Clinical Trial Details
— Status: Active, not recruiting
Administrative data
| NCT number |
NCT02825979 |
| Other study ID # |
H16-00617 |
| Secondary ID |
|
| Status |
Active, not recruiting |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
January 2017 |
| Est. completion date |
November 2022 |
Study information
| Verified date |
October 2022 |
| Source |
University of British Columbia |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
The EARLY-AF study is centered on an evaluation of the impact of the early invasive
management of Atrial Fibrillation. The primary goal of the study is to evaluate the clinical
effectiveness of an early invasive approach. Specifically, the investigators are aiming to
evaluate if PVI performed with the Arctic Front cryoballoon is superior to AAD as first-line
therapy in preventing atrial arrhythmia recurrences (arrhythmia related symptoms,
hospitalisations, and health care utilization) and health care utilisation at one year of
follow-up. The aim of the extended follow-up phase of the trial (PROGRESSIVE-AF) is to
evaluate if the initial treatment choice (ablation vs. pharmacotherapy) influences AF disease
progression, as measured by continuous cardiac monitoring. The outcomes of interest are
disease progression, quality of life, and healthcare utilisation.
Description:
Atrial fibrillation (AF) is the most common sustained arrhythmia seen in clinical practice,
affecting approximately 1-2% of the overall population. Contemporary guidelines recommend
AADs as the "first-line" therapy for the maintenance of sinus rhythm. However, these
medications have only modest efficacy at maintaining sinus rhythm. Moreover, these agents are
associated with significant non-cardiac side-effects, as well as the potential for
pro-arrhythmia, heart failure, or organ toxicity. Conversely, the success rate of catheter
ablation in maintaining sinus rhythm is universally superior to that of drug therapy when
AADs have been ineffective, are contra-indicated, or cannot be tolerated. While catheter
ablation has not been definitively proven to improve survival, it has been shown to be
superior to AADs for the improvement of symptoms, exercise capacity, and quality of life.
Why consider early invasive intervention? Given the superiority of ablation over AAD therapy,
it is postulated that early invasive intervention with catheter ablation offers an
opportunity to halt the progressive pathophysiological and anatomical changes associated with
AF. While catheter ablation has not been definitively proven to impact mortality in
unselected patients, there are certain patient groups (e.g. younger patients, those with
newly diagnosed AF, and those with heart failure) who may derive significant benefit from
ablation. In addition, early invasive intervention may result in a significant reduction in
overall health care utilitization.
The evidence supporting "first-line" catheter ablation (i.e. as an initial therapy prior to
AAD) with radiofrequency (RF) energy is promising, but far from definitive. To date three key
studies have been performed. The MANTRA-PAF Study and the RAAFT studies randomized patients
to either first-line ablation or first-line AADs. Despite disparate ablation techniques,
these studies collectively demonstrated an improved freedom from recurrent arrhythmia (37%
reduction in AF recurrence vs. AAD therapy), an improved freedom from symptomatic AF (43%
reduction in symptomatic AF vs. AAD therapy), and a reduction in the overall AF burden (50%
reduction over AAD therapy). While the results of these previous studies suggest that
ablation is more effective than AAD therapy as first-line treatment, a significant proportion
of patients in the intervention group experienced arrhythmia recurrence.
STUDY DESIGN - The study is a multicenter prospective, open label randomized clinical trial
with blinded adjudication of endpoints. Patients with untreated AF will be randomized in a
1:1 ratio to either first-line antiarrhythmic therapy or first-line AF ablation using
cryothermal energy. Randomization will be performed with concealed allocation using permuted
block randomization according to a computer-generated sequence (Dacima, Montreal, Canada). An
independent, blinded statistician will generate the block randomization scheme. Outcomes will
be adjudicated by personnel who are blinded to subjects' randomization status.
