- Email: [email protected]
D -dimer determination as a screening tool to exclude atrial thrombi in atrial fibrillation
D-Dimer
Determination as a Screening Tool to Exclude Atrial Thrombi in Atrial Fibrillation
Miklo´ s Somlo´ i,
MD,
Ja´ nos Tomcsa´ nyi, MD, PhD, Erzse´ bet Nagy, and Attila Bezzegh, MD
onversion of atrial fibrillation (AF) to sinus rhythm carries a definite risk of systemic emboC lism. This risk can be reduced to an acceptable level by prior anticoagulation for 3 weeks or, alternatively, by exclusion of atrial thrombi with transesophageal echocardiography (TEE) before cardioversion.1 Although earlier cardioversion according to TEE-guided strategy has potential advantages,2,3 TEE requires special equipment and advanced skills, which may limit its availability. D-dimer, an indirect marker of fibrin formation, has been demonstrated to be a sensitive marker of activation of coagulation in various clinical conditions.4 –7 In AF, elevated D-dimer levels have been reported to be associated with the duration of AF,8 left atrial appendage dysfunction,9 and the presence of atrial thrombus.10,11 The potential role of D-dimer in refining embolic risk prediction in AF remains to be determined. The aims of our study were to analyze the relation of serum D-dimer to embolic risk determined on clinical grounds in patients with AF and to assess the test’s diagnostic utility to predict the presence or absence of atrial thrombi. •••
In a prospective design, we measured the plasma D-dimer concentration of consecutive patients admitted to our echocardiography laboratory for TEE before cardioversion. The local ethics committee approved the protocol. The examinations were performed after obtaining written informed consent. Patients with AF of ⱖ48 hours duration or atrial flutter with documented history of AF were eligible. The exclusion criteria included any thromboembolic events within the previous 2 months and anticoagulant therapy for ⬎7 days. Subjects underwent transthoracic and TEE. Echocardiographic studies were performed with an ATL instrument (HDI 3500 CV, Philips Ultrasound, Bothell, Washington) using a 1.67- to 3.2-MHz, phased-array head (P4 to P2) for transthoracic examination, and a 4- to 7-MHz omniplane probe (MPT7 to MPT4) for TEE. An intravenous line was placed and blood samples were obtained without tourniquet immediately before TEE. D-dimer measurements were obtained with the use of a quantitative sandwich immunochromatographic technique (Cardiac D-dimer; Roche Diagnostics, Mannheim, Germany). The invesFrom the Department of Cardiology and the Clinical Laboratory, Polyclinic of Hospitaller Brothers of St. John of God in Budapest; and Department of Hematology, St. La´ szlo´ Hospital, Budapest, Hungary. Dr. Somlo´ i’s address is: Department of Cardiology, Polyclinic of Hospitaller Brothers of St. John of God in Budapest, Budapest, Hungary, A´ rpa´ d fejedelem u´ tja 7, 1027-Hungary. E-mail: [email protected]. Manuscript received November 19, 2002; revised manuscript received and accepted March 19, 2003. ©2003 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 92 July 1, 2003
MD,
Imre Bodo´ ,
MD, PhD,
TABLE 1 Basal Characteristics of Patients (n ⫽ 73) Age (yrs) Men Atrial fibrillation at presentation Systemic hypertension Coronary heart disease Diabetes mellitus Systemic embolism (history) Severe mitral regurgitation Left ventricular ejection fraction ⱕ 0.35
69 38 63 39 7 8 4 14 10
(43–88) (52%) (86%) (53%) (9%) (11%) (5%) (19%) (14%)
Values are expressed as mean (range) or number (%).
