D-dimer test for excluding the diagnosis of pulmonary embolism

  • Protocol
  • Diagnostic

Authors


Abstract

This is a protocol for a Cochrane Review (Diagnostic test accuracy). The objectives are as follows:

To investigate the ability of the D-dimer test to rule out a diagnosis of acute PE in patients managed in the hospital outpatient setting who have had a pre-test probability (PTP) for PE determined using a clinical prediction rule (CPR) but are not already established on anticoagulation at the time of recruitment to the study by estimating sensitivity and specificity. 

To investigate the following as potential sources of heterogeneity: age, sex, previous VTE, prolonged immobilisation, and type of reference standard. However, we recognise that all of these listed items except type of reference standard are patient-specific rather than study-specific, and so study reports may lack the necessary level of detail to enable an informative analysis.

Background

Venous thromboembolism (VTE) is the collective term for deep vein thrombosis (DVT) and pulmonary embolism (PE). PE can occur when a thrombus (blood clot) travels through the general circulation and lodges in the arteries of the lungs producing an obstruction. There are a variety of estimates for the incidence of PE in different populations; in the USA the number of first-time PE ranges from 71 to 117 cases per 100,000 (White 2003).

People who are thought to be at risk include those with cancer or who have had a recent surgical procedure, women who are pregnant, or those who have experienced long periods of immobilisation. The clinical presentation can vary but unexplained respiratory symptoms such as difficulty breathing, chest pain and an increased respiratory rate are commonly observed (Ainish 1999). As these features can also be present in a number of other conditions including myocardial infarction, pneumonia and heart failure (Goldhaber 1998), the diagnosis of PE can be difficult to rule out on the basis of the clinical presentation alone, and it is estimated that 25% of patients who present with symptoms and signs of PE actually have the condition (van Belle 2006). Failure to diagnose accurately and treat a PE can be fatal, and immediate treatment with an anticoagulant to prevent further clots developing is critically important. Several radiological and laboratory tests are used to diagnose PE and these exhibit different accuracies, have different costs and, because some are invasive and others non-invasive, they are associated with different levels of risk (Goodacre 2006; Yoo 2012).

D-dimer is a piece of protein released into the circulation when a blood clot breaks down, either as a result of normal body processes or with prescribed fibrinolytic medication. The normal level of plasma D-dimer is usually less than 500 micrograms per litre (µg/L) (upper limit of normal can vary depending on method of measurement) and a higher level of D-dimer may indicate the presence of a DVT or PE. The coated latex particles contained in assay testing kits agglutinate in the presence of plasma containing D-dimer. The degree of agglutination is directly proportional to the concentration of D-dimer in the plasma (Than 2009). However, plasma D-dimer levels can also be influenced by a person's age, whether he or she has cancer or has had recent surgery, or in pregnancy leading to false positive test results. As D-dimer antigen levels are raised in the acute phase of PE for around seven days, patients with a PE who present late may have low levels of D-dimer (Schreiber 2002).

The use of D-dimer in the diagnostic pathway is usually preceded by the calculation of a pre-test probability with a clinical prediction rule (CPR) such as the Charlotte or Wells score (see Figure 1 and Clinical pathway section below). Patients who are judged likely to have PE (have a high pre-test probability) do not usually receive a D-dimer test; they receive a computerised tomography pulmonary angiography (CTPA) or a ventilation/perfusion scintigraphy (V/Q scan). Patients who are judged to have a low pre-test probability have a D-dimer test. If the result of the D-dimer is positive, those patients will then have a CTPA or a V/Q scan. Those who have a negative D-dimer test following a low probability CPR score are considered not to have a PE (NCGC 2012).

Figure 1.

Clinical pathway

A previous systematic review included patients recruited with VTE (that is both DVT and PE) in both inpatient and outpatient settings (Di Nisio 2007). Our Cochrane review will focus on patients with PE in the outpatient setting alone. Most inpatients who experience the symptoms or signs suggestive of PE are likely to have a raised D-dimer for other reasons, making the test of little use (Schrecengost 2003).

