Author + information
- Received August 8, 2017
- Revision received October 25, 2017
- Accepted November 2, 2017
- Published online May 21, 2018.
- Matthew R. Reynolds, MD, MSca,b,∗ (, )
- J. Scott Allison, MDc,
- Andrea Natale, MDd,
- Ian L. Weisberg, MDe,
- Kenneth A. Ellenbogen, MDf,
- Mark Richards, MD, PhDg,
- Wen-Hua Hsieh, PhDb,
- Julie Sutherland, MDb and
- Christopher P. Cannon, MDb,h
- aLahey Hospital & Medical Center, Burlington, Massachusetts
- bBaim Institute for Clinical Research, Boston, Massachusetts
- cHeart Center Research, Huntsville, Alabama
- dTexas Cardiac Arrhythmia Research Foundation, Austin, Texas
- eBaptist Heart and Vascular Institute, Pensacola, Florida
- fVirginia Commonwealth University, Richmond, Virginia
- gProMedica Toledo Hospital, Toledo, Ohio
- hBrigham & Women’s Hospital, Boston, Massachusetts
- ↵∗Address for correspondence:
Dr. Matthew R. Reynolds, Baim Institute for Clinical Research, 930 Commonwealth Avenue, Boston, Massachusetts 02215.
Objectives This study sought to determine whether uninterrupted apixaban would have similar rates of bleeding and thromboembolic events as does minimally interrupted apixaban at the time of atrial fibrillation (AF) ablation and to compare those results with rates in historical patients treated with uninterrupted warfarin.
Background The safety, efficacy, and optimal dosing regimen for apixaban at the time of AF ablation are uncertain.
Methods This prospective, multicenter clinical trial enrolled 306 patients undergoing catheter ablation for nonvalvular AF and randomized 300 to uninterrupted versus minimally interrupted (holding 1 dose) periprocedural apixaban. A retrospective cohort of patients treated with uninterrupted warfarin at the same centers was matched to the apixaban-treated subjects for comparison. Endpoints included clinically significant bleeding, major bleeding, and nonhemorrhagic stroke or systemic embolism (SE) from the time of ablation through 30 days.
Results There were no stroke or SE events. Clinically significant bleeding occurred in 11.3% of 150 evaluable patients on uninterrupted apixaban and 9.7% of 145 evaluable patients on interrupted apixaban (risk difference: 1.7% [95% confidence interval: −5.5% to 8.8%]; p = NS). Rates of major bleeding were 1.3% with uninterrupted apixaban, and 2.1% with interrupted (risk difference: −0.7%; p = NS). The rates of clinically significant and major bleeding were similar for all apixaban patients combined (10.5% and 1.7%), compared with the matched warfarin group (9.8% and 1.4%).
Conclusions Both uninterrupted and minimally interrupted apixaban at the time of AF ablation were associated with a very low rate of thromboembolic events, and rates of both major (<2%) and clinically significant bleeding were similar to uninterrupted warfarin. (Apixaban Evaluation of Interrupted Or Uninterrupted Anticoagulation for Ablation of Atrial Fibrillation [AEIOU]; NCT02608099)
Catheter ablation within the left atrium has become a commonly performed procedure for the management of atrial fibrillation (AF). Since the inception of this procedure, anticoagulation has been used to mitigate a small but known risk of periprocedural stroke (1,2). Anticoagulation, however, likely contributes to a risk of procedural bleeding complications, which are more common than strokes and can be serious (3,4).
Before the widespread use of non–vitamin K antagonist oral anticoagulants (NOACs), a series of nonrandomized (5) as well as 1 randomized study (6) established that the strategy of performing AF ablation without interruption of warfarin was associated with a lower risk of stroke or transient ischemic attack (TIA) as well as minor bleeding compared with a strategy of interrupted warfarin with periprocedural bridging anticoagulation. Since then, a number of observational (7–10) and 2 randomized (11,12) studies have compared the use of NOACs with no or minimal interruption (e.g., holding 1 or 2 doses) to uninterrupted warfarin at the time of AF ablation. These studies have found that NOACs used in this manner are associated with a very low rate of ischemic events, and a similar or lower rate of bleeding complications than uninterrupted warfarin.
