A Systematic Review and Meta-analysis of D-dimer as a Rule-out Test for Suspected Acute Aortic Dissection

doi:10.1016/j.annemergmed.2015.02.013

Annals of Emergency Medicine

Volume 66, Issue 4, October 2015, Pages 368-378

https://doi.org/10.1016/j.annemergmed.2015.02.013 Get rights and content

Study objective

The aim of this systematic review and meta-analysis is to determine the diagnostic accuracy of D-dimer as a rule-out test for acute aortic dissection. Previous meta-analyses have had methodological problems with conflicting conclusions, and new diagnostic accuracy studies have been published since.

Methods

All prospective cross-sectional analytic studies of D-dimer as a diagnostic test for acute aortic dissection were included where diagnosis was confirmed by an accepted reference standard. Studies were identified with MEDLINE, EMBASE, Medion, Google Scholar, Web of Science, and bibliographies of relevant articles and previous systematic reviews. Two reviewers independently screened articles for inclusion, assessed study quality, and extracted data.

Results

Abstracts from 800 articles were reviewed, yielding 30 potentially relevant studies that were reviewed in full text. Five studies met all eligibility criteria. Data from 4 studies (1,557 participants) that used a D-dimer cutoff of 0.50 μg/mL were pooled to estimate sensitivity, specificity, and positive and negative likelihood ratios. Overall, sensitivity and negative likelihood ratio were 98.0% (95% confidence interval [CI] 96.3% to 99.1%) and 0.05 (95% CI 0.03 to 0.09), respectively. These measurements had little statistical heterogeneity. Specificity (41.9%; 95% CI 39.0% to 44.9%) and positive likelihood ratio (2.11; 95% CI 1.46 to 3.05) showed significant statistical heterogeneity. When applied to a low-risk population as defined by the American Heart Association (prevalence 6%), the posttest probability for acute aortic dissection was 0.3%.

Conclusion

This meta-analysis suggests that a negative D-dimer result may be useful to help rule out acute aortic dissection in low-risk patients.

Introduction

Acute aortic dissection is a disorder with a high mortality rate of 1% to 2% an hour if not treated promptly.1, 2 Clinicians must have a low threshold to consider this lethal disease, but there are limited screening tools to rule it out without resorting to advanced imaging. Current guidelines recommend performing computed tomography (CT), magnetic resonance imaging (MRI), or transesophageal echocardiography to identify or exclude acute aortic dissection.³ These diagnostic imaging techniques are expensive and time consuming, carry risks of radiation exposure and contrast reactions, and are not accessible in all hospitals. A rapid, economical, and accessible biomarker used as a screening or triage test for acute aortic dissection could reduce the number of invasive diagnostic procedures and reduce the time necessary to exclude acute aortic dissection.

Editor’s Capsule Summary

What is already known on this topic

Individual studies have shown various results on the diagnostic utility for D-dimer in patients with acute aortic dissection.

What question this study addressed

To determine the utility of a negative D-dimer result to rule out aortic dissection.

What this study adds to our knowledge

In this systematic review of 5 studies, with little statistical heterogeneity in sensitivity, the pooled sensitivity was 98% (95% confidence interval 96% to 99%). Results for specificity were heterogeneous; pooled specificity was 42% (95% confidence interval 39% to 45%).

How this is relevant to clinical practice

Although not definitive, this meta-analysis suggests that sensitivity may be sufficiently high to rule out aortic dissection in low-risk patients with a negative test result.

