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(Chest. 2005;128:2183-2189.)
© 2005 American College of Chest Physicians

Latex-Enhanced Immunoassay D-dimer and Blood Gases Can Exclude Pulmonary Embolism in Low-Risk Patients Presenting to an Acute Care Setting*

Michael Hlavac, MBChB, FRACP; Julie Cook, BN; Rob Ojala, BSc, MBChB; Ian Town, MBChB, FRACP, MD and Lutz Beckert, MD, FCCP

* From the Canterbury Respiratory Research Group (Drs. Hlavac, Town, and Beckert and Ms. Cook), Christchurch School of Medicine & Health Sciences, University of Otago; and Department of Emergency Medicine (Dr. Ojala), Christchurch Hospital, Christchurch, New Zealand.

Correspondence to: Michael Hlavac, MBChB, FRACP, Adelaide Institute for Sleep Health, Repatriation General Hospital, Daw Park 5041, South Australia, Australia


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Background: Pulmonary embolism (PE) is common, and diagnosis is often difficult. Investigation has traditionally required expensive imaging procedures that are frequently nondiagnostic. Consequently, current practice favors noninvasive diagnosis of PE using algorithms combining risk assessment and d-dimer. Despite the proven safety of this approach, concern persists about such strategies to exclude PE, largely due to variable d-dimer sensitivity. The aim of this study was to prospectively assess the safety of a new algorithm combining a novel, rapid d-dimer test (IL Test; Instrumentation Laboratory; Lexington, MA), PaO2 measurement, and risk factor assessment in excluding PE in subjects presenting to an acute care setting.

Methods: All patients aged 18 to 60 years presenting to the emergency department of Christchurch Hospital with suspected PE underwent measurement of d-dimer (IL Test latex-enhanced immunoassay) and PaO2, and were assessed for the presence of major clinical risk factors. Those with no risk factors, normal d-dimer findings, and PaO2 ≥ 80 mm Hg (study arm A) were discharged and followed up by telephone questionnaires over 12 months. Those with elevated d-dimer levels, PaO2 < 80 mm Hg, or one or more risk factors (study arm B) were managed as per hospital guidelines. Outcome data were collected on these patients. Our primary outcome was incidence of PE in group A during the first 3-month follow-up period.

Results: Three hundred twenty-eight patients were enrolled, of whom 149 were assigned to group A and 179 were assigned to group B. In none of the group A patients was PE diagnosed over the subsequent 3-month period (0%; 95% confidence interval, 0 to 2.1%). PE was diagnosed in 37 group A patients (21%).

Conclusions: The latex-enhanced immunoassay d-dimer and normal arterial oxygen pressure levels can safely exclude PE in a low-risk population presenting to an acute care setting. While these results cannot be extrapolated to all patients with suspected PE, they do confirm the safety of this approach in a population with a low underlying risk of PE.

Key Words: d-dimer • hypoxemia • latex-enhanced immunoassay • pulmonary embolism


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Pulmonary embolism (PE) is a common disorder, with substantial associated morbidity and mortality.123 It typically has a nonspecific clinical presentation and often poses a significant diagnostic challenge.456 Traditional investigation has relied heavily on one of several imaging techniques, each of which has important limitations with respect to reliability when used as stand-alone tests.789101112 Consequently, the approach to suspected PE has evolved significantly over the last few years. Contributing to this has been the advent of rapid, reliable d-dimer measurement techniques, and to the amalgamation of d-dimer into algorithms that can safely and rapidly exclude PE. Such algorithms involve an initial assessment of likelihood of PE using either a validated pretest probability score such as the Wells score or Geneva criteria,1314 or screening for one of a number of major risk factors such as are outlined in the British Thoracic Society guidelines for management of PE (Table 1 ).15 Patients then have a d-dimer test performed, with subsequent management depending largely on the result. If the d-dimer result is normal and the clinical risk is low, then PE is believed to be excluded and patients are considered for discharge. If the d-dimer level is elevated, further imaging is recommended, with diagnosis or exclusion of PE based on the results. The safety of this approach has now been well validated in several prospective studies,161718 and a recent systematic review19 of this strategy in exclusion of deep vein thrombosis (DVT) has confirmed it to be safe irrespective of d-dimer method


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  		Table 1.. Major Risk Factors for VTE as per British Thoracic Society Guidelines

 
Despite good published evidence of the safety of such an approach, there is a persisting reluctance to manage patients with suspected PE in this manner. Clinicians continue to be concerned about the sensitivity of d-dimer for PE, which remains below 100% in most studies irrespective of the d-dimer method.20 In addition to concern over d-dimer, calculation of clinical risk scores is infrequently undertaken and results are influenced by the level of clinical experience, as shown in a study21 undertaken by our group.