FUNDING The EARLY-AF study is funded by a peer-reviewed grant from the Cardiac Arrhythmia
Network of Canada. In addition, the trial is supported by an unrestricted grant from
Medtronic. The funding sources had no role in the design of this study and will not have any
role during its execution, analyses, interpretation of the data, or decision to submit
results.
STUDY POPULATION Patients aged ≥18 years with symptomatic, treatment naïve AF will be
screened for eligibility. At least 1 episode of AF must be documented on 12-lead
electrocardiogram (ECG), transtelephonic monitor (TTM), or Holter monitor within 24 months of
randomization.
INTERVENTIONS All study participants will undergo the implantation of an ICM for the purpose
of arrhythmia monitoring (Reveal LINQ™). The timing of the ICM implant will be no later than
24 hours after AAD initiation ("first-line" AAD group), and no later than 24 hours after the
ablation procedure ("first-line" ablation group). ICM programmed parameters are summarized in
Table 2. Participation in the trial is not possible without an ICM.
Patients randomized to AAD arm will start regular (daily) AAD therapy within 1 week of
randomization. The use of AAD therapy will be based on local clinical practice, and according
to guideline-suggested management for symptomatic patients with paroxysmal AF.4, 5 Suggested
AAD titration and monitoring protocols are provided in Appendix E. During the titration
phase, the ICM data will be reviewed by study personnel on a weekly basis, with AAD therapy
progressively up-titrated to the maximum tolerated dose with a goal of complete AF
suppression. In the event of clinical inefficacy or intolerable side effects, a change to a
second or to a third AAD will be undertaken, insofar as the patient remains within the
blanking period. Once the blanking period has ended, any further changes made to AAD therapy
for recurrence of symptomatic or asymptomatic AF, atrial flutter, or atrial tachycardia would
be considered a primary endpoint.
Patients randomized to catheter cryoablation will undergo the procedure within 2 months of
randomization. Ablation may be performed under conscious sedation or general anesthesia, per
local practice. The 28 mm cryoballoon catheter (Arctic Front Advance, Medtronic) will be
advanced through the steerable sheath into the LA with a 20-mm small-diameter circular
mapping catheter inserted in the central lumen of the CB and used as a guidewire. In
exceptional circumstances the 23-mm cryoballoon may be used for PV diameters <20 mm and based
on physician judgment. Cryoablation with a minimum ablation duration of 3 minutes will be
utilized. Lesions that fail to isolate the vein within 60 seconds (if real-time PV potential
monitoring is feasible) or achieve a temperature colder than minus 35oC after 60 seconds of
ablation should be considered ineffectual and be terminated (except for common ostia).
Thereafter the balloon and/or guidewire should be repositioned and a new lesion delivered.
Once PVI has been achieved a single "bonus" application of 3 minutes will be delivered
following the rewarming phase (to +20oC). Should the operator fail to isolate the PV
(excluding common ostia) after a minimum of 3 attempted cryoballoon applications then focal
ablation with the 8mm cryocatheter targeted to sites of LA-PV breakthrough will be permitted
at operator discretion.
Post therapeutic intervention "Blanking period" In accordance with 2017 expert consensus
statement for reporting outcomes in AF ablation trials, a blanking period of 3 months is
incorporated for both groups.19 The rationale for the post-procedure blanking period is based
on the observation that early recurrences of arrhythmias are common during the initial 3
month period post ablation, and is predicated on the assumption that not all early
recurrences of atrial tachyarrhythmias (AF/AFL/AT) will lead to later recurrences and, as
such, does not necessarily represent treatment failure. Correspondingly the 3-month "blanking
period" in the AAD group will allow for drug titration and optimization. For this group the
ICM data will be reviewed on a weekly basis to guide AAD titration during the blanking
period.