tigators and attending physicians were blinded to the D-dimer test results. The final interpretations of the TEEs were the result of the consensus of the same 2 experienced investigators based on real-time observation or off-line analysis of the studies. For D-dimer results below the measurement range, 0.1 g/ml was entered. Values are presented as mean ⫾ SEM. To obtain normal distribution, D-dimer values were logarithmically transformed, and unpaired 2-tailed t tests were used to compare means. The independent predictive role of embolic predictors for log D-dimer was evaluated by multiple regression analysis. Sensitivity, specificity, and predictive values were calculated using standard formulas. A p value ⬍0.05 was considered statistically significant. Analyses were performed with SAS for Windows 8.02 (SAS Institute Inc., Cary, North Carolina) and GraphPad Prism, version 3.00 (GraphPad Software, San Diego, California) statistical software packages. After an initial screening, 75 patients were examined. Two patients were excluded because of equivocal transesophageal echocardiographic results. Basal characteristics of the enrolled 73 patients are listed in Table 1. The log D-dimer concentrations were compared between groups of patients dichotomized by the presence or absence of each independent predictor of embolism. These predictors were based on previous clinical trials and included: age ⱖ70 years; history of hypertension, diabetes mellitus, ischemic heart disease, and previous systemic embolization; left ventricular ejection fraction ⱕ0.35; moderate to severe mitral regurgitation; left atrial dimension ⱖ45 mm; peak left atrial appendage flow ⱕ0.4 m/s; heavy spontaneous echo contrast; and presence of atrial thrombus.1 There was a tendency for most of these predictors to be associated with elevated D-dimer levels, reaching statistical significance in those aged ⬎70 years, in patients with severe mitral regurgitation, and in the presence of atrial thrombus. (Table 2) In multiple regression analysis, older age and severe mitral regurgitation 0002-9149/03/$–see front matter doi:10.1016/S0002-9149(03)00476-4
85
TABLE 2 Log D-dimer Levels (g/ml) According to Clinical and Echocardiographic Predictors of Embolism Absent Embolic Predictors
Mean ⫾ SEM
Age ⱖ70 yrs Hypertension Diabetes Ischemic heart disease History of systemic embolism AF at presentation* LVEF ⱕ0.35 Severe mitral regurgitation Left atrium ⱖ45 mm Peak LAA flow ⱕ0.4 m/s Heavy SEC Atrial thrombus
⫺0.55 ⫺0.48 ⫺0.46 ⫺0.44 ⫺0.44 ⫺0.57 ⫺0.45 ⫺0.50 ⫺0.52 ⫺0.52 ⫺0.45 ⫺0.48
⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾
Present 95% CI ⫺0.67, ⫺0.63, ⫺0.56, ⫺0.54, ⫺0.54, ⫺0.89, ⫺0.56, ⫺0.60, ⫺0.65, ⫺0.64, ⫺0.57, ⫺0.58,
0.06 0.07 0.05 0.05 0.05 0.14 0.05 0.05 0.06 0.06 0.06 0.05
⫺0.44 ⫺0.34 ⫺0.35 ⫺0.34 ⫺0.34 ⫺0.25 ⫺0.35 ⫺0.41 ⫺0.40 ⫺0.40 ⫺0.34 ⫺0.38
Mean ⫾ SEM ⫺0.33 ⫺0.40 ⫺0.27 ⫺0.38 ⫺0.37 ⫺0.41 ⫺0.32 ⫺0.15 ⫺0.35 ⫺0.36 ⫺0.39 ⫺0.10
⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾
0.07 0.07 0.12 0.16 0.14 0.05 0.11 0.11 0.07 0.08 0.08 0.10
95% CI ⫺0.47, ⫺0.53, ⫺0.56, ⫺0.78, ⫺0.82, ⫺0.51, ⫺0.57, ⫺0.39, ⫺0.50, ⫺0.52, ⫺0.56, ⫺0.34,
⫺0.18 ⫺0.27 ⫺0.02 ⫺0.01 ⫺0.09 ⫺0.31 ⫺0.06 ⫺0.09 ⫺0.21 ⫺0.20 ⫺0.22 ⫺0.13
p Value 0.0154 0.3745 0.2260 0.7108 0.7235 0.2557 0.3281 0.0026 0.0733 0.1158 0.5611 0.0078
*Patients not presenting with AF had atrial flutter. CI ⫽ confidence interval; LAA ⫽ left atrial appendage; LVEF ⫽ left ventricular ejection fraction; SEC ⫽ spontaneous echo contrast.
