Introduction
Methods
Results
Discussion
Limitations
Conclusion

INTRODUCTION

Pulmonary embolism (PE) is a deadly disease, often with rapid onset and ensuing precipitous decline.¹ It is, therefore, imperative for physicians to be able to safely rule out PE. The complicated nature of the workup has led to numerous publications describing the diagnostic workup of potential PE.^2-11 The American College of Physicians recommends CTPA as the first diagnostic test for patients who have a high pretest probability (PTP) of PE,⁹ with D-dimer testing not recommended as a stand-alone test to rule out PE in this group. This is also the guideline of other societies, including the American College of Radiology,¹⁰ the American Academy of Family Physicians,¹² and websites such as UpToDate.¹¹ The American College of Emergency Physicians is an exception, having a Level C recommendation to perform two negative tests to rule out PE in high PTP patients.⁸ In this study, we sought to validate this guideline by testing the ability of a negative CTPA with a negative D-dimer to rule out PE in high-risk patients.

METHODS

We used data from a previous prospective, observational study conducted in 12 emergency departments (ED) in the United States from July 1, 2003, until November 30, 2006, using methodology previously described in a report validating the Pulmonary Embolism Rule-out Criteria (the PERC rule).¹³ This study was approved by the institutional review boards for the conduct of human subject research at all institutions. Of note, the original study included a New Zealand site; however, given the potential for practice variation between U.S. sites and a single NZ site, we limited our analysis to the U.S. sites. This is consistent with previously published work from this dataset.^14,15

Patients were enrolled in the ED and included if they had signs or symptoms that the treating physician interpreted as sufficient to warrant testing for PE (at least one of the following: D-dimer blood test, CTPA, or ventilation-perfusion scan) and they indicated willingness to participate by process of informed consent. Patients were excluded if they were already being treated for venous thromboembolic disease (PE or deep venous thrombosis [DVT]) with therapeutic levels of anticoagulation as well as patients with CTPA, ventilation-perfusion scintillation, or duplex Doppler testing performed within the preceding seven days that was diagnostic of PE or DVT. Also excluded were patients with overt circulatory shock or respiratory failure, as well as those with social circumstances that have been highly predictive of loss to follow-up, including homelessness or imprisonment.

All clinical data, including signs, symptoms, and variables (including Wells score criteria), were entered before recording the results of final PE testing while patients were in the ED. Using the standard definitions of negative, Liatest, VIDAS, and MDA D-dimers were considered negative at concentrations of <500 ng / ml, Biopool Minutex at <250 ng/ mL, Hemosil at <244 ng / mL, and the advanced D-dimer at <1.6 lg/ mL. The outcome of interest was a diagnosis of acute PE during the index ED visit or within 45 days of the patient’s ED evaluation. We considered patients to have PE if they were evaluated for possible PE in the ED, and had radiologic confirmation of the diagnosis of either PE or DVT during the index visit or within 45 days of the index visit, or if they died of PE during the 45-day follow-up period. Confirmatory imaging included CTPA or conventional angiography showing a pulmonary arterial or deep venous filling defect interpreted as positive for PE or DVT, high-probability V/Q scan, or positive venous ultrasound consistent with DVT in the proximal or distal vasculature of the upper or lower extremities. All imaging results were based on the dictated report of board-certified attending radiologists not affiliated with (and blinded to) the study. Patients were followed for 45 days using a previously validated, published methodology that included chart review and telephone follow-up.^13,16

Population Health Research Capsule

What do we already know about this issue?

Pulmonary embolism (PE) is a deadly disease, and in patients with high pretest probability (PTP) of PE, computed tomography pulmonary angiography (CTPA) can often miss PE.

What was the research question?

Is negative CTPA along with a negative D-dimer sufficient to rule out PE in high PTP patients?

What was the major finding of the study?

In patients with high PTP of PE, neither negative CTPA nor negative CTPA plus negative D-dimer is sufficient to rule out PE.

How does this improve population health?

In patients with high PTP for PE, more aggressive workup strategies may be required despite initial negative testing.

Testing threshold was set at 1.8% based on the Pauker and Kassirer method.^17,18 Proportions are described with confidence intervals (CI) using mid-p exact calculations. We used Microsoft Excel for all calculations.

