Keywords
atrial fibrillation - Hemophilia A - von Willebrand Disease - catheter ablation -
anticoagulant - bleeding
Introduction
Life expectancy in patients with hemophilia (PWHs) has increased significantly to
almost normal.[1] They are therefore more likely to be confronted with age-related comorbidity like
cardiovascular disease (CVD). CVD mortality has been reported to be lower than the
general population but numbers are increasing.[2]
[3] A common CVD in the aging population is atrial fibrillation (AF). AF can cause ischemic
stroke. The risk of an ischemic stroke in patients without bleeding disorders can
be estimated with the so-called CHA2DS2-VASC score,[4] but its applicability in hemophilia is questioned.[5] Management of PWH and AF is complex in finding the balance between coagulation and
anticoagulation. In a large cross-sectional study, the prevalence of AF in PWH was
comparable with that of the general population; however, anticoagulation management
was diverse.[6] The most challenging patients are those with a high bleeding and stroke risk. In
these patients, we question if the use of catheter ablation (like pulmonary vein isolation
[PVI]) is a feasible option to treat these patients. However, the feasibility of PVI
in patients with bleeding is unknown. Here we describe our experience in patients
with bleeding disorders undergoing PVI to treat their arrhythmia-related symptoms.
Methods
In this retrospective single-center cohort, we collected data from patients visiting
the hemophilia treatment center (Van Creveldkliniek, University Medical Center Utrecht,
The Netherlands) who underwent a PVI between 2014 and 2018. Data on baseline characteristics,
type of bleeding disorder, comorbidity, reason for PVI, and procedural outcomes were
extracted from the medical files. This project was approved by the local medical ethical
committee.
Pulmonary Vein Isolation
Prior to PVI, evaluation of three-dimensional (3D) cardiac imaging was done by a cardiac
computed tomography (CT) scan providing detailed left atrial anatomy and confirming
the absence of a left atrium appendage thrombus.
Electrophysiological studies were performed in a sedated, fasting state. Catheters
were introduced through the right femoral vein using three sheaths (once 7 French
and twice 8.5 French). An octapolar catheter was positioned in the coronary sinus.
The left atrium was reached by means of a transseptal puncture. A 3D cardiac mapping
system (Carto; Biosense Webster, Diamond Bar, California, United States) was used
to obtain a 3D reconstruction of the cardiac anatomy. An irrigated tip catheter (ThermoCool
SmartTouch, Biosense Webster) was used to widely encircle the right and left pulmonary
veins (PVs) at their antrum with point-by-point ablation lesions. Procedures were
performed as described before.[7] Endpoint of ablation procedure was electrical isolation of all PVs, as determined
with the circular mapping catheter. PV isolation had to be consistent after a waiting
period of 30 minutes after the last ablation application.
At the end of the procedure, sheaths were removed followed by manual compression of
the femoral vein for at least 10 minutes. Thereafter compression dressing was placed
for a least 4 hours and after its removal additional bedrest was continued for another
4 hours.
Definition of Success
There were two different definitions of success. During the “blanking period,” the
period after the procedure, reoccurrence of AF is normally not seen as failure.
Success rate of single PVI: no signs of AF following the 3-month “blanking period”
through the last follow-up. Overall success rate: no AF following one or more PVIs
and a 3-month “blanking period” through the last follow-up.[8]
Coagulation Management
Patients with baseline FVIII > 0.20 IU/mL started at least 4 weeks prior to PVI with
anticoagulation: vitamin K antagonist (VKA) or direct oral anticoagulant (DOAC) dabigatran
110 mg twice daily.
Clotting factor correction aiming at a peak FVIII level of 0.8 to 1.0 IU/mL was started
1 hour before the procedure. Target trough levels were aimed at 0.5 IU/mL and peak
levels were maintained at 0.8 to 1.0 IU/mL for the first 24 hours, for which two additional
bolus injections were given with 12-hour interval.
Anticoagulation during the PVI procedure was according to the local standard protocol
with unfractionated heparin (UFH) therapy with a target activated clotting time (ACT)
of 300 to 350 seconds.
