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Clinical Decision Rules for Excluding Pulmonary Embolism: A Meta-analysis

Wim Lucassen, MD; Geert-Jan Geersing, MD; Petra M.G. Erkens, MSc; Johannes B. Reitsma, MD, PhD; Karel G.M. Moons, MD, PhD; Harry Büller, MD, PhD; and Henk C. van Weert, MD, PhD
[+] Article and Author Information

From Academic Medical Center, Amsterdam, University Medical Center Utrecht, Utrecht, and University of Maastricht, Maastricht, the Netherlands.


Acknowledgment: The authors thank Faridi van Etten, clinical librarian, Academic Medical Center, for assistance in the literature search.

Grant Support: By the Dutch Heart Foundation (project 2006B237).

Potential Conflicts of Interest: Dr. Lucassen: Grant (money to institution): Dutch Heart Foundation. Dr. van Weert: Grant: Dutch Heart Foundation. Disclosures can also be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M11-0905.

Requests for Single Reprints: Wim Lucassen, MD, Department of General Practice, Academic Medical Center, J2-128, Box 22660, 1100 DD Amsterdam, the Netherlands; e-mail, w.a.lucassen@amc.uva.nl.

Current Author Addresses: Drs. Lucassen and van Weert: Department of General Practice, Academic Medical Center, Box 22660, Amsterdam 1100 DD, the Netherlands.

Drs. Geersing, Reitsma, and Moons: Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Box 85500, Utrecht 3508 GA, the Netherlands.

Ms. Erkens: Department of Family Medicine, University of Maastricht, Box 616, Maastricht 6200 MD, the Netherlands.

Dr. Büller: Department of Vascular Medicine, Academic Medical Center, Meibergdreef 9, Room F4-276, Amsterdam 1105 AZ, the Netherlands.

Author Contributions: Conception and design: W. Lucassen, G.J. Geersing, K.G.M. Moons, H. Büller, H.C. van Weert.

Analysis and interpretation of the data: W. Lucassen, G.J. Geersing, P.M.G. Erkens, J.B. Reitsma, K.G.M. Moons, H. Büller, H.C. van Weert.

Drafting of the article: W. Lucassen, G.J. Geersing, K.G.M. Moons, H.C. van Weert.

Critical revision of the article for important intellectual content: G.J. Geersing, P.M.G. Erkens, J.B. Reitsma, K.G.M. Moons, H. Büller, H.C. van Weert.

Final approval of the article: G.J. Geersing, P.M.G. Erkens, J.B. Reitsma, K.G.M. Moons, H. Büller, H.C. van Weert.

Provision of study materials or patients: H. Büller.

Statistical expertise: G.J. Geersing, J.B. Reitsma.

Obtaining of funding: H.C. van Weert.

Administrative, technical, or logistic support: P.M.G. Erkens, H. Büller, H.C. van Weert.

Collection and assembly of data: W. Lucassen, G.J. Geersing, P.M.G. Erkens, H. Büller.


Ann Intern Med. 2011;155(7):448-460. doi:10.7326/0003-4819-155-7-201110040-00007
Text Size: A A A

Background: Clinical probability assessment is combined with d-dimer testing to exclude pulmonary embolism (PE).

Purpose: To compare the test characteristics of gestalt (a physician's unstructured estimate) and clinical decision rules for evaluating adults with suspected PE and assess the failure rate of gestalt and rules when used in combination with d-dimer testing.

Data Sources: Articles in MEDLINE and EMBASE in English, French, German, Italian, Spanish, or Dutch that were published between 1966 and June 2011.

Study Selection: 3 reviewers, working in pairs, selected prospective studies in consecutive patients suspected of having PE. Studies had to estimate the probability of PE by using gestalt or a decision rule and verify the diagnosis by using an appropriate reference standard.

Data Extraction: Data on study characteristics, test performance, and prevalence were extracted. Reviewers constructed 2 × 2 tables and assessed the methodological quality of the studies.