To date, information specific to apixaban in this setting is limited to several nonrandomized series, each involving 1 or a few centers (13–15). In addition, the potential advantages and disadvantages of using apixaban in a minimally interrupted versus fully uninterrupted fashion have not been explored. We therefore planned a study to compare the risks and benefits of uninterrupted and interrupted apixaban at the time of AF ablation, while also comparing the combined apixaban experience with a reference group of patients treated with uninterrupted warfarin at the same centers.
The AEIOU (Apixaban Evaluation of Interrupted Or Uninterrupted Anticoagulation for Ablation of Atrial Fibrillation) study (NCT02608099) was a prospective, multicenter, randomized, open-label clinical trial of 2 apixaban dosing strategies for periprocedural anticoagulation during catheter ablation of AF, and included a retrospective cohort of matched AF patients treated with uninterrupted warfarin. The study protocol was approved by the Institutional Review Board at each enrolling site. All subjects enrolled in the prospective apixaban portion of the study provided written, informed consent.
Eligible patients for the prospective apixaban cohort were ≥18 years of age and scheduled for catheter ablation for the treatment of nonvalvular AF, with planned continuation of oral anticoagulation for a minimum of 1 month after the procedure. Patients with mechanical heart valves, advanced hepatic or renal (creatinine clearance <15 ml/min or on dialysis) dysfunction, ongoing or planned dual antiplatelet therapy, history of stroke or TIA within 6 months, any history of prior intracranial bleeding, or significant baseline anemia or thrombocytopenia were excluded.
For the retrospective nonrandomized warfarin cohort, the same eligibility criteria as for the apixaban cohort were applied. Additionally, subjects in the warfarin cohort were required to have documented clinical follow-up for at least 30 days after the ablation procedure.
In the prospective cohort, subjects who met eligibility requirements were treated with apixaban at Food and Drug Administration–labeled doses (5 mg or 2.5 mg twice daily) for a minimum of 21 days before the planned ablation procedure, taken either as pre-existing therapy, or newly initiated upon study entry. Subjects were randomized ≤3 days before the procedure to treatment with either fully uninterrupted or minimally interrupted (defined by omitting the morning dose on the day of catheter ablation) apixaban. Treatment compliance was assessed by subject self-report.
At the same study centers, a retrospective cohort of patients treated with uninterrupted warfarin was identified, using medical records to match (on a 1:1 basis) the apixaban patients on age (±5 years), sex, and AF pattern (paroxysmal or persistent). Per protocol, matched warfarin patients were to have had their ablation procedures performed on or after September 1, 2013 (2 years before the planned start of enrollment in the prospective arm of the study). However, to identify a complete cohort of warfarin subjects with suitable matching characteristics, patients treated earlier were accepted if more recent matches could not be found. Also, in some cases, matching warfarin subjects could only be identified at study centers other than where the corresponding apixaban subjects were enrolled.
Ablation procedures were performed according to standard techniques at the discretion of the local investigators (4). All nonpermanent AF patterns and Food and Drug Administration–approved ablation technologies were permitted. Both initial and repeat ablation procedures were included, provided that left atrial access and ablation were planned. Pre-procedure transesophageal echocardiography (TEE) was not required. Sites were instructed to administer a heparin bolus before transseptal puncture and to maintain a target ACT >300 s. In the evening of the procedure day, patients resumed apixaban at their usual dose (usually 5 mg) if no prohibitive complications occurred. Oral anticoagulation was then continued for at least 1 month post-procedure, when the final study visit was scheduled.
Endpoints were assessed from the time of randomization (in the apixaban groups) or ablation (in the warfarin group) through 30 days. No endpoint events occurred between randomization and ablation in the apixaban subjects. The primary safety endpoint was clinically significant bleeding, defined as any event meeting Bleeding Academic Research Consortium (BARC) criteria ≥2 (16). The primary efficacy endpoint was nonhemorrhagic stroke or systemic embolism (SE). Key secondary endpoints included the composite of stroke or SE or major (BARC criteria ≥3) bleeding, the composite of nonhemorrhagic stroke or TIA, and the individual components of those composites. Additional secondary endpoints included death and cardiovascular death.
