Clinical Trial Update: Interview with Shephal K. Doshi, MD

Describe the ENABLE trial. What is the purpose of the trial? The ENABLE (ENdoscopic ABlation using Light Energy) trial is a prospective, randomized, pivotal, multicenter, IDE clinical trial using an investigational endoscopically-guided laser balloon catheter (CardioFocus, Inc.) for the treatment of atrial fibrillation (AF). The study objective is to demonstrate the safety and effectiveness of this visually-guided endoscopic ablation system (EAS) in participants presenting with recurrent, paroxysmal, symptomatic AF by creating electrical isolation of the pulmonary veins (PVI). Currently there are no catheters approved in the United States for the ablation of AF. This trial is designed to assess the efficacy and safety of this new technology, as well as measure freedom of documented atrial fibrillation symptoms for 1 year post treatment. What are the start and end dates? When did enrollment begin? How many patients do you expect to treat? The study has already begun enrollment. We enrolled and performed the first visually-guided laser balloon ablation for AF in the United States in mid March of this year. There will be up to 20 study sites. Approximately 180 patients will be randomized to laser balloon ablation versus antiarrhythmic drug therapy (AAD). Patients who develop AF on AAD therapy can cross over to EAS ablation. Again, the primary effectiveness endpoint is freedom of documented atrial fibrillation symptoms for 1 year post treatment. Describe endoscopic catheter ablation with the use of the investigational video camera. As real-time intracardiac imaging for ablation has been clinically limited to ultrasound technology, we have had to rely on image integration with CT scan/MRI/fluoroscopy and 3D mapping tools to visualize the areas where we ablate. However, in this study we are investigating the use of a 500 micron (2 French) diameter endoscopic camera with a wide field of view. It provides a direct view into the left atrium on the front, side and part of the back of the balloon. Balloon contact with the tissue can then be observed. Using these live images, we can adjust the actual location of the projected energy, essentially aiming the laser. In this study, the EAS catheter is seated and inflated at the ostium of the PV. An aiming beam is displayed onto the surface, and using the endoscope, is adjusted to desired locations. The laser is then discharged over this surface, creating arcs of ablation. The laser energy for the system is delivered through a diode laser system. PVI is documented in all veins at 30 minutes post ablation. Describe the first case treated at your institution. How long did the case take? The first case was a man in his late 50s who had been experiencing symptomatic arrhythmia for over a year. He was diagnosed with paroxysmal atrial fibrillation. He had tried and failed antiarrhythmic drugs, and continued to be very symptomatic, having a few episodes a day that lasted several minutes at a time to hours. His symptoms were primarily palpitations, fatigue, difficulty sleeping, and occasional lightheadedness. Previously he had been a very active man, but was now having breakthrough arrhythmias on three medications. He was also on anticoagulation with warfarin. All these things significantly affected his quality of life. Therefore, he was looking for a more curative approach to treating his atrial fibrillation. We discussed with him the different options of catheter ablation and the risks associated with it, including but not limited to: stroke, pulmonary vein stenosis, and injury to the esophagus. He had done his own research and was also concerned about the risks associated with RF spot ablation catheters, including thrombus formation and inconsistent lesion formation. We discussed with him an alternative approach, specifically the ENABLE trial with the use of an endoscopically-guided laser balloon, with direct visualization of the surface to have laser ablation. The patient was very interested and enrolled in the study. He was randomized to the treatment (laser ablation) arm. The procedure, from the point when we started to laser to when we finished, including a 30-minute waiting period to document persistent PVI, took a little over three hours. Who can participate in this trial? The ENABLE trial is geared for patients between the ages of 18 and 65. It is designed for symptomatic paroxysmal to recently persistent AF patients. Specifically, we are looking for patients who have trigger-based AF. Most experts agree that the majority of paroxysmal AF cases are related to triggers from the pulmonary veins. The focus of the ENABLE trial will be to study how PVI using this visually-guided endoscopic ablation system will affect this population of patients. Patients with chronic or permanent AF are not being studied in the ENABLE trial, as their AF is thought to have a more significant role of substrate changes; it is unknown whether PVI can provide significant efficacy. In addition, please describe the PROTECT AF study. What is the objective of this trial? How many patients have been enrolled so far? We are very active in the PROTECT AF study, which stands for WATCHMAN^® Left Atrial Appendage System for Embolic PROTECTion in Patients with Atrial Fibrillation (PROTECT AF). This is another prospective, randomized, pivotal, multicenter, IDE study that deals with the implantation of the WATCHMAN left atrial appendage (LAA) system (Atritech Inc.). The study compares the WATCHMAN device to long-term warfarin therapy, demonstrating the treatment arm is non-inferior to the control arm. There are well over 400 patients enrolled (as of April 2007). It is designed to demonstrate the safety and effectiveness of this LAA occluder implant in patients with non-valvular paroxysmal, persistent or permanent AF who require treatment for potential thrombus formation, are eligible for warfarin therapy, and have risk factors for embolic complications like stroke. A CHADS stroke risk stratification score of 1 or greater is required for the patient to be eligible. We have known for years that warfarin, although previously the only real option proven to reduce the risk of stroke in AF patients (by 70%), is not a perfect answer. There is an increased risk of bleeding including intracranial hemorrhage, variability and lability of anticoagulation levels, and interactions with many other medications. Many patients have a reduced quality of life because of this; therefore, we continue to search for better options for AF patients. A majority of patients with AF and stroke have been shown to have thrombus in the LAA. Therefore, the concept of this trial is to implant an occluder device (in a one-time procedure) at the ostium of the LAA to seal it off. The implant procedure has typically taken us 30 minutes. In a majority of patients, a transesophageal echo done at 45 days post-implant verifies successful occlusion of the LAA, at which time the warfarin is stopped. The follow-up period is up to five years. I believe this trial may also have an enormous impact in the way we manage patients with minimal or asymptomatic AF. If the study results are positive, this could affect millions of people in this country with AF. Are you currently involved with any other clinical trials? Which ones? We are involved in a unique trial involving defibrillation; it is called POWER (Pulse width Optimized Waveform Evaluation tRial). All modern ICDs utilize a biphasic waveform for defibrillation. It has been clearly shown that biphasic waveforms reduce the energy required for internal defibrillation of the heart. Not all biphasic waveforms are the same, however, and there is no consensus on which pulse widths are best for defibrillation. Recent studies have also shown that some patients may respond with lower defibrillation thresholds (DFTs) from optimized waveforms based on the tissue membrane constant. The POWER trial is unique in that it is a multicenter study in which patients are randomized to different fixed pulse width waveforms to identify the membrane constant that provides the lowest DFT. This study will hopefully address a concept that we all sometimes take for granted: defibrillation. By developing a better understanding of how to optimize and lower patient DFTs, we can not only have quicker charge times and shock delivery with lower battery drain, but perhaps more importantly, we can potentially improve safety margins, especially for patients with changing or high DFTs, thereby improving safety. There are 50 patients enrolled at the time of this interview (April 2007). When do you expect to see study results for the POWER trial? We hope to complete enrollment by the end of this calendar year. I believe by early next year we should have the trial results. The author can be reached via email at skdoshi@pacificheart.com For more information about the ENABLE trial, please visit: www.cardiofocus.com For more information about the PROTECT AF study, please visit: www.atritech.net