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European Heart Journal Advance Access originally published online on November 6, 2007
European Heart Journal 2007 28(24):3067-3075; doi:10.1093/eurheartj/ehm484
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2007. For permissions please email: journals.permissions@oxfordjournals.org

D-dimer in ruling out acute aortic dissection: a systematic review and prospective cohort study

Gottfried Sodeck1, Hans Domanovits1,*, Martin Schillinger2, Marek P. Ehrlich3, Georg Endler4, Harald Herkner1 and Anton Laggner1

1 Department of Emergency Medicine, Medical University Vienna, Vienna, Austria
2 Department of Angiology, Vienna General Hospital, Medical University Vienna, Vienna, Waehringer Guertel 18-20, A- 1090 Vienna, Austria
3 Department of Cardiothoracic Surgery, Medical University Vienna, Vienna, Austria
4 Department of Laboratory Medicine, Medical University Vienna, Vienna, Austria

Received 23 March 2007; revised 19 September 2007; accepted 28 September 2007; online publish-ahead-of-print 6 November 2007.

* Corresponding author. Tel: +43 1 40400 1964; fax: +43 1 40400 1965. E-mail address: hans.domanovits{at}meduniwien.ac.at


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 Limitations
 Conclusion
 Contributions
 References
 
Aims: Blood D-dimer testing has been proposed as diagnostic marker with high sensitivity for exclusion of acute aortic dissection (AAD). We performed a systematic review and validated the findings in a prospective patient cohort.

Methods and results: We searched MEDLINE, EMBASE, CINAHL, and BIOSIS from inception until January 2007 using a combination of search terms for aortic dissection and D-dimer. Study type, type of assay used, predefined cut-off level, result of D-dimer testing, sensitivity, and specificity were abstracted. In 16 identified studies (437 patients), the reported cut-off values ranged from 0.1 to 0.9 µg/mL. D-dimer testing provided high sensitivity (0.97 95% CI 0.94–0.98) and negative likelihood ratio (0.06 95% CI 0.02–0.13). In our cohort of 65 patients (36 male, 55%; median age 59 years, IQR 49–67) with proven AAD, D-dimer levels scattered from 0.24 to 137.88 µg/mL (median 3.47; IQR 1.55–14.49). Mean NPV for the different cut-off levels ranged from 92 % for a cut-off level of 0.9 µg/mL to 100% for a cut-off level of 0.1 µg/mL in our study population.

Conclusion: Current evidence supports a routine measurement of D-dimer in excluding AAD. A D-dimer <0.1 µg/mL will exclude AAD in all cases.

Key Words: Aortic dissection • Diagnosis • D-dimer


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 Limitations
 Conclusion
 Contributions
 References
 
Acute aortic dissection (AAD) represents a catastrophic vascular emergency that requires early diagnosis and treatment.1 Currently, diagnosis or exclusion of AAD by clinical parameters remains challenging, since no biomarker for AAD diagnosis is available in clinical routine. Aortic dissection may present with a variety of clinical symptoms that may delay or even misslead correct diagnosis.2 A biomarker- aided approach to diagnose or exclude aortic dissection therefore would be desirable. In this context, recent studies proposed the measurement of normal D-dimer levels which may exclude AAD with 100% sensitivity.3–5 A validated and uniform cut-off level of normal in AAD is, however, still missing.6

In the present study, we performed a systematic review and meta-analysis of published literature to determine sensitivity and optimal cut-off level to exclude the presence of AAD by determination of D-dimer levels. We then validated the findings of the systematic review in a study population of patients with proven AAD.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 Limitations
 Conclusion
 Contributions
 References
 
Systematic review
We identified clinical trials and case reports assessing the clinical value of D-dimer levels in diagnosis of AAD. We searched MEDLINE, EMBASE, CINAHL, and BIOSIS from inception until January 2007 using an Ovid-based web interface (Ovid technologies, NY, USA). The search string was [(aorta) or (aortic) or (dissection) or (aneurysm) and/or (fibrin fragment D) or (D-dimer)]. Editorial comments, review articles, and abstracts as publications in other languages than English, German, French, Dutch, Danish, Spanish, Italian, or Portuguese were excluded from further review. We predefined a variety of endpoints for assessment of clinical validity: study design, number of patients, classification of AAD, types of assay used, predefined thresholds, levels of D-dimer, sensitivity, and specifity of D-dimer measurement in diagnosis of AAD.

Two reviewers (G.H.S. and H.D.) independently abstracted data from each trial and entered the data in a predefined database. We compared the results and resolved disagreement by discussion among reviewers.