All potential endpoints were reviewed and adjudicated by an independent endpoints committee. Other procedure-attributable adverse events not meeting endpoint criteria were reviewed by safety officers of the study sponsor as well as the principal investigators. In the apixaban groups, all adverse and serious adverse events were systematically collected at the sites and reviewed centrally.
The AEIOU study was exploratory and was designed to enroll up to 300 evaluable apixaban patients and 300 matched warfarin control subjects. There were no formal superiority or noninferiority hypotheses. With this sample size we estimated the 95% confidence interval (CI) of the risk difference for bleeding between the warfarin and the combined apixaban groups would be ±3.35%, assuming a 4% event rate, and that the 95% CI of the risk difference between the 2 apixaban groups would be ±5.00%. Sample size calculations for stroke or SE were not performed, as it was known with the low rate of these events that a prohibitively large sample size would have been needed for formal hypothesis testing.
All endpoint analyses were conducted on the evaluable patient population, which included all intention to treat subjects who were randomized, had an ablation procedure initiated (defined by obtaining venous access), and completed follow-up through either 30 days or the occurrence of a study endpoint—along with the corresponding matched warfarin subjects.
Incidence rates and exact 2-sided 95% CIs were calculated for the primary and secondary endpoints, and for the risk differences between the apixaban groups (Wilson method), as well as between the combined apixaban and warfarin groups. The p values were calculated using 2-sample Student's t-tests for continuous variables and the Fisher exact tests for dichotomous variables. Analyses were performed using SAS version 9.4 (SAS Institute, Cary, North Carolina).
Given that comparisons between the combined apixaban and warfarin groups were nonrandomized, and that differences between these groups were observed (mainly in procedural variables), we performed a secondary analysis to adjust for potential confounding. To address this, we constructed multivariable logistic regression models for clinically significant (BARC ≥2) and major (BARC ≥3) bleeding, adjusting for all demographic, clinical, and procedural characteristics that differed between groups, generating unadjusted and fully adjusted odds ratios for the apixaban group relative to warfarin for these outcomes (see Online Appendix).
Study population and procedural characteristics
Between December 2015 and January 2017, 306 patients scheduled for ablation of nonvalvular AF were enrolled at 18 U.S. sites, of whom 300 were randomized to treatment with uninterrupted (n = 152) or minimally interrupted (n = 148) apixaban (Figure 1). Of the 300 randomized apixaban subjects, 5 did not have an ablation procedure initiated, mainly due to unexpected findings on pre-procedure TEEs, including left atrial thrombus or dense spontaneous echo contrast in 2, and were excluded from the evaluable analysis population. The remaining 295 apixaban subjects were matched with 295 patients who underwent AF ablation utilizing an uninterrupted warfarin strategy at the same study centers between February 2011 and February 2017. In the evaluable apixaban population, 99% of subjects took the 5-mg twice daily dose, and 94% were taking apixaban before study enrollment.
The study population was roughly two-thirds men with a mean age of 63 years. Approximately two-thirds of the patients had paroxysmal AF. The mean CHA2DS2-VASc score was 2.4. There were no significant differences found in the demographic or clinical characteristics between the 2 randomized apixaban groups (Table 1). By chance, the use of aspirin was higher in the uninterrupted group. The baseline characteristics of the combined apixaban and warfarin groups were also similar, although the mean body mass index was slightly higher in the warfarin group and aspirin use was slightly higher in the warfarin patients (Table 1).
Technical aspects of the ablation procedures are shown in Table 2. Procedural practices did not differ between the randomized apixaban arms, but a number of differences were seen when comparing the combined apixaban and warfarin groups. The warfarin patients were more likely to have had a prior AF ablation, more likely to have a TEE within 48 h of the ablation procedure (68% vs. 46%), more likely to have a double-transseptal approach, and less likely to be treated with a force-sensing radiofrequency ablation catheter or robotic catheter manipulation (Table 2).