This study has been specifically designed to assess the safety and practicality of using a simple algorithm combining a new, rapid d-dimer test, a simplified risk assessment, and measurement of PaO2 levels in an emergency department (ED) setting. The IL Test (Instrumentation Laboratory; Lexington, MA) is a new, fully automated, latex-enhanced immunoassay that provides a rapid quantitative measurement of d-dimer that has been shown to correlate well with enzyme-linked immunosorbent assay (ELISA) methods.2223 The IL Test has been in use since the late 1990s, but there is little literature assessing its performance in a clinical setting, and no large-scale validation trials or clinical prospective studies have been conducted assessing its value in excluding thromboembolic disease. We have simplified clinical risk estimation using the presence of one or more major clinical risk factors for PE, as outlined in the British Thoracic Society Guidelines15 (Table 1). Arterial oxygen levels have been shown to enhance the ability of d-dimer measurement to exclude PE in work previously undertaken by our group.24 Arterial oxygen levels are believed to be an important safety aspect of this algorithm through identification of patients with false-negative d-dimer results, and preventing discharge of significantly hypoxemic patients.

The aim of this study was to investigate the hypothesis that patients presenting from the community to an acute care setting with suspected PE who have no major clinical risk factors, normal PaO2 levels, and normal IL Test d-dimer results have a very low risk for clinically significant PE and can therefore be safely discharged with no further investigations.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Setting
The study was conducted in the ED of Christchurch Hospital, a university teaching hospital affiliated with the Christchurch School of Medicine and Health Sciences, University of Otago. Christchurch Hospital is in the Canterbury region of the South Island of New Zealand and serves a population of approximately 500,000 people. The ED sees approximately 67,000 patients per year and has a 50% admission rate.

Participants
We prospectively recruited consecutive patients aged 18 to 60 years presenting acutely to the ED of Christchurch Hospital with recent onset of symptoms suspicious of PE between April 2001 and November 2002. Exclusion criteria included refusal or inability to provide written informed consent, pregnancy, unstable cardiovascular state, therapeutic anticoagulation for > 72 h, a life expectancy of < 3 months, or living in an area inaccessible for follow-up. The study protocol was approved by the Canterbury Ethics Committee, and all participants provided written informed consent.

Study Design
The study was a prospective study with comprehensive 12-month follow-up period for all participants. At the time of enrollment, all participants underwent d-dimer testing, had PaO2 measured, and were assessed for the presence of one or more major clinical risk factors. D-dimer levels were measured using the IL Test automated latex immunoassay, with a normal value being < 250 nmol/L. Arterial blood gases were obtained with the participant breathing room air for at least 20 min; samples were analyzed immediately and reported within 15 min. Risk factors were as outlined in the British Thoracic Society guidelines for management of suspected PE (Table 1).15 Participants were then assigned to one of two groups, depending on the above results (Fig 1 ).



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  		Figure 1.. Flow chart summarizing algorithm and outcomes for subjects with suspected PE.

 
Participants with a normal d-dimer level, PaO2 ≥ 80 mm Hg, and no major clinical risk factors were assigned to study arm A. In this group, it was considered that a PE had been excluded, and the patients were discharged from the ED with no further investigations. The patients were then followed up over the subsequent 12 months.

Participants with a d-dimer level > 250 nmol/L, PaO2 < 80 mm Hg, and/or one or more major clinical risk factors were assigned to study arm B. In this group, it was considered that PE could not be excluded. These patients were admitted and managed according to hospital guidelines for thromboembolic disease at the discretion of the attending physician.

Follow-up
Subjects assigned to group A and discharged from hospital were issued a card with contact details for the senior investigators and instructions to return to the ED immediately if their presenting complaint worsened significantly or if new symptoms developed such as dyspnea or chest pain. Any patients re-presenting with any of the above symptoms were admitted for formal investigation for PE with either CT pulmonary angiography (CTPA) or ventilation/perfusion (/) scanning.