Anticoagulation All patients will be systemically anticoagulated based on perceived stroke
risk as per treatment guidelines and physician discretion. The decision to initiate oral
anticoagulation will be made based on the risk of stroke as per the CCS algorithm. In
patients <65 years of age and with a CHADS score of 0, aspirin alone or no specific
antithrombotic therapy may be considered at treating physician discretion. For those >65
years of age, or with a CHADS score of 1 or more, OAC is strongly recommended. In the
ablation group, all patients with a CHA2DS2-VASc ≥1 will remain anticoagulated with oral
vitamin K antagonists (target INR between 2-3), low molecular weight heparin, or non-VKA oral
anticoagulant medications for a minimum of 1 month prior to ablation and up to a minimum of 3
months post ablation. Thereafter, discontinuation of oral anticoagulation may be considered
for patients <65 years of age and with a CHADS score of 0 (as above).
Minimization of Cross-Over All efforts will be undertaken to avoid patients switching from
their randomized group to the alternate treatment strategy. However, patients with documented
symptomatic arrhythmia recurrence may "change treatment strategy" (e.g. from AAD to ablation,
or vice versa) if the arrhythmia event occurs outside the 90-day blanking period (i.e.
constitutes a primary endpoint for the study). A "cross-over" will be defined if the patient
changes treatment strategy within the blanking period or in the absence of documented AF.
For patients to "change treatment strategy" from the AAD group to the ablation group or vice
versa, the symptomatic sustained arrhythmia recurrence must occur outside the blanking
period. In the AAD group, recurrence must occur despite a therapeutic dose of AAD therapy
(defined as flecainide >50 mg BID, sotalol >80 mg BID, or propafenone >150 mg BID, or
dronedarone 400 mg BID). The recurrence should be of sufficient clinical severity to warrant
the performance of an ablation procedure, as per standard clinical practice. Prior to
permitting a patient to "change treatment strategy", an independent committee will review the
rationale for change, the medication profile (to ensure adequate AAD dosing), and the
arrhythmia episodes (which will have been independently adjudicated by the clinical events
committee). Following this review, a change in treatment strategy may be permitted if the
pre-specified criteria were met. If the patient is changing to ablation, the procedure should
preferentially occur after the conclusion of the study follow-up but can occur sooner based
on clinical necessity. The ablation procedure performed will preferably be a
cryoballoon-based PVI (as outlined above).
ASSESSMENTS All patients will be followed for a minimum of 12 months after the index ablation
procedure or medication initiation. This duration is based on the 2017 expert consensus
statement for reporting outcomes in clinical trials of AF ablation, as well as the knowledge
that most recurrences transpire during the first year after ablation.
Table 3 details the planned visits and procedures. For both groups, a one-week post treatment
telephone call will occur followed by scheduled visits at 3, 6, and 12-months from index
ablation procedure or medication initiation. A clinical evaluation and ECG will be performed
at each of the scheduled clinical encounters. A specific patient interview will be conducted
at each clinical visit to ascertain symptomatic AF. Information regarding disease specific
HRQOL, generic HRQOL and an AF symptoms score will be assessed at each follow-up visit. In
addition, information regarding health care resource use will be prospectively collected
(emergent acute care visits, emergency department visits, hospitalizations, cardioversions,
re-ablation, and planned/unplanned follow-up visits, and medication usage).
Automatic transmissions from the ICM will be obtained on a daily basis. In addition, we have
instructed patients to identify symptomatic episodes through the use of the loop recorder's
patient activator
Primary outcome - Time to first recurrence of symptomatic or asymptomatic AF, atrial flutter,
or atrial tachycardia (AF/AFL/AT) documented by 12-lead ECG, surface ECG rhythm strips,
24-hour ambulatory ECG (Holter) monitor, or on ICM between days 91 and 365 following AAD
initiation or AF ablation.
Secondary outcomes are listed in Table 4 of the Supplementary Appendix. These outcomes focus
on AF progression ("time to first episode of persistent AF (>7 days)") and AF burden ("% time
in AF"), including examining the relationship between AF burden and healthcare utilisation,
and the relationship between AF burden and HRQOL.
