FDA panel supports premarket approval of implantable pulse generator for HF
The Circulatory Systems Device Panel of the FDA today voted 12-1 and 11-2, respectively, in favor of the safety and efficacy of an implantable pulse generator, based on available data, to support a premarket approval application for use in patients with HF.
The panel also voted 12-0, with one abstention, that the benefits of the device outweigh the risks.
The Optimizer Smart implantable pulse generator (Impulse Dynamics) is a breakthrough device that delivers cardiac contractility modulation therapy to the right ventricular septum of the heart in patients with moderate to severe chronic HF, according to the FDA’s executive summary memorandum.
Industry and FDA members presented information during the advisory committee meeting on the safety and efficacy of the implantable pulse generator for this population and also discussed indications for use, benefit and risk, and a post-approval study.
The Optimizer Smart device was previously recognized by the FDA as a breakthrough device.
“The device is considered to be a breakthrough device [in 2015] and is indicated to provide cardiac contractility modulation, otherwise called CCM, for class III heart failure patients who are not responding to optimal medical therapy,” Richard A. Lange, MD, president of Texas Tech University Health Sciences Center El Paso, dean of the Texas Paul L. Foster School of Medicine and panel chairperson, said during the presentation.
The proposed indication for cardiac contractility modulation (CCM) therapy through an implantable pulse generator was for patients with NYHA class III or ambulatory class IV HF who are symptomatic after guideline-directed medical therapy, a normal sinus rhythm with left ventricular ejection fraction between 25% and 45% and do not have an indication for cardiac resynchronization therapy to improve quality of life, exercise tolerance and functional status.
“Cardiac contractibility is substantially different from pacing,” Ingmar Viohl, PhD, lead reviewer and senior staff fellow of the implantable electrophysiology devices branch in the division of cardiovascular devices in the office of device evaluation at the FDA, said during the presentation. “The reason for that is it’s delivered during the total refractory period.”
The device received a CE mark in 2016 and more than 3,000 devices have been implanted outside of the United States, Daniel Burkhoff, MD, PhD, medical director of Impulse Dynamics, said during the presentation.
“One of the key safety features of a CCM delivery algorithm is to ensure that the signal is never delivered on a T wave, a feature which has been validated through more than 8,400 patient-hours of Holter monitoring in 186 patients,” Burkhoff said.
Vote on safety, efficacy
“I came to the meeting prepared to vote no, and, in listening to the material that was presented today, I felt that I should vote yes because given the lower bar that needs to be satisfied under this device approval pathway, I thought that, that had to be considered,” panel member John Hirshfeld Jr., MD, emeritus professor CE of medicine at University of Pennsylvania Perelman School of Medicine, said after the vote. “I also came away convinced that somewhere out there, there is a population of people who actually benefit from this device. We don’t know who they are, but I don’t think that it would be right to stop investigation of this device and prevent it from ultimately being available to people who would really benefit from it.”
Some panel members who voted no cited a lack of long-term evidence on use of the device.
“The data I have seen are short-term and marginal at best,” Vasilios Papademetriou, MD, director of cardiovascular medicine at VA Medical Center in Washington, D.C., said after the vote. “I abstained for the [question about benefit outweighing risk] because I couldn’t decide if it was beneficial or not.”
Safety and efficacy of the system was assessed in the FIX-HF-5 study, in which researchers assigned patients with HF to receive guideline-directed medical therapy (n = 213; mean age, 59 years; 71% men) or CCM therapy (n = 215; mean age, 58 years; 74% men). The primary safety endpoint — defined as a composite event rate of all-cause hospitalizations and all-cause mortality through 50 weeks — occurred in 3.3% in the medical therapy arm vs. 4.9% in the CCM therapy arm. None of the deaths were caused by the implant procedure or the device itself. The rates of events that required invasive treatment or hospitalization were balanced in both groups.
The primary effectiveness endpoint — difference in responder rates between the device and control groups — was 5.9%, with 17.6% in the cardiac contractility modulation therapy group and 11.7% in the control group. The difference was not statistically significant (P = .093).
The system was also assessed in the FIX-HF-5C study, which included a similar patient population from the FIX-HF-5 study. In this study, 160 patients were assigned standard of care or standard of care with system implantation. The primary safety endpoint was defined as the percentage of patients assigned the system who had either a device- or procedure-related complication through 24 weeks of follow-up. Nearly 90% of patients were free from complications at follow-up. The primary effectiveness endpoint in the FIX-HF-5C study was mean difference in peak VO2 between both groups at 24 weeks. Researchers added data from nearly 30% of patients from the FIX-HF-5 study when assessing this endpoint. When imputation of zeroes was performed to account for six deaths, peak VO2 was 14.21 ml/kg/min for the control arm vs. 15.04 ml/kg/min for the device arm. Both groups had an original peak VO2 of 15.4 ml/kg/min.
“The totality of evidence supports that CCM therapy is a safe and effective treatment option for these patients with heart failure,” William Abraham, MD, director of the division of cardiovascular medicine and professor of internal medicine, physiology and cell biology at Wexner Medical Center at The Ohio State University, said during the sponsor presentation.
The benefits of the system shown in these studies may be critical to all people involved including the patient.
“The approval of this device would provide an important tool for clinicians, important symptom relief for patients and an effective and safe therapy for symptomatic patients who are not candidates for cardiac resynchronization therapy,” JoAnn Lindenfeld, MD, director of advanced HF/cardiac transplantation and professor of medicine at Vanderbilt University Medical Center, said during the sponsor presentation.
Before using the system, physicians are required to be trained, which involves didactic course work, hands-on interaction, implant training and allied health professional training
“Impulse Dynamics is committed to the continued demonstration of long-term safety and effectiveness of the Optimizer system for the treatment of patients with HF according to the proposed indication for use,” Burkhoff said during the presentation.
A registry for a post-approval study is currently being proposed to collect information from a minimum of 300 patients for 2 years, which will be formatted similarly to approved left atrial appendage occlusion and transcatheter aortic valve replacement registries. Researchers plan to review all-cause mortality and 1- and 2- year mortality assessment compared with the Seattle Heart Failure Model scoring system.
The FDA is not required to follow the recommendations of its advisory committees, but it usually does. – by Darlene Dobkowski
Disclosures: Cardiology Today was unable to confirm relevant financial disclosures at the time of publication.