All subjects in group A were telephoned by a research nurse at 1 week, 3 months, 6 months, and 1 year to administer a short questionnaire. The initial questionnaire sought demographic details, information on overseas air travel, family history, and oral contraceptive use, and all responses were carefully evaluated for any evidence of subsequent thromboembolic events. Mortality and hospital admissions were checked on local and national databases at the same intervals, and any suspected or diagnosed thromboembolic event was further assessed and recorded. When any patient was readmitted to hospital for any reason, the hospital case notes were reviewed. For any patients receiving anticoagulation, all episodes of major bleeding were recorded (defined as any intracerebral, joint, or retroperitoneal bleed, or any bleed requiring a transfusion).

The case notes of patients in group B were reviewed 1 month following discharge from hospital. Data on investigations, diagnosis, management, length of stay, treatment, and any complications were collected.

For patients in group A, the diagnosis of PE required either positive CTPA or / scan findings. CTPAs were read and scored by an experienced thoracic radiologist in accordance with the protocol of Qanadli et al.25 / scans were interpreted by an experienced nuclear medicine physician using the Prospective Investigation of Pulmonary Embolism Diagnosis criteria.7 For patients in group B, the results of investigations were recorded, but diagnosis and exclusion of PE was based on the judgement of the attending clinician.

Statistical Analysis
Our primary outcome for this study was the proportion of subjects in group A with a diagnosis of venous thromboembolism (VTE) during the initial 3-month follow-up period. This outcome has been used by a number of other investigators131617 in assessing the safety of such an algorithm in excluding VTE. Our sample size enabled us to accept an upper-limit 95% confidence interval (CI) of 4%, which has been accepted as safe in similar outcome studies including a recent study by Wells et al,26 in which 0.9% (95% CI, 0.1 to 3.3%) of those with low clinical risk scores and normal d-dimer results subsequently received a diagnosis of DVT during 3-month follow-up. We also planned to assess the utility of both the algorithm and IL Test d-dimer alone in excluding PE by calculating the negative predictive value for each.


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Study Participants
During the 18-month study period, 471 patients aged 18 to 60 years attended the ED with a history suggestive of PE. Of this group, 366 patients (78%) were screened for entry into the study. The remaining 105 potential patients were missed primarily due to missed opportunity for enrollment rather than any particular patient characteristic. A screening log of these patients revealed that the potential patients missed were slightly younger than the study population (mean age ± SD, 34 ± 8.9 years vs 41 ± 10.8 years, respectively; p < 0.001) but had a similar gender distribution (female gender, 66% vs 68%).

Of the 366 patients screened, 37 patients (10%) were excluded due to refusal or inability to provide consent (n = 23), anticoagulation at onset of symptoms (n = 11), and life expectancy < 3 months and inability to be followed up (n = 3). In addition, one patient was recruited but later excluded, as her initial assessment had taken place in a specialist clinic after having symptoms for > 1 month, rather than the acute care setting of the ED. This left a study population of 328 who provided written informed consent. Of these, 149 patients met the criteria for entry into group A (PE excluded), and 179 patients met the criteria for entry into group B (PE not excluded).

Study Arm A
Of the 149 participants in group A, 140 patients (94%) completed the 3-month follow-up. The remaining nine patients were unable to be contacted, but in all cases no deaths or thromboembolic events were recorded in either local or national databases. In the 140 patients there were no documented cases of PE over this initial follow-up period, giving a 3-month thromboembolic risk of 0% (95% CI, 0 to 2.1%). The negative predictive value for the algorithm in excluding PE over this 3-month period was thus 100% (95% CI, 97.9 to 100%) [Table 2 ]. Further loss of patients to follow-up resulted in 12-month data only being available for a total of 126 participants (85%); however, there were no documented deaths among any of the group A patients according to national mortality and admission database information over the 12-month follow-up period.


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  		Table 2.. Performance of Algorithm and D-dimer at 3-Month Follow-up*

 
Five participants re-presented with further symptoms suggestive of PE, and in each case this was excluded by either normal / scan or CTPA results. In the majority of cases, no formal cause of initial presenting symptom was determined, although follow-up confirmed a subsequent diagnosis in 24 of 149 patients (16%). Fourteen patients eventually received treatment for a lower respiratory tract infection, 7 patients were investigated for a cardiac cause of chest pain, 1 patient was found to have a pneumothorax that had been missed in an initial chest radiograph, and in 2 patients the symptoms were believed to be due to a rheumatologic disorder and cholelithiasis, respectively.