During the past decade, there have been many studies published on the use of D-dimer as a rule-out test for acute aortic dissection. This literature has also been summarized and pooled in 6 systematic reviews or meta-analyses.4, 5, 6, 7, 8, 9 The conclusions have been conflicting despite largely the same literature’s being evaluated in each review. However, all of these conclusions are far from robust because of the inclusion of low-quality studies. Many included studies were retrospective chart reviews, case series, and case-control studies, designs that provide unreliable estimates of diagnostic accuracy that tend to be overly optimistic.¹⁰ There were also design flaws in these systematic reviews,¹¹ such as single reviewers rather than 2 independent reviewers of the literature,5, 8, 9 lack of peer review,⁹ lack of a formal quality assessment of included studies,5, 6, 8 and overly generous assessment of study quality.4, 7 As an example, the first question in the quality assessment of diagnostic accuracy studies (QUADAS) quality assessment tool¹² was frequently answered yes by reviewers4, 7 despite the tool’s directing reviewers to score studies of case-control design as no. Furthermore, we are aware of several prospective diagnostic accuracy studies published in the last 5 years that were not included in these reviews.

For these reasons, an up-to-date systematic review and meta-analysis using only prospective diagnostic accuracy studies of a cross-sectional design (the ideal for the assessment of triage tests) was warranted. Our clinical question was, In patients presenting to the hospital with suspected acute aortic dissection, can a negative D-dimer result rule out this diagnosis? The aim was to determine the sensitivity, specificity, and positive and negative likelihood ratios of the D-dimer test for the diagnosis of acute aortic dissection. We also planned to discuss how the results of this meta-analysis could be used as part of an algorithm to evaluate patients with suspected acute aortic dissection.

Section snippets

Materials and Methods

A computer-aided search of MEDLINE (1946 to July 2014) and EMBASE (1974 to July 2014) was conducted through the OVID SP Web site (https://ovidsp.ovid.com), using the search strategies outlined in Table 1. No limits were applied to the search strategy. A search of the Medion database (http://www.mediondatabase.nl/) was performed in July 2014. The category “Circulation” was selected for “ICPC code” and the categories “Laboratory tests” and “Medical Imaging” were selected for “Signssymp.” We

Results

Eight hundred studies were identified through the database searches (Figure 1). After the exclusion of duplicates, nonrelevant studies, and other studies that met exclusion criteria on screening of the title and abstract, 30 potentially relevant studies were retrieved for full review. Four of these studies were published in Chinese journals and only the title was available. We were unable to obtain either the abstract or full text. A further 3 foreign-language studies (French, Dutch, and

Limitations

Several limitations should be considered when interpreting the results of this study. The accuracy of the estimates of test characteristics depended on the quality of the included studies. The main problem with the included studies was that authors failed to report important aspects of methodology that would allow the reader to determine the likelihood for bias, such as whether the D-dimer result was available to individuals enrolling participants, and timing of index and reference test.

Discussion

Our study was designed to evaluate the diagnostic performance of D-dimer for the diagnosis of acute aortic dissection. The major strength of this meta-analysis is that we included only diagnostic accuracy studies that enrolled patients prospectively and were of a design that provided reliable estimates of test parameters. The included studies were all of moderate or higher methodological quality. This meta-analysis demonstrated the D-dimer result to be a potentially useful risk-stratification

