The Added Benefit of Closed Loop Stimulation: The AVAIL CLS/CRT Study

Describe the main objectives of the AVAIL CLS/CRT Study. In addition, please describe the Closed Loop Stimulation (CLS) technology from BIOTRONIK. The AVAIL Study s main objective is to demonstrate safety and effectiveness of biventricular pacing over conventional right ventricular pacing in patients with persistent, symptomatic atrial fibrillation (AF) undergoing atrioventricular (AV) node ablation. There was a prior study with a similar design called PAVE; this study was the first to demonstrate that biventricular pacing is superior to RV apical pacing in a similar patient population. In the AVAIL Study, we are going to broaden the findings of PAVE and explore the additional benefits of an algorithm developed by BIOTRONIK called CLS, which stands for Closed Loop Stimulation. We are going to investigate how biventricular pacing affects synchrony of ventricular contraction after AV nodal ablation this has not been studied until now. CLS is an algorithm that helps the pacemaker to determine the appropriate heart rate for a given metabolic need, such as exercise. There are multiple algorithms and sensors that have been developed over the years and incorporated into pacemakers that gage patient heart rate based on the patient s level of exercise. As you know, when a healthy person exercises, their heart rate goes up. Sometimes, when a pacemaker is implanted, it has to take over the normal function of the heart which we call pacemaker dependency and the device adjusts all heart rates and rhythms. For example, the heart rate may slow while the patient is asleep or increase while the patient is exercising. The pacemaker manages the heart rate, and there are multiple algorithms that have been developed to help it do that the majority of which measure the amount of body motion exerted by a patient to extrapolate a change in heart rate, which isn t always physiologic. BIOTRONIK has developed a self-learning algorithm that reestablishes heart rate by integrating into the inotropic arm of the cardiovascular control system (how hard the heart contracts or pumps) by measuring changes in intracardiac impedance as a reflection of the current contractility level. The pacemaker can measure the impedance over a period of time and compare the relative changes in contractility between rest and exertion. The pacemaker interprets an increase in contraction dynamics to mean a need for increased heart rate the harder the heart beats, the faster it should beat as well. This essentially allows the pacemaker to tie into the autonomic nervous system and respond appropriately to various metabolic demands. Conversely, traditional devices can only guess what the autonomic nervous system is demanding based on some secondary parameter, such as body motion, and they are often under-responsive. Since every patient has different exercise tolerances and various degrees of cardiovascular disease, it is important that the device be able to adjust to each unique patient. This is a self-learning clinical system that receives constant feedback from the heart, allowing it to automatically and optimally adjust over time to changes in exercise tolerance and disease state. Therefore, this algorithm can provide probably the most physiologic response for the most levels of exercise. What is really interesting is that through this mechanism, the CLS technology responds to emotional stress there are no pacemakers in the world that can respond to emotions and stress, yet as healthy individuals, you and I have a metabolic need for increased heart rates when we experience fear or frustration. Now, let s go back to the AVAIL Study. Patients with uncontrolled atrial fibrillation are frequently subjected to a common treatment procedure, AV node ablation, which allows to drastically slow down ventricular rate and avoid a number of unwanted consequences of rapid AF. Unfortunately, though, a consequence of AV node ablation is that the patient then becomes dependent on the pacemaker. You can imagine that for these patients the pacemaker needs to have the most physiologic response to different autonomic stressors; the CLS algorithm is likely to provide for this. AV node ablation is a relatively old procedure for uncontrolled AF. Historically after AV node ablation, patients received a standard pacemaker and were paced from the right ventricle. It turns out that many patients do better with that, although some do not and some do actually get worse (worsening contractility, heart failure, etc.). Relatively recently, biventricular pacing which is when both the right and left ventricles are paced was shown to be beneficial for certain subsets of heart failure patients and superior to RV pacing only. In the AVAIL Study, we re going to further explore the benefits of biventricular pacing in patients with uncontrolled AF and see if fine tuning of the heart rate response with CLS confers an additional benefit. Describe the design of this study, including the three study groups that will be assigned. Group 1 will be implanted with a dual chamber pacemaker capable of closed loop stimulation (Protos DR/CLS). Currently there are no biventricular pacemakers on the market available with the CLS algorithm. Therefore, we will use a standard dual chamber pacemaker for biventricular pacing, which is possible in patients with AF. Group 2 will be implanted with a standard biventricular pacemaker (Stratos LV). Group 3 will receive right ventricular pacing only with Stratos LV to be reprogrammed to biventricular pacing at the end of the study. The CLS algorithm is not approved for biventricular pacing yet. One of the goals of this study is to show that it has enough benefit for heart failure patients. How many patients are enrolled so far? When do you expect to find out the results of this study? At the time of the Heart Rhythm meeting, there were 25 or 26 patients enrolled. Currently, though, we have 33 patients enrolled, and 11 of 30 sites are open to enrollment. We plan to enroll approximately 265 patients total. The patients will be followed for six months, and assuming that the enrollment will go at the current rate, we should be hopefully done with enrollment in a year or so. We hope to have some preliminary results in six months; however, final data analysis won t be available until a year and a half to two years from now. What has been the experience of your patients in the trial so far? Currently there are five patients from my institution in the study. Patients receiving biventricular pacing are doing very well compared to right ventricular pacing only. It seems that CLS allows for wider heart rate distribution, but we need to confirm that this will translate into additional clinical benefit. Is there anything you would like to add? First of all, I hope that we will have a successful trial. Future patients requiring AV nodal ablation for control of their AF will likely benefit from biventricular pacing.The addition of CLS technology will allow for a more physiologic heart rate response in patients who require it the most, and as I have mentioned in the beginning, we are returning to them the ability to have an "emotional heart" by providing heart rate response to emotions with the unique pacing algorithm. For more information, please visit: www.biotronik.com www.protos-cls.com