The tests used to give a definite diagnosis of PE include pulmonary angiography, CTPA, magnetic resonance (MR) pulmonary angiography (MRPA) or V/Q scanning. Pulmonary angiography is an invasive procedure involving insertion, via either the arm, groin or neck, of a catheter into the vascular system which is then guided until it reaches the pulmonary artery. Once the catheter is in place, a contrast agent is injected into the catheter and a series of x-rays are taken, allowing the contrast agent to indicate blockages in the arteries. Aside from possible injury from the catheter, patients receive a dose of radiation. In V/Q scanning patients have to inhale a gaseous radionuclide and have an injection of a radioactive agent. A scintillation camera then captures images that show the circulation of both air and blood in the patients' lungs by detecting the radiation. CTPA is less invasive than pulmonary angiography but also requires use of a nephrotoxic contrast agent and x-rays. MRPA does not use x-rays but instead models the response of hydrogen atoms within the body to very strong magnetic fields to produce images. It is therefore unsuitable for patients fitted with pace-makers or other metallic devices, or for those who suffer from claustrophobia due to the narrow space patients have to lie in for the MRPA scan to take place. Both CTPA and MRPA are considered less burdensome on the patient and are therefore generally used in preference to either pulmonary angiography or V/Q scanning. However, all these tests have drawbacks whether from their invasive nature, the use of chemicals, or comparative lack of accessibility; for example, CT or MR scanner time is not always readily available in comparison to the D-dimer test. Their advantage over D-dimer is that they are more accurate and we will use these tests as reference standards.

Target condition being diagnosed

Acute pulmonary embolism

Index test(s)

The D-dimer test is a laboratory assay currently used to rule out the presence of high D-dimer plasma levels and, by association, VTE. It is used as an add-on test in practice and is not used alone, that is a normal D-dimer on its own is not sufficient to rule out PE. Using routine blood samples these tests are rapid, simple and inexpensive. D-dimer tests are classified in three different ways according to the manner in which the test results are obtained (with final detection using fluorescence, immunosorbent assay or agglutination techniques) and these are quantitative, semi-quantitative and qualitative (Goodacre 2006).

Quantitative D-dimer tests measure the plasma concentration of D-dimer and require laboratory facilities. Examples of these D-dimer tests are enzyme-linked immunofluorescent immunoassays (ELFAs), a microplate enzyme-linked immunosorbent assay (ELISA), latex quantitative and latex semi-quantitative tests. Qualitative D-dimer tests are whole blood assays which are a different type of D-dimer test as they are usually used on whole blood samples, do not require laboratory facilities and can be used at the bedside. They have a rapid turn-round time and are inexpensive. The results are interpreted visually (Wells 2007). The lack of standardisation of D-dimer assays means that the results from one assay cannot be generalised to other assays.

A second systematic review found that a variety of thresholds have been used in primary studies even for the same tests (Becker 1996). Therefore, we intend to include all evaluations of the diagnostic test accuracy of D-dimer regardless of the threshold used to define a positive test result.

Pre-test probability score using clinical prediction rules (CPRs)

As an assessment of the pre-test probability (PTP) of a PE is considered a standard component of current clinical practice, we intend to include only studies which assess the PTP of PE using a CPR. There are many CPRs in existence for assessing the PTP of PE. A systematic review identified those which have been most extensively subjected to validation (Ceriani 2010; Wells 1997). We intend to include studies which assess the PTP of PE using any one of the following CPRs as part of the diagnostic strategy involving any D-dimer test: Geneva (including Revised and Revised Simplified), Wells (two-level, three-level, and simplified), and the Charlotte rule. Table 1 shows commonly used CPRs and their scoring systems in assessing the PTP of PE. We are not using the Miniati rule, which was also assessed in the systematic review (Ceriani 2010), as it does not provide an easy method of scoring patients. Users of the Miniati rule have to calculate a probability from the coefficients of a logistic regression model, making it less likely to be used than those CPRs with easy scoring systems (Laupacis 1997).

Table 1. Examples of clinical prediction rules used for a pre-test probability score for pulmonary embolism (PE)
CPRPredictive elements and scoring system
Three-level Wells score

The predictive elements of this CPR are: clinical signs and symptoms of DVT (3 points), alternative diagnosis less likely than PE (3 points), heart rate > 100 beats per minute (1.5 points), immobilisation for more than 3 days or recent (< 4 weeks) surgery (1.5 points), previous VTE (1.5 points), haemoptysis (1 point), cancer treatment in the previous 6 months or palliative care (1 point).

