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Report by Richard Body, Specialist Registrar
Search checked by Babak Allie, Specialist Registrar
Manchester Royal Infirmary
A short cut review was carried out to establish whether a negative D‐dimer will accurately rule out an atrial thrombus in a patient presenting with atrial fibrillation. Ten papers seemed relevant to the clinical question. The author, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses of these papers are tabulated. The clinical bottom line is that a negative D‐dimer suggests that it is safe to cardiovert a patient with recent onset of atrial fibrillation.
In [patients with atrial fibrillation being considered for electrical or pharmacologic cardioversion] does [measurement of D‐dimer] allow [exclusion of atrial thrombus]?
A 45‐year‐old man presents to the emergency department with a 48 hour history of palpitations, postural light‐headedness and exertional dyspnoea. ECG demonstrates atrial fibrillation (AF) at a rate of 130 beats/minute. There are no apparent reversible causes following history, examination, chest radiography, urinalysis and haematological and biochemical screening.You feel that pharmacologic or electrical cardioversion to sinus rhythm rather than rate control would be most beneficial to the patient, but as you are aware of the possibility of atrial thrombus and systemic embolism you opt for rate control and refer for anticoagulation. You wonder if measuring D‐dimer, a product of clot breakdown, would have allowed accurate exclusion of atrial thrombus, thus enabling the safe acute administration of flecainide.
All via the Ovid interface: Medline 1950–2007 February Week 4 CINAHL 1982 – 2007 March Week 1 Embase 1980 – 2007 Week 9 Cochrane Central Register of Controlled Trials (CCRCT) <1st Quarter 2007> ACP Journal Club 1991 to January/February 2007 Cochrane Database of Systematic Reviews (CDSR) <1st Quarter 2007> Database of Abstracts of Reviews of Effects (DARE) <1st Quarter 2007> [exp Atrial Fibrillation/OR exp Atrial Flutter/OR (atrial fibrillation OR AF OR atrial flutter OR (cardiac adj thromb$) OR (intracardiac adj thromb$) OR ((atrial OR atrium) adj3 thromb$)).mp. OR ] AND [exp Fibrin Fibrinogen Degradation Products/OR D‐dimer$.mp.].
Altogether 110 papers were identified using Medline, 2 using CINAHL, 141 using Embase, 12 in CCRCT, 4 in ACP Journal Club, 1 in CDSR and 0 in DARE. Ten were relevant to the three‐part question (table 22).
Cardioversion of AF to sinus rhythm carries a small but definite risk of systemic thromboembolism from atrial thrombus, typically within the left atrial appendage. Although the risk is greatest when the arrhythmia has lasted for over 48 hours, atrial thrombi may occur earlier (Stoddard et al, 1995; Manning et al, 1995). As the left atrial appendage is not easily visualised on transthoracic echocardiography (TTE), transoesphageal echocardiography (TOE) is necessary to exclude thrombus. However, this test is invasive, carries a small but definite risk of complications, is unpleasant for the patient and not readily available in most centres.
Current European Society of Cardiology guidelines state that patients must either have TOE or anticoagulation for 3–4 weeks prior to attempted cardioversion unless there is an immediate indication (Fuster et al, 2001). A quick, non‐invasive test such as D‐dimer, that is easily applied in the emergency department and may allow confident institution of appropriate early treatment to restore sinus rhythm, is therefore highly desirable.
Preliminary data has demonstrated that peripheral D‐dimer estimation correlates with atrial coagulation activity (Li‐Saw‐Hee et al, 1999). Two studies (Kimura et al, 1995; Nakagawa et al, 2001) have demonstrated higher D‐dimer levels in the presence of low atrial flow, a risk factor for developing atrial thrombus, although another study (Black et al, 1993) did report conflicting results. Several studies (Hayashi et al, 1991; Yasaka et al, 1991; Sakai et al, 1994; Heppell et al, 1997; Somloi et al, 2003) have demonstrated significantly raised D‐dimer levels in the presence of atrial thrombus.
Studies that have investigated the clinical utility of D‐dimer for exclusion of atrial thrombus in AF have yielded promising results. Using data from the study by Yasaka et al (1991), D‐dimer excluded atrial thrombus with a negative predicitive value (NPV) of 86% in a population with a high prevalence of atrial thrombi (40%). It is possible that the test would perform better in the Emergency Department population. Further, D‐dimer had a sensitivity of 100% for the detection of mobile thrombi, which represent a higher embolic risk.
The high NPV of 98% reported by Somloi et al (2003) means that, in a population with a 12.3% pre‐test probability of atrial thrombus, the post‐test probability following a negative test is 2%. If 100 patients were treated according to D‐dimer results, one false negative diagnosis would be expected, but early cardioversion would be possible for a further 68 patients without atrial thrombus.
This compares favourably with TOE for detection of atrial thrombus, which has been reported to have a sensitivity of 93.3% and a NPV of 98.9%. As such, for every 100 patients treated according to TOE results, 1 false negative would be expected (Hwang et al, 1993). Further, although warfarin has been shown to effectively reduce atrial thrombus, 14% of patients may have residual thrombus following 4 weeks of treatment (Collins et al, 1995).
The evidence therefore suggests that D‐dimer has great potential for clinical use in the emergency department to exclude atrial thrombus prior to attempted electrical or pharmacological cardioversion. Further evidence from large studies would be desirable before implementation.
It is important to stress, however, that the coagulation system is activated following electric, but not pharmacologic cardioversion (Giansante et al, 2000). The risk of atrial thrombus formation and systemic embolism therefore persists even after reversion to sinus rhythm following electric cardioversion. As such, successful electric cardioversion following a negative D‐dimer result would not avoid the need for anticoagulation with warfarin. European Society of Cardiology guidelines state that patients should be anticoagulated for 3–4 weeks post‐procedure (Fuster et al, 2001).
D‐dimer is promising as an early marker of mural thrombus in atrial fibrillation and may be no less effective than either transoesophageal echocardiography or anticoagulation for 4 weeks. The evidence suggests that a negative result enables safe early cardioversion, although further evidence from large studies would be desirable.
Level 2 – Studies considered were neither 1 or 3.
The authors identified a number of studies that were relevant to the three‐part question but were in Japanese language. Although no translator was available, it was felt that excluding these studies by limiting the search strategy to English language would ignore some important evidence. The abstracts have therefore been tabulated, although it should be recognised that there are significant limitations to appraising only the abstract of a study.