Author + information
- S.Ahmed Tejan-Sie, MD*,
- R.Daniel Murray, PhD*,
- Ian W. Black, MD†,
- Susan E. Jasper, RN*,
- Carolyn Apperson-Hansen, MStat‡,
- Jianbo Li, MS, PhD‡,
- Elizabeth A. Lieber, BA‡,
- Richard A. Grimm, DO*,
- Allan L. Klein, MD*,* (, )
- ACUTE Investigators
- ↵*Reprint requests and correspondence:
Dr. Allan L. Klein, Department of Cardiovascular Medicine, Cleveland Clinic Foundation, Desk F-15, 9500 Euclid Avenue, Cleveland, Ohio 44195, USA.
Objectives This study was designed to determine the characteristics and outcomes of spontaneous conversion (SC) to sinus rhythm (SR) in patients with atrial fibrillation (AF) of more than two days.
Background The Assessment of Cardioversion Using Transesophageal Echocardiography (ACUTE) multicenter study was a prospective trial in which transesophageal echocardiography (TEE)-guided treatment was compared with conventional anticoagulation treatment for the management of patients with AF >2 days undergoing direct current cardioversion (DCC). In an ancillary analysis, we evaluated the baseline and outcome data in patients who underwent SC to SR before scheduled DCC.
Methods We identified 1,041 patients for this analysis after excluding patients on pre-existing antiarrhythmic agents. Patients with SC in the TEE-guided and conventional groups were first compared then pooled and compared with non-spontaneous conversion (No-SC) patients.
Results Overall, 167 of 1,041 (16%) patients underwent SC, with twice as many in the conventional compared with the TEE-guided group (110/523 [21%] vs. 57/518 [11%]; p < 0.001). When compared with No-SC patients, a higher proportion of SC patients maintained SR at eight weeks (87.2% vs. 48.9%, p < 0.001), without statistically significant differences in bleeding, thromboembolism or mortality. Multivariate predictors of SC were shorter duration of AF, New York Heart Association (NYHA) functional class 1 or 2, smaller left atrial size, and absence of left atrial spontaneous echo contrast.
Conclusions Spontaneous conversion was associated with shorter duration of AF, lower NYHA class, smaller left atrial size, and absence of left atrial spontaneous echo contrast. There was a better SR outcome in the SR group, but no differences in the other clinical end points. The conventional treatment strategy allowed greater opportunity for SC. In the absence of favorable predictors of SC, the TEE-guided approach should be considered.
The Assessment of Cardioversion Using Transesophageal Echocardiography (ACUTE) multicenter study was a prospective randomized trial in which transesophageal echocardiography (TEE)-guided treatment with short-term anticoagulation was compared with a conventional anticoagulation strategy for the management of patients with atrial fibrillation (AF) >2 days undergoing electrical cardioversion. The ACUTE study demonstrated that a TEE-guided cardioversion with short-term anticoagulation was a safe and clinically effective alternative to the conventional approach (1). It was also recognized, especially in the conventional group, that before scheduled cardioversion, a significant proportion of patients in the study underwent spontaneous conversion (SC) to sinus rhythm (SR).
Management options in hemodynamically stable patients with AF >48 h include initiation of rate control with anticoagulation alone (2)or electric or pharmacologic cardioversion with either the conventional anticoagulation or TEE-guided strategies. However, all these approaches can be associated with significant morbidity and mortality (2–4)as well as bleeding and thromboembolic complications. In patients with AF <48 h, waiting for SC may be the most cost-effective option (5), although SC has also been associated with complications (6–8). Therefore, identification of patients likely to undergo SC may be important in order to direct appropriate therapy and to postpone pharmacologic or electric cardioversion.
There has not been a large prospective multicenter study evaluating SC in patients with AF of >2 days duration. Therefore, in the ACUTE study, we performed an ancillary analysis to: 1) determine the incidence of SC; 2) outline characteristics and outcomes of SC patients between the TEE-guided and conventional groups; and 3) compare the pooled SC patients to pooled non-spontaneous conversion (No-SC) patients. We also sought to determine independent predictors of SC to more accurately identify patients likely to undergo SC.
