ATS Reading List

Pulmonary Embolism

Risk Stratification Using D-Dimer

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. Large prospective cohort study using the SimpliRED d-dimer assay (which has sensitivity lower than, and specificity higher than, some other d-dimer tests) found the combination of a low clinical suspicion for PE and a negative d-dimer safely ruled out pulmonary embolism without additional testing.
PMID: 11453709

van Belle A, Buller HR, Huisman MV, et al. Effectiveness of managing suspected pulmonary embolism using an algorithm combining clinical probability, D-dimer testing, and computed tomography. JAMA 2006; 295:172-9. This study classified 3,306 patients as "PE likely" or "PE unlikely" based on a dichotomized version of Wells criteria. "PE unlikely" plus a negative D-dimer sufficiently ruled out PE without further testing (0.5% with PE diagnosis in subsequent 3 months). Patients with "PE likely" or a positive D-dimer underwent CT angiogram. 95% of patients with a negative CT had anticoagulation withheld without further testing and 1.3% were subsequently diagnosed with PE over 3 months. 88% of scans were multidetector row studies.
PMID: 16403929
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Righini M, Van Es J, Den Exter PL, et al. Age-adjusted D-dimer cutoff levels to rule out pulmonary embolism: the ADJUST-PE study. JAMA 2014; 311:1117-24. This study explored the reliability of using a higher normal cut-off d-dimer level for patients > 50 years old with low clinical probability of PE (age-adjusted d-dimer level = patient age x 10). Among 337 patients with d-dimer levels above the standard cut-off of 500 mcg/L but below their age-adjusted cut-off in whom treatment was withheld, 0.3% had a DVT or PE during the ensuing 3 months. The age-adjusted cut point increased the proportion of negative d-dimer studies by 12%. The study utilized 6 different assays and it is unclear whether the variability in the proportion of patients with negative results was due to assay characteristics vs. differences in patient characteristics.
PMID: 24643601
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Diagnostic Imaging

PIOPED Investigators. Value of the ventilation / perfusion scans in pulmonary embolism: results of the PIOPED. JAMA 1990;263:2753-9. This ubiquitously-cited study found that VQ scans are useful when they are high probability and normal, but that most of the time PE can't be ruled in or out by VQ scan. Includes a useful table comparing clinical suspicion and VQ scan result relative to PA gram result.
PMID: 2332918

Perrier A, Roy PM, Sanchez O, et al. Multidetector-row computed tomography in suspected pulmonary embolism. N Engl J Med 2005; 352:1760-8. Study of 756 patients found it is safe to withhold anticoagulation and defer additional evaluation in patients with a low or intermediate clinical probability of PE and a negative D-dimer. This study also found a low risk of withholding treatment in patients with a negative multidetector-row CT. The overall 3-month risk of VTE in patients with a negative evaluation based on clinical probability, D-dimer, and chest scans, but without lower extremity ultrasound, would have been 1.5%.
PMID: 15858185
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Stein PD, Fowler SE, Goodman LR, et al. Multidetector computed tomography for acute pulmonary embolism. N Engl J Med 2006; 354:2317-27. The PIOPED II study of 824 patients found CT angiogram had a sensitivity of 83% and specificity of 96%, excluding the 6% with poor quality images. The sensitivity improved to 90% with addition of CT venography. The predictive value was 96% when the result was concordant with a high or low clinical suspicion, but CT was non-diagnostic if there was discordance. For instance, there were 42% false-positives among patients with low clinical suspicion and a positive scan, and 40% false negatives among patients with high clinical probability but negative scan. CTs were primarily performed with 4-slice scanners. The results of a subsequent RCT by Anderson DR et al (JAMA 2007;298:2743-53) also suggest CT angio may yield false-positive results or diagnose clinically insignificant clot.
PMID: 16738268
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Anderson DR, Kahn SR, Rodger MA, et al. Computed tomographic pulmonary angiography vs. ventilation-perfusion lung scanning in patients with suspected pulmonary embolism. JAMA 2007; 298:2743-53. This RCT found that of 531 patients with a positive d-dimer but negative CT, only 1.3% had a positive lower extremity ultrasound. Of note, patients randomized to CT were more likely to be diagnosed with PE than with VQ scanning (19.2% vs. 14.2%), but there was no significant difference in the diagnosis of venous thromboembolism in the subsequent 3-month follow-up period. This raises the possibility of false-positive results or identification of clinically insignificant clot with CT. (see also Stein PD, et al study below)
PMID: 18165667
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Acute Management of submassive PE

