dimer for diagnosis of deep venous thrombosis. Am J Clin Pathol. 1989;91:82-85. 9. Wells PS, Anderson DR, Rodger M, et al. 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. Ann Intern Med. 2001;135:98-107. 10. Wicki J, Perneger TV, Junod AF, et al. Assessing clinical probability of pulmonary embolism in the emergency ward. A simple score. Arch Intern Med. 2001;161:92-97. 11. Remy-Jardin M, Remy J, Wattine L, et al. Central pulmonary thromboembolism: diagnosis with spiral volumetric CT with the singlebreath-hold technique; comparison with pulmonary angiography. Radiology. 1992;185:381-387. 12. Teigen CL, Maus TP, Sheedy PF, et al. Pulmonary embolism: diagnosis with electron beam CT. Radiology. 1993;188:839-845. 13. Stein PD, Fowler SE, Goodman LR, et al. Multidetector computed tomography for acute pulmonary embolism. N Engl J Med. 2006;354: 2317-2327. 14. Stein PD, Woodard PK, Weg JG, et al. Diagnostic pathways in acute pulmonary embolism: recommendations of the PIOPED II investigators. Am J Med. 2006;119:1048-1055.