In the ACUTE study, 1,222 patients were enrolled between August 6, 1994, and August 18, 1999, from 70 sites. The methods have been fully described elsewhere (1,9). In brief, patients were enrolled and randomized to either a strategy of treatment guided by the findings of TEE with short-term anticoagulation, or a conventional treatment strategy of anticoagulation (Fig. 1). Patients randomized to the TEE-guided group were therapeutically anticoagulated before electrical direct-current cardioversion (DCC). Inpatients were typically treated with intravenous unfractionated heparin (target activated partial thromboplastin time = 1.5 to 2.5 times control) and outpatients received warfarin (target international normalized ratio = 2.0 to 3.0). Using TEE, the patients were then stratified on the basis of the presence or absence of thrombus. Patients assigned to the conventional group received three weeks of therapeutic warfarin therapy prior to cardioversion, followed by a four-week period of post-cardioversion warfarin according to the American College of Chest Physicians (ACCP) guidelines. Full details of anticoagulation and patients monitoring have been previously described (9).
The institutional review board of each participating medical center approved the protocol and informed consent was obtained from each trial participant.
In the ACUTE study, patients who were candidates for electrical cardioversion and at least 18 years old with AF for at least 2 days were eligible for enrollment. Similar patients with atrial flutter and a history of AF were also eligible. Hemodynamically unstable patients and those with pure atrial flutter without a history of AF were excluded. All patients were enrolled in an intention-to-treat analysis and followed from enrollment to day 56 when end points were assessed.
For the purposes of this ancillary study, patients who underwent SC to SR before DCC were identified as SC patients. All other patients who underwent DCC or chemical cardioversion were classified as No-SC. Patients on pre-existing Vaughn-Williams Class 1 or 3 antiarrhythmic agents before enrollment were excluded from the analysis. The resulting study population was 1,041 patients. Baseline characteristics and outcomes of SC were first compared between the TEE-guided and conventional groups before the entire patient cohort was pooled and evaluated by SC and No-SC patient subgroups. The study protocol is illustrated in Figure 1.
Outcomes assessed in this analysis were embolism, which was a composite of cerebrovascular accidents, transient ischemic attacks, and peripheral embolism; all-cause mortality; major or minor bleeding complications; functional status (measured by the Duke Activity Status Index); and success or maintenance of SR. Additional outcomes of this ancillary analysis were time to spontaneously convert from enrollment and independent multivariate predictors of SC.
In the univariate analysis, data are expressed as mean ± SD, as medians with interquantile ranges or as frequencies or percentages with 95% confidence intervals. Chi-square tests were used for the comparison of categorical variables in the treatment groups. Wilcoxon two-sample test was used for the comparison of continuous variables. Potential predictors of SC were assessed using multivariate logistic regression with stepwise selection with SAS software (SAS/STAT release 8.2, 2000; SAS Institute Inc., Cary, North Carolina). One thousand bootstrap samples (random sample of 80% of the total with replacement) were used in the analysis for identification of clinical and echocardiographic predictors. Variables with high frequency (50% or higher) of being a predictor in individual bootstrapping were selected for a final model. Receiver-operating characteristic curve were used to identify the optimal AF duration and left atrial (LA) size. The results are expressed as the area under the curve with 95% confidence intervals. All statistical testing was conducted at a significance level of 0.05 with a two-tailed alternative hypothesis.
TEE-guided vs. conventional treatment groups
Out of the total 1,041 patients, 167 (16%) underwent SC to SR: 57 in the TEE-guided group and 110 in the conventional group. Table 1compares the baseline characteristics of patients in the TEE-guided and conventional groups who underwent SC to SR. Almost twice as many conventional group patients underwent SC compared with the TEE-guided group (21% vs. 11%, p < 0.001) although there were no differences in age, functional status, and proportion of patients with atrial flutter, or median estimated duration of AF. Table 1also shows the outcomes of the SC patients in the TEE-guided and conventional groups at eight weeks. There were no statistically significant differences in incidence of composite embolism, major or minor bleeds, functional capacity, mortality or maintenance of SR at eight weeks between the treatment groups of the study for patients who underwent SC.
SC versus NO-SC
Patients who underwent SC to SR in both the TEE-guided and conventional groups were pooled and compared to the No-SC patients. Table 2illustrates the baseline characteristics of the two groups. There were no differences in age, rhythm at enrollment, or functional status in the two groups. However, SC patients had smaller mean LA size (22.7 ± 7.9 cm2vs. 26.2 ± 9.3 cm2, p < 0.001), higher mean left ventricular ejection fraction (LVEF) (53.2 ± 13.8 vs. 50.1 ± 15.5, p = 0.02), shorter median estimated duration of AF before enrollment (8 vs. 14 days, p < 0.001) and tended to have a lower frequency of congestive heart failure (22.4% vs. 29.9%, p = 0.06). However, a higher proportion of SC patients used calcium channel blockers (39.4% vs. 29.9%, p = 0.02) but a lower proportion used digoxin (46% vs. 57%, p < 0.01).
