Pulmonary Embolism

Diagnosis without use of chest CT scans

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. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=2332918&query_hl=24&itool=pubmed_docsum

Wells PS, Ginsberg JS, Anderson DR, et al.Use of a clinical model for safe management of patients with suspected pulmonary embolism. Ann Intern Med 1998;129:997-1005. Study used a "minimally invasive" approach to managing patients with suspected PE, emphasizing use of serial dopplers rather than PA grams in patients with a non-diagnostic initial work-up. Approach is comparable to the 1999 ATS guidelines; it does not include CT angiography. A particular strength of the study was the use of set criteria to establish clinical suspicion. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=9867786

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. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11453709

 Studies suggesting chest CT alone is sufficient to evaluate for PE

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%. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15858185&query_hl=24&itool=pubmed_docsum 

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. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=16403929&query_hl=21&itool=pubmed_docsum

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) http://www.ncbi.nlm.nih.gov/pubmed/18165667?ordinalpos=34&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum

Studies suggesting chest CT alone is not sufficient to evaluate for PE

Musset D, Parent F, Meyer G, et al. Diagnostic strategy for patients with suspected pulmonary embolism: a prospective multicenter outcome study. Lancet 2002;360:1914-20 This prospective cohort study found the combination of a good quality negative single-row-detector CT and negative lower extremity ultrasound safely excluded PE in outpatients with low or moderate clinical probability (0.8% diagnosed with PE during follow-up). Among inpatients, 4.8% with negative CT and ultrasound were diagnosed with PE, or possibly had a PE, during follow-up.  Of note, 15% of patients diagnosed with PE had a negative CT but positive ultrasound.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12493257

Stein PD, Fowler SE, Goodman LR, et al. Multidetector computed tomography for acute pulmonary embolism.  N Engl J Med 2006; 354:2317-27. The much-anticipated 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 positive 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. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=16738268&query_hl=24&itool=pubmed_docsum

Other diagnostic studies

Oudkerk M, van Beek EJ, Wielopolski P, et al. Comparison of contrast-enhanced magnetic resonance angiography and conventional pulmonary angiography for the diagnosis of pulmonary embolism: a prospective study. Lancet 2002;359:1643-7.  MRA is a potentially attractive alternative in the substantial number of patients with a non-diagnostic work-up and a contraindication to CT angiogram. This study included 118 unselected patients with non-diagnostic perfusion scans who all underwent MRA and PA-grams.  MRA had a sensitivity of 77% and specificity 98% with higher sensitivity for central clot. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12020524

Nicod P, Peterson K, Levine M, et al. Pulmonary angiography in severe chronic pulmonary hypertension. Ann Intern Med 1987;107:565-8. This study established the safety of angiography in patients with chronic, severe pulmonary hypertension. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=3631791

Treatment

Schulman S, Granqvist S, Holmstrom M, et al. The duration of oral anticoagulation after a second episode of venous thromboembolism. N Engl J Med 1997; 336:393-8. Randomized trial comparing anticoagulation for 6 months compared to indefinitely in patients with a history of recurrent embolism (including idiopathic and with risk factors). Recurrent thromboembolism occurred in 21% of patients in the 6-month group and in 2.7% of the indefinite group after 4 yrs of f/u. Major bleeding occurred in 5% of patients, of whom 18% died. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=9010144

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 life-long anti-coagulation. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12834314

Ridker PM, Goldhaber SZ, Danielson E, et al. Long-term, low-intensity warfarin therapy for the prevention of recurrent venous thromboembolism. N Engl J Med 2003; 348:1425-34. The PREVENT study is often cited as the basis for using chronic low-dose anticoagulation to prevent recurrence of idiopathic venous thromboembolism following initial full course of treatment, particularly in patients with erratic INR results. The study compared placebo to target INR of 1.5 to 2.0 in 508 patients and found higher recurrence in the placebo than the warfarin group (7.2 vs. 2.6/100 patient-years). There was no significant difference in major hemorrhage events between groups. http://www.ncbi.nlm.nih.gov/pubmed/12601075?ordinalpos=258&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum

Kearon C, Ginsberg JS, Kovacs MJ, et al. Comparison of low-intensity warfarin therapy with conventional-intensity warfarin therapy for long-term prevention of recurrent venous thromboembolism. N Engl J Med 2003; 349:631-9. Findings of the ELATE study suggest some advantage to conventional warfarin dosing. ELATE randomized 738 patients following treatment of idiopathic venous thromboembolism to either long-term warfarin with target INR of 1.5 to 1.9 or to a target of 2.0 to 3.0 and found a modest reduction in recurrent thromboembolic events in the conventional group (0.7 vs. 1.9/100 person-years). The 2 groups had similar risk of major bleeding, and this study is cited by advocates for conventional dosing for long-term prophylaxis in this population, particularly among patients with consistent warfarin dose requirements. http://www.ncbi.nlm.nih.gov/pubmed/12917299?ordinalpos=61&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum

Konstantinides S, Geibel A, Heusel G, et al. Heparin plus altepase 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 those opposed to 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. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12374874

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. This is the only randomized trial involving filters. All patients were aniticoagulated 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. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=9459643

Thromboendarterectomy for chronic thromboembolic disease

Snyder WA, Kent DC, Baisch BF. Successful endarterectomy of chronically occluded pulmonary artery: clinical report and physiologic studies. J Thorac Cardiovasc Surg 1963; 45:482-9. This, and the Moser article below, is the first reports of the procedure. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=13993170

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. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14602267