Device Improves Scores, Short of Efficacy Goal

ORLANDO — Cardiac contractility modulation, an innovative device therapy for advanced heart failure, significantly improved peak VO2, quality of life scores, and New York Heart Association functional class in the randomized 50-center FIX-HF-5 trial.

“I'm extremely encouraged by the results of this study, and I think there's a future for cardiac contractility modulation. It has the potential to be a real breakthrough,” Dr. William T. Abraham said at the annual meeting of the American College of Cardiology.

There's a hitch, however. The FIX-HF-5 trial did not meet its primary efficacy end point, which was achievement of at least a 20% improvement in anaerobic threshold on metabolic exercise testing. That end point, imposed by the Food and Drug Administration, has never been used as a pivotal outcome in a heart failure study, and in hindsight it was a poor choice, according to Dr. Abraham, professor of medicine, physiology, and cell biology, and director of cardiovascular medicine, at Ohio State University, Columbus.

“In other trials of metabolic exercise testing and heart failure there seems to be a disconnect between peak VO2 and anaerobic threshold. Peak VO2 may improve significantly with little or no change in anaerobic threshold. I just don't think it's the right measure of exercise capacity in heart failure. We'll look to use a different primary end point in our confirmatory study,” he explained.

Cardiac contractility monitoring (CCM) involves implantation of a pacemaker-like device with leads to the right heart. The device, known as the Optimizer III, delivers an electrical signal during the absolute refractory period of the cardiac cycle; thus, unlike a pacemaker, the Optimizer III signal does not initiate a heartbeat. Instead, it upregulates genes involved in cardiac calcium channels to boost cardiac contractility at a lower work level, thus improving overall cardiac efficiency. The system relies on a transcutaneously charged battery, promoting long device life.

FIT-HF-5 was an unblinded study in which 428 patients with advanced heart failure were placed on optimal medical therapy and randomized to receive the Optimizer III or not. Roughly 90% of participants were NYHA class III, the rest were class IV. The average QRS duration was 101 ms. The Optimizer III operated for 5 hours per day during the 12 months of follow-up.

A 20% or greater improvement in anaerobic threshold occurred in 17.6% of the CCM group and 11.7% of controls, a nonsignificant difference.

The real action involved the prespecified secondary end points—which in other heart failure trials with metabolic exercise testing have been the primary end points. Peak VO2 worsened over the course of the year in controls but improved in the CCM group, with a highly significant mean difference of 0.65 mL/kg per min between the two groups.

There was also a mean 10-point difference favoring the CCM group in quality of life as measured by the Minnesota Living With Heart Failure Questionnaire. “That meets or exceeds the benefit seen with other device or drug therapies,” Dr. Abraham noted.

More than 44% of the CCM group experienced at least a 1-grade improvement in NYHA functional class, which was nearly twice the rate in controls.

Roughly half of FIX-HF-5 participants were NYHA class III with a left ventricular ejection fraction of 25% or more. The magnitude of benefit with CCM seen in this subgroup exceeded that in other participants. For example, they had a mean 1.3 mL/kg per min advantage in peak VO2 compared with controls, which is better than that seen in the controlled trials of cardiac resynchronization therapy. These are the type of patients to be enrolled in the pivotal trial now being planned, according to the cardiologist.

Discussant Clyde W. Yancy, president-elect of the American Heart Association, observed that new therapies with novel mechanisms of action are desperately needed in the field of heart failure, and said he is pleased that further studies of CCM are planned. But he sounded a note of caution.

“This is a very provocative study, but by the same token there is something about CCM that bespeaks of an inotropic effect, so we have to continue to be very thoughtful and circumspect and follow up larger populations for a longer period of time,” said Dr. Yancy, medical director of the Baylor Heart and Vascular Institute, Dallas.

Dr. Abraham has received research grants and consulting fees from Impulse Dynamics, sponsor of FIT-HF-5.

ORLANDO — Cardiac contractility modulation, an innovative device therapy for advanced heart failure, significantly improved peak VO2, quality of life scores, and New York Heart Association functional class in the randomized 50-center FIX-HF-5 trial.

“I'm extremely encouraged by the results of this study, and I think there's a future for cardiac contractility modulation. It has the potential to be a real breakthrough,” Dr. William T. Abraham said at the annual meeting of the American College of Cardiology.

There's a hitch, however. The FIX-HF-5 trial did not meet its primary efficacy end point, which was achievement of at least a 20% improvement in anaerobic threshold on metabolic exercise testing. That end point, imposed by the Food and Drug Administration, has never been used as a pivotal outcome in a heart failure study, and in hindsight it was a poor choice, according to Dr. Abraham, professor of medicine, physiology, and cell biology, and director of cardiovascular medicine, at Ohio State University, Columbus.

“In other trials of metabolic exercise testing and heart failure there seems to be a disconnect between peak VO2 and anaerobic threshold. Peak VO2 may improve significantly with little or no change in anaerobic threshold. I just don't think it's the right measure of exercise capacity in heart failure. We'll look to use a different primary end point in our confirmatory study,” he explained.

Cardiac contractility monitoring (CCM) involves implantation of a pacemaker-like device with leads to the right heart. The device, known as the Optimizer III, delivers an electrical signal during the absolute refractory period of the cardiac cycle; thus, unlike a pacemaker, the Optimizer III signal does not initiate a heartbeat. Instead, it upregulates genes involved in cardiac calcium channels to boost cardiac contractility at a lower work level, thus improving overall cardiac efficiency. The system relies on a transcutaneously charged battery, promoting long device life.