Data Synthesis: 52 studies, comprising 55 268 patients, were selected. Meta-analysis was performed on studies that used gestalt (15 studies; sensitivity, 0.85; specificity, 0.51), the Wells rule with a cutoff value less than 2 (19 studies; sensitivity, 0.84; specificity, 0.58) or 4 or less (11 studies; sensitivity, 0.60; specificity, 0.80), the Geneva rule (5 studies; sensitivity, 0.84; specificity, 0.50), and the revised Geneva rule (4 studies; sensitivity, 0.91; specificity, 0.37). An increased prevalence of PE was associated with higher sensitivity and lower specificity. Combining a decision rule or gestalt with d-dimer testing seemed safe for all strategies, except when the less-sensitive Wells rule (cutoff value ≤4) was combined with less-sensitive qualitative d-dimer testing.

Limitations: Studies had substantial heterogeneity due to prevalence of PE and differences in threshold. Many studies (63%) had potential bias due to differential disease verification.

Conclusion: Clinical decision rules and gestalt can safely exclude PE when combined with sensitive d-dimer testing. The authors recommend standardized rules because gestalt has lower specificity, but the choice of a particular rule and d-dimer test depend on both prevalence and setting.

Primary Funding Source: Dutch Heart Foundation.

Figures

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Appendix Figure 1.
Literature search and selection.

CDR = clinical decision rule; DVT = deep venous thrombosis; PE = pulmonary embolism; PERC = Pulmonary Embolism Rule-out Criteria.

* Listed is the primary reason for exclusion of each study.

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Appendix Figure 2.
Quality of included studies.

QUADAS = Quality Assessment of Diagnostic Accuracy Studies.

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Figure 1.
Forest plot of sensitivity of gestalt and different decision rules.
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Figure 1—
Continued

Studies are ordered from low to high prevalence of pulmonary embolism. PERC = Pulmonary Embolism Rule-out Criteria; PIOPED = Prospective Investigation of Pulmonary Embolism Diagnosis.

* Proportion of patients with pulmonary embolism (N) who had a positive test result (n).

† Validation study.

‡ Derivation study.

§ Study excluded from meta-analysis because of high cutoff value.

|| Study with revised Geneva dichotomized cutoff.

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Figure 2.
Forest plot of specificity of gestalt and different decision rules.
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Figure 2—
Continued

Studies are ordered from low to high prevalence of pulmonary embolism. PERC = Pulmonary Embolism Rule-out Criteria; PIOPED = Prospective Investigation of Pulmonary Embolism Diagnosis.

* Proportion of patients without pulmonary embolism (N) who had a negative test result (n).

† Validation study.

‡ Derivation study.

§ Study excluded from meta-analysis because of high cutoff value.

|| Study with revised Geneva dichotomized cutoff.

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Appendix Figure 3.
Relationship between prevalence of pulmonary embolism and sensitivity, as derived from the bivariate model.

Rule type and log-transformed prevalence were added as covariates.

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Appendix Figure 4.
Relationship between prevalence of pulmonary embolism and specificity, as derived from the bivariate model.

Rule type and log-transformed prevalence were added as covariates.

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Figure 3.
Forest plot of the failure rate of gestalt and the different decision rules.

* Patients with symptomatic and confirmed venous thromboembolism during follow-up (n) divided by the total number of patients with negative results on both rule or gestalt and d-dimer testing (N).

† Validation study.

‡ Derivation study.

§ Study excluded from meta-analysis because of high cutoff value.

|| Study with revised Geneva dichotomized cutoff.

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Figure 4.
Forest plot of the efficiency of gestalt and different decision rules.

* Patients with a negative result on both the rule or gestalt and d-dimer testing (n) divided by all included patients (N).

† Validation study.

‡ Derivation study.

§ Study excluded from meta-analysis because of high cutoff value.

|| Study with revised Geneva dichotomized cutoff.

