Conversion to Sinus Rhythm with Ibutilide During Atrial Fibrillation Ablation is not Associated with Long Term Sinus Rhythm Maintenance

DOI: 10.19102/icrm.2014.050902

^1,2MAXIM V. GOREV, MD, ²PEDRAM KAZEMIAN, MD, ²SHAW NATAN, MD, ^2,3JOHN V. WYLIE, MD and ^2,3MICHAEL V. ORLOV, MD, PhD

¹Moscow City Clinical Hospital #23, Moscow, Russia

²Steward St. Elizabeth's Medical Center of Boston, Boston, MA
³ Tufts University School of Medicine, Boston, MA

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ABSTRACT. Patients who remain in atrial fibrillation (AF) after ablation likely represent those in whom the critical drivers of AF were not ablated. We hypothesized that organization of AF or its termination with ibutilide defines a group of patients with a more benign arrhythmia substrate and a better long-term outcome. The aim was to evaluate the predictive role of intra-procedural response to ibutilide in patients who had remained in AF after ablation on long-term procedural outcome. Clinical and follow-up data of 92 AF ablation procedures performed in 77 consecutive patients with drug-refractory symptomatic AF between 2007 and 2012 were retrospectively analyzed. Spontaneous sinus rhythm (SR) restoration after ablation (SR group), successful cardioversion with ibutilide (IBU group) and failed cardioversion with ibutilide (IBU-DCCV group) were selected as primary ablation procedure outcomes. The cardioversion efficacy of ibutilide in our study was 45.5%. Sixteen patients in the SR group (43.2%), 17 patients in the IBU group (68.0%), and 20 patients in the IBU-DCCV group (66.7%) failed to maintain SR within the first 12 months after ablation. The assigned group was not associated with a statistically significant difference in the time to failure (p = 0.23). Conversion to SR with ibutilide is not associated with long-term rhythm maintenance after AF ablation.

KEYWORDS. atrial fibrillation, catheter ablation, ibutilide, cardioversion, follow-up, sinus rhythm maintenance.

The authors report no conflicts of interest for the published content.
Manuscript received July 15, 2014, final version accepted August 1, 2014.

Address correspondence to: Michael V. Orlov, MD, PhD, Associate Professor of Medicine, Director of Cardiac Arrhythmia Service, Steward St. Elizabeth’s Medical Center of Boston, 736 Cambridge St. Boston, MA 02135.
E-mail: mvoepdoc@gmail.com;michael.orlov@tufts.edu

Introduction

Catheter-based radiofrequency ablation procedures for atrial fibrillation (AF) are well established in the management of symptomatic AF.¹ Identifying predictors of successful ablation would allow for more accurate patient selection and an improved long-term outcome.²

These procedures commonly involve a step-wise approach that includes electrical isolation of pulmonary veins (PVs) followed by linear and focal lesions targeting potential triggers of AF.³ Conversion to sinus rhythm (SR) during ablation has been suggested as a predictor of long-term success.⁴

Patients who remain in AF after ablation likely represent those in whom the critical drivers of AF were not ablated.⁵ In these patients, cardioversion is often attempted by intra-procedural administration of ibutilide. By prolonging refractory periods, this agent reduces areas with very short cycle lengths, which are believed to play a role in maintenance of AF.^6,7 Ibutilide frequently terminates AF or organizes the fibrillatory electrograms to other arrhythmias amenable to further ablation.⁶ Elimination of these more organized arrhythmias may result in a better long-term SR maintenance.⁸ We hypothesized that organization of AF or its termination with ibutilide defines a group of patients with a more benign arrhythmia substrate and a better long-term outcome.

The primary goal of this retrospective study was to evaluate the predictive role of intra-procedural response to ibutilide in patients who had remained in AF after ablation on long-term procedural outcome.

Methods

Patients

This is a retrospective observational study of 92 AF ablation procedures that were performed in 77 consecutive patients with drug-refractory symptomatic AF between 2007 and 2012 who satisfied the study selection criteria. Patients were eligible for the study if they remained in AF after the ablation procedure and the ibutilide was used in the attempt to restore SR (see below in the “Ibutilide administration and cardioversion” section). Patients spontaneously converting to SR during ablation at the same time period were used as controls (SR group). Patient demographics and clinical characteristics were extracted from the electronic medical records and are summarized in Table 1. Of 92 AF ablation procedures 69 were undertaken for the first time.

Patient-specific procedural data were obtained from a detailed review of procedure notes as well as recorded three-dimensional (3D) electro-anatomic maps. Baseline clinical and follow-up data were obtained by chart review. The study protocol was approved by the institutional review board at Steward St. Elizabeth’s Medical Center of Boston.

