Efficacy of transesophageal echocardiography–guided cardioversion of patients with atrial fibrillation at 6 months: A randomized controlled trial

Electrophysiology

Efficacy of transesophageal echocardiography–guided cardioversion of patients with atrial fibrillation at 6 months: A randomized controlled trial Allan L. Klein, MD,a Richard A. Grimm, DO,a Susan E. Jasper, BSN,a R. Daniel Murray, PhD,a Carolyn Apperson-Hansen, MStat,a Elizabeth A. Lieber, BA,a Ian W. Black, MD,b Ravin Davidoff, MB, BCH,c Raimund Erbel, MD,d Jonathan L. Halperin, MD,e David A. Orsinelli, MD,f Thomas R. Porter, MD,g Marcus F. Stoddard, MDh, and The ACUTE Steering and Publications Committee for the ACUTE Investigators* Cleveland, OH; Manley, New South Wales, Australia; Boston, MA; Essen, Germany; New York, NY; Columbus, OH; Omaha, NE; and Louisville, KY

Background Electrical cardioversion in patients with atrial fibrillation (AF) is associated with an increased risk of stroke. We compared a transesophageal echocardiography (TEE)–guided strategy with a conventional strategy in patients with AF N2 days’ duration undergoing electrical cardioversion over a 6-month follow-up. Methods

The ACUTE study was a multicenter, randomized, clinical trial, with 1222 patients. Six-month follow-up was available in 1034 patients (85%), 525 in the TEE group and 509 in the conventional group. The primary composite end points were cerebrovascular accident, transient ischemic attack, and peripheral embolism at 6 months, which was a prespecified time point. Secondary end points were hemorrhage, mortality, and sinus rhythm.

Results At 6 months, there was no difference in composite embolic events between the TEE group and the conventional group (10 [2%] vs 4 [0.8%]; risk ratio (RR) 2.47, 95% CI 0.78-7.88; P = .11). However, the hemorrhagic rate was significantly lower in the TEE group (23 [4.4%] vs 38 [7.5%]; RR 0.58, 96% CI 0.35-0.97; P = .04). There was no difference between the 2 treatment groups in all-cause mortality (21 [4%] vs 14 [2.8%]; RR 1.48, 95% CI 0.76-2.92; P = .25) and in the occurrence of normal sinus rhythm between the 2 groups (305 [62.2%] vs 280 [58.1%]; P = .51). Sinus rhythm at 6 months was more common in the TEE-guided group, in those patients who had direct current cardioversion (238 [62.5%] vs 151 [53.9%]; P = .03). Conclusion The TEE-guided strategy may be considered a clinically effective alternative to a conventional anticoagulation strategy for patients with AF of N2 days’ duration undergoing electrical cardioversion over a 6-month period. (Am Heart J 2006;151:380 - 9.) Atrial fibrillation (AF) is a common arrhythmia that affects over 2.3 million Americans and is increasing in frequency.1 It is estimated that, by the year 2050, N5.6 million people will develop AF.2 Electrical cardioversion in patients with AF is associated with an increased risk of embolic stroke (0.6%-5.6%), which may result when thrombi in the left atrial appendage are

From a The Cleveland Clinic Foundation, Cleveland, OH, bManly Hospital, Manly, New South Wales, Australia, cBoston Medical Center, Boston, MA, dUniversita ¨ tsklinikum– Essen, Essen, Germany, eMount Sinai School of Medicine, New York, NY, fOhio State University, Columbus, OH, gUniversity of Nebraska, Omaha, NE, and hUniversity of Louisville, Louisville, KY. *See Appendix for the affiliations of authors with names and affiliations of ACUTE Investigators. Submitted February 22, 2005; accepted July 12, 2005. Reprint requests: Allan L. Klein, MD, Department of Cardiovascular Medicine, The Cleveland Clinic Foundation, 9500 Euclid Ave, Desk F15, Cleveland, OH 44195. E-mail: [email protected] 0002-8703/$ - see front matter n 2006, Published by Mosby, Inc. doi:10.1016/j.ahj.2005.07.011

dislodged after the resumption of normal sinus rhythm.3-5 Patients with AF undergoing electrical cardioversion are conventionally treated with therapeutic anticoagulation for 3 weeks before and 4 weeks after cardioversion to decrease the risk of thromboembolism.6 Transesophageal echocardiography (TEE) with shortterm anticoagulation has been proposed as an alternative strategy to guide anticoagulation management in patients with AF undergoing electrical cardioversion.7 This approach was proposed as a means to safely expedite cardioversion by excluding thrombi.5,8,9 The results of the ACUTE multicenter study, which compared the TEE-guided strategy to the conventional strategy over a relatively short 8-week study period, were published.10 There has never been a randomized trial that assessed these 2 strategies with long-term follow-up over 6 months (prespecified time end point). Therefore, the objective of this study was to prospectively compare the TEE-guided strategy with short-term anticoagulation to a conventional anticoagulation strat-

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Figure 1

Klein et al 381

Table I. Baseline characteristics in the TEE-guided and conventional groups of the ACUTE Trial

Mean age, y Male sex, n (%) Inpatients, n (%) Hypertension, n (%) CHF, n (%) NYHA III or IV, n (%) LVEF (%) Previous DCC, n (%) History of embolism, n (%) Rhythm (AF/AFL), n (%) AF duration, median days (range) Antiarrhythmic therapy Anticoagulation therapy Warfarin only, n (%) Heparin only, n (%) Warfarin and heparin, n (%)

A schematic diagram showing the derivation of the 6-month study population of 1034 patients with 525 patients in the TEE-guided group and 509 patients in the conventional group.

egy for patients with AF of N2 days’ duration undergoing electrical cardioversion over a 6-month period.