Table 2also shows outcomes of patients in the SC and No-SC groups. There was a higher maintenance of SR in SC patients at eight weeks compared with No-SC (87.2% vs. 48.9%, p < 0.001). However, there were no differences in functional capacity, composite embolism, bleeding, or mortality between SC and No-SC patients.
Duration of pre-existing AF and time to SC
The duration of pre-existing AF in patients ranged from 2 to 453 days. Figure 2illustrates SC rates as related to duration of pre-existing AF at enrollment in weeks. The majority of patients (51%) who underwent SC had a history of one week or less of AF. As AF duration increased, the proportion of patients with SC decreased.
Spontaneous conversion patients converted earlier to SR after enrollment when compared with No-SC (median duration 4 days, interquantile range 1 to 19 days vs. 7 days, interquantile range 1 to 29 days), and reflected the trend of early achievement of SR (p = 0.09). Figure 3illustrates the proportion of patients who underwent SC to SR in the first week following enrollment. The highest proportion of patients (41 patients, 24.5%) underwent SC to SR in the first day of enrollment. Because TEE-guided patients were cardioverted earlier due to study design (3 days vs. 31 days) (1), more TEE-guided patients underwent SC in the first week than conventional patients.
Multivariate predictors of SC
Controlling for other variables using a logistic regression model, several variables were statistically significant as independent predictors of SC as illustrated in Table 3.
Clinical predictors were shorter duration of pre-existing AF (p < 0.0001) and the presence of New York Heart Association (NYHA) functional class 1 or 2 functional classification (p < 0.04). Echocardiographic predictors were smaller LA size measured by two-dimensional transthoracic echocardiogram (TTE) planimetry (p < 0.0001) and absence of LA spontaneous echo contrast (p < 0.01). Receiver-operating characteristic curves were used to determine the optimal atrial size and duration of pre-existing AF associated with SC. In the case of LA size, this was 23.3 cm2(C-statistic or area under the curve = 0.64, 95% confidence interval 0.59 to 0.69, p < 0.001). The optimal duration of pre-existing AF associated with SC was nine days or less (C statistic or area under the curve 0.61, 95% confidence interval 0.56 to 0.68, p < 0.001).
Although patients with AF have been reported to spontaneously convert to SR, this has not been prospectively investigated in patients with AF >48 h duration. Our SC ancillary study in the ACUTE multicenter study is the largest to date on SC and showed the following: 1) SC occurred in 16% of patients studied; 2) there were no differences in adverse clinical outcomes between patients in the TEE or conventional groups that underwent SC; 3) patients who underwent SC were more likely to have a shorter duration of pre-existing AF and undergo conversion to SR earlier; 4) SC patients were more likely to have a higher LVEF and smaller LA size and less likely to have congestive heart failure; 5) patients who underwent SC had no difference in thromboembolism, bleeding or mortality but a higher proportion was in SR at eight weeks compared with No-SC patients; and 6) independent predictors of SC were shorter duration of pre-existing AF, NYHA functional class 1 or 2, smaller LA size (<23.3 cm2), and absence of LA spontaneous echo contrast.
In our prospective study, patients in the TEE-guided group were noted to have a lower rate of SC compared with the conventionally treated patients (11% vs. 21%), which may reflect the study design, because patients in the TEE arm were cardioverted much sooner (3 days vs. 31 days) (1).
The overall rate of SC (16%) was much lower than reported in previous studies where rates of SC have been derived from studies on chemical cardioversion of AF. In previous studies, SC rates have also varied according to the duration of pre-existing AF. In one study involving digoxin, SC rates were 44% in patients with AF up to 7 days (10). However, SC rates were as high as 72% in patients with AF of 24 h or less in a study involving amiodarone (11). In a goat model of artificially induced AF, it was demonstrated that the likelihood of successful conversion to normal SR diminished with increasing duration of AF (12). On the other hand, in our study the duration of pre-existing AF ranged from 2 days up to 453 days, thus accounting for the relatively low SC rate. However, in patients with AF of 1 week or less, the SC rate of 51% compares favorably with that of patients who underwent SC in the digoxin study (10).
