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Keywords:

  • computed tomography;
  • diagnosis;
  • management studies;
  • pulmonary embolism;
  • subsegmental

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Disclosure of Conflict of Interests
  9. References
  10. Supporting Information

Summary.  Background: Multiple-detectors computed tomographic pulmonary angiography (CTPA) has a higher sensitivity for pulmonary embolism (PE) within the subsegmental pulmonary arteries as compared with single-detector CTPA. Multiple-detectors CTPA might increase the rate of subsegmental PE diagnosis. The clinical significance of subsegmental PE is unknown. We sought to summarize the proportion of subsegmental PE diagnosed with single- and multiple-detectors CTPA and assess the safety of diagnostic strategies based on single- or multiple-detectors CTPA to exclude PE. Patients and methods: A systematic literature search strategy was conducted using MEDLINE, EMBASE and the Cochrane Register of Controlled Trials. We selected 22 articles (20 prospective cohort studies and two randomized controlled trials) that included patients with suspected PE who underwent a CTPA and reported the rate of subsegmental PE. Two reviewers independently extracted data onto standardized forms. Results: The rate of subsegmental PE diagnosis was 4.7% [95% confidence interval (CI): 2.5–7.6] and 9.4 (95% CI: 5.5–14.2) in patients that underwent a single- and multiple-detectors CTPA, respectively. The 3-month thromboembolic risks in patients with suspected PE and who were left untreated based on a diagnostic algorithm including a negative CTPA was 0.9% (95% CI: 0.4–1.4) and 1.1% (95% CI: 0.7–1.4) for single- and multiple-detectors CTPA, respectively. Conclusion: Multiple-detectors CTPA seems to increase the proportion of patients diagnosed with subsegmental PE without lowering the 3-month risk of thromboembolism suggesting that subsegmental PE may not be clinically relevant.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Disclosure of Conflict of Interests
  9. References
  10. Supporting Information

The diagnosis of pulmonary embolism (PE) remains a common challenge confronting physicians in daily clinical practice. PE is considered in the differential diagnosis of many clinical presentations and in a wide variety of clinical settings.

Ventilation-perfusion lung scanning has been the non-invasive imaging procedure of choice in patients with suspected PE for many years. However, a majority of patients with suspected PE undergoing a ventilation-perfusion scan have a non-diagnostic examination (low or intermediate probability of PE) [1,2]. More recently, the computed tomographic pulmonary angiography (CTPA) has been introduced as an alternative non-invasive test. A CTPA provides a clear result (either positive or negative for PE) and possibly an alternative diagnosis to explain the patient’s symptoms. Multiple-detectors CTPA has a higher sensitivity for PE as compared with single-detector CTPA [3–6]. In particular, multiple-detectors CTPA allows better visualization of segmental and subsegmental pulmonary arteries [3,4], hence the proportion of patients with suspected PE in whom isolated subsegmental thrombus are reported may be higher using multiple-detectors CTPA compared with single-detector CTPA. A proportion of isolated subsegmental PE as high as 30% has previously been reported [7].

The clinical significance of subsegmental PE is unknown [5,7,8]. In particular, it is unclear whether the risk benefit ratio of anticoagulant therapy is favorable in such patients. In the PIOPED study, PE limited to subsegmental pulmonary arteries on pulmonary angiography was most prevalent among patients with low-probability ventilation/perfusion scans [9]. According to PIOPED criteria, patients with subsegmental-only defects on a ventilation-perfusion scan are classified as having a ‘low probability’ ventilation perfusion scan [2]. Although some of them have subsegmental perfusion defects, patients with non-diagnostic (low or intermediate probability) ventilation-perfusion scans can be safely managed with serial lower extremities ultrasonography without anticoagulation [10,11]. Nonetheless, patients with isolated subsegmental PE detected on CTPA more commonly receive anticoagulation than not [7].

We sought to determine the rate of subsegmental PE detected by single- and multi-detectors CTPA. We also assessed the safety of diagnostic strategies based on CTPA by comparing the 3-month thromboembolic risk in patients left untreated after a diagnostic algorithm including a negative CTPA to rule out PE (single and multiple detectors).

