Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT04101539 |
| Other study ID # |
IRB00183327 |
| Secondary ID |
|
| Status |
Recruiting |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
September 1, 2019 |
| Est. completion date |
November 2025 |
Study information
| Verified date |
September 2023 |
| Source |
Johns Hopkins University |
| Contact |
David Spragg, MD |
| Phone |
4105501973 |
| Email |
dspragg1[@]jhmi.edu |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Catheter ablation is an established cornerstone of therapy for patients with symptomatic
atrial fibrillation (AF) who wish to avoid anti-arrhythmic drug therapy or for whom
anti-arrhythmics have proven ineffective. Pulmonary vein isolation (PVI), in which
circumferential ablation is performed around the ostia of the pulmonary vein - left atrial
junctions, is the standard ablation approach internationally. Single-procedure success rates
(1y, freedom from AF, off anti-arrhythmics) for patients with paroxysmal AF is roughly 70%,
and even worse (roughly 50%) for patients with persistent AF.
A number of strategies have been developed to improve outcomes in patients undergoing AF
ablation, particularly in patients with persistent AF. Unfortunately, large prospective
randomized trials (including STAR-AF II, published in NEJM in 2015) have demonstrated a
failure of ancillary ablation techniques to improve AF ablation outcomes relative to PVI
alone.
In a collaborative effort between the Cardiology electrophysiology group and the Trayanova
laboratory (Biomechanical Engineering), investigators have developed a strategy of
patient-specific modeling to identify pro-arrhythmic sites in AF patients that may be
amenable to ablation. In this approach, patients undergo a pre-ablation cardiac MRI with late
gadolinium enhancement, to delineate regions of healthy atrial tissue and regions of scar
(this scan is clinically indicated, and performed currently in patients undergoing PVI for
AF). A novel in silico modeling to determine regions supporting electrical reentry in the
atrium, driving ongoing AF, has been developed by the Trayanova lab. In preliminary studies,
investigators have demonstrated the ability to identify and target these regions with
catheter ablation in patients undergoing PVI.
Investigators would like to conduct a prospective, randomized clinical trial in patients
undergoing ablation for symptomatic persistent AF. All patients enrolled would undergo
standard pre-procedure imaging (LGE-MRI) prior to the day of procedure. Investigators have
developed methodology termed OPTIMA (OPtimal Target Identification via Modeling of
Arrhythmogenesis) to determine, based on non-invasive patient-specific anatomic and tissue
data from late gadolinium enhancement cardiac MRI (LGE-CMR) and simulation of cardiac
electrical function, personalized ablation targets for persistent AF in patients with
fibrotic remodeling.. Patients would be randomized to receiving PVI only versus PVI + OPTIMA
ablation at the time of ablation. Patients would then be followed in standard clinical
fashion at 3m, 6m, and 12m to assess for ablation efficacy and for procedural complications.
Investigators postulate a 20% improvement in freedom from AF with PVI + OPTIMA ablation form
50% to 70% (compared to PVI alone), investigators anticipate that in 1:1 randomization, a
sample size of 80 patients in each arm will yield a power calculation of 80% with an alpha of
0.05. Investigators anticipate that enrollment and 1y clinical follow-up for 160 patients
(total) undergoing AF ablation will require a 4y timeline.
Description:
Background: Atrial fibrillation (AF) is the most commonly encountered clinical arrhythmia.
Symptoms arising from AF are common, and may include palpitations, fatigue, exertional
intolerance, and angina. Relief of symptoms is achieved by rhythm control strategies
including drug therapy and catheter ablation for AF. Catheter ablation is more effective than
drug therapy, is the preferred method of rhythm control for patients in whom drug therapy has
been ineffective or intolerable, and is increasingly used as first-line therapy. However,
success rates for AF control after catheter ablation are imperfect, with AF recurrence rates
between 30 - 50% at 1 year. Currently, catheter ablation focuses almost exclusively on
electrical isolation of the pulmonary vein (PV) ostia (PV isolation; PVI), to eliminate
triggering activity from ectopic foci in the PVs that, in the vast majority of patients,
initiate AF. A number of strategies have been developed to improve outcomes in patients
undergoing AF ablation, particularly in patients with persistent AF. Unfortunately, large
prospective randomized trials (including STAR-AF II, NEJM 2015) have demonstrated a failure
of ancillary ablation techniques to improve AF ablation outcomes relative to PVI alone. The
failure of PVI and ancillary ablation techniques to deliver reasonable outcomes is
exacerbated in patients with persistent AF (PsAF), who develop fibrosis in the atria. These
patients have AF ablation outcomes that are demonstrably worse than those seen in patients
with persistent AF. Investigators have recently developed methodology (termed OPTIMA, OPtimal
Target Identification via Modeling of Arrhythmogenesis) to determine, based on non-invasive
patient-specific anatomic and tissue data from late gadolinium enhancement cardiac MRI
(LGE-CMR) and simulation of cardiac electrical function, personalized ablation targets for
persistent AF in patients with fibrotic remodeling. These targets, which are determined off
line pre-procedure, are then used to steer patient treatment. This technology is intended to
make the procedure accurate and efficacious in persistent AF patients with fibrosis, and to
eliminate the need for repeat ablations, offering long-term freedom from AF.