RESULTS

A total of 7,940 patients were prospectively enrolled in the original study,¹³ of whom 257 had Wells score > 6 and thus had high PTP. The table shows baseline characteristics of these patients. The overall rate of PE in these high PTP patients was 37.4% (95% CI [31.5%–43.6%]). Of the 205 high PTP patients who underwent CTPA, four had CTs that were either incomplete or indeterminate. Of the remaining 201 valid CTPAs, 130 were negative for PE. Sixteen of these 130 patients, or 12.3% (95% CI [7.4%–19.5%]), were ultimately positive for PE (Figure 1a.). One of these 16 patients had an intermediate V/Q scan and a proximal clot on extremity Doppler. Seven patients had DVTs found on CT venogram. An additional two had proximal DVTs on extremity Doppler, and one had distal DVT on extremity Doppler. The remaining patients were diagnosed on follow-up.

Eighty-two of the 257 high PTP patients underwent both CTPA and D-dimer (Figure 1b). Sixteen of these patients had negative CTPA and negative D-dimer, and two of these 16 (12.5% [95% CI {2.2%–40.0%}]) were positive for PE. One of these patients had DVT on CT venogram, and the other was diagnosed on follow-up.

DISCUSSION

This analysis was undertaken to determine if current guidelines can rule out PE in high PTP patients. Our analysis suggests that neither negative CTPA (by itself) nor negative CTPA with negative D-dimer can sufficiently rule out PE in high-risk patients. This is in line with previous research. Multiple studies have shown that CTPAs miss some PE.^19-22 In the landmark PIOPED-II trial, the sensitivity of CTPA was 83%; moreover, in the subset of high-risk patients, 40% of patients with negative CTPA were diagnosed with PE or DVT.²³ Moreover, our analysis suggests that adding a negative D-dimer to a negative CTPA may still be insufficient to rule out PE in high-risk patients.

This appears to be in contrast to literature suggesting that a D-dimer and CTPA algorithm is safe.^5,7 However, studies that evaluated these algorithms included relatively small numbers of high-risk (Wells score > 6) patients, so the apparent safety of the CTPA plus D-dimer strategy may be influenced by the much larger numbers of non-high-risk patients in these studies. When stratifying for high-risk patients, all diagnostic tests have much lower abilities to rule out PE.^3,6,23,24 This is supported by a recent study in which even 64-slice CTPA missed a significant number of PEs in high-risk patients,²⁵ most of whom were diagnosed by additional imaging within the index visit (with the other few diagnosed during three-month clinical follow-up).²⁵ Our study shows that in patients with high Wells score, not only is a negative CTPA insufficient to rule out PE, but also that a negative CTPA along with a negative D-dimer still misses a substantial number of PEs.

It is possible that newer CTs with more slices are more sensitive at picking up PEs, and therefore would yield fewer false-negative CTs. However, a Bayesian calculation using meta-analysis data of prevalence of PE in high-probability patients²⁶ and CTPA sensitivity and specificity¹⁹ also yields an unacceptably high miss rate of 10.4% (95% credible region 6.0%– 15.3%) – similar to our empirical findings of a miss rate of 12.3% (95% CI [7.4%–19.5%]). In other words, to go from a PTP of 37.4% (this prevalence of PE in our cohort was lower than in Ceriani’s²⁶ meta-analysis) to a post-test probability of 1.8%, the negative likelihood ratio (LR[−]) of the test would have to be lower than 0.03. However, a CT sensitivity of 88.9% and specificity of 94.6% (as per the meta-analysis by Hogg et al¹⁹) yields a LR(−) of only 0.12; other meta-analyses would yield even higher LR(−)s, and therefore make PEs even harder to rule out.^20-22

Furthermore, a recent study by Moores et al.²⁵ looked prospectively at outcomes in high-risk patients who underwent 64-slice CTPA. The study found that among patients with high Wells score and negative CTPA, 5.2% had PE or DVT. Therefore, even the newest CT scanners miss an unacceptable amount of PEs in high PTP patients.