TABLE 3 Influence of Clinical and Echocardiographic Embolic Predictors on Log D-Dimer Variable
F Value
p Value
All variables Age ⱖ70 yrs Hypertension Diabetes mellitus Ischemic heart disease History of systemic embolism AF at presentation LVEF ⱕ0.35 Severe mitral regurgitation Left atrium ⱖ45 mm Peak LAA flow ⱕ0.4 m/s Heavy SEC Atrial thrombus Model after backward elimination All variables Age ⱖ70 yrs Severe mitral regurgitation Peak LAA flow ⱕ0.4 m/s
30.59 4.12 0.01 0.64 0.04 0.00 0.63 0.05 7.02 0.27 1.79 0.00 2.02
⬍0.0001 0.0467 0.9132 0.4272 0.8436 0.9538 0.4293 0.8277 0.0103 0.6027 0.1856 0.9582 0.1602
94.79 5.79 14.06 5.49
⬍0.0001 0.0188 0.0004 0.0220
Abbreviation as in Table 2.
remained significant independent predictors of the log D-dimer levels. Using a backward elimination method, after stepwise elimination of variables with p ⬎0.5, the low peak left atrial appendage flow also became a significant predictor (Table 3). Atrial thrombi were detected by TEE in 9 patients (12%). To assess the usefulness of the D-dimer test for the diagnosis of atrial thrombi, a receiver-operator characteristic curve analysis was performed (Figure 1). The cut-off value of D-dimer concentration was set at 0.60 g/ml to optimize for negative test results; thus, 67% of patients fell into the normal range. Sensitivity and specificity were 89% and 75%, respectively, using TEE as the gold standard. For our population, the positive predictive value was 33%, and the negative predictive value was 98%. The only patient with a false–negative D-dimer test result was a 65-year-old man presenting with atrial flutter of unknown duration. He had a history of hypertension but was without structural heart disease. The echogenic structure in the left atrial appendage 86 THE AMERICAN JOURNAL OF CARDIOLOGY姞
VOL. 92
FIGURE 1. Receiver-operating characteristic curve of D-dimer to atrial thrombus detected by TEE. The corresponding D-dimer concentrations in micrograms per milliliter are indicated. The p value refers to the difference from random results. AUC ⴝ area under the curve; CI ⴝ confidence interval.
showed no change in shape or size after 3 weeks of effective anticoagulant therapy. The patient’s sinus rhythm was then restored applying electrical cardioversion without complication. Fifty of 55 cardioversion attempts in patients without thrombus were successful. No embolic event was recorded. •••
The relation of the markers of accelerated coagulation to clinical or echocardiographic risk factors for thromboembolism is controversial.12 Our investigation clearly demonstrated a positive correlation of the clinically predicted embolic risk to the D-dimer concentration. The pathogenesis of thrombus formation in AF is not fully understood. Our results suggest that the clinical conditions causing increased embolic risk are additive and share a common final pathway leading to enhanced fibrin generation. Even in the absence of a JULY 1, 2003
detectable thrombus, patients with signs of accelerated coagulation are at risk for thrombus formation in the future. Although the exclusion of thrombus by TEE defines a low immediate hazard of embolism, D-dimer may be a better single marker of overall thromboembolic risk. Although the specificity and positive predictive values were moderate, low levels of D-dimer reliably excluded the presence of atrial thrombi. The optimal cut-off point and negative predictive value were similar to those established for the diagnosis of venous and pulmonary thromboembolism.13 One of the patients with left atrial appendage thrombus had