Konstantinides S, Geibel A, Heusel G, et al. Heparin plus alteplase compared with heparin alone in patients with submassive pulmonary embolism. N Engl J Med 2002; 347:1143-50. This randomized, double blind study is cited by both advocates and skeptics of lytic therapy in submassive PE. The study found lytics did not improve mortality. Patients randomized to lytics were significantly less likely than the placebo group to require escalation of therapy, which primarily entailed administration of lytics. The indication for rescue therapy was worsening respiratory symptoms, short of intubation, two-thirds of the time.
PMID: 12374874
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Meyer G, Vicaut E, Danays T, et al. PLEITHO investigators. Fibrinolysis for patients with intermediate-risk pulmonary embolism. N Engl J Med 2014; 370:1402-11. Multicenter trial randomized 1006 hemodynamically stable patients with elevated troponin levels and evidence of right-heart strain by echo or chest CT to unfractionated heparin plus either tenecteplase or placebo. Subsequent hemodynamic instability was more common in the placebo group (5.0 vs 1.6%), while stroke (2.4 vs 0.2%) as well as major extracranial bleeding (6.3 vs. 1.2%) were more likely in the lytics group, and all-cause mortality did not differ between groups.
PMID: 24716681
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Kearon C, Akl E, Ornelas J, et al. Antithrombotic therapy for VTE disease: CHEST guideline and expert panel report. CHEST. 2016; 149:315-52. This update on antithrombotic therapy modifies recommendations on a number of clinical issues. Notably, it recommends new oral anticoagulants (NOACs), over warfarin in cases of VTE without cancer.  In patients with subsegmental PE and no proximal lower extremity DVT clinical surveillance, rather than anticoagulation, is recommended if there is a low risk for recurrent VTE .
PMID: 26867832
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Agnelli G, Prandoni P, Becattini C, et al. Extended oral anticoagulant therapy after a first episode of pulmonary embolism. Ann Intern Med. 2003; 139:19-25. Randomized, non-blinded study of extending anticoagulation beyond 3 months in patients with first episode of idiopathic PE and PE associated with temporary risk factors. Extending anticoagulation in patients with idiopathic PE from 3 to 12 months only delayed onset of what proved to be a high recurrence rate (4-5% per patient-year once off anticoagulation). A more recent study by Campbell IA et al. BMJ 2007;334;674 reported similar findings. These studies highlight the need for new ways of identifying patients at high risk of recurrence to allow selective use of lifelong anticoagulation.
PMID: 12834314

Becattini C, Agnelli G, Schenone A, et al. Aspirin for preventing the recurrence of venous thromboembolism. N Engl J Med. 2012; 366:1959-67. Randomized 2-year trial evaluated 100 mg daily aspirin vs. placebo for thromboembolism prophylaxis in 405 patients who had completed 6 – 18 months of oral anticoagulant treatment following a first ever unprovoked venous thromboembolism (VTE). VTE occurred in significantly fewer patients receiving aspirin (6.6%/year vs 11.2%/year for placebo), but there were no significant differences in incidence of pulmonary embolism or in mortality. Major bleeding was uncommon and did not differ between groups.
PMID: 22621626
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EINSTEIN–PE Investigators, Büller HR, Prins MH, Lensin AW, et al. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med. 2012; 366:1287-97. Randomized trial of 4832 patients with acute symptomatic pulmonary embolism found treatment with the oral factor Xa inhibitor rivaroxaban non-inferior to standard therapy with enoxaparin followed by oral vitamin K antagonists (events in 2.1% vs. 1.8%). Major bleeding was more common in the standard therapy group (1.1% vs 2.2%, p = .003).
PMID: 22449293
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Prevention with vena caval filters.

Decousus H, Leizorovicz A, Parent F, et al. A clinical trial of vena caval filters in the prevention of pulmonary embolism in patients with proximal DVT. N Engl J Med 1998; 338:409-15. All patients were anticoagulated and LMW and unfractionated heparin were equally effective. 4.8% of patients receiving anticoagulation alone had PE vs. 1.1% in filter + anticoagulation group at study day 12. There was no difference in rate of PE after anticoagulation was discontinued, but the filter group had significantly more recurrent DVT.
PMID: 9459643
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Mismetti P, Laporte S, Pellerin O, et al. Effect of a retrievable inferior vena cava filter plus anticoagulation vs anticoagulation alone on risk of recurrent pulmonary embolism: a randomized clinical trial. JAMA 2015; 313:1627-1635. This randomized, open-label, blinded trial compared anticoagulation with and without IVC filter placement in 399 patients admitted to the hospital with acute symptomatic pulmonary embolism with residual lower limb venous thrombosis plus at least one risk factor for severity (roughly ⅔ had evidence of right ventricular dysfunction).  Hemodynamic data were not included. Filter removal was attempted at 3 months and patients were followed for 6 months. They found no difference in the rate of recurrent thrombosis at 3 or 6 months.
PMID: 25919526
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Thromboendarterectomy for chronic thromboembolic disease

Mayer E, Jenkins D, Lindner J, et al. Surgical management and outcome of patients with chronic thromboembolic pulmonary hypertension: results from an international prospective registry. J Thorac Cardiovasc Surg 2011;141:702-10. This description of experience within an international, multi-institutional setting offers a comparison with the San Diego experience described in the article by Jamieson et al. Preoperative PVR was somewhat lower in this group, circulatory arrest time was the same, and one-year mortality was 7%. An interesting discussion, including a member of the San Diego group, follows the references.
PMID: 21335128

Jamieson SW, Kapelanski DP, Sakakibara N, et al. Pulmonary endarterectomy: experience and lessons learned in 1,500 cases. Ann Thorac Surg 2003; 76:1457-64. Summarizes entire UCSD experience with thromboendarterectomy. The most recent 500 cases (through 12/02) are discussed in greater detail. 30-day mortality in this group was 4.4%, which varied according to type of thrombotic lesion and preoperative hemodynamics.
PMID: 14602267
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Pulmonary embolism in pregnancy

Leung AN, Bull TM, Jaeschke R, et al. An official American Thoracic Society/Society of Thoracic Radiology clinical practice guideline: evaluation of suspected pulmonary embolism in pregnancy. Am J Respir Crit Care Med 2011; 184:1200-8. This clinical practice guideline is noteworthy for recommending V/Q scan as the initial step in diagnosis in pregnant women suspected of having PE who have no leg symptoms and a normal CXR. This recommendation is based primarily on the future malignancy risk posed to young mothers.
PMID: 22086989

Last Reviewed: June 2017