Ablation procedure

The typical ablation protocol at our institution has been previously described.⁹ Intra-procedural imaging includes rotational atriography with 3D reconstruction and electro-anatomical mapping (EnSite NavX, St. Jude Medical, St. Paul, MN). Images obtained from both modalities are merged.⁹ A multipolar circular mapping catheter (Inquiry Optima, St. Jude Medical, or Lasso, Biosense Webster, Diamond Bar, CA), a decapolar coronary sinus catheter (XPT, C.R. Bard, Lowell, MA), and a 3.5-mm irrigated-tip ablation catheter (Celsius ThermoCool, Biosense Webster, or Cool Path, St. Jude Medical) were used for mapping and ablation. Intravenous heparin was administered before the transseptal puncture to maintain an activated clotting time of 300–400 s throughout the procedure. In patients undergoing first AF ablation, RF therapy was applied circumferentially around the antral aspect of each PV to achieve PV isolation (“entrance block”) at power settings of 20–30 W. “Exit block” from all PVs was confirmed after restoration of SR by pacing from within each PV. For those undergoing repeat AF ablation, RF energy was applied at the sites of PV reconnection and “entrance” and “exit” block were confirmed. If AF persisted after PV isolation, a step-wise approach that involved creating lines of ablation in the left atrial (LA) roof, LA floor connecting the right and left lower PVs along the coronary sinus, and mitral isthmus was applied.³

Ibutilide administration and cardioversion

In 55 procedures, patients received intravenous infusion of 2 g of magnesium sulfate followed by 1 mg of intravenous ibutilide over 10 min, followed by a second 1 mg over 10 min if conversion did not occur with the first dose, which resulted in cardioversion of 25 patients (IBU group). In five of the 25 patients in the IBU group, administration of ibutilide resulted in organization of AF into atrial tachycardia (AT) or atrial flutter (AFL), which was mapped, and RF ablation was applied to restore SR. In 30 patients, no change in AF was observed within 30 minutes of ibutilide administration (n = 16) or further ablation did not terminate the AT/AFL (n = 14) and, subsequently, direct current cardioversion (DCCV) was performed (IBU-DCCV group). After restoration of SR, conduction block across all previously created lines of ablation, if achieved, was confirmed.^3,10

Follow-up

After the ablation procedure patients were followed with serial ambulatory monitoring and routinely in the clinic at 3–6-month intervals during 33 (16–77) months. Maintenance of SR was confirmed by clinical status, electrocardiogram (ECG) at each clinic visit, and ambulatory monitoring if patients developed any symptoms suggestive of arrhythmia. Recurrence of AF after 3 months’ blanking period and its timing if documented were recorded into the study database.

Statistical analysis

Descriptive statistics

Variables were reported as proportions, mean ± standard deviation or median and range where appropriate. Continuous variables were compared between groups using ANOVA. Categorical data were compared using chi-square and Fisher’s exact test where appropriate.

Acute response to ablation and ibutilide administration

Univariate logistic regression was used to identify baseline variables affecting the likelihood of spontaneous SR restoration after ablation and the likelihood of cardioversion after ibutilide administration. For the first analysis, those who were not in SR after AF ablation were combined into a single group. Using univariate logistic regression, the odds ratios of achieving SR after ablation for each of the baseline parameters were obtained. In the second analysis, among those who did not convert to SR after ablation, the odds ratios of conversion to SR after ibutilide administration for each of the baseline parameters were obtained using a univariate logistic regression model.

Potential explanatory variables with p-values less than 0.2 from univariate screening were selected and included in a multivariable logistic regression model to obtain adjusted odds ratios. Variables with more than 20% missing values of the total observations were excluded from the model.

Association of treatment groups with survival free from atrial fibrillation

The univariate Cox proportional hazard regression model was used to identify variables with significant association with survival time free from AF after ablation and to calculate the crude hazard ratios (HR). Parameters that were most significant in the univariate analysis (p<0.2) were entered into a multivariate Cox regression model and the adjusted HRs for groups were calculated after controlling for differences in important co-variables. CHADS2 is a categorical variable with seven levels. To explore whether CHADS2 score is best used as a categorical or continuous variable in the survival model, univariate Cox regressions of the primary outcome (i.e. time free from AF) with CHADS2 as categorical variable, categorical variable with combined scores of 4 and 5, untransformed continuous variable, and second degree polynomial transformation of CHADS2 score were created. Comparison of the Akaiki Information Criteria (AIC) of the four models showed the lowest AIC value for the model with CHADS2 score as a simple continuous variable and therefore, it was used as such in the survival analysis.

The proportional hazards assumption was tested for all the covariates in the Cox regression models, using Martingale residuals method and was confirmed to be valid.

Kaplan–Meier curves comparing groups were constructed and using the log-rank test, statistical significance between groups was assessed. p-Values <0.05 were considered statistically significant. All statistical analyses were performed with Microsoft Excel 2003 (Microsoft Corporation, Redmond, WA), STATA (V.12.1 for Mac, StataCorp, TX) and SAS (V.9.3 for Windows, SAS Institute, Cary, NC).