false low D-dimer levels. This patient presented with atrial flutter without significant structural heart disease and had a low pretest probability of atrial thrombus. In addition to having true false–negative results, there are other possible explanations for the discrepancy. An atrial thrombus formed during a previous episode of AF may have been organized by the time of the current examination. Alternatively, a nonthrombotic anatomic structure may have been mistakenly diagnosed as thrombus. In studies using open-heart surgery as the reference standard, TEE adequately ruled out atrial thrombi. However, in these trials the average positive predictive value of TEE was only 89%.14 –20 Because of the lower embolic risk, the false–positive rate of TEE may be higher in our AF patients without valvular disease requiring surgery. Although an actual false–negative result cannot be formally excluded, both described alternatives (e.g., organized thrombus or nonthrombotic structure) explain the low D-dimer level and the resistance to anticoagulant therapy, and both conditions confer a low risk for embolism. In conclusion, the D-dimer determination as a single test adequately defined a low thromboembolic risk associated with cardioversion of AF in 2/3 of our patients. Further confirmation of our results in larger trials would provide us with a simple, objective, and widely available screening test before cardioversion without the drawbacks of TEE. Our investigation suggests that the serum Ddimer level is a useful marker of overall embolic risk in patients with AF and reflects a cumulative prothrombotic effect of clinical and echocardiographic predictors of stroke. A low level of D-dimer reliably excludes the presence of atrial thrombus. Acknowledgment: We are indebted to Zsolt Kara´ nyi, MS, of the Medical & Health Sciences Center, University of Debrecen, Debrecen, Hungary, for his expert guidance on statistical analysis, and to Ferenc Follath, MD, of University Hospital Zu¨ rich, Zu¨ rich, Switzerland, for his valuable comments.
1. Fuster V, Ryden LE, Asinger RW, Cannom DS, Crijns HJ, Frye RL, Halperin JL, Kay GN, Klein WW, Levy S, et al. ACC/AHA/ESC guidelines for the management of patients with atrial fibrillation. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines and Policy Conferences (committee to develop guidelines for the management of patients with atrial fibrillation) developed in collaboration with the North American Society of Pacing and Electrophysiology. Eur Heart J 2000;22:1852–1923. 2. Klein AL, Grimm RA, Murray RD, Apperson-Hansen C, Asinger RW, Black IW, Davidoff R, Erbel R, Halperin JL, Orsinelli DA, Porter TR, Stoddard MF. Use of transesophageal echocardiography to guide cardioversion in patients with atrial fibrillation. N Engl J Med 2000;344:1411–1420. 3. Weigner MJ, Thomas LR, Patel U, Schwartz JG, Burger AJ, Douglas PS, Silverman DI, Manning WJ. Early cardioversion of atrial fibrillation facilitated by transesophageal echocardiography: short-term safety and impact on maintenance of sinus rhythm at 1 year. Am J Med 2002;110:694 –702. 4. Becker DM, Philbrick JT, Bachhuber TL, Humphries JE. D-dimer testing and acute venous thromboembolism. A shortcut to accurate diagnosis? Arch Intern Med 1996;156:939 –946. 5. Bounameaux H, Cirafici P, de Moerloose P, Schneider PA, Slosman D, Reber G, Unger PF. Measurement of D-dimer in plasma as diagnostic aid in suspected pulmonary embolism. Lancet 1991;337:196 –200. 6. 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;90:2236 –2240. 