Before April 2016, 4 to 8 hours after the procedure therapeutic dosed low molecular
weight heparin (LMWH: dalteparin, twice daily 100 IE/kg) was started in combination
with VKA. LMWH was stopped when a therapeutic international normalized ratio (INR) > 2.0
was obtained. Duration of VKA therapy was dependent on the extent and result of PVI,
with a minimum of 4 weeks. During VKA therapy FVIII trough levels were kept above
0.2 IU/mL.
Since April 2016 dabigatran (110 mg twice-daily) was used instead of VKA therapy,
avoiding the need for bridging with LMWH during PVI. In patients with FVIII > 0.2
IU/mL, it was started 4 weeks before the procedure. In patients with FVIII < 0.2 IU/mL,
it was started 4 to 8 hours after the procedure. Postprocedural DOAC was continued
for at least 4 weeks, in combination with FVIII suppletion with a target FVIII trough
level above 0.2 IU/mL.
Results
Patients
Five patients with hemophilia A and one with von Willebrand disease underwent a total
of eight PVIs at a mean age of 62.2 years ([Table 1]). Two patients had severe hemophilia and three mild. One patient had a history of
a past inhibitor against FVIII, but currently has a normal FVIII half-life. Median
duration of AF before the first PVI was 5 (interquartile range [IQR]: 4.75–7) years.
Median CHA2DS2-VASC score was 0.5 (IQR: 0–2.25). All patients were suffering from symptomatic AF.
Median follow-up after the last PVI was 33 months (IQR: 10.25–43.75).
Table 1
Patient characteristics
|
Patient
|
Age
|
Bleeding disorder
|
Clotting factor level (IU/mL)
|
Reason for intervention
|
CHA2DS2 VASC
|
Duration (y)
|
Prior therapy
|
On chronic anticoagulation before PVI
|
|
1
|
70
|
HA
|
FVIII 0.35
|
AF: dyspnea and fatigue
|
3
|
5
|
CV, ECV
|
VKA
|
|
2
|
72
|
HA
|
FVIII < 0.01
|
pAF: with severe fatigue
|
1
|
7
|
BB
|
No
|
|
3
|
59
|
HA
|
FVIII 0.23
|
pAF: bradycardia with decreased ejection fraction
|
0
|
4
|
ECV, flecainide
|
No
|
|
4
|
50
|
HA
|
FVIII < 0.01
|
pAF: frequent tachycardia
|
0
|
5
|
CV, flecainide, BB
|
No
|
|
5
|
55
|
HA
|
FVIII 0.06
|
pAF: persistent paroxysm under medication
|
0
|
5
|
Flecainide, BB
|
No
|
|
6
|
67
|
VWD
|
vWF RCo 19%
FVIII 0.50
|
AF: dyspnea and fatigue
|
2
|
7
|
VATS Maze; ECV
|
No
|
Abbreviations: AF, atrial fibrillation; BB, beta-blocker; CV, chemical cardioversion;
ECV, electric cardioversion; HA, hemophilia A; pAF, paroxysmal atrial fibrillation;
RCo, ristocetin cofactor (IU/dL); VWD, von Willebrand disease; vWF, von Willebrand
factor; VATS Maze: video assisted thoracoscopic surgery.
Table 2
Interventions—outcome and complications
|
Intervention
|
Patient
|
Outcome
|
AC before
|
AC after procedure
|
Stopped VKA/DOAC
|
Periprocedural groin bleeding
|
|
1
|
PVI
|
1
|
SR, later pAF
|
VKA
|
3 mo VKA (LMWH[b])
|
No: recurrent pAF
|
Day 5: Hb drop 3.22 g/dL
|
|
2
|
PVI (redo)
|
1
|
SR
|
Dabigatran[a]
|
Dabigatran[a]
|
No
|
No
|
|
3
|
PVI
|
2
|
SR, later pAF
|
No
|
1 mo VKA (LMWH[b])
|
Yes, as planned after 1 mo
|
Day 3: Hb drop 4.83 g/dL
|
|
4
|
PVI (redo)
|
2
|
SR under sotalol
|
No
|
1 mo VKA (LMWH[b]), 2 mo ASA
|
Yes, as planned after 1 mo
|
Postprocedure oozing during 4 h
|
|
5
|
PVI
|
3
|
SR
|
Dabigatran[a]
|
6 mo dabigatran[a]
|
Yes, after 6 mo
|
No
|
|
6
|
PVI
|
4
|
SR
|
No
|
6 wk VKA (LMWH[b])
|
Yes
|
No
|
|
7
|
PVI
|
5
|
SR
|
No
|
6 wk dabiagtran[a]
|
Yes
|
No
|
|
8
|
PVI
|
6
|
SR
|
No
|
6 wk dabigatran[a]
|
Yes
|
No
|
Abbreviations: AC, anticoagulation; ASA, 38 mg acetylsalicylic acid; Hb, hemoglobin:
3.22 g/dL = 2.0 mmol/L; 4.83 g/dL = 3.0 mmol/L; pAF, paroxysmal atrial fibrillation;
PVI, pulmonary vein isolation; SR, sinus rhythm; VKA, vitamin K antagonist: target
INR 2.0–3.0.
a 110 mg BID 4 weeks before PVI, last dose 24 h before intervention.
b Therapeutic LMWH until therapeutic INR.