Patients and methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Disclosure of Conflict of Interests
  9. References
  10. Supporting Information

Data sources and searches

We conducted a systematic literature search strategy to identify potential studies on MEDLINE (1950 to September week 4 2009), EMBASE (1980 to 2009 week 12), the Cochrane Register of Controlled Trials (2nd quarter of 2009) and OVID Health Star (1999 to February 2009) using the OVID interface. We also sought publications through a hand-search of potentially relevant journals and International Society of Thrombosis and Haemostasis conference proceedings for the past 6 years (2003–2009). We reviewed the references of included studies and narrative reviews for additional potential studies. The systematic search strategy is documented in Appendix S1 (on-line). The search was restricted to humans. There were no restrictions on language, publication year or type of publication.

Study selection

Using a structured question format to aid our literature search strategy, we reviewed all abstracts. We reviewed potentially relevant articles in full length to ensure that they satisfied three criteria: (i) prospective enrollment of consecutive patients with suspected PE; (ii) a PE diagnostic algorithm including CTPA testing; and (iii) one or more of the primary or secondary outcomes were reported. Studies were excluded if the study design was retrospective; patients were not recruited consecutively; asymptomatic PE was included; or if duplicated data were reported.

Outcome measures

Our primary outcome measure was the diagnosis subsegmental PE. Subsegmental PE was defined as the largest pulmonary filling defects reported at the subsegmental pulmonary artery level on a CTPA with satisfactory visualization of all pulmonary arteries at the segmental or higher level. The rate of subsegmental PE was determined by dividing the number of PE limited to subsegmental pulmonary arteries by the total number of PE. The rate of subsegmental PE was stratified according to the number CTPA detectors [Single and multiple (4, 16, and 64 detectors)].

Our secondary outcome measure was the 3-month thromboembolic risk of the diagnostic strategy using a negative CTPA (single and multiple detectors) to rule out PE. The 3-month thromboembolic risk was defined as the frequency of objectively documented symptomatic VTE during a 3-month follow-up period in patients with suspected PE who were left untreated based on a diagnostic algorithm including a negative CTPA.

Data extraction and quality assessment

Two reviewers (M.C. and G.L.) independently assessed eligibility of articles identified in the initial search strategy for inclusion in the review; discussed those deemed potentially eligible; independently extracted data (baseline characteristics, definition of outcomes, numbers of events) using a standardized data abstraction form; and assessed studies’ methodological quality (using the Risk of Bias Assessment Tool from the Cochrane Handbook for randomized trials, and the Newcastle – Ottawa Quality Assessment scale for observational studies) [12,13]. The two reviewers independently reviewed articles written in English, French and Spanish. Articles written in Japanese (n = 1), Polish (n = 1), Turkish (n = 1), German (n = 2) and Mandarin (n = 1) were translated by physicians and reviewed by the reviewers (M.C. and G.L.). Discrepancies were adjudicated by a third party (M.R.). Corresponding authors of studies were contacted if outcome measures were not reported in the original article.

Data synthesis and analysis

To estimate the weighted rates and 95% confidence intervals for the review’s primary outcomes, after extraction, individual study rates were transformed into a quantity using the Freeman–Tukey variant of the arcsine square root transformed proportion [14]. We then calculated a pooled proportion as the back-transform of the weighted mean of the transformed proportions, using a random effects model [15]. The weighting of outcomes accounts for differences in sample size and between the individual studies. Analyzes were performed using StatsDirect software version 2.7.3 (StatsDirect Ltd, Cheshire, UK).

We report rates stratified by the number of CTPA detectors as single and multiple detectors, the latter including CTPA with 4, 16 and 64 detectors.

The I2 statistic was used to estimate total variation among the pooled estimates across studies. An I2 of < 25% was considered as low-level heterogeneity, 25–50% was moderate level and higher than 50% was considered as high level [16].

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Disclosure of Conflict of Interests
  9. References
  10. Supporting Information

A total of 1677 citations were identified by our literature search and 113 articles were deemed potentially eligible (Appendix S2, on-line) [17–38]. Twenty-two articles were included in the review (20 studies were management outcome studies [17–29,31–36,38]; two were randomized controlled trials [30,37]). The baseline characteristics of the included studies are depicted in Tables 1 and 2. Single- and multiple-detectors CTPA were evaluated in 15 and 11 studies, respectively. Two studies included a mix of patients that underwent either single- or multiple-detectors CTPA [29,30].