Low probability - less than 2; intermediate probability - 2 to 6; high probability - more than 6.

Two-level Wells scoreThe predictive elements of the two-level Wells score are the same as the three-level Wells score but patients are categorised into two as opposed to three categories, PE likely or PE unlikely based on a score of more than 4 or 4 or less points respectively.
The simplified Wells scoreThe same predictive elements as the three-level Wells score are used but the points scoring has been simplified - each item now scores 1 point. Patients are regarded as low risk if they have 1 point or less, and high risk if they score more than 1.
The Geneva score

The predictive elements of the Geneva score are: recent surgery (3 points), previous history of PE or DVT (2 points), heart rate > 100 beats per minute (1 point), 60-79 years old (1 point), 80 or more years old (2 points), chest radiograph showing atelectasis (1 point), chest radiograph showing elevated hemidiaphragm (1 point), partial pressure of oxygen (PaO2) < 49 mm Hg (4 points), PaO2 49-59 mm Hg (3 points), PaO2 60-71 mm Hg (2 points), PaO2 72-82 mm Hg (1 point), and partial pressure of carbon dioxide (PaCO2) < 36 mm Hg (2 points), PaCO2 36-38.9 mm Hg (1 point).

Risk of PE is scored low (0 - 4 points), intermediate (5 - 8 points), or high (9 or more points).

The revised Geneva score

The predictive elements of the revised Geneva score are: age > 65 years old (1 point), previous history of PE or DVT (3 points), surgery with general anaesthesia or fracture within one month of the symptoms arising (2 points), active malignancy (2 points), heart rate 75-94 beats per minute (3 points), heart rate > 94 beats per minute (5 points), pain on leg venous palpation and unilateral oedema (4 points), haemoptysis (2 points), and unilateral leg pain (3 points).

This CPR is scored low risk (0 - 3 points), intermediate (4 - 10 points), or high risk (11 or more points).

The simplified revised Geneva score

The same predictive elements are used as in the revised score Geneva score but the points scoring has been simplified. Each item now scores 1 point.

The risk of PE is scored low (0 - 1 point), intermediate (2 - 4 points), or high (5 or more points).

The Charlotte rule

The elements of the Charlotte rule are: > 50 years old, heart rate higher than the systolic blood pressure, unexplained hypoxaemia (O2 < 95%), recent surgery (previous four weeks), haemoptysis, and unilateral leg swelling.

The risk score from the Charlotte rule is classified as either safe (all of the predictive elements absent), or unsafe (any of the predictive elements present).

See also Table 1.

Clinical pathway

As explained above, symptomatic patients generally undergo PTP testing by the PE Wells test prior to any D-dimer test (Ceriani 2010; NCGC 2012; Wells 2006). The two-level Wells test is a CPR that gives the patient points for each criterion met (for example a previous history of PE or DVT, clinical signs of PE, recent surgery or immobilisation, heart rate > 100 beats per minute (bpm)). The maximum score is 12.5 points and the clinical probability of PE is considered unlikely if the score is 4 or less, and high if more than 4 points. The three-level Wells test uses the same scoring system, with scores 0 to 1 to indicating a low risk, 2 to 6 an intermediate risk, and more than 6 a high risk (Damlo 2007; Wells 2007).

Symptomatic patients considered to be at low risk by the CPR will generally undergo D-dimer testing. A normal D-dimer in patients with a low or unlikely PTP can be used to rule out PE. In these circumstances doctors will look for non-PE causes of the symptoms. Patients with a low risk score but a positive D-dimer test are referred for V/Q scanning or CTPA. Patients with a high risk score may not receive a D-dimer test but be directly referred for CTPA or V/Q scanning if rapidly available. Furthermore, patients may be offered anticoagulation treatment prior to the CTPA scan if rapid access is not available and they are either classed as high risk by the CPR or have a positive D-dimer test. The Wells prediction rule has better accuracy in younger patients without comorbidities or a history of VTE. In older patients a D-dimer assay alone may not be adequate to rule out VTE even in people with low clinical probability (Damlo 2007).