Uninterrupted versus minimally interrupted apixaban
The frequency of primary and major secondary endpoint events in each of the study groups are shown in Table 3 and Figure 2. There were no statistically significant differences between the randomized apixaban groups for any of the study endpoints. The primary efficacy endpoint of stroke or SE was not observed in any subject. There were 2 events, 1 in each apixaban arm, adjudicated as TIA. As shown in Figure 2, clinically significant (BARC ≥2) bleeding events occurred in 11.3% of patients on uninterrupted apixaban and 9.7% of patients on minimally interrupted apixaban (risk difference: 1.7% [95% CI: −5.5% to 8.9%]). The rate of major (BARC ≥3) bleeding was 1.3% in the uninterrupted apixaban group, and 2.1% in the interrupted group (risk difference: −0.7% [95% CI: −4.7% to 2.9%]; p = NS). In the apixaban patients, a total of 5 major bleeding events occurred: 3 were access site related (all in the interrupted arm; 1 pseudoaneurysm) and the other 2 were pericardial effusions (both in the uninterrupted group).
Apixaban versus warfarin
There were no statistically significant differences between the combined apixaban group and the matched warfarin group for any of the study endpoints. There were no stroke or SE events. There were 4 events adjudicated as transient ischemic attacks: 2 in the combined apixaban group and 2 in the warfarin arm. The rate of clinically significant bleeding for the combined apixaban group was 10.5%, compared with 9.8% for the warfarin group (risk difference: 0.7% [95% CI: −4.3% to 5.6%]). A total of 5 (1.7%) major (BARC ≥3) bleeding events occurred in the apixaban patients, as detailed above, and 4 (1.4%) in the warfarin patients (risk difference between combined apixaban and warfarin: 0.3% [95% CI: −2.0% to 2.7%]). There were no deaths.
The majority of bleeding events were adjudicated as BARC 2 and all occurred <7 days after the ablation procedure. Details regarding the nature and management of the minor (BARC 2) bleeding events are shown in Online Table 1.
In the warfarin group, 2 of the major bleeds were access site related (1 pseudoaneurysm) and the other 2 were pericardial effusions. One warfarin patient received a blood transfusion (for a major access site bleed) and 2 received anticoagulant reversal agents (1 fresh frozen plasma and the other vitamin K).
Among all apixaban patents combined, 2 (1 each in the uninterrupted and minimally interrupted groups) received blood transfusions. One patient treated with uninterrupted apixaban had major bleeding related to the transseptal puncture. The operators were unable to place a pericardial drain percutaneously and the patient was successfully managed with emergent sternotomy. This patient was given protein complex concentrate in an effort to reverse the effects of apixaban. No other patients received anticoagulant reversal agents.
Although there were a number of procedural variables that differed between the apixaban and warfarin groups, none of these were found to be associated with bleeding events in statistical analysis. The frequency (or mean value) of these parameters, stratified by treatment group and the presence or absence of bleeding events, are shown in Online Tables 2 and 3. In the uninterrupted warfarin patients, the maximum activated clotting times tended to be higher, whether bleeding occurred or not, than in the apixaban patients, despite lower mean heparin doses.
In logistic regression models run on the endpoints of clinically significant (BARC ≥2) and major (BARC ≥3) bleeding, the unadjusted odds ratios for treatment group (combined apixaban, compared with warfarin) were 1.08 (95% CI: 0.63 to 1.84) and 1.25 (95% CI: 0.33 to 4.72), respectively. After adjusting for 17 clinical and procedural variables that potentially differed between groups, the odds ratios were minimally changed at 1.14 (95% CI: 0.58 to 2.22) and 1.48 (95% CI: 0.27 to 8.01). In the multivariable models, baseline aspirin use was not significantly associated with either major bleeding or any (BARC ≥2) bleeding.
We found that both uninterrupted and minimally interrupted apixaban used at the time of AF ablation were associated with a very low rate of ischemic events (0 stroke, <1% TIA), a low (<2%) rate of major bleeding and an approximately 10% rate of clinically significant bleeding (using the BARC criteria), all of which were similar to event rates observed in a matched cohort of patients treated with uninterrupted warfarin at the same centers.