Methods Study design The ACUTE study was a controlled, randomized, multicenter trial that compared clinical outcomes using the TEE-guided or conventional anticoagulation strategies in patients with AF undergoing electrical cardioversion. The study design for the ACUTE multicenter study has been published previously.11 The branched tree for both treatment groups has been previously presented.10 Patients were randomly assigned to a treatment group immediately after study enrollment. After randomization, the patients in the TEE-guided group were therapeutically anticoagulated before cardioversion. Inpatients were typically treated with intravenous unfractionated heparin (target activated partial thromboplastin time [PTT], 1.5-2.5 times control), and outpatients received warfarin (target international normalized ratio [INR], 2.0-3.0). Using TEE, the patients were stratified on the basis of the presence or absence of thrombus. Patients assigned to the transesophageal echocardiography group were given anticoagulant therapy at their initial visit with the intention that they would receive therapeutic anticoagulation at the time of cardioversion and for 4 weeks thereafter. Patients assigned to the conventional group received 3 weeks of therapeutic warfarin therapy before cardioversion, followed by a 4-week period of postcardioversion warfarin. After 8 weeks, the continuation of warfarin was left up to the clinician who evaluated the clinical risk factors for stroke and bleeding. The study period included patient data from randomization to 6 months’ follow-up. The institutional

TEE-guided

Conventional

n = 525

n = 509

P

65.6 F 12.4 356 (68.2) 359 (68.4) 288 (55.0) 148 (28.4) 82 (20.3) 50.6 F 15.7 62 (11.9) 40 (7.6) 500/25 (4.8) 12 (4-45)

65.7 F 12.7 341 (67.7) 318 (62.5) 295 (58.1) 153 (30.4) 76 (19.8) 49.8 F 15.2 64 (12.7) 54 (10.7) 486/23 (4.6) 12 (5-50)

.96 .85 .05 .31 .49 .89 .44 .69 .09 .91 .22*

425 (82)

413 (82)

.98

79 (15) 121 (24) 113 (22)

82 (16) 112 (22) 107 (22)

.62 .62 .81

DCC, Direct current cardioversion; LVEF, left ventricular ejection fraction. *Wilcoxon test.

review board at each participating site approved the study, and informed consent was obtained from all patients.

Patients Patients who were candidates for electrical cardioversion were eligible for enrollment if they were 18 years or older and had AF of N2 days’ duration. Patients with atrial flutter (AFL) with a history of AF were also eligible. Patients in pure AFL, as well as patients with hemodynamic instability, were excluded from the study. Also excluded were patients on chronic warfarin therapy (N7 days’ duration), patients with contraindications to warfarin or TEE, women of childbearing potential, and patients who may need elective procedures requiring discontinuation of anticoagulation. Patients who were on antiarrhythmic medication were not excluded from the study, but commencement of antiarrhythmic therapy was permitted only after therapeutic anticoagulation. The 1222 patients from 70 clinical sites were randomly assigned to either the TEE-guided group (n = 619) or the conventional group (n = 603). One hundred eighty-eight patients (94 patients in each group) were lost to follow-up between 8 weeks and 6 months. Thus, the study population with 6-month follow-up data was 1034 patients: 525 patients in the TEE group and 509 patients in the conventional group (Figure 1). The first patient was enrolled on August 6, 1994. Enrollment was terminated on August 18, 1999, with a total of 1222 patients. The database for the 6-month follow-up was locked in March 2001.

Outcomes The prespecified primary outcome was a composite of cerebrovascular accident, transient ischemic attack, and peripheral embolism at 6-month follow-up. Secondary outcomes were major and minor bleeding events, all-cause mortality, and

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382 Klein et al

Table II. Baseline characteristics for patients with a 6-month follow-up compared with patients without a 6-month follow-up in the TEE-guided group and conventional group of the ACUTE trial

Mean age, y Male sex, n (%) Inpatients, n (%) Hypertension, n (%) CHF, n (%) NYHA III or IV, n (%) LVEF (%) Previous DCC, n (%) History of embolism, n (%) Rhythm (AF/AFL), n (%) AF duration, median days (range)

6-m Follow-up

No follow-up

n = 1034

n = 188

P

65.7 F 12.6 697 (67.9) 677 (65.5) 583 (56.5) 301 (29.4) 158 (20) 50.2 F 15.5 126 (12.3) 94 (9.1)

64.7 F 12.6 115 (61.5) 109 (58) 106 (57.3) 23 (12.6) 17 (12.5) 54.8 F 14.8 31 (16.8) 9 (4.9)

.31 .09 .05 .84 b.001 .04 .001 .09 .06

984/50 (4.9) 12 (5-47)

171/17 (9.1) 11 (4-39)

.02 .25*

*Wilcoxon test.

maintenance of sinus rhythm. A central and independent Events Review Committee adjudicated all serious adverse events. A bleeding complication was considered major if it was fatal, required transfusion, or required surgical procedure to terminate the bleeding.

