Four Electrophysiology Trials to Watch

For clinicians interested in emerging developments in electrophysiology, Cleveland Clinic’s Section of Cardiac Electrophysiology is a good place to keep an eye on these days. The section’s staff are playing lead roles in at least 10 recent or ongoing major clinical trials in various aspects of the subspecialty. This article profiles the essentials of four of those studies.

STOP AF First

Results of this multicenter randomized trial (NCT03118518) were presented in a late-breaking clinical trials session in August at the virtual European Society of Cardiology Congress 2020. [Editor’s note: The study was since published in full in the New England Journal of Medicine: nejm.org/doi/full/10.1056/NEJMoa2029554.] They showed that initially treating symptomatic paroxysmal atrial fibrillation (AF) with cryoballoon ablation to isolate the pulmonary vein is more effective in maintaining freedom from arrhythmias than antiarrhythmic drug therapy — and it entails a low risk of complications.

“Improvements in the safety and efficacy of cryoballoon catheter ablation have increased interest in this therapy for atrial fibrillation,” says the study’s national principal investigator (PI), Oussama Wazni, MD, Section Head of Cardiac Electrophysiology at Cleveland Clinic. “This prospective trial provides good evidence that it’s a reasonable first-line option.”

STOP AF First was prompted by the fact that while there is plenty of supportive data for catheter ablation as second-line treatment for AF, few randomized controlled trials have evaluated it — particularly cryoballoon catheter ablation — as first-line therapy.

The trial involved 203 patients with symptomatic paroxysmal AF at 24 U.S. sites. Patients were randomized to pulmonary vein isolation with cryoballoon ablation (n = 104) or to antiarrhythmic drug therapy (n = 99). All underwent ECG monitoring at baseline and at one, three, six and 12 months. The primary efficacy endpoint was freedom from treatment failure at 12 months, defined as any of the following: acute procedural failure; need for subsequent AF surgery or left atrial ablation; documented AF, atrial tachycardia or atrial flutter after 90 days; cardioversion after 90 days; and class I or III antiarrhythmic drug use after 90 days (ablation arm only).

Freedom from treatment failure at 12 months was achieved by 75% of patients in the cryoballoon ablation group versus 45% of patients in the antiarrhythmic drug therapy group (P < 0.0001 for the difference).

Only two patients in the cryoballoon ablation arm had a serious adverse event (one significant pericardial effusion, one myocardial infarction), representing a 1.9% incidence of serious adverse events — significantly lower than the prespecified safety performance goal of < 12% (P < 0.0001).

“STOP AF First found that this catheter intervention is safe and effective for symptomatic paroxysmal AF without the requirement that patients be drug-refractory,” Dr. Wazni concludes. “If approved for first-line use, it could provide an important therapy option in this setting.”

OPTION

The multicenter OPTION trial (NCT03795298) is investigating whether left atrial appendage (LAA) closure with the Watchman FLX™ device is a reasonable alternative to oral anticoagulation following percutaneous catheter ablation for high-risk patients with nonvalvular AF.

“We know patients may continue to have some atrial fibrillation following an ablation procedure, and no large prospective trials have assessed the safety of discontinuing oral anticoagulation after an apparently successful ablation,” says Walid Saliba, MD, Medical Director of Cleveland Clinic’s Atrial Fibrillation Center and Cleveland Clinic’s PI for the OPTION trial (Cleveland Clinic’s Dr. Wazni serves as global PI for the multicenter trial). As a result, guidelines recommend that patients continue oral anticoagulation after catheter ablation based on their stroke risk profile.

To determine whether some patients might be liberated from this requirement, the prospective OPTION trial aims to randomize 1,600 patients from 93 centers in the U.S., Europe and Australia to one of two post-ablation management strategies:

• Watchman FLX implantation with a modified post-implant drug regimen
• Standard oral anticoagulation therapy for the duration of the trial

Efficacy will be assessed as a composite of stroke, all-cause death and systemic embolism over 36 months, with nonprocedural bleeding over 36 months serving as the primary safety outcome and major bleeding as a secondary outcome. Watchman therapy will be assessed for noninferiority in terms of efficacy and major bleeding and for superiority in terms of nonprocedural bleeding. Study completion is by late 2024.

“If the findings are positive,” Dr. Saliba says, “this study will expand the indication for LAA closure with Watchman and give high-risk ablation patients the option to discontinue oral anticoagulation by having the device implanted at the time of AF ablation or shortly after.”

Parallel Mapping for Ventricular Tachycardia

Catheter ablation of scar-mediated ventricular tachycardia (VT) is helpful in reducing the frequency of implantable defibrillator (ICD) therapies, including ICD shocks. However, the procedure is associated with an unacceptably high recurrence rate (~30% after 12 months). This is partly due to suboptimal mapping methods for identifying the critical VT sites during sinus rhythm, which often results in insufficient ablation of critical sites and unnecessary ablation of other sites not involved in VT.

The recent international PHYSIO-VT study showed that ventricular mapping during activation from multiple activation directions can enhance the accuracy of mapping and targeting critical VT sites in comparison to standard mapping methods during sinus rhythm. “This method helps reveal additional sites that may be responsible for VT,” says PHYSIO-VT lead author Elad Anter, MD, Associate Section Head of Cardiac Electrophysiology and Director of Cleveland Clinic’s VT Program.

To build on these findings, Cleveland Clinic recently launched a study, Parallel Mapping for Ventricular Tachycardia (NCT04477499), that uses a new mapping algorithm that may improve the workflow and efficacy of ventricular mapping during activation from multiple directions. The algorithm, developed by Biosense Webster, allows creation of simultaneous maps during activation from different directions. “This investigation is a natural progression of the PHYSIO-VT study,” explains Dr. Anter. “Its goal is to simplify the process of mapping while retaining the highest possible accuracy for identifying critical VT sites that can then be targeted with ablation.”

The prospective single-center study will include 30 patients with scar-mediated VT refractory to medication therapy who are referred for catheter ablation. Ablation in these patients will be guided by findings derived from mapping the ventricle from multiple directions. The primary endpoint is freedom from VT recurrence. Secondary outcomes are freedom from ICD shocks as well as reduction in mapping time and ablation time relative to historical controls. Results are expected at the end of 2022.

SyncAV Post-Market Trial

This large post-marketing study (NCT04100148) is designed to determine whether cardiac resynchronization therapy (CRT) devices programmed with SyncAV software ON have improved long-term CRT response relative to devices programmed with conventional CRT settings (fixed atrioventricular delay).

The prospective multicenter study will enroll 1,400 patients with heart failure who are scheduled to receive a new CRT implant or an upgrade from an existing ICD/pacemaker implant. Two to six weeks after successful implant, patients will be randomized on a 1:1 basis to one of the two programming options above. QRS duration and other rhythm measurements will be collected through 12 months of follow-up.

The primary outcome measure is reduction in left ventricular end systolic volume from baseline to 12 months. Secondary outcomes include the percentage of CRT responders as well as results on the primary and secondary outcomes specifically in female patients. Trial completion is expected in 2023.

The algorithm behind SyncAV was developed at Cleveland Clinic, and Cleveland Clinic electrophysiologist Niraj Varma, MD, PhD, serves as this study’s international PI.

“SyncAV takes the concept of ‘fusion pacing’ to the next level by allowing us to program the patient’s pacemaker for the optimal combination of their heart’s own natural rhythm with customized pacing support to deliver the greatest possible resynchronization therapy,” notes Daniel Cantillon, MD, who serves as the study’s local PI at Cleveland Clinic.