Rationale

Pulmonary embolism is difficult to rule out on the basis of clinical features and false positive test results are likely, yet the unnecessary treatment of patients with anticoagulants carries risk. The mortality rate for those people with PE in whom the condition is not recognised and consequently remains untreated is 22% (Wells 2007). A quick, accurate diagnostic test which can rule out the condition and reduce the need for diagnostic imaging is a clear improvement for people with this acute condition.

Objectives

To investigate the ability of the D-dimer test to rule out a diagnosis of acute PE in patients managed in the hospital outpatient setting who have had a pre-test probability (PTP) for PE determined using a clinical prediction rule (CPR) but are not already established on anticoagulation at the time of recruitment to the study by estimating sensitivity and specificity. 

Secondary objectives

To investigate the following as potential sources of heterogeneity: age, sex, previous VTE, prolonged immobilisation, and type of reference standard. However, we recognise that all of these listed items except type of reference standard are patient-specific rather than study-specific, and so study reports may lack the necessary level of detail to enable an informative analysis.

Methods

Criteria for considering studies for this review

Types of studies

We will include cross-sectional studies evaluating the diagnostic test accuracy of D-dimer and diagnostic cohort studies including both prospective and retrospective designs. Diagnostic case-control studies (two-gate design) will be excluded. Case-control designs are known to overestimate the sensitivity and specificity that a diagnostic test has in clinical practice (Rutjes 2005). In this review, we will consider studies that use a CPR with D-dimer testing to rule out patients with PE in outpatient departments. Specifically, we will use studies that recruited symptomatic outpatients with low, intermediate or high risk CPR scores.

Participants

Adults who are managed in hospital outpatient settings and who are suspected of acute pulmonary embolism (PE) as a result of clinical features such as breathlessness, increased respiratory rate, chest pain, tachycardia, coughing up blood, low blood pressure and fainting in whom a PTP of PE has been assessed using a CPR for PE (examples of which can be found under the heading Index test(s) above) will be eligible for inclusion in the review. If possible, we shall also group patients according to whether they received anticoagulant treatment or not, the specific CPR, and the D-dimer assay as these are not standardised (Schreiber 2002).

Patients with indeterminate or conflicting test results may undergo repeat imaging and the most commonly used imaging test for this is CTPA or V/Q scanning, but the review eligibility criteria only include studies investigating the diagnostic accuracy of the initial D-dimer test. We will also exclude studies that include pregnant women, people with cancer and mixed groups of patients where results are not reported separately for those who are pregnant or with and without cancer.

Index tests

Quantitative, semi-quantitative and qualitative D-dimer tests

Target conditions

Acute pulmonary embolism (PE)

Reference standards

We will use various reference standards (RS) encompassing: MRPA, pulmonary angiography, V/Q scintigraphy and CTPA. All patients' D-dimer tests (index tests) will be judged against these reference tests.

Search methods for identification of studies

There will not be any restrictions in terms of date, language of publication or publication status. No diagnostic methodology search filters will be employed.

Electronic searches

The following databases will be searched using the search strategies shown in Appendix 1 and Appendix 2:

  • MEDLINE (OvidSP);

  • EMBASE (OvidSP).

In addition, similar search strategies will be designed for:

  • CINAHL (via EBSCO);

  • LILACS (Bireme);

  • DARE (Database of Abstracts of Reviews of Effects) and the Health Technology Assessment Database (HTA) in The Cochrane Library;

  • ISI Conference Proceedings Citation Index - Science;

  • British Library Zetoc conference search.

The search terms appropriate for each of these databases will be based on the MEDLINE search terms.

We will also search MEDION (www.mediondatabase.nl/) using the 'Systematic Reviews of Diagnostic Studies' search filter.

We will request a search of the Cochrane Register of Diagnostic Test Accuracy Studies for further relevant studies.

The following trial databases will be searched for details of ongoing and unpublished studies:

Searching other resources

We will handsearch the reference lists of the primary studies and reviews identified from the electronic searches.