Study Arm B
Review of case notes was completed in 176 of the 179 patients assigned to group B. PE was confirmed in 37 patients (21%), of whom 36 patients (97%) had a positive d-dimer finding (> 250 nmol/L), 21 patients (57%) had a PaO2 < 80 mm Hg, and 21 patients (57%) had at least one identifiable risk factor for thromboembolic disease. This group included one individual with a normal d-dimer finding (172 nmol/L), but he was significantly hypoxemic at the time of enrollment and thus was not discharged as per our algorithm.

Of the 37 patients with PE, 25 diagnoses were made by CTPA and 11 diagnoses were made by / scan. PE was diagnosed in one further patient on clinical grounds, having had a previous PE 5 months earlier, with changes on / scanning that were indeterminate.

Of the 139 patients in whom PE was excluded, 17 patients had normal CTPA findings, 63 patients had normal / scan results, 1 patient had a normal pulmonary angiogram (PA) finding, and 1 patient had a normal leg vein ultrasound. Twenty-one patients underwent both / and CTPA, 1 patient underwent both CTPA and PA, and 1 patient underwent both leg vein ultrasound and PA. A further 34 subjects were deemed to have had PE excluded on clinical grounds alone with no formal diagnostic testing: musculoskeletal chest pain (n = 13), lower respiratory tract infection (n = 10), esophagitis (n = 1), renal colic (n = 1), and pulmonary metastases (n = 1); in the remaining 8 patients, no formal diagnosis was made.

D-dimer
Of the 316 patients followed up at 3 months, the initial IL Test d-dimer result was normal in 184 patients. Of this group, PE was subsequently diagnosed in one patient, giving a 3-month risk of PE of 0.5% (95% CI, 0 to 3.0%). The negative predictive value of d-dimer in excluding PE at 3 months was 99.5% (95% CI, 97.0 to 100%). Of the 132 patients with a positive d-dimer result, 36 patients had subsequently confirmed PE, giving a positive predictive value of 27.3% (95% CI, 20.4 to 35.4%) [Table 2].


   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
In this study of consecutive patients presenting to a major hospital ED over an 18-month period with suspected PE, we have demonstrated that an algorithm using a combination of risk factor assessment, PaO2 levels, and IL Test d-dimer measurement is effective in ruling out PE with a negative predictive value of > 99%. In practical terms, employing this strategy enabled us to reliably exclude PE in 149 of 329 patients (45%) presenting with suspected PE from the community to an acute care setting, without resorting to any further diagnostic testing or the use of empiric anticoagulation while awaiting further assessment.

It has been argued that a normal d-dimer alone is sufficient to exclude PE, and Perrier et al18 recently showed that the quantitative rapid ELISA method can safely do this with a 3-month thromboembolic risk of 0% (95% CI, 0 to 1.4%). However, these results cannot be extrapolated to other methods of measuring d-dimer, in which there is insufficient evidence to support their use as the sole method of excluding PE. A recent evidence-based review20 on d-dimer methods concluded that while a negative ELISA d-dimer test result was good enough to use as a stand-alone test, non-ELISA methods performed less well and could not be relied on to exclude PE when used alone. Our study has shown that when used prospectively to exclude PE, the IL Test d-dimer taken on its own has a 3-month risk of PE of 0.5% (95% CI, 0 to 3.0%), which suggests that it may be safe enough to use in isolation to exclude PE.

One limitation of this study is the relatively large number of potential subjects who were not enrolled. By keeping a screening log of all potential subjects within the recruitment period, we found that there was not a systematic bias in those who were missed, and the failure to recruit was not due to any particular patient characteristic or concern about the safety of the algorithm. Indeed, those missed were significantly younger than the study population, with a likely lower overall risk for thromboembolic disease than those recruited. Nonetheless, results are less generalizable than if all potential patients had been recruited.

The decision to exclude patients > 60 years old was made in light of the fact that over this age there is a dramatic increase in risk of PE.3 Our aim was to assess an algorithm that enabled rapid and safe exclusion of PE, and we believe that the increased risk over this age plus the likelihood of significant comorbidity would complicate what we had intended to be a simple and rapid process. Thus, these results cannot be directly extrapolated to an older population. Rather, they reflect our initial intent, which was to assess the safety of a simple strategy to rapidly exclude PE in a low-risk population.