Results

The time to recurrence of AF as the primary outcome was compared among the SR, IBU, and IBU-DCCV groups. The baseline characteristics of patients in each group are summarized in Table 1. The only statistically significant difference between the groups was the higher rate of patients with paroxysmal AF in the SR group (p = 0.014). There was also a trend towards lower rate of diabetes mellitus (DM) (p = 0.06) and lower body mass index (BMI) (p = 0.068) in the SR group compared to other groups.

Restoration of SR after ablation and the effect of ibutilide

Spontaneous conversion to SR after RF ablation was achieved in 37/92 (40%) procedures. In 55/92 (60%) procedures, ibutilide was administered. Conversion to SR with ibutilide was observed in 25/92 (27%) procedures, which represents an efficacy rate of 45.5% (25/55). In 30/92 (33%) procedures in which ibutilide was unsuccessful, SR was restored by DCCV. The presence of paroxysmal AF (OR_crude = 6.42, 95% CI 1.63–25.3, p = 0.0079), absence of DM (OR_crude = 5.60, 95% CI 1.15–27.26, p = 0.03) and lower BMI (OR_crude = 0.93, 95% CI 0.87–0.99, p = 0.02, for 1 kg/m² increase in BMI) were individually associated with spontaneous SR restoration after ablation (Table 2). After adjusting for other baseline parameters, the presence of paroxysmal AF remained the only significant predictor of conversion to SR after ablation (OR_adjusted = 4.987, 95% CI 1.085–22.915, p = 0.039). However, none of the clinical or procedural parameters were associated with acute conversion to SR by ibutilide post ablation (Table 3).

Association of treatment groups with AF-free survival

The study involved 13,417 patient-days of follow-up. Sixteen patients in the SR group (43.2%), 17 patients in the IBU group (68.0%), and 20 patients in the IBU-DCCV group (66.7%) failed to maintain SR within the first 12 months after ablation. The median times to recurrence of AT/AFL/AF (time to failure) for SR, IBU, and IBU-DCCV groups were 211, 163, and 83 days, respectively. Using the log-rank test, the unadjusted “survival” curves for the groups were not statistically different (p = 0.22) (Figure 1).

Using univariate regression analysis, the crude hazard ratios of failure to maintain SR after ablation for the baseline parameters were calculated (Table 4). The assigned group was not associated with a statistically significant difference in the time to failure (HR_Crude(IBU versus SR) = 1.56, 95% CI 0.80–3.07; HR_Crude(IBU-DCCV versus SR) = 1.75, 95% CI 0.90–3.41; p = 0.23) (Table 4). Potential confounder parameters were selected from the baseline variables using the univariate Cox regression model as explained in the “Methods” section. Five parameters were found to be significantly associated with the time to failure: gender, age, AF duration since diagnosis, CHADS2 score, and RF ablation time. To obtain an adjusted hazard ratio for the group variable, the potential confounder variables were included in a multivariable Cox regression model. After adjustment for significant baseline variables, the assignment group was still not statistically significant in predicting the time to failure (p = 0.605).

Duration of RF ablation (HR_Crude = 1.014, 95% CI 1.001–1.027, p = 0.034) and the time since AF diagnosis (HR_Crude = 1.117, 95% CI 1.046–1.193, p = 0.001) were the only baseline parameters associated with AF recurrence after ablation.

Discussion

The main finding of this study is that the intra-procedural response to ibutilide is not associated with a higher likelihood of SR maintenance after RF ablation performed for AF. Furthermore, none of the baseline clinical or procedural parameters were predictive of the acute response to ibutilide.

Although spontaneous restoration of SR during ablation was associated with a trend towards longer AF-free survival compared to those who required ibutilide with or without DCCV, the difference did not reach statistical significance.

Acute post-procedural response to ibutilide

Ibutilide has an efficacy of approximately 50% in cardioversion of AF.^11,12 Several prior studies have suggested various predictors of AF conversion using ibutilide but the results have been inconsistent.^13–15 In patients undergoing RF ablation, the drug has been more efficacious with shorter AF duration, smaller scar area by voltage mapping and smaller LA size.^14,16 The cardioversion efficacy of ibutilide in our study (45.5%) was similar to previously reported in a non-ablation setting but lower than that documented after AF ablation. The latter is probably due to a higher proportion of patients with persistent AF in the present study.¹⁷ None of the baseline parameters were associated with successful cardioversion in the present study. The retrospective nature of the present study may be responsible for this discrepancy. However, predictive factors from previous small studies may reflect the peculiarities of small datasets that make the prediction models inherently unstable and non-reproducible.

