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Three Part Question

In [patients with suspected cardiac chest pain presenting to the Emergency Department] do [normal plasma D-dimer levels] enable [exclusion of acute coronary syndrome]?

Clinical Scenario

An anxious forty year-old lady with a family history of ischaemic heart disease presents with tight central chest pain of one hour's duration. The pain eases with reassurance in the ambulance and the ECG at presentation is normal.
You don't believe this lady is having an acute coronary syndrome but are unwilling to risk missing the diagnosis and refer for troponin testing at 12 hours. Having explained that you need to rule out a clot in the coronary artery, the lady states that her husband recently had a blood test to rule out a clot in the leg and wonders why you can't do the same test.
You therefore wonder if plasma D-dimer would enable accurate exclusion of acute coronary syndrome.

Search Strategy

OVID Medline 1966 - 2005 August Week 3
OVID Embase 1980 - 2005 Week 35
[exp Myocardial Infarction/ OR exp Angina, Unstable/ OR exp Coronary Thrombosis/ OR (myocard$ adj (infarct$ OR ischaem$ OR ischem$)).mp. OR (acute coronary syndrome OR ACS OR MI OR AMI OR heart attack).mp.] AND [(exp Fibrin Fibrinogen Degradation Products/ OR D-dimer.mp.)] limit to human and English language

Search Outcome

284 papers were identified in Medline and 246 in Embase. 5 were relevant to the three-part question. Other relevant papers are discussed.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Shitrit et al (Role of ELISA D-dimer test...) 2004 Israel	81 patients with 'UA' and normal ECG, presenting to the Emergency Department. Blood taken at admission. Only patients with continuous or recurrent chest pain underwent coronary catherisation during hospitalisation.	Prospective observational cohort	Correlation of D-dimer and catheterisation findings	Significantly positively correlated (r=0.31, P=0.02). Patients with three-vessel disease had higher levels than patients with one- or two-vessel disease.	ACS already 'ruled in' at inclusion. Subjective criteria for diagnosis of UA. Only 22% of patients underwent coronary catheterisation; many patients with normal ECG and enzyme levels may have actually had non-cardiac chest pain. Length of stay and catheterisation findings are surrogate outcomes. Mortality and adverse cardiac events would be more clinically relevant.
			D-dimer and length of stay (multivariate analysis)	D-dimer an independent predictor (P=0.018).
			D-dimer and catheterisation findings (multivariate analysis)	D-dimer not an independent predictor.
Shitrit et al (Determinants of ELISA...) 2004 Israel	54 patients with 'UA' presenting to the Emergency Department. All patients underwent coronary angiography within 24 hours of admission.	Prospective observational study	D-dimer for detection of 1-, 2- or 3-vessel disease vs. normal coronary arteries on angiography	At the optimal cut-off of 270ng/ml, sensitivity 70%, specificity 50%, PPV 86%, NPV 72%. At a cut-off of 200ng/ml, sensitivity 95%, specificity 20%, PPV 40%, NPV 48%. Study prevalence 82%.	Patients included following clinical diagnosis of 'UA'. Application in an undifferentiated population with suspected cardiac chest pain would be more clinically relevant and would yield a lower study prevalence, increasing NPV. Subjective definition of UA, based on clinical (e.g. "new-onset angina") but not angiographic, ECG or biochemical criteria. Time of blood sampling not stated.
Derhaschnig et al 2002 Austria	184 eligible (of 200 consecutive) patients presenting to the Emergency Department with suspected cardiac chest pain. Blood taken before any intervention (median time from onset 6 hours in UA, 3 hours in AMI).	Prospective diagnostic cohort	D-dimer for diagnosis of ACS	Patients with ACS had on average 111% higher D-dimer than those without (P<0.001). To obtain arbritrary specificity of 93%, sensitivity of D-dimer 35%.	Subjective criteria for diagnosis of UA. No gold standard for diagnosis of non-cardiac pain and no clinical follow-up data reported. Optimal sensitivity not reported, arbritrary cut-off utilised. The reported sensitivity of 35% is therefore of very limited value.
Bayes-Genis et al 2000 Spain	257 eligible (of 300 consective) patients presenting to the Emergency Department with suspected cardiac chest pain <6 hours (mean 160 min.). Blood taken on admission.	Prospective diagnostic cohort	D-dimer for diagnosis of ischaemic pain	Significantly higher with ischaemic (656ug/l, 95% CI 484-865) than non-ischaemic (338ug/l, 95% CI 305-375), P<0.01 even after adjustment for age, previous IHD and fibrinogen	Now out-dated gold standard for diagnosis of AMI (CK-MB) Relatively large proportion (14%) of patients excluded for various reasons.
			D-dimer for diagnosis of AMI and UA	Significantly higher in AMI (mean 925ug/l, P<0.001) and UA (mean 484ug/l, P<0.05). Significantly higher in AMI than in UA (P<0.02)
			Performance of D-dimer >500ng/l to identify AMI	Sensitivity 65%, specificity 80%, PPV 36%, NPV 93%
Mair et al 1997 Austria	31 patients with evolving AMI, within 6 hours of symptom onset (mean 135 min), admitted to CCU Blood taken on admission to CCU	Prospective diagnostic cohort	D-dimer for diagnosis of AMI	Sensitivity 13% (95% CI 4-31%)	Selection bias: diagnosis already ruled in, patients included after admission to CCU Now out-dated gold standard diagnosis of AMI (CK-MB not troponins) Small numbers
			TAT for diagnosis of AMI	Sensitivity 60% (95% CI 41-77%)
			Either TnT, CKMBmass or myoglobin +ve for diagnosis of AMI	Sensitivity 48% 95% CI 30-67%)
			Admission ECG for diagnosis of AMI	Sensitivity 77% (95% CI 58-90%)

