Discussion
To the best of our knowledge, our study is the first prospective RCT to
evaluate the safety of a single bolus administration of heparin (100
U/kg) without ACT monitoring under the condition of uninterrupted NOACs
in patients with AF undergoing CBA. No thromboembolic or fatal events
occurred during the 30-day follow-up period following CBA.
Notwithstanding the low CHA2DS2-VASc
scores, patients undergoing AF ablation have the greatest risk for
intra- and post-procedural thromboembolism development. An appropriate
anticoagulation management is, therefore, essential throughout the
entire procedural period. Current guidelines recommend uninterrupted
systemic OAC therapy for at least 3 weeks before and 2 months after AF
ablation, regardless of the CHA2DS2-VASc
score. Moreover, intra-procedural administration of unfractionated
heparin prior to or immediately after transseptal puncture as well as
additional dose adjustment every 15-30 min to maintain ACT above 300 s
should be recommended. However, this recommendation about
intra-procedural heparin administration was based on the results of
studies using VKA in patients with AF undergoing RFCA.
In terms of the initial loading dose of heparin, previous studies
revealed that the administration of a higher dose of heparin was
required to achieve the target ACT in AF patients with uninterrupted
NOACs intake than in those with uninterrupted VKA
intake.15-18 In addition, Yamaji et
al.19 reported that an adequate loading dose of
heparin was different for each NOAC because NOACs have different
mechanisms of action. In the present study, although the average ACT in
the ACT group was over 300 seconds (335.2±59.9), there was significant
difference in mean ACT between patients who took rivaroxaban and those
who took edoxaban (p=0.003). This finding is in line with that reported
in previous studies.
A previous study demonstrated that radiofrequency (RF) energy was
significantly more thrombogenic than cryoenergy, with a higher incidence
of thrombus formation and larger thrombus volumes.20Compared to cryoablation, RF ablation resulted in a >5-fold
increased risk of thrombus formation with larger thrombus volumes for
endocardial ablation lesions of equal size in equivalent cardiac
chambers. Specifically, the thrombus volume was positively correlated
with the extent of hyperthermic tissue injury, whereas it was not
related to the degree of hypothermic tissue injury. They suggested that
these results probably reflected the histological observation that
cryoablation resulted in well-delineated and discrete lesions with
preservation of tissue ultrastructure, including the endothelial cell
layer. In contrast, RF energy-induced lesions had serrated edges with
extensive endothelial cell destruction.
However, several studies evaluating the incidence of acute silent
cerebral lesions after PVI using magnetic resonance imaging (MRI) have
demonstrated that CBA may not be associated with a lower risk of
thromboembolic cerebral events than RFCA.21-23 These
results underline the hypothesis that thrombus formation originating
from an extended destruction of the endothelium surface is probably not
the only cause of acute cerebral lesions. Although the definite cause of
micro-cerebral infarctions associated with AF ablation has not been
fully elucidated, several possible embolic sources are considered, such
as gaseous emboli or microthrombi entrapped within the sheath during
catheter insertion or extraction, platelet-rich microthrombi formed at
the endothelial injury site, gaseous emboli formed during blood heating,
and microparticles (char) as a result of rapid hyperthermal tissue
damage. Among these possible embolic sources, the first can be the
presumable cause of microthromboembolism associated with CBA. Therefore,
the systemic use of intravenous heparin does not appear to fully
eliminate the CBA-related microthromboembolic risk. Instead,
intermittent flushing with heparinized saline through the central lumen
of the steerable sheath during the entire CBA procedure appears to be
more effective in preventing the formation of gaseous emboli or
microthrombi at the gap portion between the steerable sheath and CB
shaft.24
A recent meta-analysis demonstrated a significantly shorter procedure
time in CBA compared to RFCA.25 The total procedural
time in previous studies has been reported from 73.5±16 min to 192.9±44
min during CBA and from 118.5±15 minutes to 283.7±78.0 minutes during
RFCA.26 In the present study, the total procedure and
LA indwelling times were 79.0±14.3 min and 60.4±13.2 min, respectively.
If the LA indwelling time is less than 60 min, additional administration
of heparin would not be necessary, especially in patients with ACT of
above 300 s at 30-min after transseptal puncture. Peripheral vascular
complications are cumulatively reported in approximately 1-2% of cases,
and cardiac perforation was noted in 0.1-3.2% of
cases.27-29 The incidence of stroke or TIA has been
reported to be lower than 1% despite a relatively high rate of silent
cerebral embolic lesions.30 In the present study, no
patient developed thromboembolic events and fatal complications. Any
bleeding rate was 3.2% in all enrolled patients. Minor bleeding
complications, including groin hematoma, laryngopharyngeal bleeding, and
hemoptysis, were only observed in the ACT group, with no statistically
different between two groups.
As VKA and NOACs have different effects on the intrinsic and/or
extrinsic blood coagulation cascade, the same intra-procedural
anticoagulation strategy could not be applied in patients with
uninterrupted VKA and NOACs intake. However, the recommendation about
intra-procedural anticoagulation regimens has not been changed, even
though different ablation modalities such as CBA are widely used in
clinical practice. Indeed, intra-procedural anticoagulation with
unfractionated heparin might cause minor or major bleeding
complications, which could be increased in patients undergoing CBA for
whom a 15-Fr sheath is used. Therefore, the results of the present study
may be meaningful for reappraising the intra-procedural anticoagulation
strategy under the condition of uninterrupted NOACs at timely manner.
This study had several limitations. First, the sample size was not large
enough and the number of events was small. Thus, it might be
insufficient to identify a significant difference in clinical outcomes
depending on whether or not an additional dose of heparin was
administered. Furthermore, highly experienced operators performed the
procedure in the present study, which could reduce the sensitivity of
the results. Second, only two NOACs were evaluated in this study. In
order to maintain a similar inhibitory effect of endogenous factor Xa
between two groups, we enrolled only patients who had been taking
once-daily NOACs (rivaroxaban and edoxaban) at night, and the maximum
interval between the last pre-ablation NOACs dose and the ablation
procedure was 12 h. Therefore, the results could not be extrapolated to
all NOACs. Third, silent stroke was not reflected in thromboembolic
events because routine MRI before and after CBA was not performed in
this study. Lastly, we could not measure the peak level of ACT because
we measured ACT at 30 min after the initial bolus administration of
heparin. However, it might be unnecessary to assess the peak ACT level
because the LA indwelling time was relatively short.