Statistical analyses Simple descriptive statistics were used to summarize the data and included frequencies and percentages for categorical variables and means, medians, and SDs for continuous variables. In addition, graphical presentations were created for selected continuous and categorical variables. Treatment group comparisons for baseline characteristics were conducted and tested by v 2 or analysis-of-variance methods. The baseline characteristics assessed were sex, history of embolism, age, left ventricular ejection fraction, duration of arrhythmia, previous direct current cardioversion, rhythm (AF/AFL), inpatient status, and New York Heart Association class (NYHA), as well as the presence of hypertension, diabetes, or congestive heart failure (CHF). Time-to-event analyses comparing the 2 groups were performed for the composite end point of cerebrovascular accident and peripheral embolism, as well as major/minor bleeding and all-cause mortality. Kaplan-Meier estimates were generated, and the equality of the curves was tested. Risk ratios (RR) with 95% CIs and P values were reported. Unless otherwise stated, statistical testing was conducted using 2-sided alternatives with a type I error level of .05.

Results Baseline characteristics There were no differences found in the baseline clinical and echocardiographic variables for the 2 groups (Table I). Two thirds of the patients were inpatients at the time of randomization. The primary diagnosis was hypertension. Of note, patients in the 6-month study group tended to be sicker than those who were lost to follow-up (Table II).

Table III. Clinical outcomes in the TEE-guided and conventional treatment groups

All embolic events, n (%) CVA TIA Peripheral Bleeding events, n (%) Major Minor Death from all causes, n (%) Cardiac death Noncardiac death Unknown

TEE-guided

Conventional

n = 525

n = 509

10 (1.9) 8 (1.5)* 3 (0.6) 0 23 (4.4)y 5 (1.0) 19 (3.6) 21 (4.0) 10 (1.9) 9 (1.7) 2 (0.38)

4 (0.8) 3 (0.6) 1 (0.2) 0 38 (7.5) 10 (2.0) 28 (5.5) 14 (2.8) 10 (2.0) 4 (0.8) NA

CVA, Cerebrovascular accident; TIA, transient ischemic attack. *One patient had both CVA and TIA (counted as 1 patient in composite). yOne patient had both major and minor bleedings (counted as 1 patient in composite).

Treatment outcomes after assignment The anticoagulation and antiarrhythmic status at study enrollment for the 1034 patients in the 2 treatment groups is shown in Table I. There was no difference between the 2 groups in the number of patients on antiarrhythmic therapy at enrollment (425 [82%] vs 413 [82%]; P = .98) and no difference at 6 months (427 [87%] vs 421 [86%]; P = .75). Figure 1 shows the study population. Of the 525 patients in the TEE group, 359 (68.4%) had TEE and cardioversion at a mean of 2.7 F 4.27 days from randomization; of which, 295 (82.2%) were successful. Of the 79 patients who had TEE but no cardioversion, cardioversion was postponed secondary to thrombus in 62 (78%) patients. Of the 509 patients in the conventional group, 292 (57.4%) had electrical cardioversion at a mean of 31.4 F 10.4 days, and of these, 229 (78.4%) were successful. Of the 217 patients who did not have a cardioversion, 110 (51%) had a spontaneous or chemical cardioversion. Embolic outcomes Table III shows the adjudicated 6-month embolic events, including the primary composite end point of cerebrovascular accidents, transient ischemic attacks, and peripheral embolism for both groups. A summary of all 14 embolic outcomes is shown in Table IV. Mean age of the patients with embolic events was 68.5 F 8.0 years, and 12 (85.7%) of the 14 patients had risk factors for stroke at the time of enrollment. Of note, in the TEE-guided group, 5 of the 10 events occurred between 8 weeks and 6 months after direct current cardioversion. Five of these patients were in normal sinus rhythm at the time of the event, and only 2 patients had a therapeutic INR/PTT. In contrast, in the conventional group, 3 of the 4 events occurred within 8 weeks

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Table IV. Summary of adjudicated embolic events during the 6-month study period in the TEE-guided and conventional treatment groups Event

Age/sex

TEE-guided CVA CVA CVA CVA CVA CVA CVA

70/M 77/F 73/M 58/M 67/M 57/M 79/M

TIA 65/M TIA 79/M TIA 61/F Conventional CVA 65/F CVA 68/F CVA 75/F TIA 57/M

Risk factors HTN, DM, SEC SEC HTN, cancer, SEC HTN, complex AP Acute infection NYHA3, CABG, LVEF b40% CABG, thrombus, GI tract bleeding, amiodarone toxicity, CRI HTN, LVEF b40%, complex AP, SEC HTN, NYHA3, CABG Mechanical MV None HTN, DM, LVEF b40% Uncontrolled HTN HTN, DCM, LVEF b40%