Although the 12-month telephone follow-up was only completed in 85% of patients in group A, there is a low risk that thromboembolic events may have gone undetected in the remainder. All patients were recruited at a single center, and within New Zealand there is an accurate national database recording hospital encounters. We are thus confident that we have not missed any clinically significant events.

The overall prevalence of PE in our study population was approximately 11%. While this is similar to the prevalence of 9.2% found by Wells et al17 in a comparable study, it is low for studies of this nature in which the prevalence is usually 15 to 25%.1618 We believe that this reflects both the low-risk population we are studying and the relatively broad inclusion criteria that we have used. These features of the study reflect current practice, as d-dimer has become more widely available and is used more as a screening tool than a specific diagnostic test. As a result, our results are applicable to the setting and population we have studied, but they may not be able to be generalized to a higher-risk population such as an inpatient group or patients presenting to a specialist thrombosis service.

We were surprised to find that 43% of subjects with confirmed PE had no identifiable risk factors, given that it has been estimated that one or more predisposing factor is present in 80 to 90% of all cases of PE.27 There are a number of potential reasons for the unexpectedly low rates of risk factors in the group with confirmed PE. Our upper age limit of 60 years has meant that we have studied a relatively young population, and a number of major risk factors, such as immobility, malignancy, and previous surgery, are more common in the elderly. Similarly, such risk factors are much more prevalent in inpatient populations and are likely to be less common in the outpatient population we have studied. Finally, subjects with limited life expectancy and those already receiving anticoagulation were excluded, again factors that are likely to reduce the prevalence of major risk factors in our study population as a whole. In no case, did the presence of a risk factor alone enable diagnosis of PE that would have otherwise been missed. It is tempting to suggest that d-dimer and blood gases alone are sufficient to exclude PE, but given the numbers in our study we believe that some form of risk assessment needs to remain as part of any algorithm to exclude PE.

Of the patients screened for recruitment, one patient had normal d-dimer levels but subsequently received a diagnosis of PE. The patient presented within 24 h of the onset of symptoms, at which time the d-dimer value was 172 nmol/L, but he had a resting PaO2 of 52 mm Hg on room air and was thus assigned to group B according to our algorithm. A history of previous VTE was not documented, but the patient was later found to have had a previous PE for which he had received anticoagulation for 6 months. CTPA demonstrated multiple thrombi in the left lower lobe and in the right lower, middle, and upper lobe vessels. The diagnosis of PE was made based on this scan, and the patient was received anticoagulation during a 4-day hospital stay. We would accept this case as an example of a false-negative d-dimer result, although a specialist review suggested that CTPA changes were probably due to chronic rather than acute pulmonary thromboembolic disease. However, we believe this justifies the inclusion in the algorithm of blood gas analysis to protect against inadequate assessment for risk factors or for a false-negative d-dimer result.

The algorithm assessed in this study was not designed to provide a pathway for the management of all patients with suspected PE. Rather, it was intended to allow for rapid exclusion of PE in those patients in whom it was unlikely but could not be excluded on clinical grounds alone. We believe that these results support this approach and validate the use of the IL Test as part of a simple strategy to exclude PE in those patients who are low risk. This strategy is easily and simply applied at the bedside and has the potential to quickly identify those patients who present to the ED or after-hours services with suspected PE in whom it can be ruled out without further investigation. This approach has been proven to be safe and supports the use of the IL Test method of measuring d-dimer in this clinical setting.

In summary, we have demonstrated that a simple algorithm combining IL Test d-dimer measurement, PaO2 measurement, and risk factor assessment can safely exclude PE in a population presenting from the community to an acute care setting. These findings demonstrate the safety of using the IL Test as part of such a strategy to exclude PE, and add to the body of evidence supporting the use of d-dimer as part of the initial assessment of patients with suspected PE.


   Footnotes
 
Abbreviations: CI = confidence interval; CTPA = CT pulmonary angiography; DVT = deep vein thrombosis; ED = emergency department; ELISA = enzyme-linked immunosorbent assay; PA = pulmonary angiogram; PE = pulmonary embolism; / = ventilation/perfusion; VTE = venous thromboembolism

Received for publication November 23, 2004. Accepted for publication April 15, 2005.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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