A higher proportion of SC patients maintained SR at eight weeks, which may reflect a smaller LA size at baseline and a shorter median duration of pre-existing AF. Despite generally better baseline health of SC patients, there were no differences in incidence of thromboembolism, mortality, or bleeding complications when compared with No-SC patients. However, the incidence of adverse events was low and the study lacked adequate statistical power to suggest equivalence for these end points in this ancillary study.
Certain clinical and echocardiographic variables have been reported to be associated with a higher likelihood of SC (13,14). The finding of a smaller LA size being associated with greater success of conversion to SR in our study concurs with some previous studies (14), but not with others (15). Dittrich et al. (16)did not demonstrate any correlation between success or maintenance of SR and LA size, but this was a small retrospective study in which LA size was assessed by M-mode echocardiography. It has been demonstrated in previous studies that persistent AF leads to progressive atrial enlargement (17), which may in turn reduce the likelihood of conversion to SR (18). Our study was larger than previous ones investigating the role of LA size. We also measured LA size by two-dimensional TTE planimetry and we believe our data are consistent with pathophysiologic evidence from both human and animal studies. We could not replicate normal LVEF as an independent positive predictor of SC, which has been reported in some studies; this may have been due to limitations in our sample size and statistical power. An additional independent predictor of SC was NYHA functional lass 1 or 2 that may reflect patients with less severe forms of congestive heart failure with better left ventricular function who may have smaller atria, thus making SC more likely. Patients with a shorter history of pre-existing AF were more likely to undergo SC and that is consistent with previous studies (10,11).
The ACUTE study was not primarily designed to assess SC even though SC was a predetermined outcome. The number of SC patients in the TEE-guided group may have been underestimated because patients without thrombus in this group were cardioverted sooner due to study design. Thus, they were not given time to undergo SC. This study was limited to patients with AF of least 48 h duration and may not be applicable to patients with a shorter history of AF. Although a statistically significant higher proportion of SC patients were on calcium-channel blockers, studies have shown that these agents are effective in rate control only (19,20)and in some cases may even reduce the likelihood of SC (21). However, other studies have suggested that verapamil may reduce recurrence of AF following electrical DCC in patients (22). It is thus unclear whether calcium-channel blockers had any influence on the higher spontaneous conversion rates in our study.
In hemodynamically stable patients with AF of at least 48 h duration with favorable predictors of SC, it is not unreasonable to recommend that conventional treatment of rate control and anticoagulation be initiated while waiting for SC to occur, rather than performing TEE-guided DCC. Such predictors include a better NYHA functional class, shorter duration of pre-existing AF, smaller LA size, and absence of LA spontaneous echo contrast. This approach may result in performing fewer procedures (TEE and DCC), with potential cost savings. On the other hand, in the absence of favorable predictors it may be prudent to proceed to TEE-guided DCC rather than wait for SC. In our study, the majority of patients underwent SC in the first four days following enrollment, although the decision when to proceed to TEE-guided cardioversion should be individualized depending on the status of the patient.
In the ACUTE trial ancillary study, SC occurred in 16% of patients and was associated with shorter duration of AF, lower NYHA class, smaller LA size and absence of spontaneous echo contrast. There was a better SR outcome in the SC group; however, there were no differences in embolism, bleeding, and mortality between the two groups. The conventional treatment strategy allowed greater opportunity for SC. In the absence of favorable predictors of SC, the TEE-guided approach should be considered rather than waiting for SC.
We would like to express our thanks and appreciation to Marie Campbell of the Department of Cardiovascular Medicine, Cleveland Clinic Foundation, and the investigators and sites that participated in this trial Appendix.
☆ We acknowledge support from the American Medical Association Educational and Research Foundation, the American Society of Echocardiography, and Phillips Medical Systems (Advanced Technology Laboratory).
- Assessment of Cardioversion Using Transesophageal Echocardiography study
- atrial fibrillation
- direct-current cardioversion
- left atrial
- left ventricular ejection fraction
- non-spontaneous conversion
- New York Heart Association
- spontaneous conversion
- sinus rhythm
- transesophageal echocardiography
- transthoracic echocardiogram
- American College of Cardiology Foundation
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