Table 1.   Baseline characteristics of the included studies assessing single-detector computed tomographic pulmonary angiography in patients with suspected PE
StudyDateDesignBlinded assessment of CTPANumber of patientsNumber of SDCTNumber of VTENumber of PE on CTPANumber of SSPENumber of single SSPE3-month VTE risk of negative CTPA
  1. CTPA, computed tomographic pulmonary angiography; SDCT, single-detector computed tomographic pulmonary angiography; NA, not assessed; PE, pulmonary embolism; RCT, randomized controlled trial; SSPE, subsegmental pulmonary embolism; VTE, venous thromboembolism.

Goodman [17]1995Prospective cohortYes20201181NANA
Van Rossum [18]1996Prospective cohortYes185185686400NA
Perrier [19]2001Prospective cohortYes29929911881000/181
Musset [20]2002Prospective cohortNA1041104136929912124/498
Nilsson [21]2002Prospective cohortYes909033324NA0/57
Tillie-Leblond [22]2002Prospective cohortNo3343348181553/171
Ruiz [23]2003Prospective cohortYes6666252100NA
Van Strijen [24]2003Prospective cohortNA512510129124222/376
Van Strijen [25]2003Prospective cohortNA52625213512813NANA
Perrier [26]2004Prospective cohortNo9653476262103/252
Van Strijen [27]2005Prospective cohortYes51723712810566NA
Elias [28]2005Prospective cohortNo27410811091NA0/90
Van Belle [29]2006Prospective cohortYes3306258838212NA4/175
Anderson [30]2007RCTYes70117426260NA0/148
Table 2.   Baseline characteristics of the included studies assessing multiple-detectors computed tomographic pulmonary angiography in patients with suspected PE
StudyDateDesignNumber of detectorsBlinded assessment of CTPANumber of patientsNumber of MDCTNumber of VTENumber of PE on CTPANumber of SSPENumber of single SSPE3-month VTE risk of negative CTPA
  1. CTPA, computed tomographic pulmonary angiography; MDCT, multi-detectors computed tomographic pulmonary angiography; NA, Not assessed; PE, pulmonary embolism; RCT, randomized controlled trial; SSPE, subsegmental pulmonary embolism; VTE, venous thromboembolism.

Qanadli [31]2000Prospective cohort2Yes15815762594NANA
Perrier [26]2004Prospective cohort4No9652466262102/159
Winer-Muram [32]2004Prospective cohort4Yes9393182611NA
Revel [33]2005Prospective cohort4Yes21621654548NA2/111
Perrier [34]2005Prospective cohort4No7564681691691523/277
Perrier [34]2005Prospective cohort16No756562525100/26
Stein [35]2006Prospective cohort4, 8 or 16Yes8247731921508NANA
Van Belle [29]2006Prospective cohortNAYes3306192167455198NA14/1330
Anderson [30]2007RCT4 or 16Yes701472133898NA2/383
Schoepf [36]2007Prospective cohort16Yes3636232352NA
Righini [37]2008RCT16 or 64No181910793603021034/696
Douma [38]2009Prospective cohort64Yes10710724245NANA

Study quality of the randomized controlled trials is summarized in Appendix S3 (on-line). Both randomized controlled trials reported adequate sequence generation, allocation concealment, blinding and outcome reporting (Appendix S3). Both trials had a blinded independent adjudication committee. One trial had a study protocol available (Trial isrctn.org Identifier: ISRCTN65486961) [30] and all expected outcomes were reported for the other included trial [37].

The quality of the prospective cohort studies is reported in Appendix S4 (on-line). Fourteen (70%) studies reported blinded assessment of the CTPA. Ten studies (50%) had adequate follow-up. All studies had adequate representativeness and assessment of outcome measures.