It may be that some of these “missed PEs” are subsegmental PEs (SSPE). There is debate as to whether SSPEs need to be treated. On one hand, many SSPEs may not be PEs at all but radiological artifacts,²⁷ and their clinical significance may be limited.²⁸ On the other hand, patients with SSPE appear to have similar recurrence rates to those with proximal PEs, and have significantly higher mortality than those without PE.²⁹ A finding of SSPE may require calculations of risks and benefits regarding anticoagulation, especially in those at increased risk of bleeding.^30,31

The “test threshold” is meant to balance the benefits of testing (e.g., diagnoses made and treated) with the risks of testing (e.g., for CT, radiation exposure, contrast nephropathy, allergic reactions, false positive results) and to identify patients below which testing is more likely to cause harm than benefit.^17,18 We used a threshold of 1.8%, which is the same threshold calculated by Kline et al.,¹⁸ and similar to the test threshold published by Lessler et al. (1.4%).³² These thresholds are also similar to the “acceptable” miss rate of pulmonary imaging, determined by the false negative rate of catheter pulmonary angiography. We acknowledge that individual physicians and patients may have their own clinical thresholds for the percentage of PE that are acceptable to miss, and we also acknowledge that the test threshold may vary over time as technology changes and risks of testing (and PE) are recalculated. However, we believe that 1.8% is a reasonable threshold that, at the least, should be reached with diagnostic testing.

LIMITATIONS

The results of this study must be interpreted within the context of its design. Our analysis comes from data from a large, multicenter study, performed in academic and community centers, resulting in a heterogeneous population. The study was observational and noninterventional, such that we believe the results represent the real world, but probably should not be compared or contrasted to studies that purport to follow a rigid study protocol. The diagnostic criterion standard for this study was PE (or DVT) within 45 days of the index visit that was detected by standard care processes. While it is possible that a PE or DVT found during follow-up is truly a new thromboembolic event and that negative workup in the ED truly was negative at the time, it is standard in the literature to use diagnosis of PE or DVT during follow-up as the gold standard diagnostic criterion for negative workup in the ED. ^{3,5,7,19,23,25,29,33-40} The original study did not have the resources to perform radiologic testing to monitor asymptomatic patients for PE or DVT. It remains possible that a few patients had a PE or DVT and went undiagnosed during the follow-up period, and these patients were incorrectly classified as true-negatives.

Since this was a multicenter trial, multiple different D-dimers were used. We feel this strengthens the generalizability of our findings. However, although our data analysis did not suggest this, it is possible that some assays are more prone to false negatives than others.

Despite the fact a large number of patients were enrolled, relatively few patients had a high Wells score. This is consistent with observations from our prior work.^15,33 The relatively small number of patients with Wells score > 6 may be why our empiric data revealed only 16 high-risk patients with negative CTPA and negative D-dimer. However, while this particular sample size led to a wide confidence interval, this 95% CI still did not cross the 1.8% threshold at which further workup for PE can be stopped.^18,32,41

CONCLUSION

Our study suggests that in patients with high pre-test probability for PE, a negative CT should be interpreted with caution, and that even two high-sensitivity tests may be insufficient to rule out PE in these high-risk patients. Further studies should evaluate long-term outcomes in high PTP patients – in particular, those who have been “ruled out” by diagnostic testing.

Footnotes

Section Editor: Christopher Tainter, MD

Full text available through open access at http://escholarship.org/uc/uciem_westjem

Address for Correspondence: Murtaza Akhter, MD, University of Arizona College of Medicine–Phoenix, Maricopa Integrated Health System, ABC-1 Bldg. Room 319, 425 N. 5th Street, Phoenix, AZ 85004-2157. Email: murtazaakhter@gmail.com. 5 / 2018; 19:487 – 493

Submission history: Revision received August 26, 2017; Submitted October 1, 2017; Accepted October 16, 2017

Conflicts of Interest: By the WestJEM article submission agreement, all authors are required to disclose all affiliations, funding sources and financial or management relationships that could be perceived as potential sources of bias. No author has professional or financial relationships with any companies that are relevant to this study. Dr. Akhter has a career development grant from the Emergency Medicine Foundation for his basic science research in traumatic brain injury. Dr. Bhattarai has no conflicts of interest. Dr. Courtney’s institution has received grant funding from the National Institutes of Health for investigator-initiated research. Dr. Kabrhel reports grant money to Massachusetts General Hospital to conduct research conceived and sponsored by Diagnostica Stago, Siemens Healthcare, and Janssen. Dr. Kline’s institution has received grant funding from the National Institutes of Health for investigator-initiated research; Dr. Kline also reports grant money to Carolinas Medical Center and Indiana University to conduct research conceived and sponsored by Roche, Janssen, and Pfizer.

