- Email: [email protected]
Incidence of Cerebral Embolism after Cardioversion of Atrial Fibrillation: A Prospective Study with Transesophageal Echocardiography and Cerebral Magnetic Resonance Imaging
Incidence of Cerebral Embolism after Cardioversion of Atrial Fibrillation: A Prospective Study with Transesophageal Echocardiography and Cerebral Magnetic Resonance Imaging Peter Bernhardt, MD, Harald Schmidt, MD, Christoph Hammerstingl, MD, Berndt Lüderitz, MD, PhD, FESC, FAHA, FACC, and Heyder Omran, MD, Bonn, Germany
Background: After cardioversion of atrial fibrillation the risk for cerebral embolism is increased. There is little knowledge about the incidence of cerebral embolism for patients with transesophageal echocardiography (TEE)-guided cardioversion under oral anticoagulation. Methods: Consecutive patients with atrial fibrillation and TEE-guided cardioversion were included in the study. We performed serial TEE studies, Holter electrocardiography, cranial magnetic resonance imaging, and clinical examinations during a period of 4 weeks before and after cardioversion. Oral anticoagulation was continued or initiated in all patients.
Patients with nonvalvular atrial fibrillation (AF) and
electrical cardioversion have a particularly increased risk for cerebral embolism. The rate of embolic events is 5% to 7% depending on the patient population.1-5 Either anticoagulation or transesophageal echocardiography (TEE)-guided cardioversion in patients with AF is recommended to reduce the risk of embolic complications to 0% to 2%.2-4,6-14 However, there is little knowledge about the outcome of patients with TEE-guided cardioversion and the incidence of embolism in those patients under continued oral anticoagulation therapy. Cranial magnetic resonance (MR) imaging (MRI) has a high accuracy for detecting cerebral embolism and allows detection of clinically silent cerebral microembolism.15-18 We conducted a prospective and serial study with From the Department of Medicine–Cardiology, University of Bonn, and St Marien Hospital Bonn (H.S., H.O.). Supported by a grant by the University of Bonn BONFOR No. 0-707. Reprint requests: Peter Bernhardt, MD, MRT-Center at the St Gertrauden-Hospital, Paretzer Str 12, 10713 Berlin, Germany (E-mail: [email protected]). 0894-7317/$30.00 Copyright 2005 by the American Society of Echocardiography. doi:10.1016/j.echo.2004.09.022
Results: During the observation period 6 of 127 (4.7%) patients had new embolic lesions after cardioversion documented on cerebral magnetic resonance imaging. Patients with an event were significantly older (P ⴝ .04) and had a larger left atrium (P ⴝ .04) than patients without event. Conclusion: Patients with atrial fibrillation and oral anticoagulation have a low rate of clinical apparent cerebral embolism after TEE and anticoagulationguided cardioversion. The rate of silent cerebral embolism is almost 5%. Age and left atrial size are predictors for an event. (J Am Soc Echocardiogr 2005; 18:649-53.)
the following aims: (1) to assess the fate of cardioverted patients under continued anticoagulation therapy; (2) to evaluate the incidence of cerebral embolism during a follow-up period of 4 weeks postintervention by means of serial cranial MRI scanning; and (3) to determine predictors of cerebral embolism.
METHODS Study Patients Between 1999 and 2001 all patients older than 18 years with AF scheduled for cardioversion were included in the study. Exclusion criteria were: contraindication to cerebral MRI, TEE, or oral anticoagulation; carotid artery stenosis greater than 50%; and the inability to give written informed consent. Written informed consent was obtained from all patients and the study was approved by the institutional review board of the University of Bonn, Germany. Study Protocol All patients were examined clinically. At the index admission we assessed cardiovascular risk factors (arterial hypertension, smoking, diabetes mellitus, hypercholesterol-
649
Journal of the American Society of Echocardiography June 2005
650 Bernhardt et al
emia, and a history of embolism). A 12-lead surface electrocardiogram (ECG) was obtained. During the follow-up the patients were examined serially 24 hours and 4 weeks after cardioversion. Echocardiographic Studies All studies were conducted with commercially available equipment (Vingmed 800c, System V, GE, Milwaukee, Wis). For transthoracic echocardiography, a 1.7-/3.4-MHz electronic transducer was used. The M-mode left atrial (LA) dimension and left ventricular ejection fraction were measured according to the recommendations of the American Society of Echocardiography.19 TEE was performed with a 6.7-MHz multiplane electronic transducer as previously reported by our study group.20,21 Cineloops of the LA and the LA appendage were stored. The sample volume of the pulsed Doppler was placed 1 cm into the orifice of the LA appendage and the profile of the velocities recorded. Echocardiographic Data Analysis Echocardiographic evaluations were performed by two independent observers examining the digitized images after the original examination. The images were displayed in random order without clinical information about the patient and analyzed by means of the evaluation software provided by the manufacturer (Echopac, GE). Interobserver differences were resolved by a third observer. The cineloops of the LA and LA appendage were examined for thrombi and spontaneous echocontrast. A thrombus was defined as an echodense intracavitary mass distinct from the underlying endocardium and not caused by pectinate muscles. The degree of spontaneous echocontrast was categorized as being absent (0), mild (1⫹), mild to moderate (2⫹), moderate (3⫹), or severe (4⫹) on the basis of the system described by Fatkin et al.22 