Before PVI
Two patients were on anticoagulation therapy before the PVI ([Table 2]). Patient 1 (with a CHA2DS2-VASC 3 and FVIII 0.35 IU/mL) was on long-term VKA therapy before his first PVI and
on long-term dabigatran before the second PVI. The other (patient 3) was on dabigatran
before PVI for 4 weeks.
During PVI
According to the protocol, during all the procedures, boluses of UFH were administered,
based on the ACT results, without any complications.
In all cases of hemophilia, target FVIII levels periprocedural were met. The mean
dose of the first bolus was 31.7 IU/kg (IQR: 16.9–43.9) and the mean peak FVIII was
1.14 IU/mL. The patient with von Willebrand disease reached a peak von Willebrand
factor activity level of 0.66 IU/mL, despite weight-based suppletion of 3,000 IU of
Von Willebrand factor (Wilfactin; LFB, Les Ulis, France) half an hour before the blood
collection. The FVIII level was at that moment 0.52 IU/mL).
After PVI
Several hours (4–8 hours) after the procedure, therapeutic LMWH and VKA (n = 4) or dabigatran (n = 4) were started.
For anticoagulation management after PVI, see [Table 2]. VKA anticoagulation was stopped in three out of four procedures after a mean of
4.7 weeks. Dabigatran was stopped in three out of four procedures after a mean use
of 12.7 weeks. Patient 1 continued AC after both procedures because of a CHA2DS2-VASC 3 and factor level > 0.20 IU/mL.
Four interventions were followed by intensive factor suppletion during 4 to 6 weeks
(mean duration of 5 weeks) aiming and achieving trough FVIII levels of > 0.20 IU/mL.
The mean total clotting factor use was 76,625 IU (824 IU/kg) during this period.
Success rates
The success rate of a single PVI was 67% (4/6); for two recurrent AFs, a second PVI
(9 and 16 months after the first PVI) was performed ([Table 2]).
Only two patients met the definition of long-term follow-up of over 36 months, with
a 100% success rate. However, the final overall success rate was five out of six:
one patient had recurrent AF 42 months after the second PVI.
Complications
Clinically relevant bleeding complications (grade 2 World Health Organization bleeding
scale) occurred from the femoral vein puncture in two out of eight procedures ([Table 2]).
Patient 1 developed a small groin hematoma on the day of the procedure. He was agitated
during the procedure and nonadherent to bedrest. His FVIII level was completely corrected
for 36 hours. He was on therapeutic LMWH therapy before the procedure because of INR
of <2.0 despite VKA. LMWH was stopped the evening after the procedure, because an
adequate INR of 3.2 was obtained. He was discharged with a stable hematoma; hemoglobin
level was not measured. Five days later he was readmitted in another hospital with
a progressive groin hematoma and low hemoglobin (−5.16 g/dL) and a FVIII of 0.71 IU/mL.
His INR at admission was 2.4. However, he had a good periprocedural FVIII recovery
and trough levels and no inhibitor; it was assumed that his FVIII levels after discharge
from, and at readmission at, the hospital must have been at least 0.35 IU/mL. He was
successfully treated with high-dose clotting factor concentrate for 1 day to stop
bleeding. The hematoma completely resolved, and patient functionally fully recovered.
In patient 2 the procedure was complicated by an acute coughing spell. He reported
a progressive discomfort and hematoma of his groin 3 days after the procedure with
decreased hemoglobin. At that time his trough FVIII level was 0.31 IU/mL (the lowest
during his hospital stay), the INR was 3.0, and he was still on therapeutic LMWH therapy.
Because of the bleeding, FVIII was continued at higher dose aiming at trough levels
of >0.40 IU/mL and LMWH was stopped. He was discharged with 2 days delay. VKA was
continued and FVIII was given (1,500 IU once-daily) aiming at trough levels >0.40
IU/mL for 2 weeks. The patient fully recovered within these 2 weeks and thereafter
the target through level was decreased to 0.20 IU/mL.
Both patients with a severe groin bleed needed a redo PVI because of recurrent AF.