7. Kumagai K, Fukunami M, Ohmori M, Kitabatake A, Kamada T, Hoki N. Increased intracardiovascular clotting in patients with chronic atrial fibrillation. J Am Coll Cardiol 1990;16:377–380. 8. Lip GY, Lowe GD, Rumley A, Dunn FG. Fibrinogen and fibrin D-dimer levels in paroxysmal atrial fibrillation: evidence for intermediate elevated levels of intravascular thrombogenesis. Am Heart J 1996;131:724 –730. 9. Igarashi Y, Kashimura K, Makiyama Y, Sato T, Ojima K, Aizawa Y. Left atrial appendage dysfunction in chronic nonvalvular atrial fibrillation is significantly associated with an elevated level of brain natriuretic peptide and a prothrombotic state. Jpn Circ J 2001;65:788 –792. 10. Yasaka M, Miyatake K, Mitani M, Beppu S, Nagata S, Yamaguchi T, Omae T. Intracardiac mobile thrombus and D-dimer fragment of fibrin in patients with mitral stenosis. Br Heart J 1991;66:22–25. 11. Heppell RM, Berkin KE, McLenachan JM, Davies JA. Haemostatic and haemodynamic abnormalities associated with left atrial thrombosis in non-rheumatic atrial fibrillation. Heart 1997;77:407–411. 12. Lip GY. The prothrombotic state in atrial fibrillation: new insights, more questions, and clear answers needed. Am Heart J 2000;140:348 –350. 13. van der Graaf F, van den Borne H, van der Kolk M, de Wild PJ, Janssen GW, van Uum SH. Exclusion of deep venous thrombosis with D-dimer testing— comparison of 13 D-dimer methods in 99 outpatients suspected of deep venous thrombosis using venography as reference standard. Thromb Haemost 2002;83: 191–198. 14. Aschenberg W, Schluter M, Kremer P, Schroder E, Siglow V, Bleifeld W. Transesophageal two-dimensional echocardiography for the detection of left atrial appendage thrombus. J Am Coll Cardiol 1986;7:163–166. 15. Acar J, Cormier B, Grimberg D, Kawthekar G, Iung B, Scheuer B, Farah E. Diagnosis of left atrial thrombi in mitral stenosis— usefulness of ultrasound techniques compared with other methods. Eur Heart J 1991;12(suppl B):70 –76. 16. Lin SL, Hsu TL, Liou JY, Chen CH, Chang MS, Chiang HT, Chen CY. Usefulness of transesophageal echocardiography for the detection of left atrial thrombi in patients with rheumatic heart disease. Echocardiography 1992;9:161– 168. 17. Olson JD, Goldenberg IF, Pedersen W, Brandt D, Kane M, Daniel JA, Nelson RR, Mooney MR, Lange HW. Exclusion of atrial thrombus by transesophageal echocardiography. J Am Soc Echocardiogr 1992;5:52–56. 18. Hwang JJ, Chen JJ, Lin SC, Tseng YZ, Kuan P, Lien WP, Lin FY, Chu SH, Hung CR, How SW. Diagnostic accuracy of transesophageal echocardiography for detecting left atrial thrombi in patients with rheumatic heart disease having undergone mitral valve operations. Am J Cardiol 1993;72:677–681. 19. Fatkin D, Scalia G, Jacobs N, Burstow D, Leung D, Walsh W, Feneley M. Accuracy of biplane transesophageal echocardiography in detecting left atrial thrombus. Am J Cardiol 1996;77:321–323. 20. Manning WJ, Weintraub RM, Waksmonski CA, Haering JM, Rooney PS, Maslow AD, Johnson RG, Douglas PS. Accuracy of transesophageal echocardiography for identifying left atrial thrombi. A prospective, intraoperative study. Ann Intern Med 1995;123:817–822.
BRIEF REPORTS
87
Determination as a Screening Tool to Exclude Atrial Thrombi in Atrial Fibrillation
Miklo´ s Somlo´ i,
MD,
Ja´ nos Tomcsa´ nyi, MD, PhD, Erzse´ bet Nagy, and Attila Bezzegh, MD