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Clinical decision rules for excluding pulmonary embolism
Posted on October 28, 2011
Giuliano, Giusti, M.D., Anna Coerezza, Giulia Cernuschi
Internal Medicine 2, Department of Clinical Sciences, University of Milan, Luigi Sacco Hospital via
Conflict of Interest: None Declared

TO THE EDITOR: We read with great interest the article by Lucassen and Colleagues (1) on the clinical decision rules for excluding pulmonary embolism (PE). The authors concluded that clinical prediction rules and clinical judgment can safely exclude PE only when combined with D-dimer testing. The post-test probability considered safe to rule out PE was set at 2% and the maximum upper confidence limit was 2.7% (1). We wonder whether this conclusion can be routinely applied to the clinical practice. Indeed, in most of the cited studies on PE diagnosis, negative clinical follow up at 3-6 months or positive findings on imaging, particularly computed tomography (CT), are used as reference standard for excluding or confirming PE. While this strategy can allow to derivate the sensitivity of the tests, it is less useful to evaluate their specificity (i.e. the false positive rate). To this regard Stein and coworkers reported that 42% of patients at low clinical risk score with a positive CT (2) for PE can be considered as false positive results. Moreover, segmentarian and sub- segmentarian PE, occur more frequently in non high risk patients (3) and some authors have questioned the need of the anticoagulant therapy in these patients, as they show a better prognosis (4). Thus, inferring form the cited literature (1) that i) a post test probability of PE taking into account that a low scale risk score or clinical judgment may vary between 4-9%; ii) about 40% of these patients could be considered as false positive results of imaging studies; iii) the mortality rate in these patients can be considered about 15% (5), we could speculate that a patient at low risk of PE by clinical risk score or clinical judgment, without assessing D-dimer, could have a mortality rate between 0.36 and 1%, thus corresponding to the mortality rate reported for patients treated with anticoagulants (4). Maybe we should ask whether we prefer to consider diagnostic accuracy (how many PE diagnosis are missed), rather mortality and morbidity rate associated with a missed diagnosis as our primary outcome in the clinical practice. As an example, a 17 years old girl came in our emergency department for acute dyspnea onset, atypical chest pain and anxiety. Her parameters were stable, blood gas analyses showed respiratory alkalosis without hypoxia. After the medical visit and some benzodiazepines she felt much better. Should we had to request a D-dimer testing?

REFERENCES

(1)

Author's Response
Posted on November 18, 2011
Wim, Lucassen, MD, Harry Buller, MD, PhD, Henk C. van Weert, MD, PhD
From Academic Medical Center, Amsterdam, University Medical Center Utrecht, Utrecht, and University
Conflict of Interest: None Declared

Dear colleague,

Thank you very much for your interesting remarks. You mention three important issues. Firstly, you question whether a D- dimer-test is needed in low-probability patients, secondly you mention the issue of the false-positivity of CT-scanning in low-risk patients and finally you question the adequacy of the outcome measure.

Stein reported that among patients with a low clinical probability of pulmonary embolism, 42% of the CT-scans were false-positive (1). Stein however included all patients with a Wells-score <2, without using a D- dimer test. In the Christopher-study (2) nearly 50% of low-risk patients (Wells-score ?4) had a negative D-dimer test and were not referred for CT- scanning. Using a D-dimer test in combination with a clinical decision rule will significantly reduce the number of low-risk patients referred for CT-scanning. Choosing the Wells rule with a high cut-off (Wells?4) will increase specificity and further decrease the number of referred patients. In our meta-analysis we showed the safety of such a strategy.

Moreover, Stein is mentioning the imperfect reference standard as one of the weaknesses of his study and finally we don't know the meaning of a false-positive CT-scan: is it due to an incorrect assessment of the radiologist or is it due to diagnosing subsegmental PE?

However, we agree that false-positivity of CT-scanning is a problem in deciding on treatment for PE. With the introduction of multi-detector row CT the number of patients with subsegmental pulmonary embolism is increasing (3). The clinical significance and natural course of subsegmental embolism however is unknown and the management of such patients is not evidence based (4).

We think that using mortality and morbidity as an outcome-measure clinically speaking is an adequate outcome measure and therefore the failure-rate (number of missed PE-cases in follow-up period) used as primary outcome measure is generally accepted in pulmonary embolism research.

In conclusion, in our meta-analysis we showed that if a suspicion for PE is really raised (not like in the case presented) a negative test result from any clinical decision rule is insufficient for decision making. The combination of clinical decision rule and D-dimer test is the best tool to stratify patients between safely withholding anticoagulants or referring for CT.

Wim Lucassen

Harry Buller

Henk van Weert

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