Hypothesis: In patients undergoing ablation for the treatment of persistent AF, using the
OPTIMA approach and performing PV isolation during ablation for AF will improve outcomes
compared to performing PV isolation alone.
Importance: In United States, Center for disease control estimates that 2.7-6.1 million
people suffer with AF and expects this number to increase with the aging population. Ablation
for AF is performed at increasing rates, and in certain population (eg patients with
paroxysmal AF) is moderately effective. Even in optimal patients, however, the rate of AF
recurrence following apparently successful PV isolation is high (2017 Heart Rhythm Society
(HRS) Consensus statement on AF ablation). Strategies to improve AF ablation outcomes should
result in improved patient health (symptom elimination), lower patient risk (reduction of the
number of patients undergoing redo ablation procedures), and reduced economic burden from
healthcare costs (reducing post-ablation treatment for AF, including redo ablation
procedures). Furthermore, demonstration of the arrhythmogenic propensity of fibrotic
remodeling in patients with persistent AF will add to investigators' collective understanding
of the fundamental mechanisms underlying AF initiation and perpetuation.
Objectives: The goal of this study is to test the efficacy of the OPTIMA approach for
determining the optimal ablation targets in patients with persistent AF and fibrosis, and to
demonstrate that elimination of AF-perpetuating sources in the fibrotic substrate, in
conjunction with PVI, during AF ablation improves rate of AF-free survival at 1 year compared
to patients undergoing standard PVI alone.
Study Procedures
This study is a prospective, randomized, single-blind study of patients undergoing either
standard PV isolation or PVI+OPTIMA ablation for the treatment of symptomatic persistent AF.
Patients referred for ablation for symptomatic persistent AF will be considered for
enrollment. Patients will have cardiac function and anatomy assessed by echocardiography in
the six-month window prior to ablation (routine care). Patients will have a baseline rhythm
assessment with Ziopatch to quantify pre-ablation AF burden. All patients will undergo
pre-procedure LGE-CMR to delineate atrial anatomy (routine care). MRI scan will be obtained
in sinus rhythm; patients will be cardiovertered before MRI if the patients are in atrial
fibrillation. All patients will be anticoagulated according to standard clinical guidelines.
Patients with a CHADS VASc score of 2 or greater will be systemically anticoagulated in the
pre-, peri-, and post-procedural periods. Patients not otherwise requiring long-term systemic
anticoagulation will be anticoagulated during the peri- and post-procedural intervals
(minimum of 2 months systemic anticoagulation following ablation). Finally, any patient
undergoing cardioversion to facilitate MRI acquisition will receive systemic anticoagulation
for a minimum of three weeks prior to cardioversion and/or have a Transesophageal
Echocardiography (TEE) performed prior to cardioversion. After CMR acquisition, patients will
be randomized to PVI versus PVI+OPTIMA ablation. Pre-procedural TEE is not required for
patients presenting in Sinus rhythm and on uninterrupted anticoagulation for at least 3
weeks, regardless of CHADS VASC score. Patients presenting either in atrial fibrillation or
not on uninterrupted anticoagulation will undergo a pre-procedural TEE, again independent of
CHADS VASC score. All patients will undergo AF ablation with PVI (routine care). At the
outset of the procedure, electroanatomical mapping of the Left Atrium (LA) will be performed
to facilitate clinical ablation, with typically 1000 datapoints captured in the LA. PVI will
be performed in all patients. In the PVI+OPTIMA arm, sites identified as targets by
pre-procedure modeling will subsequently be targeted for ablation (research procedure, during
routine ablation procedure). Additional ablation of other atrial targets (lines, complex
fractionated electrograms) will be discouraged in both arms, but ultimately targeting such
areas will be left to the discretion of the operator. In both arms, PV isolation will be
assessed by entrance block. OPTIMA lesions will be assessed by both minimum of 50 percentage
reduction in all local Electrograms (EGM), as well as non-capture by high output pacing at
the site of target ablation. Operator will have the discretion not to ablate certain OPTIMA
targets for safety reasons including but not limited to avoid critical structures and patient
hemodynamic status. Operator will document the reason for not ablating all OPTIMA targets in
the case report forms. Patients will be maintained on anti-arrhythmic drugs during the
healing phase (3m) following ablation, with medication changes (cessation, up-titration, or
drug changes) made at the discretion of the treating physician. All patients will be followed
clinically after ablation in the standard fashion (routine care), including visits at 3, 6,
and 12 months, with AF burden assessment with Zio patch at each visit.