Data collection and analysis

Selection of studies

One review author (FC) will screen the titles and abstracts retrieved from the electronic searches and a second review author (AA) will check a random sample of 10% of the studies. If agreement is less than 80%, the discrepancies will be discussed to ascertain whether the two review authors have been applying the prespecified inclusion and exclusion criteria consistently. The two review authors will agree the application of the inclusion and exclusion criteria and, if necessary, another 10% of the abstracts will be checked. Full papers will be obtained for potentially eligible studies including those identified by non-electronic means. Two review authors (FC and AA) will independently apply the inclusion criteria to the full papers and resolve any disagreements by discussion. We will use a PRISMA flow diagram to show the decision making regarding the studies (PRISMA 2009).

Given that the reporting in abstracts is necessarily sparse, the full-text articles will be checked for meeting the abstract criteria and also for fulfilling the following: a 2 x 2 contingency table is either supplied or can be back-calculated, all patients are outpatients and have a PTP calculated using one of the specified CPRs, and the reference standard is either pulmonary angiography, CTPA, MRPA or V/Q scanning. The number of studies failing these criteria will be reported in the PRISMA flow diagram.

Studies that pass the initial screening of the full text will undergo a more in-depth evaluation as described below and will be fully reported in the review.

Data extraction and management

Data extraction will be replicated independently by two review authors (FC and AA) using a standard form. Our data collection will include: details about the study design, patient population (age, sex, elements of patient history such as prolonged immobilisation, cancer, recent surgical procedures, or previous VTE), D-dimer tests (nature of the D-dimer test such as ELISA, latex agglutination assay, whole blood agglutination), CPRs and all reference standard tests and data regarding the thresholds used for each of the tests. We will also extract the methods used to conduct each test and 2 x 2 accuracy data.

The 2 x 2 accuracy data comprise the cross-tabulated results of the D-dimer tests and reference standards in 2 x 2 contingency tables. Patient level data to populate 2 x 2 contingency tables (true positives (TP), true negatives (TN), false positives (FP) and false negatives (FN)) will be extracted as reported or back-calculated from estimates of sensitivity, specificity, positive predictive value, negative predictive value, and the number of patients.

The data extraction form will also incorporate a quality assessment section comprising items from Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) (Whiting 2011). Data on mortality, adverse events, and the number of technical failures for both the D-dimer and the reference standard tests will be collected, together with information on the anticoagulant status of the patients. The review authors will corroborate their data extraction and any differences in quality assessment decisions will be resolved by discussion.

Assessment of methodological quality

We will use the QUADAS-2 (Whiting 2011) to incorporate the review question, a flow diagram for the review, and an assessment of risk of bias and applicability judgements. Review-specific signalling questions and appropriate items concerning the applicability of primary studies relative to the review, together with guidance about rating, can be found in Appendix 3. We propose that two review authors working independently will pilot the tool and an assessment of agreement will be calculated. Disagreements will be resolved by discussion or referral to a third review author.

Statistical analysis and data synthesis

We will present and use the 2 x 2 contingency tables to estimate sensitivity and specificity for each study. These estimates will be used to create receiver operating characteristic (ROC) plots and forest plots for all studies.

Quantitative D-dimer tests are used with explicit thresholds and 500 µg/L is a common choice (Schouten 2013). If there are sufficient studies using this threshold, we shall perform a bivariate random-effects model meta-analysis of sensitivity and specificity in order to produce clinically applicable summary estimates of sensitivity and specificity. However, we expect to have studies using qualitative D-dimer tests and these will have no explicit threshold, and so we will consider fitting the hierarchical summary receiver operating characteristic (HSROC) model to the data from these studies and present the results as summary ROC (SROC) curves to give an indication of the global performance of the qualitative D-dimer tests (Harbord 2007).

If the model fit of the bivariate or HSROC model is not acceptable, we shall consider performing univariate meta-analyses for sensitivity and specificity. The programs used to fit the model must converge. However, convergence is a necessary but not sufficient measure of a model having a satisfactory fit and further checks are necessary. In particular, the covariance parameter can be poorly estimated even when convergence is achieved.