Patient 1 was sedated during the second procedure and additional clotting factor correction
was given on day 4, to prevent late (re)bleeding. This time he was treated with dabigatran,
a DOAC, instead of VKA. No bleeding occurred. The redo PVI in patient 2 was complicated
by mild oozing from the puncture site for several hours while FVIII levels were corrected
completely.
None of the patients developed thrombocytopenia or other bleeding tendency.
Discussion
In this small cohort study the success rate of PVI seems comparable with that of the
general population. The success rate of a single PVI was 67% and after a second PVI
83% for achieving sinus rhythm. In the literature a success rate of up to 70% of patients
with paroxysmal AF, and around 50% in persistent AF is found, with most patients requiring
more than one procedure.[4]
In the general population 5 to 7% of patients suffer from severe complications after
PVI, of which 2 to 3% are life-threatening, but usually manageable. The most severe
complications are stroke (<1%) and pericardial tamponade (1–2%).[4] The incidence of clinical relevant groin hematoma after PVI in the general population
is 0.9%.[9] In our group it is likely that the combination of therapeutic LMWH, VKA therapy,
decreased FVIII levels and mobilization shortly after the procedure have caused the
high bleeding rate (25%). In an observational study in the general population, bridging
during ablation was associated with more bleeding complications, compared with continuing
VKA.[10] Bridging was also associated with an increased stroke risk.[11] DOAC, however, is associated with a low incidence of stroke or transient ischemic
attack and a significant reduction of major bleeding.[12] In this small cohort we see the historical transition from bridging to nonbridging
with a DOAC; in this small group no bleeding under DOAC was seen. We have chosen the
DOAC dabigatran, a direct thrombin inhibitor, in a lower dose (110 mg twice daily)
for patients with a bleeding disorder and an indication for anticoagulation. With
this DOAC we have the option to reverse the anticoagulant if needed with idarucizumab.[13] Furthermore, FVIII levels can be measured in case of emergency, in contrast to oral
anti-Xa inhibitors that interfere with our laboratory assays.
Applying anticoagulation therapy in patients with bleeding disorders is complex.
AF has the risk of atrial thrombus embolization and ischemic stroke. The applicability
of the CHA2DS2-VASC score[4] in patients with clotting factor deficiency is questioned.[5] There is lack of data on stroke and bleeding risk during anticoagulation in a population
with increased bleeding tendency. As there are no prospective trials, a European working
group (ADVANCE) gathered consensus for the management of AF in PWHs.[5] Recently we reported an updated approach in anticoagulation management in PWH with
AF.[14] We suggest to assess the bleeding risk based on clotting factor level and the thrombotic
risk using the CHA2DS2-VASc score using adjusted cutoffs. A factor level of 0.20 IU/mL is thought to be
safe for treatment with anticoagulation.
There is no data for the periprocedural management of coagulation for PVI.
Normally patients not on anticoagulation start 4 weeks before the PVI with anticoagulation.
According to our protocol only patients with factor levels above 0.20 IU/mL were treated
this way. Both patients did not report bleeding complications. On the other hand,
patients not on anticoagulation did not have embolic events during this short time.
For the future we are considering to withhold anticoagulation in patients with a low
CHA2DS2-VASc score (<4) with confirmation of absence of left atrium appendage thrombus by
cardiac CT-scan before the procedure.
During PVI clotting factor suppletion is necessary to prevent a groin bleed and therefore
anticoagulation is needed.
Following PVI, patients are treated with anticoagulation and in the case of FVIII
levels <0.20 IU/mL, daily factor suppletion for at least 4 weeks. At this moment we
think that withholding anticoagulation in patients with FVIII <0.20I U/mL is not possible,
because of an expected high risk of thrombus formation on the large coagulation area
in the cardiac atria.
In our cohort clinically relevant bleeding occurred 3 to 5 days after the procedure,
a delay not uncommon in hemophilia as clot formation is impaired. Treatment consisted
of stopping LMWH, which was already planned because of adequate INR, and increasing
the FVIII target level for a limited time. We choose not to antagonize VKA, because
postprocedural patients needed to be anticoagulated with VKA for a longer time.
Conclusion
Our results suggest that PVI is effective and a generally safe procedure in patients
with bleeding disorders, provided that a strict control of hemostasis is attained
and preferably a DOAC is used as anticoagulation. Because of the unexpected significant
groin hematomas in two patients (on VKA with LMWH bridging) despite complete clotting
factor correction for at least 24 hours, agitation during and the first hours after
the procedure and early mobilization should be avoided. Furthermore, also in patients
with bleeding disorders, DOAC seems safer compared with bridging of VKA with LMWH.