Days from enrollment

DCC

Days from DCC

Recurrence of AF afer DCC

Warfarin

PT/INR

2 5 28 55 91 113 136

Yes Yes Yes Yes SCV Yes Yes

1 5 26 52 NA 111 96

Yes Yes Yes No Yes No No

Yes Yes No No Yes No No

1.9 1.7 NA NA 1.5 NA NA

16 81 158

SCV Yes Yes

NA 72 157

No No Yes

Yes Yes Yes

2.5 1.6 3.0

12 20 57 7

Yes No No No

6 NA NA NA

No Yes Yes Yes

Yes Yes No Yes

2.4 2.7 NA 2.7

AF, Atrial fibrillation; AP, aortic plaque; CRI, chronic renal insufficiency; CABG, coronary artery bypass graft; DCC, direct current cardioversion; DCM, dilated cardiomyopathy; DM, diabetes mellitus; HTN, hypertension; LVEF, left ventricular ejection fraction; MV, mitral valve; NYHA3, New York Heart Association class III; PT, prothrombin time; SCV, spontaneous conversion; SEC, spontaneous echocardiographic contrast; SR, sinus rhythm.

from enrollment and in patients with AF with a therapeutic INR at the time of the event. Figure 2, A shows a Kaplan-Meier curve of composite stroke over the 6-month follow-up period. There was no statistically significance difference between the 2 groups (RR 2.47, 95% CI 0.78-7.88; P = .11).

Hemorrhagic events In the TEE-guided group, there were 5 major and 19 minor hemorrhagic complications in a total of 23 patients (1 patient had both major and minor bleedings). In contrast, in the conventional group, there were 10 major and 28 minor hemorrhagic complications in 38 patients. The composite of major and minor hemorrhagic events was lower in the TEE-guided group compared with the conventional group (Table III). A summary of all 15 major bleeding events is shown in Table V. Mean age of patients with major bleeding was 74.7 F 8.5 years. The primary site of major bleeding was the gastrointestinal tract, occurred within 8 weeks from enrollment, and was associated with elevated INR values in 9 (60%) of the 15 patients. Figure 2, B shows a Kaplan-Meier curve of composite bleeding over the 6-month follow-up period. There was a statistically significance difference between the 2 groups (RR 0.58, 95% CI 0.35-0.97; P = .04). Mortality Table III includes the secondary end point of all-cause mortality in the 2 treatment groups at 6 months. Summary of all 35 deaths is shown in Table V. Notably, comorbid conditions existed in 34 (97%) of the 35 cases of mortality, and only 1 death (2.8%) resulted from an

embolic event that occurred in the conventional group. Of note, there were 6 patients (29%), with thrombi in the TEE-guided group, who died reflecting the morbidity of these patients. There was no difference in cardiac mortality between the 2 groups or that related to the TEE procedure. Figure 2, C shows a Kaplan-Meier curve of all-cause mortality over the 6-month follow-up period. There was no statistically significant difference between the 2 groups (RR 1.48, 95% CI 0.76-2.92; P = .25).

Sinus rhythm There was no statistical difference in the 6-month success of electrical cardioversion to normal sinus rhythm between the TEE-guided and conventional groups (305 [62.2%] vs 280 [58.1%]; P = 0.51). Sinus rhythm at 6 months was more frequent in the TEE-guided group in those patients who underwent direct current cardioversion (238 [62.5%]) vs 151 [53.9%]; P = .03). Importantly, there was more use of antiarrhythmic therapy in the conventional group compared with the TEE-guided group at the time of cardioversion (271 [92.8%] vs 352 [87.1%]; P = .02). Of note, there was no difference in the number of episodes of AF recurrence (179/472 [37.9%] vs 188/466 [40.3%]; P = .45) or repeat cardioversions (60/494 [12.2%] vs 67/491 [13.7 %]; P = .48) between the TEE-guided and conventional groups.

Discussion The ACUTE multicenter study compared TEE-guided cardioversion with short-term anticoagulation to conventional anticoagulation therapy over a relatively

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Figure 2

Kaplan-Meier curves from enrollment to 6 months for embolism (A), bleeding (B), and mortality (C). Note that the TEE-guided group has a lower rate of bleeding than the conventional group over the 6-month study period.