A small number of studies is one but not the only common reason for non-convergence (and we would not attempt to fit the five parameter bivariate or HSROC models with fewer than six studies). Non-convergence can also happen when there is a lack of variation in threshold between studies, a possibility here given the clinical acceptance and frequent use of 500 µg/L. We note that there are many possible reasons, both statistical and clinical, why we would not undertake a SROC curve method of meta-analysis and we would want to consider both clinical and statistical sources of heterogeneity.

Performing univariate analyses, one each for sensitivity and specificity, is not always recommended. However, where studies do use a common threshold the univariate meta-analyses could be informative and would also allow meta-regression in a situation where use of the bivariate or HSROC models may not be valid.

All analyses will be performed in R 8.0 (cran.r-project.org) and SAS 9.3 (www.sas.com).

Investigations of heterogeneity

In our investigations of heterogeneity we will specifically investigate the types of reference standards and age, sex and aspects of the patients' history (prolonged immobilisation or previous VTE) by including them as covariates in the meta analysis (Di Nisio 2007).

Each meta-regression will be carried out separately for each index test and each patient group by adding the items as covariates to the bivariate model. If the data for our prespecified variables are insufficient, we may consider analysing one or two other items if the data are available and they are considered to be clinically relevant. Any such analysis, if undertaken, will clearly be labelled as post-hoc in the review.

Other potential sources will be examined graphically for signs that they are a cause of heterogeneity (Smidt 2008). Estimates will be grouped according to all the items listed as potential sources of heterogeneity and presented in forest and ROC plots for visual assessment of heterogeneity.

Sensitivity analyses

Separate meta-analyses will be performed on groups of studies where the groups are made according CPR, anticoagulant treatment, and specific D-dimer assay. The disease spectrum of the patients may vary with CPR and so affect the estimates of sensitivity and specificity. Anticoagulant treatment may cause disease progression bias if it is administered between the D-dimer testing and the reference standard. D-dimer assays are not standardised and so may have different accuracies.

Assessment of reporting bias

Methods for dealing with publication bias in reviews of diagnostic accuracy studies are relatively underdeveloped. Consequently, we shall interpret our results cautiously and with an awareness of the likelihood of publication bias. We shall consider using a funnel plot of the log of the diagnostic odds ratio (lnDOR) (Deeks 2005) providing there is low heterogeneity in the lnDOR.

Acknowledgements

This review forms part of a National Institute of Health Research (NIHR) Cochrane Programme Grant.

Appendices

Appendix 1. MEDLINE search strategy

Database: Ovid MEDLINE(R)

1. exp Pulmonary Embolism/

2. (pulmonary adj embol$).ti,ab.

3. (pulmonary adj thrombo$).ti,ab.

4. (lung adj embol$).ti,ab.

5. (lung adj thrombo$).ti,ab.

6. (PE or PTE).ti,ab.

7. or/1-6

8. Fibrin Fibrinogen Degradation Products/an, me [Analysis, Metabolism]

9. Biological Markers/an, bl, me [Analysis, Blood, Metabolism]

10. Enzyme-Linked Immunosorbent Assay/

11. "Nephelometry and Turbidimetry"/

12. d-dimer.ti,ab.

13. (fibrin adj2 d).ti,ab.

14. dimeri?ed plasmin.ti,ab.

15. elisa?.ti,ab.

16. elfa?.ti,ab.

17. enzyme linked.ti,ab.

18. latex agglutination.ti,ab.

19. (latex adj3 assay?).ti,ab.

20. blood agglutination.ti,ab.

21. Immunoturbidimetr$.ti,ab.

22. turbidimetr$.ti,ab.

23. SimpliRed.ti,ab.

24. Minutex.ti,ab.

25. NycoCard.ti,ab.

26. "Instant I.A".ti,ab.

27. Vidas.ti,ab.

28. LIATEST.ti,ab.

29. ("IL test" or IL-DD).ti,ab.

30. Turbiquant.ti,ab.

31. Asserachrom.ti,ab.

32. Enzygnost.ti,ab.

33. Fibrinostika.ti,ab.

34. "BC DD".ti,ab.

35. (Tinaquant or Tina-quant).ti,ab.

36. TriniLIZE.ti,ab.

37. biopool.ti,ab.

