Cardiac Rhythm Management
Articles Articles 2015 August

Safety and Efficacy of New Anticoagulation Strategies in Patients Undergoing Catheter Ablation of Atrial Fibrillation

DOI: 10.19102/icrm.2014.060804

CHRISTIAN E. MACHADO, MD, ROSHNI SHAH, MD, MOHAMMAD NASSER, MD, MARCOS DACCARETT, MD and FERNANDO ALCOCER, MD

Division of Cardiology, Providence Heart Institute, Providence Hospital and Medical Centers, Southfield, MI

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ABSTRACT.Atrial fibrillation (AF) is one of the most common types of sustained cardiac arrhythmia in the United States. Anticoagulation is given to patients with this arrhythmia to prevent thromboembolic complications. Anticoagulation is especially important for patients who undergo radiofrequency catheter ablation (RFA), because of the fine balance required to prevent post-procedural thromboembolic events and intra-procedure bleeding complications. RFA anticoagulation standard of care includes uninterrupted warfarin (UW) or interrupted warfarin (IW) with heparin bridging. Contemporary anticoagulation protocols are scant, in flux, and poorly validated. We compared two post-ablation anticoagulation strategies: new oral anticoagulants (NOACs) such as dabigatran or rivaroxaban versus the current standard (UW/IW) to determine the efficacy and safety of the new anticoagulant strategies. We conducted a single center retrospective study of 161 procedures with RFA. The procedures were allocated by anticoagulation strategy to either NOACs or the current standard. The number of thromboembolic events and bleeding complications post procedure, during hospitalization, and 30 days post procedure were collected. A total of 161 procedures were included: 95 received the NOAC strategy and 66 received the standard of care anticoagulation strategy. There was only one thromboembolic event in the interrupted group for Coumadin (3.7%) compared to none in the uninterrupted Coumadin and NOAC therapy (p=0.221). There were no statistically significant differences between major and minor bleeding among the three groups (p=0.2 and p=0.4 respectively). There were fewer total complications in NOACs: 8.4% compared to 32% for IW and 13% for UW (p<0.04). In addition, the length of stay for both groups demonstrated a shorter hospitalization for the NOAC strategy of 0.67 days compared to the standard strategy of 2.07+2.4 in the IW group and 0.92+1.2 in the UW group (p<0.002). In patients undergoing AF ablation, NOACs appear to be efficacious and safe compared to the current standard of care, associated with a significantly lower length of stay.

KEYWORDS.anticoagulation, atrial fibrillation, dabigatran, heparin, radiofrequency ablation, rivaroxaban, warfarin.

The authors report no conflicts of interest for the published content.
Manuscript received June 30, 2015, final version accepted July 21, 2015.
Address correspondence to: Christian E. Machado, MD: Providence Heart Institute, Providence Hospital and Medical Centers, 16001 West Nine Mile Road, Southfield, MI 48075. E-mail: cmachado@comcast.net

Introduction

Atrial fibrillation (AF) is the most common type of sustained cardiac arrhythmia in the United States.1 It accounts for one-third of the hospital admissions for cardiac rhythm disturbances. The American Heart Association estimates that approximately 2.7 million Americans are living with AF today.

The incidence increases with age, and as the population continues to increase in longevity we expect to see higher incidence and prevalence rates of AF, with an estimate of 4 million by 2030 in the United States.2

Patients with any type of AF (paroxysmal, persistent, or permanent) carry a significant increase in morbidity and mortality, mostly secondary to thromboembolic events. Approximately 30% of all strokes are due to AF.3 Depending on individual patients’ co-morbid conditions, the risk of stroke increases up to fivefold.4

AF is considered to be a hypercoaguable state that leads to thrombus formation. This hypercoaguable state is enhanced by atrial mechanical disruption associated with sluggish blood flow predisposing the formation of thrombi that could later dislodge and travel to the brain circulation triggering a stroke.5

The treatment goal for AF consists on two main objectives: alleviation of symptoms with rate or rhythm control, reduce tromboembolic complications, such as strokes. Anticoagulation is the cornerstone therapy in AF patients for the prevention of strokes regardless of rate or rhythm control.6

If rhythm control by medical therapy fails, radiofrequency ablation (RFA) may be used. This procedure has revolutionized the treatment of AF. Several prospective studies have shown that RFA is superior to antiarrhythmic drug therapy for paroxysmal AF.7 In 2012, a global consensus by the Heart Rhythm Society, American College of Cardiology, American Heart Association, European Heart Rhythm Association, and European Cardiac Arrhythmia Society labeled RFA a Class 1A recommendation as a therapeutic modality for symptomatic patients.8

Anticoagulation techniques become especially important for patients undergoing RFA due to the fine balance between preventing post-procedural thromboembolic events and intra-procedure bleeding complications. The risk of thromboembolic events is thought to be exacerbated by an increase in the prothrombotic state induced by catheters in the left atrium, endothelial denudation, scar formation, and tissue inflammation resulting from the ablation.9 The risk of thromboembolic complications can be minimized by adequate peri-procedural anticoagulation.

