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Three Part Question

In [patient with suspected non-traumatic aortic dissection] does [negative D- dimer] predict [absence of aortic dissection]?

Clinical Scenario

A 56 years old male, who is a smoker and known case of hypertension not on any medication as well as known case of severe Gastro-eosophageal reflux disease attended emergency department with sever tearing pain retrosternally radiating to back. Examination did not reveal anything significant, and he remains heamodynamically stable through-out . Serial ECG and troponine are negative. Chest x-ray does not show any widening of mediastinum or any other evidence suggestive of Aortic dissection. Still the possibility of aortic dissection was considered due to the nature of the pain hence; D- dimer was send and the result was negative. I was wondering is it sensitive enough to rule out aortic dissection?

Search Strategy

I conducted an electronic search of MEDLINE, EMBASE, CINAHL, BIOSIS, and the Cochrane Central Register of Controlled Trials using the terms “aortic dissection” and “D-dimer”. Limited to English-language, Publications of consecutive case series of acute aortic dissection and a measured D-dimer were mainly included.
There were few systemic review and meta-analysis which were included as well in the discussion.
This search yielded 99 research articles, most of which were irrelevant. I reviewed all citation abstracts, and only original published research articles that addressed the use of D-dimer as a diagnostic tool for acute aortic dissection were included. Ten original research articles were identified that
directly addressed the use of D-dimer in acute aortic dissection.