38. TintElize.ti,ab.

39. HemosIL.ti,ab.

40. Innovance-DD.ti,ab.

41. stratus.ti,ab.

42. FDP.ti,ab.

43. Dimertest.ti,ab.

44. (LPIA or EIA).ti,ab.

45. or/8-44

46. 7 and 45

Appendix 2. EMBASE search strategy

Database: Ovid Embase

1. lung embolism/

2. (pulmonary adj embol$).ti,ab.

3. (pulmonary adj thrombo$).ti,ab.

4. (lung adj embol$).ti,ab.

5. (lung adj thrombo$).ti,ab.

6. (PE or PTE).ti,ab.

7. or/1-6

8. fibrin degradation product/cr [Drug Concentration]

9. biological marker/cr [Drug Concentration]

10. D dimer/cr [Drug Concentration]

11. enzyme linked immunosorbent assay/

12. turbidimetry/

13. d-dimer.ti,ab.

14. (fibrin adj2 d).ti,ab.

15. dimeri?ed plasmin.ti,ab.

16. elisa?.ti,ab.

17. elfa?.ti,ab.

18. enzyme linked.ti,ab.

19. Immunoturbidimetr$.ti,ab.

20. turbidimetr$.ti,ab.

21. latex agglutination.ti,ab.

22. (latex adj3 assay?).ti,ab.

23. blood agglutination.ti,ab.

24. SimpliRed.ti,ab.

25. Minutex.ti,ab.

26. NycoCard.ti,ab.

27. "Instant I.A".ti,ab.

28. Vidas.ti,ab.

29. LIATEST.ti,ab.

30. ("IL test" or IL-DD).ti,ab.

31. Turbiquant.ti,ab.

32. Asserachrom.ti,ab.

33. Enzygnost.ti,ab.

34. Fibrinostika.ti,ab.

35. "BC DD".ti,ab.

36. (Tinaquant or Tina-quant).ti,ab.

37. TriniLIZE.ti,ab.

38. biopool.ti,ab.

39. TintElize.ti,ab.

40. (HemosIL-DD or HemosIL-DDHS).ti,ab.

41. Innovance-DD.ti,ab.

42. stratus.ti,ab.

43. FDP.ti,ab.

44. Dimertest.ti,ab.

45. (LPIA or EIA).ti,ab.

46. or/8-45

47. 7 and 46

Appendix 3. QUADAS-2

Domains, Signalling Questions (SQ) and Applicability Rating criteria
Domain 1: Patient selection 
A. Risk of biasDescribe the methods of patients' selection given in the paper:
SQ1: Was a consecutive or random sample of patients enrolled?

Yes: It is stated that the sample was consecutive or a random sample

No: It is stated that the sample was not consecutive or a random sample

Unclear: The method of sampling is ambiguous

SQ2: Did the study avoid inappropriate exclusions?

Yes: The study excluded patients without CPR scores

No: The study excluded patients who had received a PTP score using CPRs.

Unclear: The test history of the patients in the study is not revealed in the report

SQ3: Did the study avoid inappropriate inclusions?

Yes: The study included only outpatients who had received a PTP score for PE using a CPR

No: The study included some inappropriate patients, for example, those without a PTP score from a CPR, or included inpatients

Unclear: The study's inclusion criteria allow for inappropriate inclusions

Applicability Question 1: Are there concerns that the included patients and setting do not match the review question?

High: The study population meets the eligibility criteria

Low: The patient population is skewed in some way, for example the study includes mainly younger patients

Unclear: Not enough information is given about the study population

B. Concerns regarding applicabilityGive the paper's description of the inclusion/exclusion criteria, including setting, prior tests, symptoms here
Domain 2: Index test 
A. Risk of biasGive the paper's description of the D-dimer assay, how it was conducted and interpreted including the training of the individual of those carrying out the test
SQ1: If a threshold was used was it prespecified?

Yes: Plasma D-dimer levels are prespecified in the study methods section as a positive test result

No: The threshold for a positive test result is not prespecified

Unclear: It is unclear if a threshold was used

B. Concerns regarding applicability 
AQ2: Are there concerns that the index test, its conduct or its interpretation differ from the review question?