Several different anticoagulation protocols for RFA exist; however, there is no established superiority among them. Guidelines recommend anticoagulation for 2 months prior to the procedure, with warfarin in patients with a CHADS2 score of two or more. In the peri-procedure period, anticoagulation can be achieved with either uninterrupted warfarin (UW) or with interrupted warfarin (IW) followed by heparin bridging.10

With the recent introduction of new oral anticoagulants (NOACs), physicians have alternative options to offer in this setting. Dabigatran (Pradaxa) and rivaroxaban (Xarelto) have been introduced as the first two alternative oral anticoagulants. Dabigatran is a direct thrombin inhibitor that was approved in 2010 by the United States Food and Drug Administration (FDA) for prevention of stroke and systemic embolism in non-valvular AF patients. Rivaroxaban is a factor Xa inhibitor that was approved by the FDA in 2011 for the same indication. Both drugs have been proven effective and safe compared with warfarin in preventing strokes and systemic emboli in the setting of non-valvular AF; however, their role in the post-ablation period has yet to be established. American College of Cardiology guidelines have not provided any recommendations on their use in this particular setting.

The NOACs are grouped together because there are more similarities than differences among these novel agents. It is true that NOAC medications have different mechanisms of action; however, they are taken orally, and both inhibit the coagulation cascade pathways. Also, they have a short onset of action of 2–4 h and a shorter half-life of 6–14 h when compared to warfarin. Most importantly, they have no food interactions and very few drug interactions. Despite their pharmacological benefits, NOAC peri-procedural use has not been widely accepted. Several factors including lack of a reliable antidote continue to be feared because of potential life-threatening bleeding. Recent trials have demonstrated equivalent or less mortality related to bleeding complications in non-valvular AF patients.11

Contemporary post-ablation anticoagulation protocols are scant, in flux and poorly validated.12 Our objective was to evaluate the effectiveness of NOACs in preventing thromboembolic events and their safety in preventing bleeding complications in the setting of AF treatment using RFA.

We conducted a retrospective analysis comparing the safety and efficacy profile of newer anticoagulants compared to standard therapy.

Study design

We conducted a retrospective single-center study in 161 patients who underwent RFA at Providence Hospital, Southfield, MI, between January 2010 and December 2012.

Methods

Our study compared two post-ablation anticoagulation strategies: NOACs (dabigatran or rivaroxaban) versus the current standard of care (UW or IW with heparin bridging) to determine the efficacy and safety of the new anticoagulant approach.

Anticoagulation

Patients taking warfarin for anticoagulation were allowed to continue therapy if they were in the uninterrupted group. The international normalized ratio was monitored and remained in the therapeutic range of 2–3. Patients in the interrupted group were told to stop warfarin 48 h prior to the day of ablation. During the day of RFA, they were given unfractionated heparin, and therapeutic activated clotting time (ACT) >300 was confirmed. No protamine was received in this group.

Patients taking dabigatran or rivaroxaban were asked to stop anticoagulation 36–48 h prior to procedure and were restarted 2–4 h post procedure, once vascular access hemostasis was achieved. The pre- and post-procedure anticoagulation strategy had been chosen independently by each patient in consultation with their cardiologist on the basis of personal preferences.

Complications

All complications were divided into thromboembolic events and bleeding complications. Bleeding complications were subdivided into major and minor. Thromboembolic complications were defined as ischemic stroke and/or transient ischemic attack. Major bleeding complications were defined as cardiac tamponade, hemodynamic instability requiring blood products, reversal of anticoagulation therapy, need for intravenous fluid resuscitation/vasopressor support, or surgical intervention. Minor bleeding complications were defined as bleeding related to hematoma, extensive ecchymosis, epistaxis, hematemesis, or hematochezia.

Data collection and analysis

All cases were divided by anticoagulation strategy post-RFA to the following three groups: NOAC, IW, UW. The number of thromboembolic events and bleeding complications post-procedure, during hospitalization, and at 30 days were analyzed through the medical records from the hospital and their follow up appointments. Patients were then interviewed by phone call to ensure no complications were lost to the local emergency room or primary care physician. No patients were lost to follow up.

The chi-square test was used to compare all categorical and ordinal variables. Fisher’s exact test was utilized for two subgroup analyses when sample sizes were too small to calculate a p-value. The Mann–Whitney U test compared non-parametric variables between both groups. Significance was defined as p<0.05.

Results

A total of 161 procedures were included; among these, 95 received the NOAC strategy, 27 underwent the IW strategy, and 39 were given UW. The baseline demographics of our patients are summarized in Table 1. The demographic analyses identified that patients on NOAC therapy were younger than IW patients p=0.033; however, with the sub analysis this value was not significant. Patients on NOACs had a lower body mass index than UW patients (p=0.025); again this value was not significant with the sub analysis. Clinical characteristics were similar among all groups, as seen in Table 2. The major thromboembolic risk factors revealed non-significant p-values when CHADS2 scores were compared, as reported in Table 3. Individual co-morbid conditions were compared in Table 4 using the Fisher exact and chi-square tests showing non-significant values among the three groups.