Validation of test sensitivity in a prospective cohort of acute aortic dissection patients
All patients with acute Stanford A aortic dissection presenting to a tertiary care non- trauma emergency department (Department of Emergency Medicine, Medical University Vienna, Austria) were eligible for study participation. The inclusion period was set between January 2003 to January 2007.

Demographic data and time from onset of clinical symptoms to presentation to the emergency department were recorded in a comprehensive database.

D-dimer was measured immediately after establishment of correct diagnosis. For determination of quantitative D-dimer values, STA® latex-agglutination test (Roche Diagnostics Vienna, Austria) was used according to the manufacturer's recommendations. The test has a lower detection limit of 0.04 µg/mL with a coefficient of variation of 10%.

All study-related procedures were in accordance with the ethical standards of the responsible committee of the Vienna Medical School.

Statistics and study endpoint
Systematic review
Continuous data are presented as the median and the interquartile range and the mean and the corresponding standard deviation, as appropriate. In articles reporting the median and the interquartile range, we took the median to be representative of the mean and converted the interquartile range into a standard deviation by dividing it by 1.35.7

We calculated a summary estimate for the true positive rate (sensitivity) using the ‘meta’ command in STATA. To handle statistical heterogeneity and to yield comparable results, we used random effect models to produce summary true positive rates. Metaregression using the ‘metareg’ command in STATA was performed to extend the random effects meta-analysis. We estimated the extent to which the cut-off value explains heterogeneity in the true positive rate. To estimate the additive between studies variance tau2 a moment estimator, using a non-iterative procedure was employed to comply with estimates of the random-effects meta-analysis. We used MS Excel 2003, STATA 8.2 (Intercooled Stata 8.2 for Windows, StataCorp LP, Houston, TX, USA), and Meta-DiSc V 1.4 (Unidad de Biostatistica Clinica, Hospital Ramon y Cajal, Madrid, Spain) for data management and calculations. Statistical heterogeneity was assessed using the I2 statistic.8 Metaregression was only performed for sensitivity as this is the parameter of main interest and there were enough studies to perform sufficient analysis. Likelihood ratio parameters, DOR, and summary-ROC estimates are based on studies where both diseased and non-diseased populations were available.

Reporting and grading of quality of evidence were performed according to the MOOSE, GRADE, QUADAS statement, respectively9–11 (Tables 1 and 2).


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  		Table 1 MOOSE statement

 

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  		Table 2 QUADAS statement

 
Prospective cohort study
Sample size estimations for the prospective cohort study were precision based, since no formal hypothesis was tested. At a given sample of 60 patients and assuming one negative patient among those, the yielded exact confidence interval ranged from 0.9106 to 0.9996. Discrete data are given as counts and percentages. Linear (Pearson) correlation was applied to test for correlation between admission levels and time of onset of symptoms. We applied sensitivity analysis to validate proposed cut-off levels of D-dimer in AAD in our study population. We sought to determine the optimal threshold level to exclude the presence of AAD on the base of D-dimer measurement at the emergency department. Finally, we calculated negative predictive values for AAD for the different D-dimer cut-off levels based on the calculated test sensitivities and a previously published prevalence of AAD in unselected patients with chest pain at our institution.12 Calculations were performed with SPSS for Windows (version 10.0). A two-sided P-value less than 0.05 was considered statistically significant.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 Limitations
 Conclusion
 Contributions
 References
 
Systematic review
The electronic search of databases resulted in 43 hits, and we retrieved 32 publications for closer inspection after deleting double-hits. Of these, 16 studies were either editorial comments,2,6,13 reviews,5,14–19 studies in other languages as predefined,2,20,21 or non-diagnostic;5,22–27 therefore 16 articles were then potentially eligible for further review3–5,28–40 (Figure 1).


Figure 1
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  		Figure 1 Progress through the stages in selecting studies for final analysis.

 
The clinical and methodological characteristics of the trials that reported at least one of the endpoints of interest are presented in Table 3. The diagnostic value of elevated D-dimer levels in AAD was evaluated in an overall population of 437 patients. In most of the instances, a cohort study design was applied;3–5,29–34,38 in nine trials, a control group of patients with chest pain was included.4,5,30–32,34,37,40


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  		Table 3 Clinical and methodological characteristics of trials, assessing the diagnostic value of D-dimer in acute aortic dissection

 
Measurement of D-dimer levels was performed using three different types of assays; ELISA in three,28,32,37 immunoturbidimetric in four,3,5,30,32 and latex agglutination test in another seven studies.4,12,23,25,30,33,36 In one study, two different assays were evaluated simultaneously.32

The reported diagnostic cut-off values ranged between 0.1 and 0.9 µg/mL. Absolute D-dimer levels in patients with AAD are given in detail in Table 4 (ranged between mean 0.98 and 10.10 µg/mL).