REFERENCES

1. Wood KE. Major pulmonary embolism: review of a pathophysiologic approach to the golden hour of hemodynamically significant pulmonary embolism. Chest. 2002;121(3):877-905.

2. Gandara E, Wells PS. Diagnosis: use of clinical probability algorithms. Clin Chest Med. 2010;31(4):629-39.

3. Righini M, Le Gal G, Aujesky D, et al. Diagnosis of pulmonary embolism by multidetector CT alone or combined with venous ultrasonography of the leg: a randomised non-inferiority trial. Lancet. 2008;371(9621):1343-52.

4. Goekoop RJ, Steeghs N, Niessen RWLM, et al. Simple and safe exclusion of pulmonary embolism in outpatients using quantitative D-dimer and Wells’ simplified decision rule. Thromb Haemost. 2007;97(1):146-50.

5. Van Belle A, Büller 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(2):172-9.

6. Roy PM, Colombet I, Durieux P, et al. Systematic review and meta-analysis of strategies for the diagnosis of suspected pulmonary embolism. BMJ. 2005;331(7511):259.

7. Perrier A, Roy P-M, Sanchez O, et al. Multidetector-row computed tomography in suspected pulmonary embolism. N Engl J Med. 2005;352(17):1760-8.

8. Fesmire FM, Brown MD, Espinosa JA, et al. Critical issues in the evaluation and management of adult patients presenting to the emergency department with suspected pulmonary embolism. Ann Emerg Med. 2011;57(6):628-52.e75.

9. Raja AS, Greenberg JO, Qaseem A, et al. Evaluation of patients with suspected acute pulmonary embolism: best practice advice from the Clinical Guidelines Committee of the American College of Physicians. Ann Intern Med. 2015;163(9):701-11.

10. Bettmann MA, White RD, Woodard PK, et al. ACR Appropriateness Criteria® Acute Chest Pain—Suspected Pulmonary Embolism. J Thorac Imaging. 2012;27(2):W28-31.

11. Thompson BT. Clinical presentation, evaluation, and diagnosis of the adult with suspected acute pulmonary embolism – UpToDate. Available at: https://www.uptodate.com/contents/clinical-presentation-evaluation-and-diagnosis-of-the-nonpregnant-adult-with-suspected-acute-pulmonary-embolism. Accessed on January 17, 2017.

12. Qaseem A, Snow V, Barry P, et al. Current diagnosis of venous thromboembolism in primary care: A clinical practice guideline from the American Academy of Family Physicians and the American College of Physicians. Ann Fam Med. 2007;5(1):57-62.

13. Kline JA, Courtney DM, Kabrhel C, et al. Prospective multicenter evaluation of the pulmonary embolism rule-out criteria. J Thromb Haemost. 2008;6(5):772-80.

14. Courtney DM, Kline JA, Kabrhel C, et al. Clinical features from the history and physical examination that predict the presence or absence of pulmonary embolism in symptomatic emergency department patients: results of a prospective, multicenter study. Ann Emerg Med. 2010;55(4):307-15.e1.

15. Kabrhel C, Mark Courtney D, Camargo CA, et al. Potential impact of adjusting the threshold of the quantitative D-dimer based on pretest probability of acute pulmonary embolism. Acad Emerg Med. 2009;16(4):325-32.

16. Kline JA, Johnson CL, Webb WB, et al. Prospective study of clinician-entered research data in the emergency department using an Internet-based system after the HIPAA Privacy Rule. BMC Med Inform Decis Mak. 2004;4:17.

17. Pauker SG, Kassirer JP. The threshold approach to clinical decision making. N Engl J Med. 1980;302(20):1109-17.

18. Kline JA. Further Illumination of the test threshold approach in the care of emergency department patients with symptoms of pulmonary embolism. Ann Emerg Med. 2010;55(4):327-30.

19. Hogg K, Brown G, Dunning J, et al. Diagnosis of pulmonary embolism with CT pulmonary angiography: a systematic review. Emerg Med J. 2006;23(3):172-8.

