Reversal of cardiomyopathy by suppression of frequent premature ventricular complexes - a prospective randomized clinical trial

Heart failure accounts for substantial morbidity and mortality in the western
world. In addition, the financial burden associated with the disease is
considerable. Prognosis is generally poor and quality of life is significantly
reduced. The causes of heart failure are diverse. Identification of the
underlying pathophysiological mechanism is essential, because a specific
patient tailored therapy may help to improve the clinical status of the
individual patient. In addition, some patients may have a potentially
reversible cardiomyopathy (CMP). The present study will focus on the role of
frequent premature ventricular contractions (PVCs) as a cause of left
ventricular (LV) dysfunction. This is a potential reversible CMP generally
unknown to the cardiological society.

Frequent ventricular ectopy in patients without structural heart disease is
generally thought to be a benign finding with no prognostic significance.
Suppression of PVCs with anti-arrhythmic drugs or catheter ablation is
therefore usually only considered when PVCs are accompanied by disabling
symptoms. However, recent data suggest that frequent monomorphic PVCs
(symptomatic or asymptomatic) can cause a form of CMP that may be reversible by
suppression of the ectopic focus. Furthermore, the high prevalence of frequent
PVCs in patients with heart disease suggests that PVC-induced CMP may be a
common phenomenon. Suppression of frequent monomorphic PVCs to improve LV
systolic function may therefore emerge as a new and effective treatment
strategy for patients with heart failure.

Beta-blockers are safe and effective anti-arrhythmic agents and are considered
the first line therapy for suppression of PVCs. Most patients with HF are
already taking a beta-blocker as part of standard therapy for their underlying
disease. According to international guidelines, other AADs can be used if
beta-blockers are ineffective, but they have potential adverse (arrhythmic)
side-effects, especially in patients with diminished LV function, and may even
be contra-indicated in this patient group. In patients with LV dysfunction and
frequent monomorphic PVCs that are refractory to beta-blockers, long-term drug
therapy and the potential adverse (arrhythmic) side-effects of AADs can be
avoided by using catheter ablation as a first alternative treatment. RFCA is
already a frequently applied, widely accepted, safe, effective and potentially
curative treatment for symptomatic drugrefractory PVCs. It has also been safely
and effectively employed in patients with tachycardia-induced CMP and patients
with PVC-induced CMP. A high acute succes rate of 93% and a very low PVC
recurrence rate of 3% have been reported. Although recent available data
suggest that elemination of the PVC source by RFCA improves LV systolic
function in HF patients, it is still applied in a limited fashion for this
indication because the evidence supporting this is weak. The patient series
published so far were not controlled and retrospective in nature. We intend to
conduct a controlled, randomized, prospective study with careful documentation
and long-term follow-up to evaluate the effect of PVC suppression therapy (with
RFCA as primary treatment) on cardiac systolic function in patients with CMP
and beta-blocker refractory frequent monomorphic PVCs. This could establish
suppression of frequent monomorphic PVCs as a potential curative treatment
strategy for patients with HF.

Primary Objective: The main objective of this study is to demonstrate that PVC
suppression therapy on top of conventional heart failure treatment improves
cardiac systolic function as assessed by quantitative echocardiography in
patients with idiopathic or ischemic CMP and frequent monomorphic PVCs.

Secondary Objectives: Secondary objectives are to demonstrate improvement in
patient functional capacity (NYHA functional class), exercise tolerance (6
minutes walking test), quality of life (Minnesota Living with Heart Failure
Questionnaire) and level of the heart failure marker NT-proBNP. and to assess
the cost-effectiveness of additional PVC suppression therapy compared to
conventional heart failure treatment.

The present study is a prospective randomized clinical trial to evaluate the
effect of PVC suppression therapy on cardiac systolic function and patient
clinical condition in patients with idiopathic or ischemic CMP and frequent
monomorphic PVCs.

Patients will be randomized into 2 groups. One group will receive PVC
suppression therapy on top of conventional heart failure therapy. The other
group will receive conventional heart failure therapy alone.

PVC suppression therapy:
PVC suppression therapy will be applied using the following treatment strategy:
PVC elimination by RFCA will be used as primary therapy. In case of
unsuccessful ablation or if the PVC focus turns out inaccessible by
percutaneous approach during electrophysiological study (EPS), drug therapy
with Amiodarone, a drug registered for the treatment of ventricular
arrhythmias, can be considered as secondary therapy.

