Dr. William Abraham talks with EP Lab Digest about a new study evaluating the safety and efficacy of the OPTIMIZER® System (Impulse Dynamics N.V.). Dr. Abraham is the Principal Investigator of the FIX-HF-5B study, Professor of Internal Medicine and Physiology and Cell Biology, Chair of Excellence in Cardiovascular Medicine, Director of the Division of Cardiovascular Medicine, and Deputy Director of the Davis Heart & Lung Research Institute in Columbus, Ohio.
Tell us about Impulse Dynamics’ new Optimizer study, the FIX-HF-5B. What are the primary goals for this follow-up study?
The primary goals of the FIX-HF-5B study are to confirm observations made in the FIX-HF-5 study, and in particular, to confirm the benefits of Cardiac Contractility Modulation (CCM) in the group of patients that emerged as the high responder group in the FIX-HF-5 study. Specifically, this group of patients was characterized as having NYHA class III heart failure and mild to moderate reduction in left ventricular ejection fraction.
When did enrollment begin? When is the expected completion?
We’ve been enrolling patients now for the last three to four months. The study start date was April 2011, and the estimated study completion date is October 2012.
How many patients do you expect to enroll, and at how many sites?
The estimated total enrollment is 230 patients, at up to 30 sites.
How does Cardiac Contractility Modulation work? What is unique about the Optimizer system?
CCM is an exciting potential therapy for heart failure patients. I believe it is poised to become the next breakthrough treatment for patients with heart failure, and I base that on its mechanism of action, as well as the totality of the clinical trial data that is available to date. In regards to its mechanism, cardiac contractility modulation, or the OPTIMIZER System, delivers an electrical impulse to the heart during the absolute refractory phase of the cardiac cycle. So this is a form of electrical therapy for the heart, but it is not a pacing therapy. The electrical impulse in the short term affects the handling of intracellular calcium, and in the long term induces changes in myocardial gene expression and proteins that result in an increase in cardiac contractility associated with a decrease in cardiac work. Therefore, the efficiency of contractions is improved — the heart works better and in a more efficient fashion. In addition, the good news about those mechanistic observations is that other therapies in heart failure that similarly improve contractility and lower myocardial workload have been associated with patient benefit, including improved patient well-being and improved patient outcomes. If we look at the clinical trial data from studies done in the US, Europe, and Hong Kong, we see very strong evidence that cardiac contractility modulation makes heart failure patients better, and of course it is the intent of the FIX-HF-5B to confirm those observations.
Describe the two treatment study arms, and the type of CCM therapy that the treatment group subjects will receive.
This is a randomized control trial. The trial design is virtually identical to the FIX-HF-5 study, and so eligible participants are patients in NYHA class III who have left ventricular ejection fraction between 25% and 45%, that meet all other eligibility criteria, and are on optimal medical therapy at baseline. Patients are then randomized to either continue optimal medical management alone or optimal medical management plus the OPTIMIZER System. The OPTIMIZER System is a pacemaker-like device; it has a pulse generator and two leads. These are implanted transvenously and reside in the right side of the heart, along the right ventricular septum. The OPTIMIZER System delivers these electrical impulses during the absolute refractory phase of the cardiac cycle intermittently throughout the day.
Discuss the primary efficacy endpoint, and how it will be measured.
This study is intended to confirm and extend the observations from the FIX-HF-5 study; the endpoints being evaluated are the same, and the primary endpoint is metabolic exercise testing, specifically looking at changes in anaerobic threshold. In addition to that, as done in the FIX-HF-5 study, other metabolic exercise parameters will also be evaluated, including peak VO2, which frankly is the more common exercise parameter used in heart failure clinical trials. Another major endpoint is patient well being, including quality of life and NYHA functional class ranking.
What can you tell us about European studies taking place with the OPTIMIZER?
FIX-CHF-4 in Europe was a multi-center, double-blind study, but unlike FIX-HF-5 it was a crossover study, so patients were randomized to either treatment or control, and then after a few months they were crossed over to the alternative therapy. It’s very interesting when you look at the FIX-CHF-4 and the FIX-HF-5 data together — the efficacy that was seen on aspects such as quality of life, exercise capacity and functional status are very similar between the two trials. That is why I mentioned earlier the totality of the clinical trial data — the data from multiple studies is really striking, and that’s what I think reassures us that the therapeutic effect of cardiac contractility modulation is absolutely real and of great potential benefit to patients.
The FIX-CHF-4 study was conducted over a three-year period and included 126 patients with refractory heart failure who were not suitable candidates for cardiac resynchronization therapy. Patients were randomized to 12 weeks of therapy with either the OPTIMIZER System or placebo and were then crossed over to the alternative assignment for another 12 weeks. Baseline average ejection fraction was 25%, peak oxygen consumption (VO2) was 14.3 mL/kg/min, and QRS duration of 120 ms. In addition, 53% of subjects had an implanted cardiac defibrillators. Use of pharmacologic heart failure therapies was comparable in the two treatment arms. At the end of the study period, the combined cohort treated with the OPTIMIZER System experienced a mean 1.25 mL/kg/min improvement in peak VO2 (P = 0.02) and improvement in self-reported quality of life. It was concluded that in patients with heart failure due to left ventricular dysfunction, CCM signals are safe and improve exercise tolerance and quality of life (MLWHFQ).
Do you expect further information on these trials to be presented soon?
There are some new analyses of the FIX-HF-5 study; the first paper included the main results, and a couple months ago the subgroup paper that I first authored appeared in the Journal of Cardiac Failure, and there are some additional analyses ongoing. I do expect that probably next year we’ll see some additional abstract presentations and maybe some publications to come out of the FIX-HF-5 study, which would be very interesting. However, our focus now is on completing recruitment on the FIX-HF-5B study so we can negotiate the regulatory pathway and get this therapy out to patients who need it.
How soon could we expect to see FDA approval for commercial marketing of the OPTIMIZER in the US?
It should take about two years to complete the confirmatory study, and then, given the typical timelines for PMA submission review and final approval, I think we’re probably still looking at three to four years, if everything goes as planned.
Is there anything else you’d like to add?
The potential for CCM really exceeds the current market for cardiac resynchronization therapy because CRT is limited to patients who have a prolonged QRS duration, and that represents only about 30% of the heart failure population. So CCM is currently being targeted to the 70% of patients who aren’t candidates for cardiac resynchronization therapy. CCM could literally reach hundreds of thousands of lives once approved.