onversion of atrial fibrillation (AF) to sinus rhythm carries a definite risk of systemic emboC lism. This risk can be reduced to an acceptable level by prior anticoagulation for 3 weeks or, alternatively, by exclusion of atrial thrombi with transesophageal echocardiography (TEE) before cardioversion.1 Although earlier cardioversion according to TEE-guided strategy has potential advantages,2,3 TEE requires special equipment and advanced skills, which may limit its availability. D-dimer, an indirect marker of fibrin formation, has been demonstrated to be a sensitive marker of activation of coagulation in various clinical conditions.4 –7 In AF, elevated D-dimer levels have been reported to be associated with the duration of AF,8 left atrial appendage dysfunction,9 and the presence of atrial thrombus.10,11 The potential role of D-dimer in refining embolic risk prediction in AF remains to be determined. The aims of our study were to analyze the relation of serum D-dimer to embolic risk determined on clinical grounds in patients with AF and to assess the test’s diagnostic utility to predict the presence or absence of atrial thrombi. •••
In a prospective design, we measured the plasma D-dimer concentration of consecutive patients admitted to our echocardiography laboratory for TEE before cardioversion. The local ethics committee approved the protocol. The examinations were performed after obtaining written informed consent. Patients with AF of ⱖ48 hours duration or atrial flutter with documented history of AF were eligible. The exclusion criteria included any thromboembolic events within the previous 2 months and anticoagulant therapy for ⬎7 days. Subjects underwent transthoracic and TEE. Echocardiographic studies were performed with an ATL instrument (HDI 3500 CV, Philips Ultrasound, Bothell, Washington) using a 1.67- to 3.2-MHz, phased-array head (P4 to P2) for transthoracic examination, and a 4- to 7-MHz omniplane probe (MPT7 to MPT4) for TEE. An intravenous line was placed and blood samples were obtained without tourniquet immediately before TEE. D-dimer measurements were obtained with the use of a quantitative sandwich immunochromatographic technique (Cardiac D-dimer; Roche Diagnostics, Mannheim, Germany). The invesFrom the Department of Cardiology and the Clinical Laboratory, Polyclinic of Hospitaller Brothers of St. John of God in Budapest; and Department of Hematology, St. La´ szlo´ Hospital, Budapest, Hungary. Dr. Somlo´ i’s address is: Department of Cardiology, Polyclinic of Hospitaller Brothers of St. John of God in Budapest, Budapest, Hungary, A´ rpa´ d fejedelem u´ tja 7, 1027-Hungary. E-mail: [email protected]. Manuscript received November 19, 2002; revised manuscript received and accepted March 19, 2003. ©2003 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 92 July 1, 2003
MD,
Imre Bodo´ ,
MD, PhD,
TABLE 1 Basal Characteristics of Patients (n ⫽ 73) Age (yrs) Men Atrial fibrillation at presentation Systemic hypertension Coronary heart disease Diabetes mellitus Systemic embolism (history) Severe mitral regurgitation Left ventricular ejection fraction ⱕ 0.35
69 38 63 39 7 8 4 14 10
(43–88) (52%) (86%) (53%) (9%) (11%) (5%) (19%) (14%)
Values are expressed as mean (range) or number (%).
tigators and attending physicians were blinded to the D-dimer test results. The final interpretations of the TEEs were the result of the consensus of the same 2 experienced investigators based on real-time observation or off-line analysis of the studies. For D-dimer results below the measurement range, 0.1 g/ml was entered. Values are presented as mean ⫾ SEM. To obtain normal distribution, D-dimer values were logarithmically transformed, and unpaired 2-tailed t tests were used to compare means. The independent predictive role of embolic predictors for log D-dimer was evaluated by multiple regression