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D-dimer measurement is useful irrespective of time from the onset of acute aortic syndrome symptoms
2023, American Journal of Emergency Medicine
In acute aortic syndrome (AAS) screening, D-dimer is a well-established biomarker whose usefulness has been scarcely studied with respect to its measurement timing. We aimed to evaluate the effectiveness of D-dimer-based AAS screening focused on the time interval between AAS onset and D-dimer measurement.
We retrospectively analyzed consecutive patients diagnosed with AAS who visited our hospital between 2011 and 2021. For the primary analysis, we divided patients according to the quartiles of the time interval between AAS symptom onset and D-dimer measurement. D-dimer level ≥ 0.5 μg/mL and age-adjusted D-dimer ≥ [age (years) × 0.01] μg/mL (minimum of 0.5 μg/mL) were defined as positive. The primary endpoint was the comparative ability of D-dimer to detect AAS within and between each time quartile. In an exploratory secondary analysis, we reported patient and AAS characteristics in the subgroup of patients who underwent repeat D-dimer measurement within 48 h of the first D-dimer measure.
The 273 AAS patients were divided into four groups based on quartiles of the time interval (Group 1, ≤1 h; Group 2, 1–2 h; Group 3, 2–5 h; and Group 4, >5 h). There were no significant differences in D-dimer levels or in the proportions with positive D-dimer (Group 1: 97%, Group 2: 96%, Group 3: 99%, Group 4: 99%; P = 0.76) or positive age-adjusted D-dimer (Group 1: 96%, Group 2: 90%, Group 3: 96%, Group 4: 97%; P = 0.32) between the groups. Of the 147 patients who had D-dimer re-measured, nine had negative D-dimer levels on either the primary or secondary measurement. Of these nine patients, eight had AAS with a thrombosed false lumen and one with a patent false lumen had a short length of dissection. In all nine patients, D-dimer levels remained low (maximum of 1.4 μg/mL).
D-dimer levels were elevated from the early stages of AAS. The clinical utility of D-dimer is not affected by the time interval from AAS onset to D-dimer measurement, but rather is influenced by AAS characteristics.
Improvement in the management of suspected acute aortic syndrome in the emergency room through a clinical algorithm and study of predictive factors
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El síndrome aórtico agudo (SAA) es poco frecuente y difícil de diagnosticar, con una gran variabilidad en su cuadro clínico inicial. Los objetivos son: 1) desarrollar un algoritmo informático, o un sistema de apoyo a las decisiones clínicas (SADC), para el manejo y la solicitud de estudios de diagnóstico por imagen en el servicio de Urgencias, en concreto de una tomografía computarizada (TC) de la aorta, ante la sospecha de SAA, 2) determinar el efecto de la implantación de este sistema, y 3) determinar los factores asociados a un diagnóstico radiológico positivo que mejoren la capacidad predictiva de los hallazgos de la TC de aorta.
Tras desarrollar e implementar un algoritmo basado en la evidencia, se estudiaron casos de sospecha de SAA. Se utilizó el test de la χ² para analizar la asociación entre las variables incluidas en el algoritmo y el diagnóstico radiológico, con 3 categorías: sin hallazgos relevantes, positivo para SAA y diagnósticos alternativos.
Se identificaron 130 solicitudes; 19 (14,6%) tenían SAA y 34 (26,2%) tenían otra patología aguda. De las 19 con SAA, 15 habían sido estratificadas como de alto riesgo y 4 como de riesgo intermedio. La probabilidad de SAA era 3,4 veces mayor en los pacientes con aneurisma aórtico conocido (p = 0,021, IC del 95%: 1,2-9,6) y 5,1 veces mayor en los pacientes con un soplo de insuficiencia vascular aórtica de novo (p = 0,019, IC del 95 %: 1,3-20,1). La probabilidad de tener una enfermedad aguda grave alternativa fue 3,2 veces mayor en los pacientes con hipotensión o choque (p = 0,02, IC del 95 %: 1,2-8,5).
El uso de un SADC en el servicio de Urgencias puede ayudar a optimizar el diagnóstico del SAA. Se demostró que la presencia de un aneurisma aórtico conocido y de insuficiencia valvular aórtica de nueva aparición aumentan significativamente la probabilidad de SAA. Se necesitan más estudios para establecer una regla de predicción clínica.
Acute aortic syndrome (AAS) is uncommon and difficult to diagnose, with great variability in clinical presentation. To develop a computerized algorithm, or clinical decision support system (CDSS), for managing and requesting imaging in the emergency department, specifically computerized tomography of the aorta (CTA), when there is suspicion of AAS, and to determine the effect of implementing this system. To determine the factors associated with a positive radiological diagnosis that improve the predictive capacity of CTA findings.
After developing and implementing an evidence-based algorithm, we studied suspected cases of AAS. Chi-squared test was used to analyze the association between the variables included in the algorithm and radiological diagnosis, with 3 categories: no relevant findings, positive for AAS, and alternative diagnoses.
130 requests were identified; 19 (14.6%) had AAS and 34 (26.2%) had a different acute pathology. Of the 19 with AAS, 15 had been stratified as high risk and 4 as intermediate risk. The probability of AAS was 3.4 times higher in patients with known aortic aneurysm (P = .021, 95% CI 1.2–9.6) and 5.1 times higher in patients with a new aortic regurgitation murmur (P = .019, 95% CI 1.3–20.1). The probability of having an alternative severe acute pathology was 3.2 times higher in patients with hypotension or shock (P = .02, 95% CI 1.2–8.5).
The use of a CDSS in the emergency department can help optimize AAS diagnosis. The presence of a known aortic aneurysm and new-onset aortic regurgitation were shown to significantly increase the probability of AAS. Further studies are needed to establish a clinical prediction rule.
Descending thoracic aortic emergencies: Past, present, and future