EPS and RFCA protocol:
EPS with subsequent RFCA is performed according to current clinical practice.
This is a widely accepted, well established procedure which is frequently
applied in our hospital. Approximately 250 RFCA procedures are performed in our
centre every year (2 per day on average) by experienced electrophysiologists
for a variety of indications. In the azM it is a standard treatment for atrial
tachycardia, AV nodal re-entrant tachycardia, ventricular tachycardia and
premature ventricular complexes. The results of the treatment in our centre are
excellent. Our electrophysiologists achieve a high acute and chronic success
rate which varies from 80-100% depending on the indication for which it is
used.
All electrophysiological procedures will be performed in the fasting state
without sedation. Anti-arrhythmic drugs will be discontinued at least 5 days
before the procedure. Patients will be locally anesthetized with Lidocaine. 7 F
multi-electrode electrophysiology catheters will be inserted into a femoral
vein and positioned in the right ventricular apex, the his bundle position and
the coronary sinus (CS). A 7,5 - 8 F multi-electrode deflectable tip ablation
catheter with a 3,5 mm tip electrode will be used for mapping and ablation. In
case of suspected right sided PVC origin, the catheter will be inserted through
the femoral vein. In case of suspected left sided PVC origin, a retrograde
aortic approach from the femoral artery will be used. Five thousand units of
heparin will be administered for right-sided procedures. Systemic
heparinization to achieve an activated clotting time of 250*300 seconds will be
performed for left-sided procedures. The origin of the PVCs will be identified
using an electro-anatomical mapping system. In case of infrequent spontaneous
ectopy during the procedure, programmed electrical stimulation will be
performed and/or isoprenaline will be administered at rates up to
10microgram/min to induce culprit PVCs. If ectopy is still infrequent despite
programmed stimulation and/or isoprenaline, pace mapping will be used to
identify the PVC origin. Using activation mapping the site of earliest
endocardial activation will be determined and radiofrequency energy will then
be delivered to this region. A 7F deflectable quadripolar ablation catheter
with a 4 mm tip electrode will be used for mapping and ablation. The
radiofrequency energy will be delivered with a preset temperature of 50 to 60
degrees Celsius at the electrode tissue interface and a power limit of 50 W.
The applications will be continued for at least 30 s if adequate heating at the
electrode-tissue surface is achieved. If the VPBs are abolished the application
will be continued for 60 s and followed by another 60 s application. If PVCs
are still present after 30 s the energy application will be terminated and
mapping will be continued. In the event of pleomorphic PVCs the predominant PVC
morphology will be targeted. Programmed electrical stimulation and/or
isoprenaline administration at 2 -10 microgram/min will be used at the end of
the procedure to confirm that PVCs are no longer inducible. Ablation is
considered acutely successful when repetitive monomorphic ventricular ectopy is
abolished during ablation and remains absent for at least 30 minutes after
ablation in the baseline state and during programmed stimulation and/or
isoprenaline infusion.
In addition, in ischemic CMP patients, the average endocardial scar area will
be assessed by electroanatomical mapping using a lower limit of 1,5 mV for
normal tissue. The average dense endocardial scar area will be assessed by
electroanatomical mapping using a cut-off of 0,5 mV.

Amiodarone protocol:
The treatment is performed according to current clinical practice. Amiodarone
is administered orally using 200 mg tablets. A loading dose of 600 mg is given
daily (3 tablets per day) for 4 weeks. Thereafter patients will take 200 mg (1
tablet) per day. Tablets should be taken during or immediately after meals.

During the period of the study, the participants will pay a maximum of 6 visits
to the hospital. During these visits baseline and follow-up measurements are
performed and treatment is administered as assigned by randomization. The total
study duration for each participant is a maximum of 6 months. The burden and
risks of the study procedures are described below.

Potential study subjects (Idiopathic/ischemic CMP; stable optimal heart failure
therapy; > 18 years, no exclusion criteria) will be enrolled in the study after
giving informed consent. They will receive a diagnostic work-up to assess their
eligibility for randomization. This work-up comprises 48 hour Holter monitoring
with a 12 lead device and an echocardiogram. These tests are common clinical
practice in patients with heart failure. They are non-invasive and do not
expose the subjects to any risks. Patients meeting all electrocardiographic and
echocardiographic criteria will be randomized to either PVC suppression therapy
on top of standard care or standard care alone.

Patients eligible for randomization will undergo further baseline evaluation
before treatment which includes NYHA assessement, 2 quality of life (QoL)
questionnaires, a cost-effectiveness questionnaire, physical examination, 12
lead ECG, standard 6 minutes walk test (6MWT) and plasma NT-proBNP measurement.
There are no risks involved with these commonly applied tests. For NT-proBNP
measurements 4ml of blood will be taken by venous puncture in the arm with a
very small needle (diameter 0,6 mm). Furthermore, an extra blood sample of 16
ml will be taken at baseline and 6 months follow-up and stored for future
research purposes. These are very small clinically irrelevant amounts of blood.
Taking this amount of blood is therefore not harmfull for the study subjects.
All the blood is taken using the same needle. Therefore study subjects do not
need to be burdened with an extra venous puncture. Ischemic CMP patients will
receive an additonal DE-CMR to assess the myocardial scar area and -burden.
During CMR a radiographic contrast agent, *Gadovist* (Gadolinium) is
administered according to hospital protocol. Side effects of this agent are
very rare. Minor side effects (pain during administration, nausea, headache,
dizziness) have been reported in 0,1 * 1% of cases. Allergic reactions
including anaphylactic shock have been reported in 0,01 * 0,1% of cases.
Nefrogenic systemic fibrosis has been reported in patients with a GFR of less
than 30 in 0,1 * 0,01 % of cases.

Patients randomized to PVC suppression therapy will be hospitalizd for 24 hours
to undergo an electrophysiological study (EPS) and RFCA. These are well
established and frequently applied techniques in our hospital. The procedure
takes about 2 to 4 hours and is relatively safe, but several complications are
possible. Minor complications (account for about 4%) include minor bleeding or
infection at the puncture site, thrombo-embolism, temporary catheter induced
rhythm disturbances, and temporary changes in blood pressure. More significant
complications (account for about 0,1%) include damage to blood vessels or
perforation of the heart wall causing cardiac tamponade, extensive bleeding or
cardiac arrest. The risk of dying during an EPS is less than 0,1%. Fluoroscopy
during EPS exposes patients to relatively low radiation dosages (average
effective dosage of 13 mSv +/- 15%). Radiation complications have never been
described.

At 3 months follow up Holter monitoring, echocardiography and QoL and
cost-effectiveness questionnaires are repeated. Follow up at 6 months includes
NYHA assessment, QoL and cost-effectiveness questionnaires, physical
examination, 12 lead ECG, standard 6MWT, Holter monitoring, echocardiography
and plasma NT-proBNP measurement. Follow up at 12 months only includes QoL and
cost-effectiveness questionnaires. Patients treated with RFCA will undergo
additional echocardiography 1 day post-ablation and additional Holter
monitoring at 2 weeks post-ablation.