analysis. Sensitivity, specificity, and predictive values were calculated using standard formulas. A p value ⬍0.05 was considered statistically significant. Analyses were performed with SAS for Windows 8.02 (SAS Institute Inc., Cary, North Carolina) and GraphPad Prism, version 3.00 (GraphPad Software, San Diego, California) statistical software packages. After an initial screening, 75 patients were examined. Two patients were excluded because of equivocal transesophageal echocardiographic results. Basal characteristics of the enrolled 73 patients are listed in Table 1. The log D-dimer concentrations were compared between groups of patients dichotomized by the presence or absence of each independent predictor of embolism. These predictors were based on previous clinical trials and included: age ⱖ70 years; history of hypertension, diabetes mellitus, ischemic heart disease, and previous systemic embolization; left ventricular ejection fraction ⱕ0.35; moderate to severe mitral regurgitation; left atrial dimension ⱖ45 mm; peak left atrial appendage flow ⱕ0.4 m/s; heavy spontaneous echo contrast; and presence of atrial thrombus.1 There was a tendency for most of these predictors to be associated with elevated D-dimer levels, reaching statistical significance in those aged ⬎70 years, in patients with severe mitral regurgitation, and in the presence of atrial thrombus. (Table 2) In multiple regression analysis, older age and severe mitral regurgitation 0002-9149/03/$–see front matter doi:10.1016/S0002-9149(03)00476-4
85
TABLE 2 Log D-dimer Levels (g/ml) According to Clinical and Echocardiographic Predictors of Embolism Absent Embolic Predictors
Mean ⫾ SEM
Age ⱖ70 yrs Hypertension Diabetes Ischemic heart disease History of systemic embolism AF at presentation* LVEF ⱕ0.35 Severe mitral regurgitation Left atrium ⱖ45 mm Peak LAA flow ⱕ0.4 m/s Heavy SEC Atrial thrombus
⫺0.55 ⫺0.48 ⫺0.46 ⫺0.44 ⫺0.44 ⫺0.57 ⫺0.45 ⫺0.50 ⫺0.52 ⫺0.52 ⫺0.45 ⫺0.48
⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾
Present 95% CI ⫺0.67, ⫺0.63, ⫺0.56, ⫺0.54, ⫺0.54, ⫺0.89, ⫺0.56, ⫺0.60, ⫺0.65, ⫺0.64, ⫺0.57, ⫺0.58,
0.06 0.07 0.05 0.05 0.05 0.14 0.05 0.05 0.06 0.06 0.06 0.05
⫺0.44 ⫺0.34 ⫺0.35 ⫺0.34 ⫺0.34 ⫺0.25 ⫺0.35 ⫺0.41 ⫺0.40 ⫺0.40 ⫺0.34 ⫺0.38
Mean ⫾ SEM ⫺0.33 ⫺0.40 ⫺0.27 ⫺0.38 ⫺0.37 ⫺0.41 ⫺0.32 ⫺0.15 ⫺0.35 ⫺0.36 ⫺0.39 ⫺0.10
⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾
0.07 0.07 0.12 0.16 0.14 0.05 0.11 0.11 0.07 0.08 0.08 0.10
95% CI ⫺0.47, ⫺0.53, ⫺0.56, ⫺0.78, ⫺0.82, ⫺0.51, ⫺0.57, ⫺0.39, ⫺0.50, ⫺0.52, ⫺0.56, ⫺0.34,
⫺0.18 ⫺0.27 ⫺0.02 ⫺0.01 ⫺0.09 ⫺0.31 ⫺0.06 ⫺0.09 ⫺0.21 ⫺0.20 ⫺0.22 ⫺0.13
p Value 0.0154 0.3745 0.2260 0.7108 0.7235 0.2557 0.3281 0.0026 0.0733 0.1158 0.5611 0.0078
*Patients not presenting with AF had atrial flutter. CI ⫽ confidence interval; LAA ⫽ left atrial appendage; LVEF ⫽ left ventricular ejection fraction; SEC ⫽ spontaneous echo contrast.
TABLE 3 Influence of Clinical and Echocardiographic Embolic Predictors on Log D-Dimer Variable
F Value
p Value
All variables Age ⱖ70 yrs Hypertension Diabetes mellitus Ischemic heart disease History of systemic embolism AF at presentation LVEF ⱕ0.35 Severe mitral regurgitation Left atrium ⱖ45 mm Peak LAA flow ⱕ0.4 m/s Heavy SEC Atrial thrombus Model after backward elimination All variables Age ⱖ70 yrs Severe mitral regurgitation Peak LAA flow ⱕ0.4 m/s
30.59 4.12 0.01 0.64 0.04 0.00 0.63 0.05 7.02 0.27 1.79 0.00 2.02
⬍0.0001 0.0467 0.9132 0.4272 0.8436 0.9538 0.4293 0.8277 0.0103 0.6027 0.1856 0.9582 0.1602
94.79 5.79 14.06 5.49
⬍0.0001 0.0188 0.0004 0.0220
Abbreviation as in Table 2.