Search Outcome

Altogether 99 papers were found of which 10 were directly relevant to the three part question.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Wen et al 2013 China	114 patients with acute aortic dissection.	A single-centre prospective study.(1b)	To evaluate the role of D-dimer and C reactive protein (CRP) in predicting inhospital death in acute aortic dissection	Increased levels of plasma D-dimer (9.84±3.53vs 4.28±1.99, P < 0.001), and aortic diameter (45.2±9.5 vs40.3±6.0, p = 0.007) were found in dead patients compared with those survived. Moreover, plasma D-dimer concentrations in type A were higher than that in type B. D-dimer and CRP levels and the type of aortic dissection were strongly associated with inhospital mortality. The OR and 95% CI were 3.272, 1.638 to 6.535; 2.322, 1.134 to 4.757; and 0.126, 0.019 to 0.853, respectively. Furthermore, the sensitivity and specificity of D-dimer ≥5.67 μg/mL in predicting inhospital death in acute AD were 90.3% and 75.9% (95% CI 0.85 to 0.96), respectively.	Small numbers. The cut off value for D-dimer 5.67 mic.g/ mL preseneted higher specifity but lower sensivity. The elevated D- dimer in the elderly were not simply due to aortic dissection with could induce false positive.
Ersel et al 2010 Turkey	113 case with D-dimer perior to CTA scan 14 patient excluded from the study due to re-attence in the study period, missing data in the chat and acute aortic rupture. 99 patient were inrolled in the study. Controled group were selected from the patient and named non AD group in whom AD has been rolled out and D-diamer was performed.	A retrospective chart review. (2C)	To determine the diagnostic accuracy of D-dimer testing for detection of acute aortic dissection.	99 patients were included in the study, 30 patients were diagnosed as having acute aortic dissection and 69 patients were evaluated in non-acute aortic dissection group. In comparison of the two groups, positive D-dimer results were found to be significantly higher in acute aortic dissection group than in non-acute aortic dissection group (p<0.001). Sensitivity of the D-dimer test in detection of acute aortic dissection was found as 96.6% and the negative predictive value of the test was 97.3%. Specificity and positive predictive value of the D-dimer test were 52.2% and 46.8%, respectively. The area under the ROC curve yielded an acceptable certainty for excluding acute aortic dissection on base of negative results (AUC: 0.764; CI 95%: 0.674-0.855; p<0.001)4.	The retrospective nature of the study is a methodological limitation because the evaluation and management were not standardized. The study analyzed D-dimer results in retrospectively created patient groups, and it cannot completely rule out that selection bias may have influenced the results of this study. In the study exact D-dimer levels over 0.771 μg/ml were not assessed. Because of, 18 patients in AAD and 6 patients in non-AAD groups had a D-dimer value over 0.771 μg/ml, a reliable statistical analysis was not possible
Suzuki et al 2009 Japan	220 patients with initial suspicion of having acute aortic dissection were enrolled, of whom 87 were diagnosed with acute aortic dissection and 133 with other final diagnoses.	prospective multicenter study.(1b)	The diagnostic performance of D-dimer testing in a study population of patients with suspected aortic dissection	D-dimer was markedly elevated in patients with acute aortic dissection. Analysis according to control disease, type of dissection, and time course showed that the widely used cutoff level of 500 ng/mL for ruling out pulmonary embolism also can reliably rule out aortic dissection, with a negative likelihood ratio of 0.07 throughout the first 24 hours	The major limitation of this study lies in the sample size. The accuracy of the analysis was limited because of subanalysis resulted in categorical groups which contained few cases. Another limitation of the study is that the entry criterion was suspicion of aortic dissection and not chest pain per se, which limits the generality of the findings in attempts to extend the interpretations to patients with chest pain in general
Sodeck et al 2007 Austria	65 patients with Stanford A acute aortic dissection, presenting to a tertiary care non-trauma ED.	prospective observational study. (1b)	D- dimaer in rulling out acute aortic dissection	D-dimer levels ranged from 0.24 to137.88 _g/mL (median 3.47 _g/mL). Sensitivity was reported as 100% (95% CI 93.1% to 100%) using 0.1 _g/mL, 98% (95% CI 90.6% to 99.9%) using 0.5 _g/mL, and 86% (95% CI 74.8% to 93.1%) using 0.9 _g/mL as the cutoff.	This study was limited by small patient numbers and a meta-analysis of trials of limited value. The definitive diagnostic study used for diagnosis is not provided in the article.
Sbarouni et al 2007 Greece	18 consecutive patients diagnosed with acute aortic dissection. Inclusion criteria were the presence of aortic dissection and a D-dimer assay result.	Prospective study. (1b)	Confirmed ATAD with elevated quantitative D-dimer	The authors found no correlation between symptom onset and D-dimer. The type of dissection cannot be determined from the study, but the authors reported no difference between Stanford A or B dissections and D-dimer values. Overall, the authors report a sensitivity of 94% (95% CI 70.6% to 99.7%), using a cutoff of 0.7 _g/mL.	Very small number of patients.
Wiegand et al 2007 Switzerland	25 cases with confirmed AD and a D-dimer test were identified.	Retrospective study. (2b)	To assess the value of the D-dimer test to rule out aortic dissection (sensitivity) using a generally accepted cut-off value of <500 mg/l.	22 patients had a true-positive and 3 patients had a false-negative D-dimer test result (cut-off <500 mg/l), resulting in a sensitivity of 88.0% (95% CI 67.7% to 96.8%).	Small number of patients. Retrospective.
Ohlmann et al. 2006 France	94 consecutive patients admitted with confirmed ATAD who had D-dimer assay at presentation. 94 matched controls presenting with clinical suspicion of dissection which was later ruled out.	Retrospective chart review. (2C)	Confirmed ATAD with elevated quantitative D-dimer	Sensitivity 99%. 93 of 94 patients had D-dimer >400 ng/ml. (95% CI 93.3% to 99.9%). One false negative result: patient with TFL and D-dimer level of 300 ng/ml. 62 patients in control group (66%) had elevated D-dimer	Retrospective.
Hazui et al, 2006 Japan	113 consecutive patients with ATAD who had a D-dimer assay at presentation.	Retrospective cohort study. (2b)	Cut-off value 400 ng/ml. Compared sensitivity of D-dimer for detection of ATAD with and without thrombosed false lumen (TFL).	104 of the 113 patients with acute aortic dissection had positive D-dimer results. Eight of the 9 patients in this study with acute aortic dissection and negative D-dimer results had thrombosed false lumens (overall sensitivity 92%; 95% CI 85.0% to 96.1%).	Small number of patients. Retrospective.
Hazui et al 2005 Japan	29 consecutive ATAD patients, 49 consecutive AMI patients. Performed Chest radiograph and D-dimer	Prospective cohort study. (1b)	Confirmed ATAD with elevated D-dimer.	Sensitivity 93.1% (95% CI 75.8% to 98.8%). 2 patients with ATAD had D-dimer < 800 ng/ml. Both had a thrombosed false lumen	Small number of patients. Patients with acute aortic dissection of the descending aorta only were excluded.
Akutsu et al 2005 Japan	78 consecutive patients with suspected AAD admitted to a coronary care unit who had a D-dimer assay at presentation. Later divided into ATAD (30) and non ATAD (48).	Prospective cohort study. (1b)	Confirmed ATAD with elevated quantitative D-dimer	All patients with acute aortic dissection had a positive D-dimer result, with a sensitivity of 100% (95% CI 85.9% to 100%).	Small number of patients. Not an emergency department setting

Comment(s)