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Table V. Summary of major bleeding events and deaths as secondary end points during the 6-month study period in the TEE-guided and conventional treatment groups Medications at event Event Major bleeding—TEE-guided Pulmonary GI GI GI Vascular Major bleeding—conventional GI GI GI GI GI GI GI Pleural Pericardium Skin

Age/sex

78/M 73/M 77/F 85/ M 72/M

75/M 71/F 61/M 60/F 69/M 86/M 67/M 83/M 70/M 87/F

Risk factors

CHF, TB, COPD Cancer DM, COPD, orthopedic surgery HTN, pneumonia CAD, CHF, cardiac surgery CAD, peptic ulcer DM, DCM None DM, peptic ulcer None CHF, H/O CVA, renal failure CHF, hyperthyroidism None Cardiac surgery HTN

Days after enrollment

DCC performed

Warfarin (PT/INR)

Heparin (PTT)

1 4 28

No Yes No

Yes (1.3) Yes (3.9) Yes (2.4)

Yes (53.7) No Yes (25.3)

22 30

No No

Yes (3.8) No

No Yes (48.0)

8 12 13 16 21 30

No No No No No No

Yes Yes Yes Yes Yes Yes

37 40 50 62

Yes Yes Yes Yes

No Yes (4.3) Yes (3.8) Yes (7.5)

(5.2) (4.6) (5.2) (3.0) (12.0) (1.0)

Antiarrhythmics (Class) Deaths—TEE-guided Cardiac (sudden)* Cardiac (sudden) Cardiac (sudden) Cardiac (sudden) Cardiac (CHF) Cardiac (CHF) Cardiac (sudden) Cardiac (sudden)* Cardiac (sudden)

33/M 72/M 68/M 74/M 80/F 85/F 63/F 89/F 66/M

Cardiac (amiodarone toxicity)* Noncardiac (CNS)

80/M 77/F

Noncardiac (resp) Noncardiac (sepsis)

78/M 33/M

Noncardiac (sepsis) Noncardiac (resp) Noncardiac (sepsis)* Noncardiac (PE) Noncardiac (postoperative) Noncardiac (aspiration pneumonia)* Unknown Unknown* Deaths—conventional Cardiac (CHF) Cardiac (sudden) Cardiac (CHF) Cardiac (sudden) Cardiac (sudden) Cardiac (CHF) Cardiac (sudden) Cardiac (sudden) Cardiac (sudden) Cardiac (sudden)

83/M 69/M 74/F 67/M 75/M 47/M 76/F 70/F 73/M 70/M 53/F 75/M 56/F 67/M 72/F 49/M 47/M 87/M

Acute CHF, DCM CAD CAD, DCM Diabetes, acute renal failure DCM, CHF SSS, CHF DCM CAD CAD, diabetes, previous CVA CAD, GI tract bleeding Diabetes, COPD, meningitis, orthopedic surgery ARDS, acute renal failure MOF, pneumonia, cardiac surgery Pneumonia, acute peritonitis Cancer, ARDS Diabetes, previous TIA Colon cancer, lung mets Diabetes, CAD CRF, acute peritonitis CAD Previous CVA SSS, CHF None RCM, CHF Acute CHF Diabetes, renal transplant CAD, CHF DCM, diabetes, LV thrombus DCM, Chagas disease CAD, diabetes Previous CVA, GI tract bleeding, CRF

No No No No No No No No No No Digoxin

4 8 11 25 30 36 36 37 83

No Yes No Yes Yes Yes Yes No Yes

No No No No Yes (III) Yes (II, IV) No Yes (IV) Yes (I, IV)

No Yes No No Yes Yes No Yes No

181 13

Yes No

Yes (III) No

No No

15 33

Spontaneous Yes

No Yes (III)

No Yes

41 47 92 153 59 111 3 6

Yes Yes Yes Yes Yes Yes Yes No

Yes Yes Yes Yes

(I) (IV) (III, IV) (III) No Unknown Yes (II) No

No Yes Yes Yes No Unknown No Yes

26 38 48 52 158 163 102 134 169 61

Yes No No Yes Yes Yes Yes Yes Yes No

Yes (III) Yes (I) No Yes (II) Yes (I, IV) No No Yes (III) Yes (II) Unknown

No No No Yes No Yes Yes No Yes Unknown

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Table V. continued Medications at event Event Deaths—conventional Noncardiac (CVA, herniation) Noncardiac (renal) Noncardiac (cancer) Noncardiac (autoimmune disease)

Age/sex

68/F 82/M 63/F 60/F

Risk factors

Diabetes, acute CHF Pneumonia, cancer Adenocarcinoma COPD

Days after enrollment

DCC performed

Warfarin (PT/INR)

Heparin (PTT)

23 34 101 179

No No Yes Yes

Yes (II) No Yes (I, IV) Yes (II)

Yes No Yes No

ARDS, Acute respiratory distress syndrome; CAD, coronary artery disease; COPD, chronic obstructive pulmonary disease; CRF, chronic renal failure; H/O, history of; Mets, metastasis; MOF, multiple organ failure; PE, pulmonary embolism; Resp, respiratory; SSS, sick sinus syndrome; TB, tuberculosis. * Thrombus. yEmbolism.

short 8-week period.10 We now extend these findings to a longer prespecified 6-month follow-up. The results show the following: (1) there was no difference for embolic event outcome between the 2 groups; (2) composite bleeding complications were lower in the TEE-guided group compared with the conventional group; (3) there was no difference in all-cause mortality between the groups; and (4) there was no statistical difference in the maintenance of sinus rhythm at 6 months between the 2 groups. However, in those patients who actually had a cardioversion, there was greater incidence of sinus rhythm at 6 months in the TEEguided group. Thus, the TEE-guided strategy with shortterm anticoagulation did allow safe and early electrical cardioversion with fewer composite hemorrhagic events than the conventional strategy, which was observed at 8 weeks and maintained over the 6-month period.