LA appendage area and peak emptying velocities were measured as previously reported.20,22 Anticoagulation All patients received oral anticoagulation with phenprocoumon 4 weeks before and 4 weeks after cardioversion. The effectiveness of anticoagulation was assessed by the international normalized ratio (INR) level. An INR ⬎ 2 was defined as therapeutic range.14,23,24 The target range of INR was 2.0 to 3.0. Cranial MRI The MR examinations were performed with a 1.5-T system (Gyroscan ACS-NT, Philips Medical Systems, Eindhoven, the Netherlands). The imaging protocol included a diffusion-weighted single shot spin echo echoplanar sequence, turbo fluid attenuated inversion recovery, and T2weighted turbo spin echo sequences as previously described by our study group.18 All MRI studies were evaluated by experienced consultant radiologists blinded to clinical and neurologic status and procedure. MRIs of the brain were evaluated for the
Table 1 Patient characteristics Patients
n Age (y) Sex (female) Previous thromboembolism Diabetes mellitus Smoking Hypertension Hypercholesterolemia (⬎220 mg/dL) Embolism during follow-up
127 59.4 ⫾ 9.7 21 (17%) 10 (8%) 21 (17%) 41 (32%) 61 (48%) 79 (62%) 6 (4.7%)
presence of focal diffusion abnormalities in a pattern consistent with embolic lesions. Diffuse alterations in the diffusion-weighted images or pattern of watershed ischemia were not considered to be embolic types of lesions. Number, size (⬍ 5 mm, 5-10 mm, ⬎ 10 mm), and vascular territory of all focal diffusion abnormalities were recorded. For patients who showed a focal diffusion abnormality, a follow-up MR investigation was performed after 3 months to define the presence or absence of a subsequent infarct at the location of the diffusion abnormality. Neurologic Examination All patients underwent neurologic assessments by a board of certified neurologists. A neurologic complication was defined as any new cranial-nerve, motor, or sensory deficiency; reflex change; pyramidal sign; or occurrence of mental alteration. Ultrasound of the Cerebral Arteries All patients underwent ultrasound examination of the carotids (HDI 3000, ATL, Bothell, Wash) at the index admission. Considering all information from B-mode, color Doppler, and Doppler ultrasound, stenoses of the common or the internal carotid artery were measured as a reduction of the luminal area according to established criteria.25 All patients with stenoses greater than 50% were excluded from the study. Statistical Analysis Data are reported as the mean ⫾ SD. Continuous variables between groups were compared by a t test for unpaired observations. Nominal data were compared by the Fisher exact test. Categorical data were compared by the Wilcoxon signed rank test for matched pairs. In all cases, a P value ⬍ .05 was considered statistically significant. The 95% confidence intervals are given. Logistic regression analysis was performed to evaluate predictors of thrombus resolution and cerebral embolism.
RESULTS Patients In all, 143 patients with AF were screened for enrollment in the study. A total of 16 patients with
Journal of the American Society of Echocardiography Volume 18 Number 6
Bernhardt et al 651
Table 2 Comparison of patients with maintenance of in sinus rhythm and with recurrence of atrial fibrillation or atrial flutter Maintenance of in sinus rhythm (N ⴝ 76)
Recurrence of AF or atrial flutter (N ⴝ 51)
113 ⫾ 84 57.0 ⫾ 10.1* 36 (47%)† 37 52 120 ⫾ 42 59 ⫾ 12 1.7 ⫾ 1.2 79 ⫾ 21* 0.36 ⫾ 0.18
128 ⫾ 91 63.1 ⫾ 7.7* 37 (73%)† 24 31 131 ⫾ 60 54 ⫾ 12 2.0 ⫾ 1.0 97 ⫾ 28* 0.33 ⫾ 0.16
Duration of AF (ds) Age (ys) Adiposity (BMI ⬎ 30) Hypertension Hypercholesterolemia (⬎220 mg/dL) LVVd (cm3) LVEF (%) SEC (grade) LAV (cm3) LAAv (m/s)
AF, Atrial fibrillation; BMI, body mass index; LAAv, left atrial appendage peak emptying velocities; LAV, left atrial volume; LVEF, left ventricular ejection fraction; LVVd, left ventricular end-diastolic volume; SEC, spontaneous echocontrast. *P ⬍.001. †P ⬍.01.
unsuccessful cardioversion, thrombi, aortic plaques greater than 4 mm, carotid stenosis greater than 50%, or a combination of these were excluded. In all, 127 patients formed the study group. Patient data are provided in Table 1. Ten (8%) patients had a history of embolism. No patient had a neurologic deficit at admission. Echocardiography Measurements of left ventricular and LA dimensions, left ventricular ejection fraction, and LA appendage peak emptying velocities are given in Table 2. In all, 89 (70%) patients had mild mitral regurgitation, but it was neither a predictor of cerebral embolism nor was its absence a predictor of in sinus rhythm persistence. At the index admission, spontaneous echocontrast was present in 86 (68%) patients. In all, 103 (81%) patients had aortic plaques less than 4 mm. None of the patients had mobile aortic atheroma. Patients with and without embolic event did not differ for degree of spontaneous echocontrast (1.9 ⫾ 1.4 vs 1.8 ⫾ 1.1, P ⫽ not significant), ejection fraction (61 ⫾ 11% vs 57 ⫾ 12%, P ⫽ not significant), or LA appendage peak emptying velocities (0.33 ⫾ 0.16 m/s vs 0.35 ⫾ 0.17 m/s, P ⫽ not significant). None of the patients had a persistent foramen ovale. ECG All patients had paroxysmal or persistent AF in the Holter ECG at the index admission and could be converted successfully with documented in sinus rhythm 24 hours after cardioversion. In the follow-up 4 weeks after cardioversion 76 (60%) patients still had in sinus rhythm, 48 (38%) had AF, and 3 (2%) atrial flutter documented on Holter ECG (Figure 1). Patients with and without cerebral embolism did not differ regarding persistent or recurrent AF as seen in the follow-up visit.
Figure 1 Chart showing Holter electrocardiographic rhythm 4 weeks after cardioversion.