Undifferentiated patients with chest pain presenting to the emergency department ultimately can be diagnosed with MI, PE, or AAD. Although treatment of PE and MI both involve anticoagulation, this therapy given to patients with a missed diagnosis of AAD carries the risk of potentially fatal hemorrhage. Antiplatelet therapy theoretically carries a similar risk, but no studies have demonstrated poor outcomes in AAD patients. While empiric antiplatelet therapy is still indicated in chest pain patients with suspicion for acute coronary syndrome, emergency physicians should withhold thrombolytic and fibrinolytic agents until they sufficiently evaluate the risk of AAD with clinical assessment and, if necessary, advanced imaging. D-dimer has been evaluated in several trials as a specific laboratory marker to rule out aortic dissection without the need for advanced imaging. A lot of research seems to be focused on using d-dimer as a rule-out strategy for acute aortic dissection. The idea is that a d-dimer <500 (which is what used for ruling out PE in low-mod risk patients) rules out dissection as well. Although the overall sensitivity for D-dimer in acute aortic dissection was high in all of the reviewed studies, no definitive population is identified as eligible for screening. Two of the 10 studies use either chest or back pain for inclusion but fail to provide any other clinical data. In addition, the prevalence of aortic dissection (14/64 and 30/78) in their populations was too high to assume that only chest pain or back pain was used exclusively for inclusion. All of the remaining retrospective studies have inclusion bias and use the diagnosis of aortic dissection as inclusion criteria without providing any valuable clinical data. The 3 remaining prospective studies fail to clarify or include selection criteria to determine the pretest probability of any of the studied populations.

Clinical Bottom Line

In patients who are having high risk clinical characteristics of acute aortic dissection, it would be unreasonable to rely on a negative D-dimer result when a further definitive investigation or treatment is needed. Furthermore, the nonspecificity of D-dimer, combined with a low-risk patient population, will likely lead to excessive advanced imaging. However, D-dimer may still have utility if it can be shown to increase detection when used in combination with a validated clinical decision rule or other clinical characteristics of acute aortic dissection. I do not believe it is safe to use D-dimer as the sole screening test for acute aortic dissection at any cutoff level. Large prospective validation studies neede to be done focusing on using clinical variables and ancillary studies in conjunction with D-dimer for acute aortic dissection.

References

1. Wen D, Du X, Dong JZ, et al. (2013) Value of D-dimer and C reactive protein in predicting inhospital death in acute aortic dissection. Heart 2013 2013; 99(16):1192-7.
2. Ersel M, Aksay E, Kıyan S, et al. (2010) Can D-dimer testing help emergency department physicians to detect acute aortic dissections?. Anadolu Kardiyol Derg 2010 2010;10(5):434-9.
3. Suzuki T, Distante A, Zizza A, et al.(2009) Diagnosis of acute aortic dissection by D-dimer: the International Registry of Acute Aortic Dissection Substudy on Biomarkers (IRAD-Bio) experience. Circulation 2009 2009;119(20):2702-7.
4. Sodeck G, Domanovits H, Schillinger M. et al. (2007) D-dimer in ruling out acute aortic dissection: a systematic review and prospective cohort study. European Heart Journal 2007 2007;28(24):3067-3075.
5. Sbarouni E, Georgiadou P, Marathias A, et al. (2007). D-dimer and BNP levels in acute aortic dissection. International Journal of Cardiology 2007 2007;122:170-172.
6. Wiegand J, Kollerb M, Bingisser R, et al. (2007). Does a negative D-dimer test rule out aortic dissection? Swiss Medical Weekly 2007 2007;137(31):462.
7. Ohlmann P, Faure A, Morel O, Petit H, et al. (2006). Diagnostic and Prognostic Value of Circulating D-Dimers in Patients with Acute Aortic Dissection. Critical Care Medicine 2006 2006;34(5):1358-64.
8. Hazui H, Nishimoto M, Hoshiga M, et al. (2006). Young adult patients with short dissection length and thrombosed false lumen without ulcer-like projections are liable to have false-negative results of d-dimer testing for acute aortic dissection ... Circulation 2006 2006;70(12):1598–601.
9. Hazui H, Fukumoto H, Negoro N, et al. (2005). Simple and Useful Tests for Discriminating Between Acute Aortic Dissection of the Ascending Aorta and Acute Myocardial Infarction in the Emergency Setting Circulation Journal 2005 2005;69(6):677-82.
10. Akutsu K, Sato N, Yamamoto T, et al. (2005). A rapid bedside d-dimer assay (cardiac D-dimer) for screening of clinically suspected acute aortic dissection. Circulation 2005 2005;69(4):397–403.