Thromboembolism At 6 months, there was no statistically significant difference in embolic events between the 2 groups, although there tended to be more in the TEE-guided group (10 vs 4). This is similar to our findings reported at the 8-week follow-up.10 The embolic rate in the trial (1.4%) over 6 months was lower than was expected for a similar group of patients with AF.11,12 Of note, in the TEE-guided group, most of the events occurred beyond 4 weeks after cardioversion. The patients in this group had many clinical risk factors (such as hypertension and aortic atheroma), had a subtherapeutic INR/PTT, and were not in AF at the time of the event. Paroxysmal AF may have contributed to the events in this group. In contrast, in the conventional group, most of the patients with the events never had a cardioversion and had a therapeutic INR at the time of the event. This suggests that, possibly, other risk factors (such as generalized atherosclerosis) may play a role in the cause of stroke in these patients. In addition to therapeutic anticoagulation, blood pressure and lipid control may have an important place in stroke prevention in patients with AF.13

Bleeding events The early advantage of the TEE-guided cardioversion in relation to the bleeding episodes at 8 weeks10,14 continued to the 6-month follow-up period. The composite bleeding rate was 1.7 times higher in the conventional group than in the TEE-guided group ( P = .04). Of note, this was mainly due to an increase in minor bleeding rather than major bleeding during the 8-week study period. Between 8 weeks and 6 months, there was a similar number of bleeding episodes in the TEE-guided versus the conventional groups (5 bleedings [all minor] vs 5 bleedings [1 major and 4 minor]), respectively. This reflects the finding that the patients randomized to the conventional group had almost double the duration of anticoagulation within the 8-week period; the effects of which extended to the 6-week period.10,11 Of note, it appears that the excessive bleeding in the conventional group could be from excessive anticoagulation level as reflected in elevated INRs in this group. As mentioned, the regulation of the INRs was left to the clinician. Mortality All-cause mortality tended to be higher in the TEE group compared with the conventional group, which is similar to the 8-week findings. However, the rate of cardiac death was similar between the 2 groups (1.9% vs 2%). It should be noted that none of the mortality was due to the TEE or cardioversion procedure itself and reflects the complexity and comorbidity of the patients enrolled in the trial.10 Return of normal sinus rhythm At 6 months, there was no statistically significant difference in occurrence of normal sinus rhythm between the groups, but there was tendency favoring the TEE group (62.2% vs 58.1%). Furthermore, in those patients who had a cardioversion, there was greater incidence of sinus rhythm at 6 months in the TEE group (62.5% vs 53.9%). There are 2 possible reasons for this finding. The first is that, with cardioversion performed

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early with the TEE-guided approach, sinus rhythm is restored sooner and is maintained at the 6-month followup. This occurs despite using less antiarrhythmics in this group. The second reason is that we excluded those patients with spontaneous conversion, which was more common in the conventional group,15 thus accounting for more sinus rhythm in the TEE group after electrical cardioversion. Another study provides indirect evidence of the former mechanism, showing greater sinus rhythm using the TEE-guided strategy by cardioverting earlier in those patients with AF of b3 weeks’ duration undergoing cardioversion compared with N3 weeks.16

Clinical implications The results of the recent AFFIRM trial 17,18 and other trials 19-21 show that rate control and prolonged anticoagulation may be the preferred strategy in patients with AF rather than rhythm control with antiarrhythmics and cardioversion. What then should be the role of TEEguided cardioversion in the management of AF based on the results of the ACUTE study?10 The TEE-guided approach may be useful for the symptomatic patient with new-onset AF, for patients at high risk for bleeding and stroke, and for patients in whom the TEE can help risk-stratify by the finding of spontaneous echocardiographic contrast, aortic atheroma, and left atrial appendage thrombus.22 Moreover, it may be useful for those patients with subtherapeutic anticoagulation in those undergoing the conventional approach.23 The recently completed ACUTE II multicenter trial has addressed the role of low molecular weight heparin (enoxaparin) as bridging therapy to warfarin by decreasing length of stay.24,25 Recently, the ACE study showed that enoxaparin was noninferior to intravenous heparin and coumadin, using the TEEguided approach.26 Limitations The study was an investigator-initiated study with limited funding, which was stopped early because of slow patient recruitment; thus, it was underpowered for the primary end point of stroke. There were some differences in the group of patients who were in the blost to follow-upQ group compared with the study population. The study population included sicker patients with more CHF; however, there were no differences between the 2 randomized groups. The anticoagulation status of the patients at 6 months was not formally evaluated. However, the 8-week data showed that the TEE-guided group was more likely to be on warfarin/acetylsalicylic acid compared with the conventional group (TEE 569/575 [99%] vs 518/538 [96.3%]; P = .003).10 This finding is despite the higher composite bleeding rate in the conventional group.