Cranial MRI and Neurologic Examination No patient had old focal diffusion abnormalities at the index admission. During the 4-week follow-up period after cardioversion, 6 (4.7%) of the patients manifested acute cerebral diffusion abnormalities in a pattern consistent with embolic lesions (Figure 2). The size of the embolic lesions was less than 5 mm in all cases. The affected vascular territories were superficial middle (n ⫽ 4) and deep middle (n ⫽ 2) cerebral arteries. No diffusion abnormalities in border zone areas or diffuse diffusion abnormalities were noted. All patients had clinical silent cerebral embolism as documented by diffusion defects. In these patients, follow-up conventional MRI was performed after 3 months. Patients developed a focal signal hyperattenuation on the T2-weighted and fluid attenuated inversion recovery imaging in the region corresponding to the original index lesion, indicating infarcted brain tissue.
652 Bernhardt et al
Figure 2 Cerebral magnetic resonance imaging in fluid attenuated inversion recovery (A), T2-weighted imaging (B), and diffusion-weighted imaging (C). New periventricular diffusion abnormality (arrow) of middle cerebral artery consistent with acute cerebral ischemia could be seen.
Carotid Artery Disease In all, 9 patients had carotid stenosis less than 50%. One of these patients had a cerebral lesion during the observation period. Anticoagulation All patients received effective oral anticoagulation 4 weeks before and at least 4 weeks after cardioversion. The average INR was 2.3 ⫾ 0.7 at the index admission and 2.5 ⫾ 0.4 during the follow-up period. Predictors of in Sinus Rhythm Persistence Clinical risk factors did not differ between patients with and without in sinus rhythm in the follow-up period. Patients with AF or atrial flutter 4 weeks postintervention were singificantly older (63.1 ⫾ 7.7 years vs 57.0 ⫾ 10.1 years, P ⫽ .0004), had significantly more adiposity (body mass index ⬎ 30) (37 [73%] vs 36 [47%], P ⫽ .0044), and had a larger LA (97 ⫾ 28 cm3 vs 79 ⫾ 21 cm3, P ⬍ .001) than patients with in sinus rhythm persistence. Predictors of Cerebral Embolism Patients with cerebral embolism were significantly older (67.3 ⫾ 9.0 years vs 59.1 ⫾ 9.6 years, P ⫽ .04) and had a significantly larger LA (110 ⫾ 32 mL vs 87 ⫾ 26 mL, P ⫽ .04). DISCUSSION One of the primary findings of our study is that the rate of silent cerebral embolism in TEE-guided cardioversion of nonvalvular AF and continued oral anticoagulation before and after cardioversion are relevant (4.7%). Similar findings were found by other study groups that revealed a thromboembolic rate after electrical cardioversion of 0% to 2%.6-14 These latter studies assessed only clinically apparent embolic events.
Journal of the American Society of Echocardiography June 2005
Most embolic events after electrical cardioversion of AF occur during the first 4 weeks postintervention.12,26 Our study showed that patients undergoing electrical cardioversion under continued oral anticoagulation have a relevant probability of silent cerebral embolism 4 weeks after the procedure as assessed by serial cranial MRI. All of our patients were observed closely and all were anticoagulated effectively during the observation period. The only independent predictors for an embolic event in our study were age and atrial dimension. Persistence of in sinus rhythm 4 weeks after successful cardioversion of AF was found in 60% of our patients. Other study groups reported similar in sinus rhythm maintenance rates of 50% to 61% in patients with AF 8 weeks after either TEE- or anticoagulation-guided electrical cardioversion.11,27,29 The only independent predictors for in sinus rhythm maintenance in our study were LA size, age, and adiposity. These findings are strengthened by other study groups.28 Verhorst et al29 showed 27% in sinus rhythm maintenance after 1 month with patient’s weight being a predictor. Other recent studies revealed LA size to be a predicting variable for the maintenance of in sinus rhythm29,30 and confirm our findings. This is the first study to assess the incidence of clinically apparent and silent cerebral embolism with modern MRI techniques for patients with nonvalvular AF and TEE-guided cardioversion under continued effective oral anticoagulation. Recent studies have shown that diffusion-weighted cranial MRI may serve as a useful surrogate end point for ischemic stroke.15-18 Cranial MRI examinations are suited to monitor objectively and quantitatively thromboembolism in patients with AF undergoing cardioversion. Continued effective anticoagulation does not prevent thromboembolic events for patients with AF after electrical cardioversion. Clinical Implications TEE-guided cardioversion under continued oral anticoagulation carries a low risk for clinical apparent, but a relevant risk for silent cerebral embolism. Further studies are warranted to show a higher anticoagulation level or a combined anticoagulation therapy with antiplatlet drugs could lower the embolic risk in these patients. Limitations The number of patients investigated was relatively small and the observation period short. However, patient data were assessed on a prospective basis. Pooled data from 32 studies show that most clinical apparent emboli (96%) occur within 1 week after cardioversion.26 However, we covered a 4-week follow-up period after cardioversion.