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The most important descending thoracic aortic (DTA) pathologies are aneurysms, dissections, and traumatic injuries. In acute settings, these conditions can constitute a significant risk of bleeding or ischemia of vital organs, resulting in a fatal outcome. Morbidity and mortality associated with aortic pathologies remain significant, despite improvements in medical therapy and endovascular techniques. In this narrative review, we present an overview of the transitions in the management of these pathologies and discuss current challenges and future perspectives. Diagnostic challenges include differentiating between thoracic aortic pathologies and cardiac diseases. Efforts have been made to identify a blood test that can rapidly differentiate these pathologies. Computed tomography is the cornerstone of diagnosing thoracic aortic emergencies. Our understanding of DTA pathologies has improved substantially due to the significant advancement in imaging modalities in the last 2 decades. On the basis of this understanding, the treatment of these pathologies has been revolutionized. Unfortunately, robust evidence from prospective and randomized studies is still lacking for the management of most DTA diseases. Medical management plays a crucial role in achieving early stability during these life-threatening emergencies. This includes intensive care monitoring, heart rate and blood pressure control, and considering permissive hypotension for patients presenting with ruptured aneurysms. Over the years, surgical management of DTA pathologies changed from open repair to endovascular repair with dedicated stent-grafts. Techniques in both spectrums have improved substantially.
Acute aortic syndromes: An internist's guide to the galaxy
2022, European Journal of Internal Medicine
Citation Excerpt :
In a recent metanalysis (n = 3804), pooled sensitivity of DD alone (cutoff of 500 ng/mL) was 98% (96.3%−99.1%), specificity was 41.9% (39.0%−44.9%), LR+ was 2.1 (1.5–3.1) and LR- was 0.05 (0.02–0.09) [55]. DD's gap in specificity is due to unspecific increase in several conditions affecting coagulation and inflammation, such as PE, sepsis, trauma, hemorrhage, cancer and advanced age [55]. Several studies, including a large prospective trial from our group (n = 1850), have shown that low probability (ADD-RS ≤1) plus negative DD (<500 ng/mL) rule-out AAS with a sensitivity of 98.9% (97.9–99.9%) and a failure rate <1%, corresponding to a missed case every 167 patients [55,56].
Acute aortic syndromes (AASs) are severe conditions defined by dissection, hemorrhage, ulceration or rupture of the thoracic aorta. AASs share etiological and pathophysiological features, including long-term aortic tissue degeneration and mechanisms of acute aortic damage. The clinical signs and symptoms of AASs are unspecific and heterogeneous, requiring large differential diagnosis. When evaluating a patient with AAS-compatible symptoms, physicians need to integrate clinical probability assessment, bedside imaging techniques such as point-of-care ultrasound, and blood test results such as d-dimer. The natural history of AASs is dominated by engagement of ischemic, coagulative and inflammatory pathways at large, causing multiorgan damage. Medical treatment, multiorgan monitoring and outcome prognostication are therefore paramount, with internal medicine playing a key role in non-surgical management of AASs.
D-dimer for screening of aortic dissection in patients with ST-elevation myocardial infarction
2022, American Journal of Emergency Medicine
Citation Excerpt :
Recently, a clinical prediction score for AAD, Aortic Dissection Detection Risk Score (ADD-RS), was developed, in which predisposing conditions, pain features, and physical examination findings were used to calculate a 0–3 score with (Table 1) [9]. Moreover, D-dimer testing has been reported to have high sensitivity (98–99%) to diagnose AAD in patients at low-moderate probability with a cut-off value of 500 ng/ml fibrinogen equivalent units (FEU) [10,11]. Notably, a point-of-care D-dimer analyzer capable of measuring in 10 min at bedside has been developed and used clinically [12].
Acute aortic dissection (AAD) with concurrent ST-segment elevation myocardial infarction (STEMI) is relatively rare and sometimes overlooked. As D-dimer testing has been reported to have high sensitivity to diagnose AAD in a clinical scale, Aortic Dissection Detection Risk Score (ADD-RS), a point-of-care D-dimer analyzer capable of measuring in 10 min would be useful to deny AAD with concurrent STEMI. However, an optimal cut-off value of D-dimer in such population remains unclear. Therefore, the aim of this study was to elucidate the optimal D-dimer threshold in patients clinically diagnosed with STEMI.
This retrospective cohort study was conducted at two tertiary care centers between 2014 and 2019. Patients clinically diagnosed with STEMI who underwent serum D-dimer measurement on hospital arrival were included. The primary outcome was the diagnosis of AAD. The area under the receiver operating characteristic curve (AUROC) for D-dimer values to diagnose AAD was evaluated, particularly in patients with low to moderate risks of AAD (1 of ADD-RS). The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated with several cut-off values.
A total of 322 patients were included, and 28 were diagnosed with AAD. The AUROC for D-dimer to diagnose AAD was 0.970 (95% confidence interval: 0.948–0.993) in 262 patients with 1 of ADD-RS. If D-dimer ≥750 ng/mL was used as a cut-off value, sensitivity, specificity, PPV and NPV were 100%, 86.4%, 37.7%, and 100%, respectively. AAD could be denied in 209 (79.8%) patients using the cut-off value (D-dimer <750 ng/mL).
Serum D-dimer ≥750 ng/mL exhibited high sensitivity and NPV to diagnose AAD with concurrent STEMI, while the ADD-RS originally utilized ≥500 ng/mL as a cut-off for any suspected AAD. A point-of-care D-dimer measurement with the new cut-off would be useful to rule-out AAD among patients with STEMI.