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  		Table 4 As total quantitative D-dimer values differed among the studies, cut-off values were highly variable, ranging from 0.1 to 0.9 µg/mL

 
Fifteen of 437 patients with AAD were reported to be D-dimer negative,30,31,37,38,40 test sensitivity ranged from 92 to 100%; further details are presented in Table 5.


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  		Table 5 Sensitivity and specifity of D-dimer measurement in diagnosis of acute aortic dissection

 
Overall, the observer agreement regarding the various components of the data extraction form reached nearly 100%. Both reviewers assigned a high clinical grade of evidence of measurement of D-dimer levels in exclusion of AAD.

Meta analysis
D-dimer testing provided high sensitivity (0.97 95% CI 0.94–0.98, I2 = 47.1%) and negative likelihood ratios (0.06 95% CI 0.02–0.13, I2 = 0.0%) within narrow confidence intervals. Summary receiver operating characteristic (SROC) curve yielded a high certainty for excluding AD on base of negative results (AUC 0.94) (Figure 2).


Figure 2
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  		Figure 2 Summary receiver operating characteristic (SROC) curve for excluding AAD on base of negative D-dimer testing (AUC 0.94).

 
Pooled specifity (0.59 95% CI 0.53–0.64, I2 = 0.0%) and positive likelihood ratios (2.58 95% CI 1.76–3.78, I2 = 0.0%) did not greatly increase the certainty of diagnosis of AD. The pooled diagnostic odds ratio was 21.27 (95% CI 11.64–38.88, I2 = 0.0%).

Meta regression revealed no influence of the cut-off value on sensitivity (DOR 1.00 95% CI 0.72–1.40, P = 0.99).

Validation of test sensitivity in a prospective cohort of acute aortic dissection patients
We identified 65 out of 70 patients with AAD diagnosed at our institution who met the inclusion criteria for further analysis (36 male, 55%; median age 59 years, IQR 49–67) (Figure 3). The median time from onset of leading symptoms to hospital admission was 4.8 h (IQR 2.4–16). Acute chest pain was the leading symptom in 43 (66%) patients. D-dimer levels at initial presentation were scattered over a wide range from 0.24 to 137.88 µg/mL (median 3.47; IQR 1.55–14.49), respectively (Figure 4). There was no correlation between admission level and time of onset of symptoms (corrected R2: 0.008, P = 0.48). Further demographic details are depicted in Table 6.


Figure 3
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  		Figure 3 Trial flow of the prospective cohort study.

 

Figure 4
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  		Figure 4 There was no correlation between D-dimer levels and time of onset of symptoms (corrected R2: 0.008, P = 0.48; n = 65).

 

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  		Table 6 Descriptive characteristics of the cohort

 
Sensitivity analysis
Applying the lowest reported cut-off value of 0.1 µg/mL, 100% sensitivity to exclude AAD based on D-dimer measurement could be achieved in our study population. Applying 0.5 µg/mL, as proposed by 7 out of 16 trials,3,5,28,32,35,36,38 diagnosis of AAD would have been missed in one patient (sensitivity 98%) in our cohort. Diagnostic sensitivity further decreases to 86% at highest reported threshold level of 0.9 µg/mL;31 applying this cut-off would have resulted in nine false-negative patients in our cohort.

Negative predictive values for different D-dimer cut-off levels ranged from 92 to 100%, assuming a prevalence of 0.23% of AAD in unselected patients presenting with acute chest pain to an emergency department12 (Figure 5).


Figure 5
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  		Figure 5 Negative predictive value analysis of D-dimer testing, stratified to different cut-off values, arbitrary to individual test specifity.

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
Limitations
 Conclusion
 Contributions
 References
 
We present a systematic review assessing the diagnostic sensitivity of serum D-dimer measurement in the clinical setting of AAD. We found that AAD can be ruled out safely by negative D-dimer testing.

Serum D-dimer is elevated due to endogenous fibrinolytic activity naturally counteracting the activation of the extrinsic pathway of the coagulation cascade.3–6 Routine measurement has already been recommended as part of the pre-operative work-up with proven AAD from the Task Force of the European Society of Cardiology.2 Recognized to be a reliable biomarker to exclude pulmonary embolism,41 it was first to Weber et al.5 in 2003 to report in a small case series about the clinical value of D-dimer testing in AAD. In subsequent studies, the value of D-dimer testing in AAD has been evaluated in a total of 437 patients so far.