20. Safriel Y, Zinn H. CT pulmonary angiography in the detection of pulmonary emboli: a meta-analysis of sensitivities and specificities. Clin Imaging. ;26(2):101-5.

21. Hayashino Y, Goto M, Noguchi Y, et al. Ventilation-perfusion scanning and helical CT in suspected pulmonary embolism: meta-analysis of diagnostic performance. Radiology. 2005;234(3):740-8.

22. Van Beek EJ, Brouwers EM, Song B, et al. Lung scintigraphy and helical computed tomography for the diagnosis of pulmonary embolism: a meta-analysis. Clin Appl Thromb Hemost. 2001;7(2):87-92.

23. Stein PD, Fowler SE, Goodman LR, et al. Multidetector computed tomography for acute pulmonary embolism. N Engl J Med. 2006;354(22):2317-27.

24. Musset D, Parent F, Meyer G, et al. Diagnostic strategy for patients with suspected pulmonary embolism: A prospective multicentre outcome study. Lancet. 2002;360(9349):1914-20.

25. Moores L, Kline J, Portillo AK, et al. Multidetector computed tomographic pulmonary angiography in patients with a high clinical probability of pulmonary embolism. J Thromb Haemost. 2016;14(1):114-20.

26. Ceriani E, Combescure C, Le gal G, et al. Clinical prediction rules for pulmonary embolism: A systematic review and meta-analysis. J Thromb Haemost. 2010;8(5):957-70.

27. Ikesaka R, Carrier M. Clinical significance and management of subsegmental pulmonary embolism. J Thromb Thrombolysis. 2015;39(3):311-4.

28. Carrier M, Righini M, Wells PS, et al. Subsegmental pulmonary embolism diagnosed by computed tomography: Incidence and clinical implications. A systematic review and meta-analysis of the management outcome studies. J Thromb Haemost. 2010;8(8):1716-22.

29. Den Exter PL, Van Es J, Klok FA, et al. Risk profile and clinical outcome of symptomatic subsegmental acute pulmonary embolism. Blood. 2013;122(7):1144-9.

30. Konstantinides SV, Torbicki A, Agnelli G, et al. 2014 ESC guidelines on the diagnosis and management of acute pulmonary embolism. Eur Heart J. 2014;35(43):3033-69.

31. Raskob GE. Importance of subsegmental pulmonary embolism. Blood. 2013;122(7):1094-5.

32. Lessler AL, Isserman JA, Agarwal R, et al. Testing Low-Risk Patients for Suspected Pulmonary Embolism: A Decision Analysis. Ann Emerg Med. 2010;55(4):316-26.e1.

33. Kabrhel C. Outcomes of high pretest probability patients undergoing d-dimer testing for pulmonary embolism: a pilot study. J Emerg Med. 2008;35(4):373-7.

34. 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(23):2743.

35. Wells PS, Anderson DR, Rodger M, et al. Derivation of a simple clinical model to categorize patients probability of pulmonary embolism: increasing the models utility with the SimpliRED D-dimer. Thromb Haemost. 2000;83(3):416-20.

36. 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(2):98-107.

37. Hendriksen JMT, Geersing G-J, Lucassen WAM, et al. Diagnostic prediction models for suspected pulmonary embolism: systematic review and independent external validation in primary care. BMJ. 2015(351):4438.

38. Kabrhel C, McAfee AT, Goldhaber SZ. The contribution of the subjective component of the Canadian Pulmonary Embolism Score to the overall score in emergency department patients. Acad Emerg Med. 2005;12(10):915-20.

39. Kline JA, Nelson RD, Jackson RE, et al. Criteria for the safe use of D-dimer testing in emergency department patients with suspected pulmonary embolism: A multicenter US study. Ann Emerg Med. 2002;39(2):144-52.

40. Ljungqvist M, Söderberg M, Moritz P, et al. Evaluation of Wells score and repeated D-dimer in diagnosing venous thromboembolism. Eur J Intern Med. 2008;19(4):285-8.

41. Kline JA, Mitchell AM, Kabrhel C, et al. Clinical criteria to prevent unnecessary diagnostic testing in emergency department patients with suspected pulmonary embolism. J Thromb Haemost. 2004;2(8):1247-55.

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