Rates of subsegmental pulmonary embolism diagnosis

A total of 2657 patients with confirmed PE were included in the analyzes. All patients received anticoagulation therapy on the basis of the PE diagnosis. Of these, 1123 and 1534 patients underwent a single- and multiple-detectors CTPA, respectively. Two studies assessing multiple detectors CTPA did not report patients’ outcome stratified by the number of detectors used for CTPA [29,30]. Table 3 shows the rates of subsegmental PE diagnosed by single- and multiple-detectors CTPA. The rate of subsegmental PE diagnosis with a single-detector CTPA was 4.7% [95% confidence interval (CI): 2.5–7.6; I-square: 72%]. The rate of subsegmental PE diagnosis with multiple-detectors CTPA was 9.4 (95% CI: 5.5–14.2; I-square: 86%). In patients with PE who underwent a multiple-detectors CTPA, the rate of subsegmental PE was 7.1% (95% CI: 3.8–11.3; I-square: 56%) with 4-detectors CTPA and 15.0 (95% CI: 7.7–24.1) with 64-detectors CTPA. Only two studies have reported rates of subsegmental PE with 64-detectors CTPA [37,38]. Sensitivity and subgroup analyzes according to the study quality did not significantly alter the rates of subsegmental PE diagnosis.

Table 3.   Rates of subsegmental pulmonary embolism diagnosis
 SDCTAll MDCTMDCT 4 detectorsMDCT 16 detectorsMDCT 64 detectors
  1. CI, confidence intervals; MDCT, multi-detectors computed tomography; SDCT, single-detector computed tomographic pulmonary angiography; SSPE, subsegmental pulmonary embolism.

Number of patients11231534461207100
Proportion of SSPE (%, 95% CI)4.7 (2.5–7.6)9.4 (5.5–14.2)7.1 (3.8–11.3)6.9 (0.7–23.3)15.0 (7.7–24.1)

Three-month risk of VTE in patients with normal CTPA

The 3-month thromboembolic risks of patients with suspected PE who were left untreated after a diagnostic algorithm including a negative CTPA are shown in Table 4. The risk of VTE in untreated patients with suspected PE and a negative CTPA was 0.9% (95%CI: 0.4–1.4; I-square: 24%) and 1.0% (95% CI: 0.7–1.4; I-square: 0%) for single- and multiple-detectors CTPA, respectively. In patients with suspected PE left untreated after a negative multiple-detectors CTPA, the risk of VTE during 3 months of follow-up was 1.4% (95% CI: 0.7–2.7; I-square: 0%) with 4-detectors CTPA and 0.8 (95% CI: 0.1–3.0) with 64-detectors CTPA. Only one study reported the risk of VTE during follow-up in untreated patients with a negative 64-detectors CTPA [37].

Table 4.   Three-month VTE risk in patients with suspected pulmonary embolism and negative computed tomographic pulmonary angiography
 SDCTAll MDCTMDCT 4 detectorsMDCT 16 detectorsMDCT 64 detectors
  1. CI, confidence intervals; MDCT, multi-detectors computed tomography; SDCT, single-detector computed tomographic pulmonary angiography.

Number of patients19432982547424239
Rate of VTE on follow-up (%, 95% CI)0.9 (0.4–1.4)1.1 (0.7–1.4)1.4 (0.7–2.7)0.6 (0.1–1.6)0.8 (0.1–3.0)

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Disclosure of Conflict of Interests
  9. References
  10. Supporting Information

Our systematic review demonstrates that multiple-detectors CTPA might increase the rate of subsegmental PE diagnosis as compared with single-detector CTPA. Our review also shows that the 3-month thromboembolic risk in patients with suspected PE who were left untreated after a diagnostic algorithm including a negative CTPA was similar between patients who underwent a single or multiple-detectors CTPA. Hence, our results suggest that the incremental rate of subsegmental PE detected by multiple-detector CTPA might not be clinically important. Further prospective studies are required to assess the risk benefit ratio of anticoagulation in patients with subsegmental PE.