Table 1: Cross sectional demographic analysis

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Table 2: Clinical characteristics

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Table 3: CHADS score comparison

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Table 4: Co-morbid condition

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Outcomes for either thromboembolic or bleeding complications are described in Table 5. We found no statistically significant difference among IW, UW, and NOACs in thromboembolic and hemorrhagic events. Major, minor, and post-30-day bleeding were more likely to happen in the IW group than the other groups, without any significant statistical association. Also, total complications were worse in the IW group (p<0.04). In addition, we compared the length of hospitalization, demonstrating a shorter hospitalization time for the NOAC strategy than for IW and UM (0.67+0.8 versus 2.0+2.4 versus 0.92+1.2; p<0.002).

Table 5: Statistical outcomes

crm-06-08-9075-t5.jpg

Discussion

Warfarin is a vitamin K antagonist that historically has been the standard of care for long-term anticoagulation in patients with AF. Because of its unpredictable response, slow onset of action, multiple drug and food interactions, and narrow therapeutic window, new anticoagulants have been developed with different pharmacological characteristics and without the pitfalls of warfarin.

In the setting of AF, for RFA-treated patients, UW or IW with heparin bridging had been the only options for anticoagulation therapy in the post-ablation period; therefore, warfarin became the standard of care in this setting too. However, with the introduction of newer anticoagulants, the current state of post-ablation therapy is shifting towards these novel agents.12

Recently, a few studies have attempted to compare new oral anticoagulants in the setting of RFA. Winkle et al.13 followed 123 consecutive patients who underwent RFA and were started on dabigatran after the procedure, finding no thromboembolic or major hemorrhagic compilations in the first 30 days. This study proved the use of NOACs was feasible but the study lacked a control group.13

A multicenter registry from Lakkireddy et al.14 described 145 patients on dabigatran who underwent RFA and compared them with an equal number of patients matched for baseline characteristics from historical archives on warfarin. A significant risk of bleeding (15.2% versus 5.3% p=0.034) and composite of bleeding and thromboembolic complications with dabigatran (21.2% versus. 8.4% p=0.020) was found. The increased bleeding complications were attributed to the pre-procedural anticoagulation strategy, stopping dabigatran only 24 h prior to the procedure; hence RFA was performed with a significant residual pharmacological effect.

Sniplsky et al.15 studied 156 consecutive patients, 31 on dabigatran, with a longer washout period than previously described (36 h prior to procedure) versus 125 patients on UW. They found no significant statistical complications among these groups within 1 week post ablation. This study had significant limitations such as the lack of proper complication documentation, as described in their discussion.15

In our study, we were able to demonstrate that NOACs are effective in preventing embolic events in patients with AF who undergo radiofrequency catheter ablation (RCA) as compared to standard of care in a community hospital setting. It is the first study to demonstrate that NOACs are safer than warfarin by producing significantly fewer bleeding complications and reducing hospital length of stay. It is important to understand that our design was different from previous publications, as we optimized anticoagulation pre- and intra-procedural anticoagulation, and isolated post-procedural complications for a better analysis. Also unique to this study is the inclusion of rivaroxaban in this setting. These novel drugs proved to be feasible and a safe alternative for anticoagulation in the setting of AF post RFA. Finally, this is the first study to compare length of stay, a new potential advantage associated with NOACs indicative of multiple benefits, including fewer complications and a potential cost-saving benefit.

We recognize our study has limitations. As a retrospective model it prevents randomization, raising the potential for bias. Age difference was found to be statistically significant between the cohorts; however, there were only 3 years difference between both groups a clinically insignificant observation. Also, grouping medications may lead to confounders unaccounted for in our results since individual analysis for each NOAC was too small to reach any statistical conclusions. Of special note is a recent editorial article by Stangeli et al.16 that emphasizes the importance of performing RFA on patients on UW anticoagulation rather than on IW therapy, as evidenced by Kuwahara et al.,17 who compared UW to IW with heparin, and found significantly reduced thromboembolic events (13/1,953 [0.67%] to 2/1,327 [0.16%], p=0.021) and no difference in terms of hemorrhagic complications (1.1% vs. 1.3% p=0.80). This last study suggests that, from now on, any study for RFA anticoagulation must be performed with continuous anticoagulation irrespectively of the agent as proven to be superior and may account for some of the different results published with these novel agents.16,17

Several randomized trials have demonstrated equivalent or lower bleeding rates when comparing NOACs to standard anticoagulation strategies peri-procedure.

Two recently published trials have demonstrated similar bleeding and thrombotic rates for interrupted dabigatran compared with uninterrupted warfarin during catheter ablation of AF.18,19 In addition, the results of the VENTURE-AF trial evaluating uninterrupted rivaroxaban with UW in a randomized fashion were recently published.20 The study demonstrated similar complication rates and safety profiles between rivaroxaban and warfarin, corroborating the importance of our study findings.

Conclusion

The NOAC strategy for patients who undergo AF RFA has proven to be efficacious and safer than the standard of care, preventing thromboembolic events while having significantly fewer bleeding complications with the additional potential of cost-saving benefit and reducing length of hospitalization.

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