Journal of the American Society of Echocardiography Volume 18 Number 6
Bernhardt et al 653
REFERENCES 1. Morris JJ, Kong Y, North WC, McIntosh HD. Experience with ‘cardioversion’ of atrial fibrillation and flutter. Am J Cardiol 1964;14:94-100. 2. Bjerklund C, Orning OM. The efficacy of anticoagulant therapy in preventing embolism related to DC electrical cardioversion of atrial fibrillation. Am J Cardiol 1969;23:208-16. 3. Weinberg DM, Mancini GBJ. Anticoagulation for cardioversion of atrial fibrillation. Am J Cardiol 1989;63:745-6. 4. Arnold AZ, Mick MJ, Mazurek RP, Loop FD, Trohmann RG. Role of prophylactic anticoagulation therapy in the prevention of embolic complications of atrial fibrillation. J Am Coll Cardiol 1992;19:851-5. 5. Roy D, Marchand E, Gagné P, Chabot M, Cartier R. Usefulness of anticoagulant therapy in the prevention of embolic complications of atrial fibrillation. Am Heart J 1986;112: 1039-43. 6. Klein AL, Grimm RA, Black IW, Leung DY, Chung MK, Vaughn SE, et al, for the ACUTE Investigators. Cardioversion guided by transesophageal echocardiography: the ACUTE pilot study; a randomized, controlled trial. Ann Intern Med 1997;126:200-9. 7. Rokseth R, Storstein O. Quinidine therapy of chronic auricular fibrillation: the occurrence and mechanism of syncope. Arch Intern Med 1963;111:184-9. 8. Manning WJ, Silverman DI, Gordon SPF, Krumholz HM, Douglas PS. Cardioversion from atrial fibrillation without prolonged anticoagulation with the use of transesophageal echocardiography to exclude the presence of atrial thombi. N Engl J Med 1993;328:750-5. 9. Stoddard MF, Dawkins P, Prince CR, Longaker RA. Transesophageal echocardiographic guidance of cardioversion in patients with atrial fibrillation. Am Heart J 1995;129:1204-15. 10. Manning WJ, Silverman DI, Keighley CS, Oettgen P, Douglas PS. Transesophageal echocardiographically facilitated early cardioversion from atrial fibrillation using short term anticoagulation: final results of a prospective 4.5-year study. J Am Coll Cardiol 1995;25:1354-61. 11. Klein AL, Grimm RA, Murray RD, Apperson-Hansen C, Asinger RW, Black IW, et al, for the Assessment of Cardioversion Using Transesophageal Echocardiography Investigators. Use of transesophageal echocardiography to guide cardioversion in patients with atrial fibrillation. N Engl J Med 2001; 344:1411-20. 12. Galagher MM, Hennessy BJ, Edvardsson N, Hart CM, Shannon MS, Oel OA, et al. Embolic complications of direct current cardioversion of atrial arrhythmias: association with low intensity of anticoagulation at the time of cardioversion. J Am Coll Cardiol 2002;40:926-33. 13. Seidl KH, Rameken M, Drögemüller A, Vater M, Brandt A, Schwacke H, et al. Embolic events in patients with atrial fibrillation and effective anticoagulation: value of transesophageal echocardiography to guide direct-current cardioversion. J Am Coll Cardiol 2002;39:1436-42. 14. Fuster V, Ryden LE, Asinger RW, Cannom DS, Crijns HJ, Frye RL, et al. American College of Cardiology/American Heart Association/European Society of Cardiology Board. ACC/AHA/ESC guidelines for the management of patients with atrial fibrillation: executive summary. 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 manage-
15.
16.
17. 18.
19.
20.
21.
22.
23.
24.
25. 26.
27.
28.
29.
30.
ment of patients with atrial fibrillation): developed in collaboration with the North American Society of Pacing and Electrophysiology. J Am Coll Cardiol 2001;38:1231-66. Moseley ME, Kucharczyk J, Mintorovitch J, Cohen Y, Kurhanewicz J, Derugin N, et al. Diffusion-weighted MR imaging of acute stroke: correlation with T2-weighted and magnetic susceptibility-enhanced MR imaging in cats. Am J Neuroradiol 1990;11:423-9. Warach S, Gaa J, Siewert B, Wielopolski P, Edelman RR. Acute human stroke studied by whole brain echo planar diffusion-weighted magnetic resonance imaging. Ann Neurol 1995;37:231-41. Schaefer PW, Grant PE, Gonzalez G. Diffusion-weighted MR imaging of the brain. Radiology 2000;217:331-45. Omran H, Schmidt H, Hackenbroch M, Illien S, Bernhardt P, von der Recke G, et al. Silent and apparent cerebral embolism after retrograde catheterization of the aortic valve in valvular stenosis: a prospective, randomised study. Lancet 2003;361: 1241-6. Henry WL, DeMaria A, Gramiak R, King DL, Kisslo JA, Popp RL, et al. Report of the American Society of Echocardiography committee on nomenclature and standards in two-dimensional echocardiography. Circulation 1980;62:212-5. Omran H, Jung W, Rabahieh R, Schimpf R, Wolpert C, Hagendorff A, et al. Left atrial chamber and appendage function after internal atrial defibrillation: a prospective and serial transesophageal echocardiographic study. J Am Coll Cardiol 1997;29:131-8. Omran H, Jung W, Schimpf R, MacCarter D, Rabahieh R, Wolpert C, et al. Echocardiographic parameters for predicting maintenance of sinus rhythm after internal atrial defibrillation. Am J Cardiol 1998;81:1446-9. Fatkin D, Kelly RP, Feneley MP. Relations between left atrial appendage blood flow velocity, spontaneous echocardiographic contrast and thromboembolic risk in vivo. J Am Coll Cardiol 1994;23:961-9. Laupacis A, Albers G, Dalen J, Dunn MI, Jacobson AK, Singer DE. Antithrombotic therapy in atrial fibrillation. Chest 1998; 114:579-89S. Hylek EM, Go AS, Chang Y, Jensvold NG, Henault LE, Selby JV, et al. Effect of intensity of oral anticoagulation on stroke severity and mortality in atrial fibrillation. N Engl J Med 2003;349:1019-26. Landwehr P, Schulte O, Voshage G. Ultrasound examination of carotid and vertebral arteries. Eur Radiol 2001;11:1521-34. Berger M, Schweitzer P. Timing of thromboembolic events after elective cardioversion of atrial fibrillation or flutter: a retrospective analysis. Am J Cardiol 1998;82:1545-7. Berry C, Stewart S, Payne EM, McArthur JD, McMurray JJ. Electrical cardioversion for atrial fibrillation: outcomes in “reallife” clinical practice. Int J Cardiol 2001;81:29-35. Frick M, Frykman V, Jensen-Urstad M, Ostergren J, Rosenqvist M. Factors predicting success rate and recurrence of atrial fibrillation after first electrical cardioversion in patients with persistent atrial fibrillation. Clin Cardiol 2001;24:238-44. Verhorst PM, Kamp O, Wellinh RC, Van Eenige MJ, Visser CA. Transesophageal echocardiographic predictors for maintenance of sinus rhythm after electrical cardioversion of atrial fibrillation. Am J Cardiol 1997;79:1355-9. Bollmann A, Husser D, Steinert R, Stridh M, Soenmo L, Olsson SB, et al. Echocardiographic and electrocardiographic predictors for atrial fibrillation recurrence following cardioversion. J Cardiovasc Electrophysiol 2003;14:S162-5.
