Primary Objective: The aim of this study is to compare efficacy of antiarrhythmic drugs (sotalol or combination of flecainide and verapamil) and catheter ablation in reducing VPB/VT burden in patients with symptomatic idiopathic VPB/VTs.
ID
Source
Brief title
Condition
- Cardiac arrhythmias
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary objective: Compare efficacy in VPB/VT burden reduction in patients with
frequent idiopathic VPB/VT after 3 months treatment with two different
antiarrhythmic drug regimens (sotalol or combination of flecainide and
verapamil) and primary catheter ablation of VPB/VT substrate.
Secondary outcome
Secondary objectives:
1. To explore the influence of different modulating factors on VPB/VT burden
and response to treatment
measured with percentage VPB/VT burden reduction and change in QOL
scores
- Sympathetic drive, assessed by positive HR-VPB correlation, i.e. correlation
between hourly VPB
density and hourly HR during 24 hours ambulatory Holter monitoring
- Gender differences in VPB/VT burden and response to different treatment
modalities.
- Effect of hormonal changes in women, i.e. explore the effect of estrogen
depletion by comparing
VPB/VT burden and response to different treatment modalities in pre-
and postmenopausal women.
2. To evaluate safety of investigational treatments, assessing:
- The rate of adverse events related to catheter ablation (especially in the
subgroup of VPB/VTs of non-
RVOT origins)
- The rate of pro-arrhythmic effects of treatment with sotalol or combination
of flecainide and verapamil.
- The rate of VPB/VT-induced CMP in our study population by early detection of
subtle changes in left
ventricular function with the use of global longitudinal strain (GLS)
Background summary
Frequent ventricular premature beats (VPB) and ventricular tachycardia (VT) in
healthy subjects without structural heart disease is considered benign.
However, it may cause invalidating symptoms or VPB/VT induced cardiomyopathy
(CMP). First choice therapy for reduction of VPB/VT burden is preferably
beta-blockers or non-dihydropyridine calcium channel blockers (verapamil or
diltiazem). However, effective reduction of VPB/VTs can be established in only
10-20% of patients using these drugs. Next step is class I and III
anti-arrhythmic drugs (AADs), but they are known for their potential severe
side effects, especially amiodarone is associated with potentially severe side
effects. Class Ic AAD (e.g. propafenone, flecainide) are effective in reducing
VPB/VT burden with 80% in 50-74% and are relatively well tolerated. Catheter
ablation is highly effective with a VPB/VT burden reduction of >90% in 80-90%
of patients. Current guidelines recommend catheter ablation in patients with
VPB/VT from right ventricular outflow tract (RVOT) origin in case of symptoms,
failure of AAD or decline in left ventricular function. (Class I, level of
evidence B).
There is only one randomized trial comparing catheter ablation and AAD in
patients with *idiopathic* VPB/VT and structural normal hearts. In that study,
catheter ablation (80.6%) was superior in efficacy compared to AADs (11.4%).
However, treatment with AADs in this study was not randomized, using
propafenone and metoprolol in a 3:1 ratio and only patients with RVOT VPB/VTs
were included. In conclusion, comparison of different AADs versus catheter
ablation in reduction of benign VPB/VTs has not been fully elucidated. We
therefore propose a three group randomized trial comparing Class III and Class
Ic AADs with catheter ablation in a 1:1:1 ratio. We hypothesise that flecainide
(combined with verapamil) has similar efficacy compared to catheter in
suppressing VPB/VTs and that sotalol is inferior in efficacy to both therapies.
The underlying mechanisms of VPB/VTs are considered a combination of triggered
activity and enhanced abnormal automaticity. Increased VPB/VT burden depends on
several factors; e.g. age, hormones and sleep apnea. The role of the autonomic
nervous system, in particular sympathovagal imbalance, plays an important role
in these patients. In patients with sympathetic overdrive, VPB/VT burden
increases during higher heart rates (HR), i.e. positive HR dependency of
ventricular ectopy. Relationship between effectiveness of different AADs and HR
was previously described in small studies with heterogeneous populations. In
the current study, we will use a cross-over design to study the effect of AADs
and HR dependency of VPB/VTs. The collected data will enable us to study the
role of the autonomic nervous system and explore the potential underlying
electrophysiological mechanisms of VPB/VTs. It is known that enhanced VPB/VT
burden is more often seen in females. Another objective of the current study is
to delineate the effect of gender on treatment efficacy and quality of life
(QOL). In addition, we will study differences in VPB/VT burden and treatment
efficacy in pre-and postmenopausal women. Finally, this study will assess
safety and efficacy of long-term treatment with flecainide and verapamil
compared with catheter ablation, especially in the subgroup of patients with
non RVOT VPB/VT foci that are anatomically challenging for catheter ablation,
e.g. aortic cusp or mitral annulus.