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Conclusion The TEE-guided strategy may be considered a clinically effective alternative to a conventional anticoagulation strategy for patients with AF of N2 days’ duration undergoing electrical cardioversion over a 6-month period.

References 1. Fuster V, Ryden LE, Asinger RW, et al. 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 Management 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. 2. Go AS, Hylek EM, Phillips KA, et al. Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA) study. JAMA 2001;285:2370 - 5. 3. Bjerkelund CJ, Orning OM. The efficacy of anticoagulant therapy in preventing embolism related to D.C. electrical conversion of atrial fibrillation. Am J Cardiol 1969;23:208 - 16. 4. Stein B, Halperin JL, Fuster V. Should patients with atrial fibrillation be anticoagulated prior to and chronically following cardioversion? Cardiovasc Clin 1990;21:231 - 47. 5. Grimm RA, Stewart WJ, Black IW, et al. Should all patients undergo transesophageal echocardiography before electrical cardioversion of atrial fibrillation? J Am Coll Cardiol 1994;23:533 - 41. 6. Singer DE, Albers GW, Dalen JE, et al. Antithrombotic therapy in atrial fibrillation: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004;126:429S - 56S. 7. Klein AL, Murray RD, Grimm RA. Role of transesophageal echocardiography–guided cardioversion of patients with atrial fibrillation. J Am Coll Cardiol 2001;37:691 - 704. 8. Manning WJ, Silverman DI, Gordon SP, et al. Cardioversion from atrial fibrillation without prolonged anticoagulation with use of transesophageal echocardiography to exclude the presence of atrial thrombi. N Engl J Med 1993;328:750 - 5. 9. Silverman DI, Manning WJ. Role of echocardiography in patients undergoing elective cardioversion of atrial fibrillation. Circulation 1998;98:479 - 86. 10. Klein AL, Grimm RA, Murray RD, et al. Use of transesophageal echocardiography to guide cardioversion in patients with atrial fibrillation. N Engl J Med 2001;344:1411 - 20. 11. Steering and Publications Committees of the ACUTE study. Design of a clinical trial for the assessment of cardioversion using transesophageal echocardiography (the ACUTE multicenter study). Am J Cardiol 1998;81:877 - 83. 12. Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke: the Framingham study. Stroke 1991;22:983 - 8. 13. Chugh SS, Blackshear JL, Shen WK, et al. Epidemiology and natural history of atrial fibrillation: clinical implications. J Am Coll Cardiol 2001;37:371 - 8. 14. Klein AL, Murray RD, Grimm RA, et al. Bleeding complications in patients with atrial fibrillation undergoing cardioversion random-

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Appendix A A.1. Clinical Coordinating Center The Cleveland Clinic Foundation—Cleveland, OH Department of Cardiovascular Medicine, Section of Cardiovascular Imaging AL Klein, MD, principal investigator RA Grimm, DO, coinvestigator RD Murray, PhD, project director

DY Leung, MD MJ Garcia, MD MK Chung, MD SE Jasper, BSN AS Goodman, BA

A.2. Data Coordinating Center The Cleveland Clinic Foundation—Cleveland, OH Department of Biostatistics and Epidemiology KL Arheart, EdD, senior biostatistician DP Miller, MA, senior biostatistician C Apperson-Hansen, MStat, research associate EA Lieber, BA, statistical programmer A.3. Economic Analysis Center Emory University—Atlanta, GA School of Public Health ER Becker, PhD SD Culler, PhD PD Mauldin, PhD A.4. Core Echocardiographic Laboratory The Cleveland Clinic Foundation—Cleveland, OH Department of Cardiovascular Medicine, Section of Cardiovascular Imaging A.5. Data Safety and Monitoring Committee S Ellis, MD, chairman (Cleveland, OH) PJ Elson, ScD (Cleveland, OH) J Olin, DO (Cleveland, OH) A.6. Adverse Events Adjudication Committee AJ Furlan, MD (Cleveland, OH) MS Lauer, MD (Cleveland, OH) A.7. ACUTE Steering and Publications Committee AL Klein, MD, Chairman (Cleveland, OH) C Apperson-Hanson, MStat, (Cleveland, OH) RW Asinger, MD (Minneapolis, MN) IW Black, MD (Manly, NSW, Australia) R Davidoff, MB, BCH (Boston, MA) R Erbel, MD (Essen, Germany) RA Grimm, DO (Cleveland, OH) JL Halperin, MD (New York, NY) RD Murray, PhD (Cleveland, OH) DA Orsinelli, MD (Columbus, OH) TR Porter, MD (Omaha, NE) MF Stoddard, MD (Louisville, KY) A.8. Clinical Centers University of Louisville (Louisville, KY), M Stoddard, MD The Cleveland Clinic Foundation (Cleveland, OH), A Klein, MD Centro Medico de Caracas (Caracas, Venezuela), H Acquatella, MD