remained significant independent predictors of the log D-dimer levels. Using a backward elimination method, after stepwise elimination of variables with p ⬎0.5, the low peak left atrial appendage flow also became a significant predictor (Table 3). Atrial thrombi were detected by TEE in 9 patients (12%). To assess the usefulness of the D-dimer test for the diagnosis of atrial thrombi, a receiver-operator characteristic curve analysis was performed (Figure 1). The cut-off value of D-dimer concentration was set at 0.60 g/ml to optimize for negative test results; thus, 67% of patients fell into the normal range. Sensitivity and specificity were 89% and 75%, respectively, using TEE as the gold standard. For our population, the positive predictive value was 33%, and the negative predictive value was 98%. The only patient with a false–negative D-dimer test result was a 65-year-old man presenting with atrial flutter of unknown duration. He had a history of hypertension but was without structural heart disease. The echogenic structure in the left atrial appendage 86 THE AMERICAN JOURNAL OF CARDIOLOGY姞
VOL. 92
FIGURE 1. Receiver-operating characteristic curve of D-dimer to atrial thrombus detected by TEE. The corresponding D-dimer concentrations in micrograms per milliliter are indicated. The p value refers to the difference from random results. AUC ⴝ area under the curve; CI ⴝ confidence interval.
showed no change in shape or size after 3 weeks of effective anticoagulant therapy. The patient’s sinus rhythm was then restored applying electrical cardioversion without complication. Fifty of 55 cardioversion attempts in patients without thrombus were successful. No embolic event was recorded. •••
The relation of the markers of accelerated coagulation to clinical or echocardiographic risk factors for thromboembolism is controversial.12 Our investigation clearly demonstrated a positive correlation of the clinically predicted embolic risk to the D-dimer concentration. The pathogenesis of thrombus formation in AF is not fully understood. Our results suggest that the clinical conditions causing increased embolic risk are additive and share a common final pathway leading to enhanced fibrin generation. Even in the absence of a JULY 1, 2003
detectable thrombus, patients with signs of accelerated coagulation are at risk for thrombus formation in the future. Although the exclusion of thrombus by TEE defines a low immediate hazard of embolism, D-dimer may be a better single marker of overall thromboembolic risk. Although the specificity and positive predictive values were moderate, low levels of D-dimer reliably excluded the presence of atrial thrombi. The optimal cut-off point and negative predictive value were similar to those established for the diagnosis of venous and pulmonary thromboembolism.13 One of the patients with left atrial appendage thrombus had false low D-dimer levels. This patient presented with atrial flutter without significant structural heart disease and had a low pretest probability of atrial thrombus. In addition to having true false–negative results, there are other possible explanations for the discrepancy. An atrial thrombus formed during a previous episode of AF may have been organized by the time of the current examination. Alternatively, a nonthrombotic anatomic structure may have been mistakenly diagnosed as thrombus. In studies using open-heart surgery as the reference standard, TEE adequately ruled out atrial thrombi. However, in these trials the average positive predictive value of TEE was only 89%.14 –20 Because of the lower embolic risk, the false–positive rate of TEE may be higher in our AF patients without valvular disease requiring surgery. Although an actual false–negative result cannot be formally excluded, both described alternatives (e.g., organized thrombus or nonthrombotic structure) explain the low D-dimer level and the resistance to anticoagulant therapy, and both conditions confer a low risk for embolism. In conclusion, the D-dimer determination as a single test adequately defined a low thromboembolic risk associated with cardioversion of AF in 2/3 of our patients. Further confirmation of our results in larger trials would provide us with a simple, objective, and widely available screening test before cardioversion without the drawbacks of TEE. Our investigation suggests that the serum Ddimer level is a useful marker of overall embolic risk in patients with AF and reflects a cumulative prothrombotic effect of clinical and echocardiographic predictors of stroke. A low level of D-dimer reliably excludes the presence of atrial thrombus. Acknowledgment: We are indebted to Zsolt Kara´ nyi, MS, of the Medical & Health Sciences Center, University of Debrecen, Debrecen, Hungary, for his expert guidance on statistical analysis, and to Ferenc Follath, MD, of University Hospital Zu¨ rich, Zu¨ rich, Switzerland, for his valuable comments.
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