Currently, diagnosis and exclusion of AAD remain challenging, since clinical examination is insufficient to exclude AAD and no biomarker is available for clinical routine;1,42 guidelines recommend to perform transesophageal echocardiography, computed tomography, or even angiography in any case of suspected aortic dissection.2 These diagnostic procedures are more or less invasive and expensive, with limited availability at different settings, and bear potential serious side effects. Therefore, D-dimer measurement for exclusion of AAD represents an advance in diagnostic pathways in patients with suspected AAD.

Our systematic review, meta-analysis, and prospective cohort study and a very recent meta-analysis by Marill43 show that D-dimer may represent a highly sensitive biomarker: exclusion of AAD based on D-dimer levels at a threshold of 0.1 µg/mL may be achieved with 100% sensitivity. At a cut-off level of 0.5 µg/mL, which represents the most commonly clinical used value for exclusion of pulmonary embolism,41 a negative predictive value of 99% will be still achieved. However, we found the reported diagnostic cut-off values to be heterogeneous, ranging between 0.1 and 0.9 µg/mL. Further-on, three different assay types have been applied in measurement of quantitative D-dimer values in the reported studies.3–5,28,30–33,35,37,38,40 This might explain, why a total of 15 patients were reported to be D-dimer false negative. It should be therefore kept in mind that particular D-dimer assays with predefined cut-off levels will differ in sensitivity and negative predictive value in patients with suspected AAD.41

Applying D-dimer testing as a rapid point of care test will help to risk stratify patients at a very early time-point and might result in a significant reduction for advanced imaging procedures. It has to be noticed that D-dimer measurement is only unidirectional due to its lack of specificity; a negative result should be used in the diagnostic pathway to exclude AAD: in patients with a low and intermediate suspicion of AAD, a negative D-dimer may be sufficient to rule out disease. In patients with a high clinical likelihood of AAD, however, appropriate imaging should be still performed, even in presence of negative D-dimer testing, since prospective controlled studies for this strategy are missing.

A positive result will be found in patients with AAD and other life-threatening conditions like pulmonary embolism or non-serious clinical conditions. This fact somewhat might limit the clinical utility of the D-dimer testing in AAD.


   Limitations
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Limitations
Conclusion
 Contributions
 References
 
Only two papers were excluded because there was no abstract available in English or in another predefined language.20,21 From their titles, it was doubtful that these were clinical trials reporting about the diagnostic sensitivity of D-dimer measurement in AAD, but we could not confirm. Some limitations of the drawn conclusions from the meta-analysis, however, have to be acknowledged. D-dimer assays will differ in sensitivity and negative predictive value in patients with suspected AAD. Even more, some D-dimer assays coefficients of variation will be high at our proposed 0.1 µg/mL cut-off value. Therefore, the most straightforward approach for determining the accuracy and cut-off of a diagnostic test would be to carry out a prospective, cross sectional study in unselected patients, with independent, blinded assessments of test and reference methods.

In patients with intermediate suspicion of AAD sample size of our own study population is modest when it comes to random variability; therefore, our findings ideally need confirmation in a larger cohort of patients. Selection bias might be a minor confounder, since 93% of the screening population could be included in our study design. However, this was a prospective, observational case series of consecutive patients with proven AAD and sensitivity of D-dimer measurement in exclusion of AAD in our study population is in line with previous investigations.


   Conclusion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Limitations
 Conclusion
Contributions
 References
 
Up to now, various non-invasive and invasive diagnostic steps are required to diagnose or to rule-out AAD in case of clinical suspicion. Determination of D-dimer in clinical routine may represent a valuable addition to the current diagnostic work-up of patients with suspected AAD. The measurement of this biomarker is likely to help triage patients and stratify them according to the urgency for more sophisticated diagnostic steps. Appropriate imaging is always required for definite diagnosis and confirmation of clinically suspected AAD. A negative D-dimer testing however will exclude the presence of AAD in up to 100% of instances.


   Contributions
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Limitations
 Conclusion
 Contributions
References
 
G.H.S.: study design, data management, statistics, first draft, final draft, and approval; H.D.: study design, scientific and statistic advisory, study monitoring, final draft, and approval; M.S.: statistics, final draft, and approval; M.P.E.; data collection, final draft, and approval; G.E.: analysis, data collection, final draft, and approval; H.H.: design, statistics, final draft, and approval; A.N.L.: design, scientific and statistic advisory, final draft, and approval.

Conflict of interest statement. None declared.


   References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 Limitations
 Conclusion
 Contributions
 References
 

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