Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) Clinical Trial
Official title:
Prolonged Monitoring to Detect Ventricular Arrhythmias in Presymptomatic ARVC Patients
Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) is an inherited condition
characterized by life threatening heart racing, presenting with palpitations, cardiac arrest
(collapse requiring an ambulance) or sudden death. The disease affects the right ventricle,
the part of the heart that pumps blood to the lungs. ARVC is diagnosed with a wide range of
tests that focus on the pumping function and the electrical signals from the right
ventricle. These factors are summarized in a score that forms the ARVC Task Force Criteria.
Genetic testing has identified 5 different genes that lead to ARVC, which are detected in
about 60% of patients with ARVC. This allows doctors to test family members of the patient
with ARVC to determine if they are at risk of developing the condition. Currently, family
members undergo testing that includes imaging and electrical tests such as a 24-hour monitor
to determine if they have evidence of ARVC. With increasing frequency, family members are
found to have the gene that may lead to ARVC, but little or no evidence that their hearts
are affected. This may be because the family member is too young to develop the condition,
or that other factors that we do not understand have protected them from developing it.
The PREPARE study will study 100 patients that carry a gene that can lead to ARVC, but do
not have anything more than minor evidence that the condition is present. These patients
will not have heart racing on their initial 24-hour monitor. These patients will undergo
long term monitoring with an implanted heart monitor that is inserted with a minor surgical
procedure, which will detect abnormal heart rhythms that may provide a clue that heart
racing from ARVC is present that is not detected with a 24-hour monitor that is performed on
an annual basis (St. Jude Confirm implantable loop recorder). These patients will be
enrolled in 10 adult and pediatric centers across Canada, and followed for 3 years after
their heart monitor is implanted. If heart racing is detected, patients will discuss these
results with their doctor to discuss what it means to them.
Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) is a familial condition characterized
by onset of life threatening ventricular arrhythmias in early adulthood, presenting with
ventricular tachycardia, cardiac arrest or sudden death. The disease is diagnosed with tests
that focus on imaging the right ventricle and assessing for ambient arrhythmia or abnormal
electrical substrate. These factors are collated into a score that forms the ARVC Task Force
Criteria, known to be specific but not sensitive. These criteria have been revised in 2010,
introducing a broader and more quantitative approach to diagnosis including genetic testing
results, intended to enhance sensitivity without reducing specificity. They account for
findings from genetic testing, confounded in part by the unknown significance of a positive
genetic test in the absence of a phenotype in a disease with variable penetrance and
expressivity. Genetic testing identifies the underlying mutation in ≈60% of clearly affected
patients. Recent access to genetic testing has demonstrated that family members of an
affected individual often harbor the culprit mutation, with little evidence that they are
affected from clinical testing. Given the risk of life threatening arrhythmia as a first
presentation of disease expression, enhanced detection of ventricular arrhythmia would help
to identify patients with manifest ARVC.
The PREPARE study will test the hypothesis that prolonged monitoring with an implantable
loop recorder (ILR) will provide evidence of progressive electrical disease in gene positive
ARVC patients with a non-diagnostic phenotype (negative or mild) who do not receive an
implantable cardioverter defibrillator (ICD). Detection of non-sustained ventricular
tachycardia will have incremental value over routine periodic clinical follow-up and
standard short term monitoring (24-48 hour Holter).
100 gene positive patients without manifest ARVC after standard screening clinical testing
will undergo ILR implantation. These patients will fail to meet 2010 revised Task Force
Criteria for definite ARVC and will not be considered candidates for a primary prevention
ICD by the local investigator. A Health Canada approved St. Jude Medical ConfirmTM loop
recorder will be implanted using standard technique with local anesthetic, and patients will
be followed for 3 years. Patients will undergo repeat clinical phenotype testing according
to the local institutions standard practice, including testing at 3 years after enrollment
to reassess Task Force Criteria (standard care), which will constitute the end of the study.
A 24-hour Holter monitor will be encouraged annually to provide standard surveillance for
ventricular arrhythmia as a comparator to loop recorder findings. In the event that
non-sustained or sustained ventricular tachycardia is detected by the loop recorder (≥8
beats) and/or Holter monitor, clinical assessment by the local investigator will take place
to review the tracing and discuss the findings with the patient. This will follow routine
clinical care.
The primary end point is detection of ≥8 beats of wide QRS complex tachycardia considered
ventricular tachycardia by the ILR. Secondary endpoints will include comparison of
ventricular arrhythmia burden between routine surveillance Holter monitoring and the ILR,
and change in 2010 Task Force Criteria Score from enrollment to 3-year follow-up.
Patients will provide written informed consent to participate in the study, with data
collected in a password-protected web based database. Patients will undergo follow-up at 1
and 4 weeks after implant, at 3 and 6 months and every 6 months thereafter. Follow-up will
capture findings from loop recorder interrogation, along with change in clinical status and
cardioactive drug use. A 24 Hour Holter monitor will be encouraged annually to provide
standard surveillance for ventricular arrhythmia as a comparator to loop recorder findings.
This is a pilot study to explore the prevalence and incidence of ambient asymptomatic
ventricular arrhythmias in presymptomatic genotype carriers of ARVC. An empiric number of
100 subjects was chosen based on disease prevalence and recruitment goals. End point
adjudication will include a 3 member adjudication committee comprised of coinvestigators. A
single interim analysis of end points will be performed by an independent Data and Safety
Monitoring Committee after 50 patients have completed at least one year of follow-up.
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Observational Model: Cohort, Time Perspective: Prospective
| Status | Clinical Trial | Phase | |
|---|---|---|---|
| Enrolling by invitation |
NCT04189822 -
Hearts in Rhythm Organization (HiRO)National Registry and Bio Bank
|