Study objective
Primary Objective: The aim of this study is to compare efficacy of
antiarrhythmic drugs (sotalol or combination of flecainide and verapamil) and
catheter ablation in reducing VPB/VT burden in patients with symptomatic
idiopathic VPB/VTs.
Study design
Prospective, randomized, multicenter trial
Intervention
Patients will be randomized in a 1:1:1 fashion into one of the following three
arms after completion of the consent procedure and baseline assessment:
(A) sotalol (n=60) = maximal tolerated dose, starting dose (and minimum dose)
80 mg BID. Maximal dose of 320 mg/day
(B) flecainide (n=60) = maximal tolerated dose, starting dose (and minimum
dose) 100 mg/day (slow release), Maximal dose of 200 mg, in combination with:
verapamil = 120 mg BID
(C) catheter ablation (n= 60)
Study burden and risks
The potential clinical benefit for patients in the AAD arms could be that they
will not be restrained from any of the potentially highly effective treatment
strategies of this trial, since a cross-over is performed between two AADs and
catheter ablation will also be offered after 6 months. In standard care,
especially combination of flecainide and verapamil, is not a conventional
combination in most centers. This study will provide access to this therapy in
a safe setting with close monitoring. For patients in the catheter ablation
group (especially patients with non-RVOT VPB/VTs) a highly successful therapy
(80-90%) treatment will be available as a primary treatment. Catheter ablation
of VPB/VT of RVOT origin is a validated and safe therapy in patients with
symptomatic drug refractory VPB/VTs with a very low amount of major
complications (<1%, consisting of rare case of RVOT rupture) and minor
complications (<3%, consisting of right bundle branch block, CVA, damage to
coronary arteries, groin haematoma, pericardial effusion) .Ablation of non-RVOT
VPB/VT origins (e.g. left ventricular outflow tract, aortic cusp or aortomitral
continuity) with more anatomically challenging approach are also associated
with low complication rate. However, available evidence is based on small
registry studies from highly experienced ablation centres like ours.
Dokter van Heesweg 2
Zwolle 8025AB
NL
Dokter van Heesweg 2
Zwolle 8025AB
NL
Listed location countries
Age
Inclusion criteria
-Patients willing and capable to provide written informed consent
- Patients with frequent symptomatic VPB/VT and/or nonsustained VTs with a
burden of * 5% AND
-Absence of structural heart disease AND
-Absence of underlying cardiac ischemia AND
-Patient is considered an acceptable candidate for catheter ablation treatment
with a
dominant morphology of VPB/VT origin judged by the treating physician.
-For those already undergoing treatment, all antiarrhythmic drugs including
digitalis must be discontinued during a 2- week washout period before entry to
the study
Exclusion criteria
-Age >75 years
- Previous catheter ablation therapy for VPB/VT
-Patients with sustained ventricular tachycardia or cardiac channelopathies
(e.g. CPVT, long- or short QT syndrome, Brugada syndrome)
-WPW syndrome
- Use of medication with risk of QTc prolongation (e.g. antidepressant,
antiemetic), except for study medication sotalol.
- Left ventricular dysfunction (LV ejection fraction <55%)
-Estimated glomerular filtration rate < 50 ml/min/1.73 m2
-Hepatic impairment defined by a total bilirubin * 2 times the upper limit
(ULN) of normal ALAT or ASAT * 3 times ULN at screening.
-Untreated hypo- or hyperthyroidism or electrolyte imbalance
- Untreated obstructive sleep apnea
-Patients with history of myocardial infarction or bypass surgery
- More than grade 1/3 valvular regurgitation and/or significant valve stenosis
(moderate or severe)
- Contraindication for any of the antiarrhythmic drugs used in this study
- Enrolment in another trial
- Woman currently pregnant or breastfeeding or not using reliable contraceptive
measures during fertile age
- Mental or physical inability to participate in the study
-Life expectancy * 12 months
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2018-001518-13-NL |
| ClinicalTrials.gov | NCT03845010 |
| CCMO | NL65761.075.18 |