According to a recent meta-analysis (17) and our own review of the literature, over 20 studies have been completed comparing NOACs to warfarin in the setting of AF ablation, including a very small randomized trial comparing interrupted dabigatran to interrupted warfarin (18), a slightly larger randomized study comparing uninterrupted rivaroxaban to uninterrupted warfarin (11), and a recent randomized study slightly larger than ours comparing uninterrupted dabigatran to uninterrupted warfarin (12). These studies have varied in their designs, endpoint definitions, and duration that NOACs were held before ablation, but in general have shown that NOACs with no (or minimal) interruption result in a similar, very low rate of stroke or SE compared with uninterrupted warfarin, and may have advantages in terms of bleeding risk.
Only a few of the previously reported studies on this topic specifically involved patients treated with apixaban (10,13–15). The most recently reported of these found a very low rate of complications with uninterrupted apixaban, but was nonrandomized and enrolled patients at only 2 centers (19). The AEIOU study therefore adds unique data on outcomes with apixaban, including the only randomized comparison between uninterrupted and (minimally) interrupted treatment, collected from a diverse group of 18 U.S. sites.
The findings of the AEIOU trial are mostly consistent with prior studies in this area. Most importantly, almost all reported studies have found a very low (<0.5% in aggregate) (17) rate of stroke or SE regardless of the NOAC used or the specific dosing regimen (10,12,19). Although this very low event rate precludes small or medium sized studies from finding differences between strategies, we find it reassuring that almost all strategies studied to date have yielded a similar, low risk of stroke.
The <2% rate of major bleeding seen in AEIOU study was also similar to that reported from most prior studies (17), although comparison between studies is hindered by variable definitions of major bleeding and other factors. Recently, the RE-CIRCUIT (Randomized Evaluation of Dabigatran Etexilate Compared to Warfarin in Pulmonary Vein Ablation: Assessment of an Uninterrupted Periprocedural Anticoagulation Strategy) study investigators (12) reported a 1.6% rate of major bleeding with uninterrupted dabigatran using the Interventional Society on Thrombosis and Haemostasis criteria (20)—a rate nearly identical to the 1.7% we observed in our combined apixaban arm using the similar BARC criteria. The rate of major bleeding among uninterrupted warfarin patients in our study was also quite low (1.4%), in contrast to the RE-CIRCUIT study, where major bleeding with uninterrupted warfarin was unusually high (6.9%). The explanation for the high rate of major bleeding in the RE-CIRCUIT study is not clear, but could have been related to use of the Interventional Society on Thrombosis and Haemostasis criteria (in which a major bleed is defined by a drop in hemoglobin of 2 g/dl or more) (20) different ablation practices in Europe, or other factors.
This generally low rate of major bleeding alleviates to an extent the concern among some practitioners of performing an invasive cardiac procedure such as AF ablation with no or minimal interruption of an anticoagulant that lacks a specific reversal agent. In the AEIOU study, there was only 1 bleeding event where active reversal of apixaban’s anticoagulant effect was felt to be necessary. This was a cardiac perforation related to transseptal access where the need for emergent intervention likely would not have been altered even had a specific reversal agent been available. The availability of a specific factor Xa reversal agent in the future should enhance clinician’s ability to manage such unusual events (21). These findings suggest that bleeding outcomes are most likely determined by factors other than small variations in the pre-procedure anticoagulation regimen.
We did observe 2 subjects with definite or possible left atrial thrombus on pre-procedure TEE despite taking apixaban for at least 1 month (in 1 case, for approximately 1 year). Both subjects had long-standing persistent AF, reported missing no apixaban doses in the 21 days before the procedure, and were randomized to the interrupted apixaban arm. Left atrial thrombus despite therapeutic anticoagulation has been reported in up to 1% to 2% of patients planned for AF ablation, and is more likely with higher CHADS2 scores and possibly with more persistent AF (22–24). This finding reinforces current consensus recommendations on the use of TEE before AF ablation (4).
The findings of the AEIOU study should be interpreted with several important limitations in mind. The sample size, although potentially adequate to find large differences between groups in bleeding rates, was not large enough to examine differences in less common outcomes, notably stroke or SE. Statistical power was more limited for comparisons between the 2 apixaban dosing strategies than for the comparisons between apixaban and warfarin. For the 2 apixaban groups, post hoc calculations suggested 95% CIs for risk differences of ±7% and ±4% for clinically significant and major bleeding, respectively. In addition, the pharmacological difference between our apixaban dosing strategies was minor, as therapeutic drug levels would still be present at the start of procedures when only a single dose was omitted. Thus, major differences in bleeding rates between the apixaban groups may not have been expected. However, we did not perceive clinical equipoise for holding apixaban any longer before the procedure.