Background: After cardioversion of atrial fibrillation the risk for cerebral embolism is increased. There is little knowledge about the incidence of cerebral embolism for patients with transesophageal echocardiography (TEE)-guided cardioversion under oral anticoagulation. Methods: Consecutive patients with atrial fibrillation and TEE-guided cardioversion were included in the study. We performed serial TEE studies, Holter electrocardiography, cranial magnetic resonance imaging, and clinical examinations during a period of 4 weeks before and after cardioversion. Oral anticoagulation was continued or initiated in all patients.
Patients with nonvalvular atrial fibrillation (AF) and
electrical cardioversion have a particularly increased risk for cerebral embolism. The rate of embolic events is 5% to 7% depending on the patient population.1-5 Either anticoagulation or transesophageal echocardiography (TEE)-guided cardioversion in patients with AF is recommended to reduce the risk of embolic complications to 0% to 2%.2-4,6-14 However, there is little knowledge about the outcome of patients with TEE-guided cardioversion and the incidence of embolism in those patients under continued oral anticoagulation therapy. Cranial magnetic resonance (MR) imaging (MRI) has a high accuracy for detecting cerebral embolism and allows detection of clinically silent cerebral microembolism.15-18 We conducted a prospective and serial study with From the Department of Medicine–Cardiology, University of Bonn, and St Marien Hospital Bonn (H.S., H.O.). Supported by a grant by the University of Bonn BONFOR No. 0-707. Reprint requests: Peter Bernhardt, MD, MRT-Center at the St Gertrauden-Hospital, Paretzer Str 12, 10713 Berlin, Germany (E-mail: [email protected]). 0894-7317/$30.00 Copyright 2005 by the American Society of Echocardiography. doi:10.1016/j.echo.2004.09.022
Results: During the observation period 6 of 127 (4.7%) patients had new embolic lesions after cardioversion documented on cerebral magnetic resonance imaging. Patients with an event were significantly older (P ⴝ .04) and had a larger left atrium (P ⴝ .04) than patients without event. Conclusion: Patients with atrial fibrillation and oral anticoagulation have a low rate of clinical apparent cerebral embolism after TEE and anticoagulationguided cardioversion. The rate of silent cerebral embolism is almost 5%. Age and left atrial size are predictors for an event. (J Am Soc Echocardiogr 2005; 18:649-53.)
the following aims: (1) to assess the fate of cardioverted patients under continued anticoagulation therapy; (2) to evaluate the incidence of cerebral embolism during a follow-up period of 4 weeks postintervention by means of serial cranial MRI scanning; and (3) to determine predictors of cerebral embolism.
METHODS Study Patients Between 1999 and 2001 all patients older than 18 years with AF scheduled for cardioversion were included in the study. Exclusion criteria were: contraindication to cerebral MRI, TEE, or oral anticoagulation; carotid artery stenosis greater than 50%; and the inability to give written informed consent. Written informed consent was obtained from all patients and the study was approved by the institutional review board of the University of Bonn, Germany. Study Protocol All patients were examined clinically. At the index admission we assessed cardiovascular risk factors (arterial hypertension, smoking, diabetes mellitus, hypercholesterol-
649
Journal of the American Society of Echocardiography June 2005
650 Bernhardt et al
emia, and a history of embolism). A 12-lead surface electrocardiogram (ECG) was obtained. During the follow-up the patients were examined serially 24 hours and 4 weeks after cardioversion. Echocardiographic Studies All studies were conducted with commercially available equipment (Vingmed 800c, System V, GE, Milwaukee, Wis). For transthoracic echocardiography, a 1.7-/3.4-MHz electronic transducer was used. The M-mode left atrial (LA) dimension and left ventricular ejection fraction were measured according to the recommendations of the American Society of Echocardiography.19 TEE was performed with a 6.7-MHz multiplane electronic transducer as previously reported by our study group.20,21 Cineloops of the LA and the LA appendage were stored. The sample volume of the pulsed Doppler was placed 1 cm into the orifice of the LA appendage and the profile of the velocities recorded. Echocardiographic Data Analysis Echocardiographic evaluations were performed by two independent observers examining the digitized images after the original examination. The images were displayed in random order without clinical information about the patient and analyzed by means of the evaluation software provided by the manufacturer (Echopac, GE). Interobserver differences were resolved by a third observer. The cineloops of the LA and LA appendage were examined for thrombi and spontaneous echocontrast. A thrombus was defined as an echodense intracavitary mass distinct from the underlying endocardium and not caused by pectinate muscles. The degree of spontaneous echocontrast was categorized as being absent (0), mild (1⫹), mild to moderate (2⫹), moderate (3⫹), or severe (4⫹) on the basis of the system described by Fatkin et al.22 LA appendage area and peak emptying velocities were measured as previously reported.20,22 Anticoagulation All patients received oral anticoagulation with phenprocoumon 4 weeks before and 4 weeks after cardioversion. The effectiveness of anticoagulation was assessed by the international normalized ratio (INR) level. An INR ⬎ 2 was defined as therapeutic range.14,23,24 The target range of INR was 2.0 to 3.0. Cranial MRI The MR examinations were performed with a 1.5-T system (Gyroscan ACS-NT, Philips Medical Systems, Eindhoven, the Netherlands). The imaging protocol included a diffusion-weighted single shot spin echo echoplanar sequence, turbo fluid attenuated inversion recovery, and T2weighted turbo spin echo sequences as previously described by our study group.18 All MRI studies were evaluated by experienced consultant radiologists blinded to clinical and neurologic status and procedure. MRIs of the brain were evaluated for the