In this study, the presence of paroxysmal AF and absence of DM were individually associated with spontaneous post procedure restoration of SR but the effect of DM was no longer significant when both factors were evaluated in the multivariate analysis. Efficacy of AF ablation is significantly higher in patients with paroxysmal arrhythmia as documented in multiple prior reports explaining the trend observed in the present study.¹⁷ On the other hand, DM represents a surrogate composite marker of other risk factors associated with persistent arrhythmia and a lower probability of maintaining SR.

Low rate of AF-free survival in study population

Long-term maintenance of SR in this study was low: about 69% of patients experienced arrhythmia recurrence within 1 year. Results were better in patients with paroxysmal AF (approximately 60% SR maintenance), consistent with a number of recent observations. Most of the patients in this study had long-standing persistent AF and the observed ablation success rate is comparable to the published long-term success rate in similar patients. Poor arrhythmia-free survival in patients with persistent arrhythmia undergoing PV isolation and even more extensive ablation procedures has been increasingly recognized.¹⁷ Our observation supports the notion that the current understanding of persistent AF mechanisms and prevailing ablation methods are in need of a major revision.

Termination of AF in response to ibutilide as a predictor of long-term SR maintenance

We hypothesized that acute intra-procedural response to ibutilide would identify patients with less extensive LA substrate for maintaining and driving of AF; therefore predicting better arrhythmia-free survival after ablation. Based on the current paradigm regarding AF pathophysiology, patients with a longer duration of AF with more extensive LA fibrosis and remodeling are expected to have higher rates of post-ablation failure. Indeed, we found that a longer history of AF was associated with a higher risk of failure post ablation.

However, our study did not show any significant difference in terms of long-term freedom from AF recurrence based on response to ibutilide. Therefore, it seems that rhythm conversion in response to ibutilide does not define the group of patients with more effective ablation or “more benign” arrhythmia substrate but rather reflects a temporary antiarrhythmic effect of the drug. This observation is likely explained by the reconnection of PVs as the main mechanism for recurrence. It has been observed in up to 80% of cases of post ablation AF recurrence that may be due to gaps in ablation lines, or failure to create transmural lesions.^18–21 Since responsiveness to ibutilide is etiologically unrelated to the process of PV reconnection, no significant differences between long-term failure rates were observed between the study groups. By the same token, does AF “organization” following ibutilide administration define an arrhythmia substrate that is worth pursuing by additional ablation? Several studies have suggested improved long-term outcome after ablation of these “organized” arrhythmias.⁶ Our data do not address this question but do suggest indirectly that ibutilide’s effect on arrhythmogenic substrate is temporary and may not bring out a clinically relevant AF mechanism.

Longer duration of RF ablation was also associated with lower SR maintenance. Why does a more extensive ablation not result in a better arrhythmia cure? This surprising finding may reflect the fact that the longer duration of RF ablation was required in patients with more extensive arrhythmia substrate/chronicity, which is a known predictor of a lower AF-free survival. However, after adjusting for the effects of potential confounders such as LA volume and type of AF, duration of RF therapy was still statistically significant in predicting procedural failure. This may suggest either the presence of another as yet unknown variable that is unaccounted for or that longer RF time by itself results in a higher failure rate after AF ablation. This raises the question of whether more extensive ablation could result in the creation of an additional arrhythmia substrate. Although the current study is not powered to answer this question, it suggests an interesting topic for future investigation.

While most studies have shown an association between spontaneous conversion to SR after AF ablation and long-term post-procedural SR maintenance,²² others have not.²³ We found a trend towards improved long-term maintenance of SR in patients who spontaneously achieved SR at the end of ablation compared to those who did not but this trend did not reach statistical significance. Termination of AF at the end of the procedure suggests modification and control of triggers and substrates for AF initiation and maintenance. On the other hand, extensive ablation could also create a substrate for future re-entrant tachycardia resulting in increased failure rates. The balance between these two opposing processes would likely determine the long-term procedural success, which may vary between studied populations.

Limitations

This is a retrospective cohort study with inherent limitations such as lack of randomization to control for confounders, variable follow-up between individuals and restriction of data collection to those that were available at the time of analysis. Every effort was made to obtain information regarding possible confounders in the study and to adjust for their role when assessing the group effect in this study. To deal with variables that had a significant number of missing values, the regression analysis was performed with and without their inclusion and the same conclusions regarding the group differences were reached in all cases.

By virtue of the retrospective nature of the study, the follow-up pattern varied among patients. However, the pattern of response to ibutilide at the time of ablation cannot plausibly affect the follow-up pattern. Moreover, there was no evidence that the duration of follow-up was significantly different between the groups (Table 1).

Conclusion

Conversion to SR with ibutilide is not associated with long-term rhythm maintenance after AF ablation. None of the baseline clinical or procedural parameters predicted the likelihood of successful cardioversion with ibutilide after AF ablation.

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