Yes: The plasma D-Dimer test did not use standard methods and is unvalidated

No:  The presence of plasma D-dimer was detected using standard D-dimer test methods previously validated

Unclear: The basis of the outcome is unclear

Domain 3: Reference standard 
A. Risk of biasGive the paper's description of the pulmonary angiography, scintigraphy, computed tomography PA and follow-up and how they were conducted and interpreted including the training of the individual of those carrying out the test
SQ1: Is the reference standard likely to correctly classify the target condition?

Yes: The reference standard(s) was either pulmonary angiography, CTPA, MRPA, or V/Q scanning

No: The reference standard(s) was not any of the above

Unclear: Information regarding the conduct of the reference standard is insufficient

SQ2: Were the reference standard test results interpreted without knowledge of the index test results?

Yes: The person classifying the RS test results was unaware of the D-dimer test results

No: The person classifying the RS test results was aware of the D-dimer test results

Unclear: No information is available regarding the blinding of test results

SQ3: Did the person conducting the pulmonary angiography, V/Q scanning, CTPA, or MRPA have expertise comparable to a radiologist?

Yes: It is stated that a radiologist or similar (e.g. vascular specialist with an interest in VTE) read the test results

No: The person conducting the pulmonary angiography, V/Q scanning, CTPA, or MRPA was not a radiologist or similar

Unclear: The expertise and background discipline of the reader is not made clear

Applicability: Could the reference standard, its conduct, or its interpretation have introduced bias?

High: The RS tests were performed by a person with expertise and were interpreted blind

Low: The RS tests were not performed by a person with expertise or were not interpreted blind.

Unclear: No information about the persons conducting the tests, or interpreting the results is given

Domain 4: Flow and timing 
A. Risk of biasDescribe the reasons why any patient recruited into the study did not contribute to the 2 x 2 table (i.e. patients who did not undergo the RS tests) referring to the flow diagram
SQ1: was there an appropriate interval between the index test and the reference standard?

Yes: The index and reference standard tests were all conducted within 7 days of each other

No: Some of the reference standard test results were obtained after more than 7 days

Unclear: No information about the relative timing of the tests is provided

SQ2: Did all the patients receive the same reference standard?

Yes: A complete set of RS test results are available for all study patients

No: The RS results are not available for all patients, or some patients had follow-up only

Unclear: It is not clear whether all patients received an acceptable reference standard

SQ3: Were all patients included in the final analysis?

Yes: Data for all study patients are reported

No: Data for all study patients are not reported

Unclear: It is not clear whether there were patients recruited but not included in the 2 x 2 table

Contributions of authors

The whole review team have contributed to the protocol. KW has developed the search strategy. FC and AA will apply the eligibility criteria, extract data from studies, perform an assessment of study quality and enter data into Review Manager. FMC will conduct the analysis. KS and DK will provide expert clinical advice.

Declarations of interest

FC: none known
AA: none known
KW: none known
KS has received support to attend educational meetings/conferences from Actelion, Amdipharm Mercury, Bayer, GSK, Pfizer and United Therapeutics.
DK reports having received consultancy fees for advisory board roles for Mitsubishi Pharma, Pfizer, Daiichi-Sankyo and Bayer, lecture fees for NovoNordisk and Mitsubishi Pharma, payment from NovoNordisk for organising and running training day for SpRs and newly qualified consultants and meeting expenses from Boehringer Ingelheim, Pfizer and Bayer to attend ISTH, SSC and WFH meetings.
FMC: none known

This review forms part of a National Institute of Health Research (NIHR) Cochrane programme grant. The review is being conducted independently of our funders, the NIHR. The NIHR have no input on the conduct or results of the review.

Sources of support

Internal sources

  • No sources of support supplied

External sources

  • Chief Scientist Office, Scottish Government Health Directorates, Scottish Government, UK.

    The PVD Group editorial base is supported by the Chief Scientist Office.

  • National Institute for Health Research (NIHR), UK.

    The PVD Group editorial base is supported by a programme grant from the NIHR.

  • National Institute for Health Research (NIHR), UK.

    This project was funded by the National Institute for Health Research. The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the NIHR, NHS or the Department of Health.

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