Table 1 Patient characteristics Patients
n Age (y) Sex (female) Previous thromboembolism Diabetes mellitus Smoking Hypertension Hypercholesterolemia (⬎220 mg/dL) Embolism during follow-up
127 59.4 ⫾ 9.7 21 (17%) 10 (8%) 21 (17%) 41 (32%) 61 (48%) 79 (62%) 6 (4.7%)
presence of focal diffusion abnormalities in a pattern consistent with embolic lesions. Diffuse alterations in the diffusion-weighted images or pattern of watershed ischemia were not considered to be embolic types of lesions. Number, size (⬍ 5 mm, 5-10 mm, ⬎ 10 mm), and vascular territory of all focal diffusion abnormalities were recorded. For patients who showed a focal diffusion abnormality, a follow-up MR investigation was performed after 3 months to define the presence or absence of a subsequent infarct at the location of the diffusion abnormality. Neurologic Examination All patients underwent neurologic assessments by a board of certified neurologists. A neurologic complication was defined as any new cranial-nerve, motor, or sensory deficiency; reflex change; pyramidal sign; or occurrence of mental alteration. Ultrasound of the Cerebral Arteries All patients underwent ultrasound examination of the carotids (HDI 3000, ATL, Bothell, Wash) at the index admission. Considering all information from B-mode, color Doppler, and Doppler ultrasound, stenoses of the common or the internal carotid artery were measured as a reduction of the luminal area according to established criteria.25 All patients with stenoses greater than 50% were excluded from the study. Statistical Analysis Data are reported as the mean ⫾ SD. Continuous variables between groups were compared by a t test for unpaired observations. Nominal data were compared by the Fisher exact test. Categorical data were compared by the Wilcoxon signed rank test for matched pairs. In all cases, a P value ⬍ .05 was considered statistically significant. The 95% confidence intervals are given. Logistic regression analysis was performed to evaluate predictors of thrombus resolution and cerebral embolism.
RESULTS Patients In all, 143 patients with AF were screened for enrollment in the study. A total of 16 patients with
Journal of the American Society of Echocardiography Volume 18 Number 6
Bernhardt et al 651
Table 2 Comparison of patients with maintenance of in sinus rhythm and with recurrence of atrial fibrillation or atrial flutter Maintenance of in sinus rhythm (N ⴝ 76)
Recurrence of AF or atrial flutter (N ⴝ 51)
113 ⫾ 84 57.0 ⫾ 10.1* 36 (47%)† 37 52 120 ⫾ 42 59 ⫾ 12 1.7 ⫾ 1.2 79 ⫾ 21* 0.36 ⫾ 0.18
128 ⫾ 91 63.1 ⫾ 7.7* 37 (73%)† 24 31 131 ⫾ 60 54 ⫾ 12 2.0 ⫾ 1.0 97 ⫾ 28* 0.33 ⫾ 0.16
Duration of AF (ds) Age (ys) Adiposity (BMI ⬎ 30) Hypertension Hypercholesterolemia (⬎220 mg/dL) LVVd (cm3) LVEF (%) SEC (grade) LAV (cm3) LAAv (m/s)
AF, Atrial fibrillation; BMI, body mass index; LAAv, left atrial appendage peak emptying velocities; LAV, left atrial volume; LVEF, left ventricular ejection fraction; LVVd, left ventricular end-diastolic volume; SEC, spontaneous echocontrast. *P ⬍.001. †P ⬍.01.
unsuccessful cardioversion, thrombi, aortic plaques greater than 4 mm, carotid stenosis greater than 50%, or a combination of these were excluded. In all, 127 patients formed the study group. Patient data are provided in Table 1. Ten (8%) patients had a history of embolism. No patient had a neurologic deficit at admission. Echocardiography Measurements of left ventricular and LA dimensions, left ventricular ejection fraction, and LA appendage peak emptying velocities are given in Table 2. In all, 89 (70%) patients had mild mitral regurgitation, but it was neither a predictor of cerebral embolism nor was its absence a predictor of in sinus rhythm persistence. At the index admission, spontaneous echocontrast was present in 86 (68%) patients. In all, 103 (81%) patients had aortic plaques less than 4 mm. None of the patients had mobile aortic atheroma. Patients with and without embolic event did not differ for degree of spontaneous echocontrast (1.9 ⫾ 1.4 vs 1.8 ⫾ 1.1, P ⫽ not significant), ejection fraction (61 ⫾ 11% vs 57 ⫾ 12%, P ⫽ not significant), or LA appendage peak emptying velocities (0.33 ⫾ 0.16 m/s vs 0.35 ⫾ 0.17 m/s, P ⫽ not significant). None of the patients had a persistent foramen ovale. ECG All patients had paroxysmal or persistent AF in the Holter ECG at the index admission and could be converted successfully with documented in sinus rhythm 24 hours after cardioversion. In the follow-up 4 weeks after cardioversion 76 (60%) patients still had in sinus rhythm, 48 (38%) had AF, and 3 (2%) atrial flutter documented on Holter ECG (Figure 1). Patients with and without cerebral embolism did not differ regarding persistent or recurrent AF as seen in the follow-up visit.
Figure 1 Chart showing Holter electrocardiographic rhythm 4 weeks after cardioversion.
Cranial MRI and Neurologic Examination No patient had old focal diffusion abnormalities at the index admission. During the 4-week follow-up period after cardioversion, 6 (4.7%) of the patients manifested acute cerebral diffusion abnormalities in a pattern consistent with embolic lesions (Figure 2). The size of the embolic lesions was less than 5 mm in all cases. The affected vascular territories were superficial middle (n ⫽ 4) and deep middle (n ⫽ 2) cerebral arteries. No diffusion abnormalities in border zone areas or diffuse diffusion abnormalities were noted. All patients had clinical silent cerebral embolism as documented by diffusion defects. In these patients, follow-up conventional MRI was performed after 3 months. Patients developed a focal signal hyperattenuation on the T2-weighted and fluid attenuated inversion recovery imaging in the region corresponding to the original index lesion, indicating infarcted brain tissue.