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Winthrop University Hospital (Mineola, NY), R Smith, MD University of Nebraska (Omaha, NE), T Porter, MD Escorts Heart Institute and Research Centre (New Delhi, India), N Trehan, MD Lancaster Heart Foundation (Lancaster, PA), R Small, MD Paulista School of Medicine (Sao Paulo, Brazil), W Mathias, Jr, MD University Gesamthochschule–Essen (Essen, Germany), R Erbel, MD University of Pittsburgh Medical Center (Pittsburgh, PA), W Katz, MD Hospitals Vera Cruz and Socor (Belo Horizonte, Brazil), M Barbosa, MD St Elisabeth Hospital Tilburg (Tilburg, Netherlands), P Melman, MD, and H Pasteuning, MD El-Azhar University (Cairo, Egypt), M Madkour, MD University of Massachusetts (Worcester, MA), L Pape, MD Instituto Cardiovascular de Rosario (Rosario, Argentina), E Tuero, MD Ospedale Civile (Cento, Italy), D Mele, MD University of California, San Diego Medical Center (San Diego, CA), D Blanchard, MD University of Rochester/Strong Memorial Hospital (Rochester, NY), J Eichelberger, MD Riverside Methodist Hospital (Columbus, OH), T Obarski, DO University of California, San Francisco Medical Center (San Francisco, CA), R Redberg, MD Queen Elizabeth Hospital (Kowloon, Hong Kong), S Li, MD The Heart Group, PC (Saginaw, MI), P Fattal, MD New England Medical Center (Boston, MA), S Schwartz, MD University of Cincinnati (Cincinnati, OH), B Hoit, MD North Shore University Hospital (Manhasset, NY), S Rosen, MD St Luke’s–Roosevelt Hospital (New York, NY), N Krasnow, MD Central Minnesota Heart Center (St Cloud, MN), R Jolkovsky, MD White River Junction VA Medical Center (White River Junction, VT), M Garcia, MD Bronx Veteran Affairs Medical Center (Bronx, NY), L Baruch, MD Medical College of Virginia (Richmond, VA), J Arrowood, MD University of Texas Southwestern Medical Center (Dallas, TX), P Grayburn, MD Harbor University of California Los Angeles Medical Center (Torrance, CA), S Shapiro, MD, PhD Hospital dos Servidores do Estado (Logoa, Brazil), J Filho, MD, and M Carneiro, MD MacNeal Center for Clinical Research (Berwyn, IL), J Briller, MD St John’s Mercy Medical Center (St Louis, MO), L Mezei, MD

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University of Chicago Medical Center (Chicago, IL), R Lang, MD Manly Hospital (Manly, NSW, Australia), I Black, MD St Nicholas Hospital (Sheboygan, WI), L Coulis, MD Loma Linda VA Medical Center (Loma Linda, CA), R Pai, MD Easton Hospital (Easton, PA), K Khalighi, MD Green Lane Hospital (Auckland, New Zealand), S Greaves, MD Prince Henry Hospital (Sydney, NSW, Australia), W Walsh, MD Methodist Hospital/Baylor College of Medicine (Houston, TX), M Quinones, MD North Central Heart Foundation (Sioux Falls, SD), D Nagelhout, MD Ospedale Generale Valduce (Como, Italy), G Corrado, MD Texas Heart Institute (Houston, TX), S Wilansky, MD Royal Victoria Hospital (Montreal, Quebec, Canada), R Haichin, MD Columbia Cardiovascular Clinic (Columbia, SC), B Feldman, MD Austin Heart (Austin, TX), G Rodgers, MD University of New Mexico (Albuquerque, NM), B Shively, MD The OH State University (Columbus, OH), D Orsinelli, MD Medical College of Wisconsin (Milwaukee, WI), K Sagar, MD Sentara Norfolk General Hospital (Norfolk, VA), G Nye, MD Southern New Hampshire Regional Medical Center (Nashua, NH), S Schwartz, MD Ochsner Medical Institutions (New Orleans, LA), F Abi-Samra, MD Blodgett Memorial Medical Center (Grand Rapids, MI), D Langholz, MD Clearwater Cardiovascular Consultants (Largo, FL), P Phillips, MD Hungarian Institute of Cardiology (Budapest, Hungary), M Lengyel, MD Hartford Hospital (Hartford, CT), L Gillam, MD Allengheny University/Hahnemann Hospital (Philadelphia, PA), P Pollack, MD Beth Israel Hospital (Boston, MA), W Manning, MD Boston Medical Center (Boston, MA), R Davidoff, MD Graduate Hospital (Philadelphia, PA), R Schlesinger, MD East Carolina University (Greenville, NC), V Sorrell, MD Michigan Capital Medical Center (Lansing, MI), M Markarian, DO The Albany Medical College (Albany, NY), S Fein, MD The University of Texas Medical Branch at Galveston (Galveston, TX), R Sheahan, MD Maine Medical Center (Portland, ME), M Cohen, MD University of Kansas Medical Center (Kansas City, Kan), D Wilson, MD Northwest OH Cardiology (Toledo, OH), B DeVries, DO