Study duration and number of study visits required of research participants.
Investigators anticipate that this study will take 3 years for enrollment and 1 year clinical
follow-up. Patient encounters include a pre-procedure clinical assessment and rhythm
assessment(zio patch) in outpatient Electrophysiology (EP) Clinic; cardiac MRI in the week
prior to ablation; the ablation procedure itself; overnight monitoring in the hospital
following ablation; clinical assessment at 3, 6 and 12 months after ablation, including
rhythm assessment with Ziopatch at each visit. Additional rhythm assessment with Ziopatch
will be performed for patients with clinical symptoms of atrial fibrillation. Of note, these
encounters are all part of current clinical practice in patients undergoing AF ablation.
Blinding, including justification for blinding or not blinding the trial, if applicable.
Patients will be blinded to the ablation strategy (PVI only versus PVI+OPTIMA ablation).
Operators by necessity cannot be blinded to the ablation strategy, as patients are performing
the ablations.
Risks
All patients in the study will undergo standard PVI, with its attendant risks. These risks
include those related to general anesthesia, risk of stroke, risk of cardiac puncture, risk
of esophageal injury, risk of other cardiac damage, and risk related to vascular access.
Patients randomized to Re-entrant Driver (RD) ablation will undergo standard PVI (with risks
listed above). During ablation, operators will target additional sites for lesion delivery.
This is anticipated to lead to increases in procedure time, left atrial dwell time, number of
lesions delivered, and increased radiation exposure.
Investigators anticipate that the additional risk to patients undergoing OPTIMA ablation (in
addition to PVI) will be minimal. Typical PVI involves lesion delivery at 50-60 sites. In
investigators early experience, patients have between 2-5 AF sources in the fibrotic
substrate that OPTIMA targets. Thus, the additional ablation in each patient is likely to be
a small component of the total ablation lesion set; additional risks are a function largely
of time manipulating catheters and ablating in the left atrium. This added time will be
minimal.
Radiation exposure Patients undergoing standard ablation procedure is estimated to be
estimated to have 0.700 rems of radiation exposure due to fluoroscopy. Patients undergoing
optima ablation are estimated to be exposed to additional 0.14 rems of radiation.
Risks of ECG patch monitor Clinical trials have so far shown the Zio XT is well-tolerated in
the overall population. The risks associated with Zio patch include mild discomfort and/or
allergic reaction to sticky pads used to attach the Zio patch.
There is a possibility that while reviewing one's patch monitor results investigators may
detect a heart rhythm abnormality that investigators did not expect to find. Investigators
will contact the patient and inform the patient and his/her clinical cardiac
electrophysiologist regarding the result. The costs for any care that may arise in reaction
to this incidental finding will not be covered by this research study.
Steps taken to minimize the risks.
Currently investigators employ a number of risk mitigation strategies, including the use of
electroanatomical mapping systems to minimize radiation exposure, the use of systemic
anticoagulation to minimize Cardiovascular Accident (CVA) risk, the use of ultrasound guided
vascular access to minimize vascular complication rates. All of these strategies will be
employed for all study participants. In addition following monitoring procedures will be
followed during the study.
- Data quality will be monitored routinely and reviewed monthly for missing data,
inconsistent data, data outliers, and potential protocol deviations.
- All adverse events and protocol deviations will be notified to PI.
- In order to minimize risks to patients enrolled in the study all adverse events will be
discussed in the monthly cardiac electrophysiology complications conference. This
conference will serve as the Global safety monitoring committee.
- All Attending physicians participating in this study including David Spragg MD, Ronal
Berger MD, Hugh Calkins, MD, Joseph Marine, MD and Hiroshi Ashikaga MD, PhD attend this
conference.
- All adverse events will be assessed in terms of relationship to device, relationship to
procedure, severity, subsequent intervention required, and resolution status.
Benefits
Strategies to improve AF ablation outcomes should result in improved patient health (symptom
elimination), lower patient risk (reduction of the number of patients undergoing redo
ablation procedures), and reduced economic burden from healthcare costs (reducing
post-ablation treatment for AF, including redo ablation procedures). Furthermore,
demonstration of the importance of elimination of the arrhythmogenic propensity of the
fibrotic substrate in patients with PsAF will add to investigators collective understanding
of the fundamental mechanisms underlying AF initiation and perpetuation.