652 Bernhardt et al
Figure 2 Cerebral magnetic resonance imaging in fluid attenuated inversion recovery (A), T2-weighted imaging (B), and diffusion-weighted imaging (C). New periventricular diffusion abnormality (arrow) of middle cerebral artery consistent with acute cerebral ischemia could be seen.
Carotid Artery Disease In all, 9 patients had carotid stenosis less than 50%. One of these patients had a cerebral lesion during the observation period. Anticoagulation All patients received effective oral anticoagulation 4 weeks before and at least 4 weeks after cardioversion. The average INR was 2.3 ⫾ 0.7 at the index admission and 2.5 ⫾ 0.4 during the follow-up period. Predictors of in Sinus Rhythm Persistence Clinical risk factors did not differ between patients with and without in sinus rhythm in the follow-up period. Patients with AF or atrial flutter 4 weeks postintervention were singificantly older (63.1 ⫾ 7.7 years vs 57.0 ⫾ 10.1 years, P ⫽ .0004), had significantly more adiposity (body mass index ⬎ 30) (37 [73%] vs 36 [47%], P ⫽ .0044), and had a larger LA (97 ⫾ 28 cm3 vs 79 ⫾ 21 cm3, P ⬍ .001) than patients with in sinus rhythm persistence. Predictors of Cerebral Embolism Patients with cerebral embolism were significantly older (67.3 ⫾ 9.0 years vs 59.1 ⫾ 9.6 years, P ⫽ .04) and had a significantly larger LA (110 ⫾ 32 mL vs 87 ⫾ 26 mL, P ⫽ .04). DISCUSSION One of the primary findings of our study is that the rate of silent cerebral embolism in TEE-guided cardioversion of nonvalvular AF and continued oral anticoagulation before and after cardioversion are relevant (4.7%). Similar findings were found by other study groups that revealed a thromboembolic rate after electrical cardioversion of 0% to 2%.6-14 These latter studies assessed only clinically apparent embolic events.
Journal of the American Society of Echocardiography June 2005
Most embolic events after electrical cardioversion of AF occur during the first 4 weeks postintervention.12,26 Our study showed that patients undergoing electrical cardioversion under continued oral anticoagulation have a relevant probability of silent cerebral embolism 4 weeks after the procedure as assessed by serial cranial MRI. All of our patients were observed closely and all were anticoagulated effectively during the observation period. The only independent predictors for an embolic event in our study were age and atrial dimension. Persistence of in sinus rhythm 4 weeks after successful cardioversion of AF was found in 60% of our patients. Other study groups reported similar in sinus rhythm maintenance rates of 50% to 61% in patients with AF 8 weeks after either TEE- or anticoagulation-guided electrical cardioversion.11,27,29 The only independent predictors for in sinus rhythm maintenance in our study were LA size, age, and adiposity. These findings are strengthened by other study groups.28 Verhorst et al29 showed 27% in sinus rhythm maintenance after 1 month with patient’s weight being a predictor. Other recent studies revealed LA size to be a predicting variable for the maintenance of in sinus rhythm29,30 and confirm our findings. This is the first study to assess the incidence of clinically apparent and silent cerebral embolism with modern MRI techniques for patients with nonvalvular AF and TEE-guided cardioversion under continued effective oral anticoagulation. Recent studies have shown that diffusion-weighted cranial MRI may serve as a useful surrogate end point for ischemic stroke.15-18 Cranial MRI examinations are suited to monitor objectively and quantitatively thromboembolism in patients with AF undergoing cardioversion. Continued effective anticoagulation does not prevent thromboembolic events for patients with AF after electrical cardioversion. Clinical Implications TEE-guided cardioversion under continued oral anticoagulation carries a low risk for clinical apparent, but a relevant risk for silent cerebral embolism. Further studies are warranted to show a higher anticoagulation level or a combined anticoagulation therapy with antiplatlet drugs could lower the embolic risk in these patients. Limitations The number of patients investigated was relatively small and the observation period short. However, patient data were assessed on a prospective basis. Pooled data from 32 studies show that most clinical apparent emboli (96%) occur within 1 week after cardioversion.26 However, we covered a 4-week follow-up period after cardioversion.