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: Supervising editor: Deborah B. Diercks, MD

: Funding and support: By Annals policy, all authors are required to disclose any and all commercial, financial, and other relationships in any way related to the subject of this article as per ICMJE conflict of interest guidelines (see www.icmje.org). The authors have stated that no such relationships exist.

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Cardiology/systematic review/meta-analysisA Systematic Review and Meta-analysis of D-dimer as a Rule-out Test for Suspected Acute Aortic Dissection

Study objective

Methods

Results

Conclusion

Introduction

Editor’s Capsule Summary

Section snippets

Materials and Methods

Results

Limitations

Discussion

Chest

Am J Cardiol

J Emerg Med

Ann Emerg Med

Int J Cardiol

J Nanjing Med University

The International Registry of Acute Aortic Dissection (IRAD): new insights into an old disease

JAMA

Circulation

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

Eur Heart J

Detection of acute thoracic aortic dissection with D-dimer

Emerg Med J

Empirical evidence of design-related bias in studies of diagnostic tests

JAMA

Conducting systematic reviews of diagnostic studies: didactic guidelines

BMC Med Res Methodol

The development of QUADAS: a tool for the quality assessment of studies of diagnostic accuracy included in systematic reviews

BMC Med Res Methodol

Does this patient have an acute thoracic aortic dissection?

JAMA

Systematic reviews of diagnostic test accuracy

Ann Intern Med

Cardiology/systematic review/meta-analysis
A Systematic Review and Meta-analysis of D-dimer as a Rule-out Test for Suspected Acute Aortic Dissection