Comment(s)

D-dimer is a degradation product of cross-linked fibrin. Its presence indicates both thrombus formation and subsequent endogenous fibrinolysis, thus confirming that both thrombin and plasmin have been generated (Sadosty et al, 2001). It is a sensitive tool for exclusion of venous thromboembolism in the low risk group (Fancher et al, 2004). Acute coronary syndromes are characterised by rupture or erosion of atherosclerotic plaque, exposure of the procoagulant lipid core to circulating blood and thrombus formation. As coronary thrombus precedes myocardial necrosis, it is possible that coagulation markers such as D-dimer are sensitive markers of ACS, potentially rising earlier than markers of myocardial necrosis including troponins. Raised D-dimer concentrations have been shown to be associated with AMI in apparently healthy males (Ridker et al, 1994). In addition, raised D-dimer concentrations have been demonstrated in AMI and UA (Kruskal et al, 1987; Fiotti et al, 2002). D-dimer has also been shown to predict long-term prognosis in patients admitted with UA (Oldgren et al, 2001). Studies investigating the utility of D-dimer for diangosis of ACS have reported varying sensitivities, from 13% to 70%. There may be various reasons for this. Mair et al reported a sensitivity of only 13% for detection of AMI but recruited only 31 patients. Although the larger study by Derhaschnig et al reported a sensitivity of only 35%, they did not select an appropriate cut-off to optimise sensitivity. Shitrit et al reported a sensitivity of 95% in a sample of 54 patients. However, the high study prevalence of 82% meant that the NPV was only 48% (post-test probability following negative test 52%). The largest relevant study, by Bayes-Genis et al, investigated 257 Emergency Department patients with undifferentiated chest pain. They reported a 65% sensitivity and 92% NPV for the identification of AMI, although they did not report the sensitivity for detection of ischaemic vs. non-ischaemic pain. The available evidence suggests that D-dimer alone is insufficiently sensitive to allow exclusion of ACS on the basis of a negative result. Investigation as part of a multimarker strategy may yield more promising results.

Editor Comment

Abbreviations: AMI: acute myocardial infarction; UA: unstable angina; ACS: acute coronary syndrome; CCU: coronary care unit; TAT: thrombin-antithrombin III complex; PPV: positive predictive value; NPV: negative predictive value; CI: confidence interval.

Clinical Bottom Line

D-dimer alone is of limited use in the exclusion of acute coronary syndromes, although it is possible that future research may identify a role for D-dimer in a multimarker strategy.

Level of Evidence

Level 2 - Studies considered were neither 1 or 3.

References

1. Shitrit D; Bar-Gil Shitrit A; Rudensky B; Sulkes J; Gutterer N; Zviony D Role of ELISA D-dimer test in patients with unstable angina pectoris presenting at the Emergency Department with a normal electrocardiogram American Journal of Haematology 2004; 77: 147-150
2. Shitrit D; Bar-Gil Shitrit A; Rudensky B; Sulkes J; Tzviony D. Determinants of ELISA D-dimer sensitivity for unstable angina pectoris as defined by coronary catheterization American Journal of Haematology 2004; 76: 121-125
3. Derhaschnig U; Laggner AN; Roggla M; Hirschl MM; Kapiotis S; Marsik C; Jilma B. Evaluation of coagulation markers for early diagnosis of acute coronary syndromes in the Emergency Room Clinical Chemistry 2002; 48(11): 1924-1930
4. Bayes-Genis A; Mateo J; Santalo M; Oliver A; Guindo J; Badimon L; Martinez-Rubio A; Fontcuberta J; Schwartz RS; Bayes de Luna A. D-dimer is an early diagnostic marker of coronary ischemia in patients with chest pain American Heart Journal 2000; 140: 379-384
5. Mair J; Genser N; Maier J; Lechleitner P; Dienstl F; Puschendorf B. Markers of activated coagulation for early diagnosis of acute myocardial infarction Clinica Chimica Acta 1997; 267: 239-245
6. Fiotti N; Di Chiara A; Altamura N; Miccio M; Fioretti P; Guarnieri G. Coagulation indicators in chronic stable effort angina and unstable angina: Relationship with acute phase reactants and clinical outcome Blood Coagulation and Fibrinolysis 2002; 13(3): 247-255
7. Oldgren J; Linder R; Grip L; Siegbahn A; Wallentin L. Coagulation activity and clinical outcome in unstable coronary artery disease Thrombosis & Vascular Biology 2001; 21(6): 1059-1064
8. Galvani M; Ferrini D; Ottani F; Elsenberg PR. Early risk stratification of unstable angina/non-Q myocardial infarction: Biochemical markers of acute coronary thrombosis International Journal of Cardiology 1999; 68 (Suppl 1): S55-S61
9. Kruskal JB; Commerford PJ; Franks JJ; Kirsch RE. Fibrin and fibrinogen-related antigens in patients with stable and unstable coronary artery disease. New England Journal of Medicine 1987; 317(22): 1361-1365
10. Ridker PM; Hennekens CH; Cerskus A; Stampfer MJ. Plasma concentration of cross-linked fibrin degradation product (D-dimer and the risk of future myocardial infarction among apparently healthy men Circulation 1994; 90(5): 2236-2240
11. Sadosty AT; Goyal DG; Boie ET; Chiu CK. Emergency Department D-dimer testing. Journal of Emergency Medicine 2001; 21(4): 423-429
12. Fancher TL; White RH; Kravitz RL. Combined use of rapid D-dimer testing and estimation of clinical probability in the diagnosis of deep vein thrombosis: systematic review. British Medical Journal 2004; 329: 821-829