Journal of the American Society of Echocardiography Volume 18 Number 6
Bernhardt et al 653
REFERENCES 1. Morris JJ, Kong Y, North WC, McIntosh HD. Experience with ‘cardioversion’ of atrial fibrillation and flutter. Am J Cardiol 1964;14:94-100. 2. Bjerklund C, Orning OM. The efficacy of anticoagulant therapy in preventing embolism related to DC electrical cardioversion of atrial fibrillation. Am J Cardiol 1969;23:208-16. 3. Weinberg DM, Mancini GBJ. Anticoagulation for cardioversion of atrial fibrillation. Am J Cardiol 1989;63:745-6. 4. Arnold AZ, Mick MJ, Mazurek RP, Loop FD, Trohmann RG. Role of prophylactic anticoagulation therapy in the prevention of embolic complications of atrial fibrillation. J Am Coll Cardiol 1992;19:851-5. 5. Roy D, Marchand E, Gagné P, Chabot M, Cartier R. Usefulness of anticoagulant therapy in the prevention of embolic complications of atrial fibrillation. Am Heart J 1986;112: 1039-43. 6. Klein AL, Grimm RA, Black IW, Leung DY, Chung MK, Vaughn SE, et al, for the ACUTE Investigators. Cardioversion guided by transesophageal echocardiography: the ACUTE pilot study; a randomized, controlled trial. Ann Intern Med 1997;126:200-9. 7. Rokseth R, Storstein O. Quinidine therapy of chronic auricular fibrillation: the occurrence and mechanism of syncope. Arch Intern Med 1963;111:184-9. 8. Manning WJ, Silverman DI, Gordon SPF, Krumholz HM, Douglas PS. Cardioversion from atrial fibrillation without prolonged anticoagulation with the use of transesophageal echocardiography to exclude the presence of atrial thombi. N Engl J Med 1993;328:750-5. 9. Stoddard MF, Dawkins P, Prince CR, Longaker RA. Transesophageal echocardiographic guidance of cardioversion in patients with atrial fibrillation. Am Heart J 1995;129:1204-15. 10. Manning WJ, Silverman DI, Keighley CS, Oettgen P, Douglas PS. Transesophageal echocardiographically facilitated early cardioversion from atrial fibrillation using short term anticoagulation: final results of a prospective 4.5-year study. J Am Coll Cardiol 1995;25:1354-61. 11. Klein AL, Grimm RA, Murray RD, Apperson-Hansen C, Asinger RW, Black IW, et al, for the Assessment of Cardioversion Using Transesophageal Echocardiography Investigators. Use of transesophageal echocardiography to guide cardioversion in patients with atrial fibrillation. N Engl J Med 2001; 344:1411-20. 12. Galagher MM, Hennessy BJ, Edvardsson N, Hart CM, Shannon MS, Oel OA, et al. Embolic complications of direct current cardioversion of atrial arrhythmias: association with low intensity of anticoagulation at the time of cardioversion. J Am Coll Cardiol 2002;40:926-33. 13. Seidl KH, Rameken M, Drögemüller A, Vater M, Brandt A, Schwacke H, et al. Embolic events in patients with atrial fibrillation and effective anticoagulation: value of transesophageal echocardiography to guide direct-current cardioversion. J Am Coll Cardiol 2002;39:1436-42. 14. Fuster V, Ryden LE, Asinger RW, Cannom DS, Crijns HJ, Frye RL, et al. American College of Cardiology/American Heart Association/European Society of Cardiology Board. ACC/AHA/ESC guidelines for the management of patients with atrial fibrillation: executive summary. 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 manage-
15.
16.
17. 18.
19.
20.
21.
22.
23.
24.
25. 26.
27.
28.
29.
30.
ment of patients with atrial fibrillation): developed in collaboration with the North American Society of Pacing and Electrophysiology. J Am Coll Cardiol 2001;38:1231-66. Moseley ME, Kucharczyk J, Mintorovitch J, Cohen Y, Kurhanewicz J, Derugin N, et al. Diffusion-weighted MR imaging of acute stroke: correlation with T2-weighted and magnetic susceptibility-enhanced MR imaging in cats. Am J Neuroradiol 1990;11:423-9. Warach S, Gaa J, Siewert B, Wielopolski P, Edelman RR. Acute human stroke studied by whole brain echo planar diffusion-weighted magnetic resonance imaging. Ann Neurol 1995;37:231-41. Schaefer PW, Grant PE, Gonzalez G. Diffusion-weighted MR imaging of the brain. Radiology 2000;217:331-45. Omran H, Schmidt H, Hackenbroch M, Illien S, Bernhardt P, von der Recke G, et al. Silent and apparent cerebral embolism after retrograde catheterization of the aortic valve in valvular stenosis: a prospective, randomised study. Lancet 2003;361: 1241-6. Henry WL, DeMaria A, Gramiak R, King DL, Kisslo JA, Popp RL, et al. Report of the American Society of Echocardiography committee on nomenclature and standards in two-dimensional echocardiography. Circulation 1980;62:212-5. Omran H, Jung W, Rabahieh R, Schimpf R, Wolpert C, Hagendorff A, et al. Left atrial chamber and appendage function after internal atrial defibrillation: a prospective and serial transesophageal echocardiographic study. J Am Coll Cardiol 1997;29:131-8. Omran H, Jung W, Schimpf R, MacCarter D, Rabahieh R, Wolpert C, et al. Echocardiographic parameters for predicting maintenance of sinus rhythm after internal atrial defibrillation. Am J Cardiol 1998;81:1446-9. Fatkin D, Kelly RP, Feneley MP. Relations between left atrial appendage blood flow velocity, spontaneous echocardiographic contrast and thromboembolic risk in vivo. J Am Coll Cardiol 1994;23:961-9. Laupacis A, Albers G, Dalen J, Dunn MI, Jacobson AK, Singer DE. Antithrombotic therapy in atrial fibrillation. Chest 1998; 114:579-89S. Hylek EM, Go AS, Chang Y, Jensvold NG, Henault LE, Selby JV, et al. Effect of intensity of oral anticoagulation on stroke severity and mortality in atrial fibrillation. N Engl J Med 2003;349:1019-26. Landwehr P, Schulte O, Voshage G. Ultrasound examination of carotid and vertebral arteries. Eur Radiol 2001;11:1521-34. Berger M, Schweitzer P. Timing of thromboembolic events after elective cardioversion of atrial fibrillation or flutter: a retrospective analysis. Am J Cardiol 1998;82:1545-7. Berry C, Stewart S, Payne EM, McArthur JD, McMurray JJ. Electrical cardioversion for atrial fibrillation: outcomes in “reallife” clinical practice. Int J Cardiol 2001;81:29-35. Frick M, Frykman V, Jensen-Urstad M, Ostergren J, Rosenqvist M. Factors predicting success rate and recurrence of atrial fibrillation after first electrical cardioversion in patients with persistent atrial fibrillation. Clin Cardiol 2001;24:238-44. Verhorst PM, Kamp O, Wellinh RC, Van Eenige MJ, Visser CA. Transesophageal echocardiographic predictors for maintenance of sinus rhythm after electrical cardioversion of atrial fibrillation. Am J Cardiol 1997;79:1355-9. Bollmann A, Husser D, Steinert R, Stridh M, Soenmo L, Olsson SB, et al. Echocardiographic and electrocardiographic predictors for atrial fibrillation recurrence following cardioversion. J Cardiovasc Electrophysiol 2003;14:S162-5.