The incidence of PE has increased since the introduction of CTPA in diagnostic strategies for PE [39]. This increased incidence has been shown to result in a lower severity of illness and lower mortality [39]. The improved outcome in PE patients diagnosed with CTPA could be as a result of earlier diagnosis or to an increasing number of smaller PE (i.e. limited to the subsegmental arteries). The clinical significance of these smaller PE is unclear. PE limited to the subsegmental arteries were shown to be most prevalent among patients with low-probability ventilation/perfusion scans in the PIOPED study [9], and many outcome studies showed that patients with low or intermediate ventilation/perfusion scan results can be safely managed with serial lower extremities ultrasonography without anticoagulation [10,11]. A randomized controlled trial comparing the utility of CTPA with ventilation-perfusion scanning for the management of patients with suspected PE has shown similar results [30]: CTPA resulted in a significantly greater number of venous thromboembolic events been diagnosed than did ventilation-perfusion scans in spite of the similar rates of thromboembolic risk during the 3-month follow-up period in patients with a negative initial diagnostic work-up. Given that the VTE risk during follow-up was similar between the two groups in whom PE was excluded, it suggests that the incremental PE detected by CTPA were clinically not relevant.

The increased incidence of subsegmental PE diagnosis by CTPA could have important consequences on patients’ care. This could result in increased numbers of patients being exposed to anticoagulation therapy. Approximately, 2% of patients receiving anticoagulation will experience a major bleeding episode [40]. The case-fatality rate of major bleeding in patients taking oral anticoagulant therapy for VTE is 13.4% (95% CI: 9.4–17.4%) and the rate of intracranial bleeding is 1.15 per 100 patient-years (CI: 1.14–1.16 per 100 patient-years) [41]. Furthermore, resource allocation for anticoagulation therapy and potential major bleeding complications need to be considered.

It is important to note limitations of our study. First, there was no head-to-head comparison between single- and multiple-detectors CTPA. Second, studies using single-detector CTPA were performed between 1995 and 2004, whereas multiple-detectors CTPA studies were conducted in more recent years. However, this is unlikely to explain our results, as the prevalence of confirmed PE among patients with suspected PE tend to decline over the years as a result of the lower threshold to initiate diagnostic imaging evaluation [42]. Third, data according to the number of detectors in patients who underwent multi-detectors CTPA could not be extracted from two studies despite corresponding with the authors. This impeded us to provide narrow estimates for each possible number of detectors. Fourth, additional diagnostic tests (duplex ultrasonography, D-dimer test) performed in patients with suspected PE and negative CTPA might have affected the results. However, the estimates reported in our review are conservative as venous thromboembolic events found on additional diagnostic tests but not on CTPA were included in the 3-month risk of thromboembolism. Fifth, the pooled rates of subsegmental PE showed significant heterogeneity. Unblinded evaluation of CTPA is some studies might account for the heterogeneity (Tables 1 and 2). Finally, many studies could not be included because they did not provide enough data regarding the localization of PE on CT.

In conclusion, the use of multiple-detectors CTPA in diagnostic strategies for PE might increase the proportion of patients diagnosed with subsegmental PE, and therefore the proportion of patients with suspected PE who will eventually receive anticoagulant treatment, without lowering the 3-month risk of thromboembolism in patients with suspected PE left untreated based on a diagnostic algorithm including a negative CTPA suggesting that subsegmental PE might be clinically unimportant. Although a randomized controlled trial would be difficult to conduct, further studies are needed to assess the risk benefit ratio of anticoagulation therapy in patients with subsegmental PE.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Disclosure of Conflict of Interests
  9. References
  10. Supporting Information

M. Carrier is a recipient of a Canadian Institute for Health Research Randomized Controlled Trials Mentoring Program Award. M. Righini is the recipient of a Career Scientist Award from the Heart and Stroke Foundation of Ontario. P. S. Wells is a recipient of a Canada Research Chair.

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  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Disclosure of Conflict of Interests
  9. References
  10. Supporting Information
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Supporting Information

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Disclosure of Conflict of Interests
  9. References
  10. Supporting Information

Appendix S1. The systematic search strategy.

Appendix S2. Flow Diagram summarizing the identification process of relevant clinical trials.

Appendix S3. Quality of included studies using the Risk of Bias Assessment Tool from the Cochrane Handbook.

Appendix S4. Quality of included studies using the Newcastle –Ottawa quality scale for cohort studies.

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JTH_3938_sm_Appendix.doc78KSupporting info item

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