Importantly, the comparisons between the apixaban and uninterrupted warfarin groups were not randomized. Although we matched these groups on several key variables, and found that most of the baseline characteristics of the groups were similar, the warfarin and apixaban groups were not truly contemporaneous, as nearly all of the apixaban patients were treated in 2016, whereas the warfarin patients were mostly treated between 2014 and 2016. Consequently, there were a number of observed differences in procedural variables, such as the use of contact force–sensing catheters or a double-transseptal approach, between the apixaban and warfarin groups. In multivariable analysis, we did not find any of these differences to be strongly associated with study outcomes or to change our primary findings, but our data could still have been affected by unmeasured confounding. A randomized trial comparing apixaban and warfarin in the setting of AF ablation is nearing completion (25).
The AEIOU study was an unblinded study. Moreover, the ascertainment of events was prospective for the apixaban subjects but retrospective for the warfarin subjects. It is possible that the likelihood of observing events may have systematically differed between the groups, but in our opinion not likely that major events were missed in either group.
Our study did not involve the routine use of brain magnetic resonance imaging to look for new “silent” brain lesions following ablation. Although the inclusion of routine imaging may enhance our understanding of potential differences between anticoagulation regimens, the clinical implication of these findings remains uncertain.
We found no strokes, and similar rates of major bleeding or any bleeding in randomized comparisons between uninterrupted or interrupted apixaban at the time of AF ablation, and similarly found no differences in the rate of these events for the apixaban strategies combined, compared with uninterrupted warfarin. Given these findings, we feel that all 3 studied anticoagulation regimens are clinically reasonable at the time of AF ablation.
COMPETENCY IN MEDICAL KNOWLEDGE: Apixaban, whether fully interrupted, or interrupted by 1 dose at the time of AF ablation, was associated with a very low (no events observed) rate of stroke or systemic embolism, and a low (<2%) rate of major bleeding. The same was true in similar patients treated with uninterrupted warfarin. There is no proven advantage to holding apixaban for longer intervals before AF ablation procedures.
TRANSLATIONAL OUTLOOK: With current procedural techniques and anticoagulation regimens, the occurrence of stroke or systemic embolism at the time of AF ablation has become rare (in the range of 0.2% or less). This is good for patients, but makes it very difficult to complete studies with adequate statistical power to find differences between different approaches. To have sufficient power to answer these questions, future studies will most likely need to adopt nonrandomized designs.
The authors thank Noah Gourlie, MS, of the Baim Institute for Clinical Research for assistance in the initial drafting of the manuscript.
The AEIOU study was an investigator-initiated study sponsored by the Baim Institute for Clinical Research, with financial support from Bristol-Myers Squibb and Pfizer. Dr. Reynolds has served as a consultant for St. Jude Medical (Abbott), Medtronic, and Sanofi. Dr. Allison has served on the Speakers Bureau for Bristol-Myers Squibb and Pfizer. Dr. Weisberg has served as a speaker for Boehringer Ingelheim, Janssen, Bristol-Myers Squibb, Pfizer, and Biosense Webster. Dr. Richards has served on the Speakers Bureau for Medtronic, Boston Scientific, Biotronik, Pfizer, Boehringer Ingelheim, and Janssen; and has served on medical advisory boards for Boston Scientific, Biotronik, Janssen, and Cardialen. Dr. Cannon has served as a consultant for AstraZeneca Pharmaceuticals, Boehringer Ingelheim, Bristol-Myers Squibb, Pfizer, and Takeda; and has received research grant support from Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo, Janssen, and Takeda. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
All authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the JACC: Clinical Electrophysiology author instructions page.
- Abbreviations and Acronyms
- atrial fibrillation
- Bleeding Academic Research Consortium
- confidence interval
- non–vitamin K antagonist oral anticoagulant
- systemic embolism
- transesophageal echocardiography
- transient ischemic attack
- Received August 8, 2017.
- Revision received October 25, 2017.
- Accepted November 2, 2017.
- 2018 American College of Cardiology Foundation
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