Adult

Pulmonary Embolism

Algorithms for Managing Suspected Pulmonary Embolism

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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van der Hulle T,  Cheung WY, Kooij S,  et al. Simplified diagnostic management of suspected pulmonary embolism (the YEARS study): a prospective, multicentre, cohort study. Lancet. 2017; 390(10091):289-297. Prospective, multicenter cohort study including 3,616 consecutive patients with suspected pulmonary embolism combined use of the YEARS criteria (clinical signs of DVT, hemoptysis, and whether PE was the most likely diagnosis) with D-dimer. PE was excluded if the YEARS criteria was 0 and D-dimer <1000 or the YEARS criteria was 1 and D-dimer <500. Of the 2946 patients ruled out for PE, only 18 (0.61%) were diagnosed with DVT/PE by 3 months follow up. This approach resulted in 14% fewer CTPA studies than if screening with the Well’s criteria and D-dimer cutoff of 500 had been used.

PMID: 28549662

Kearon C, de Wit K, Parpia S, et al. Diagnosis of pulmonary embolism with d-dimer adjusted to clinical probability. N Engl J Med. 2019; 381:2125-2134. Retrospective study of 2017 patients. In patients with a low clinical pre-test probability (Wells score of 0 to 4) and a d-dimer level less than 1000 ng/ml, none had venous thromboembolism at 3 month followup. Use of this algorithm would reduce the number of chest-imaging studies performed on patients with suspected pulmonary embolism.

PMID: 31774957

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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

Van der Pol L, Tromeur C, Bistervels I, et al.  Pregnancy-adapted YEARS algorithm for diagnosis for suspected pulmonary embolism. N Engl J Med. 2019; 380:1139-1149. The study used a d-dimer cut-off adjusted to whether the patient had 0 vs. 1 of the 3 YEARS criteria, as well as ultrasound as firstline test rather than CT if DVT symptoms present. The algorithm safely ruled out PE across all three trimesters of pregnancy and, assuming all patients with suspected PE would otherwise have undergone CT, reduced the number of scans by 39%. CT angiogram was avoided in 65% of 1st trimester patients and 32% in the 3rd trimester.

PMID: 30893534

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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

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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Chaudhury P, Gadre SK, Schneider E, et al. Impact of multidisciplinary pulmonary embolism response team availability on management and outcomes. Am J Cardiol 2019; 124:1465-69. This single-center retrospective study of outcomes before and after institution of PERT is cited by advocates for use of response teams. Among 769 consecutive inpatients with PE, PERT-era patients had significantly lower rates of major bleeding, shorter time to therapeutic anticoagulation, decreased use of IVC filters, and decrease in 30 day/inpatient all cause mortality. Of note, the PERT team was activated in only 15% of patients with intermediate or high-risk PE. 

PMID: 31495443

Anticoagulation

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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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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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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