FIT-HF-5 was an unblinded study in which 428 patients with advanced heart failure were placed on optimal medical therapy and randomized to receive the Optimizer III or not. Roughly 90% of participants were NYHA class III, the rest were class IV. The average QRS duration was 101 ms. The Optimizer III operated for 5 hours per day during the 12 months of follow-up.

A 20% or greater improvement in anaerobic threshold occurred in 17.6% of the CCM group and 11.7% of controls, a nonsignificant difference.

The real action involved the prespecified secondary end points—which in other heart failure trials with metabolic exercise testing have been the primary end points. Peak VO2 worsened over the course of the year in controls but improved in the CCM group, with a highly significant mean difference of 0.65 mL/kg per min between the two groups.

There was also a mean 10-point difference favoring the CCM group in quality of life as measured by the Minnesota Living With Heart Failure Questionnaire. “That meets or exceeds the benefit seen with other device or drug therapies,” Dr. Abraham noted.

More than 44% of the CCM group experienced at least a 1-grade improvement in NYHA functional class, which was nearly twice the rate in controls.

Roughly half of FIX-HF-5 participants were NYHA class III with a left ventricular ejection fraction of 25% or more. The magnitude of benefit with CCM seen in this subgroup exceeded that in other participants. For example, they had a mean 1.3 mL/kg per min advantage in peak VO2 compared with controls, which is better than that seen in the controlled trials of cardiac resynchronization therapy. These are the type of patients to be enrolled in the pivotal trial now being planned, according to the cardiologist.

Discussant Clyde W. Yancy, president-elect of the American Heart Association, observed that new therapies with novel mechanisms of action are desperately needed in the field of heart failure, and said he is pleased that further studies of CCM are planned. But he sounded a note of caution.

“This is a very provocative study, but by the same token there is something about CCM that bespeaks of an inotropic effect, so we have to continue to be very thoughtful and circumspect and follow up larger populations for a longer period of time,” said Dr. Yancy, medical director of the Baylor Heart and Vascular Institute, Dallas.

Dr. Abraham has received research grants and consulting fees from Impulse Dynamics, sponsor of FIT-HF-5.

ORLANDO — Cardiac contractility modulation, an innovative device therapy for advanced heart failure, significantly improved peak VO2, quality of life scores, and New York Heart Association functional class in the randomized 50-center FIX-HF-5 trial.

“I'm extremely encouraged by the results of this study, and I think there's a future for cardiac contractility modulation. It has the potential to be a real breakthrough,” Dr. William T. Abraham said at the annual meeting of the American College of Cardiology.

There's a hitch, however. The FIX-HF-5 trial did not meet its primary efficacy end point, which was achievement of at least a 20% improvement in anaerobic threshold on metabolic exercise testing. That end point, imposed by the Food and Drug Administration, has never been used as a pivotal outcome in a heart failure study, and in hindsight it was a poor choice, according to Dr. Abraham, professor of medicine, physiology, and cell biology, and director of cardiovascular medicine, at Ohio State University, Columbus.

“In other trials of metabolic exercise testing and heart failure there seems to be a disconnect between peak VO2 and anaerobic threshold. Peak VO2 may improve significantly with little or no change in anaerobic threshold. I just don't think it's the right measure of exercise capacity in heart failure. We'll look to use a different primary end point in our confirmatory study,” he explained.

Cardiac contractility monitoring (CCM) involves implantation of a pacemaker-like device with leads to the right heart. The device, known as the Optimizer III, delivers an electrical signal during the absolute refractory period of the cardiac cycle; thus, unlike a pacemaker, the Optimizer III signal does not initiate a heartbeat. Instead, it upregulates genes involved in cardiac calcium channels to boost cardiac contractility at a lower work level, thus improving overall cardiac efficiency. The system relies on a transcutaneously charged battery, promoting long device life.

FIT-HF-5 was an unblinded study in which 428 patients with advanced heart failure were placed on optimal medical therapy and randomized to receive the Optimizer III or not. Roughly 90% of participants were NYHA class III, the rest were class IV. The average QRS duration was 101 ms. The Optimizer III operated for 5 hours per day during the 12 months of follow-up.

A 20% or greater improvement in anaerobic threshold occurred in 17.6% of the CCM group and 11.7% of controls, a nonsignificant difference.

The real action involved the prespecified secondary end points—which in other heart failure trials with metabolic exercise testing have been the primary end points. Peak VO2 worsened over the course of the year in controls but improved in the CCM group, with a highly significant mean difference of 0.65 mL/kg per min between the two groups.

There was also a mean 10-point difference favoring the CCM group in quality of life as measured by the Minnesota Living With Heart Failure Questionnaire. “That meets or exceeds the benefit seen with other device or drug therapies,” Dr. Abraham noted.

More than 44% of the CCM group experienced at least a 1-grade improvement in NYHA functional class, which was nearly twice the rate in controls.

Roughly half of FIX-HF-5 participants were NYHA class III with a left ventricular ejection fraction of 25% or more. The magnitude of benefit with CCM seen in this subgroup exceeded that in other participants. For example, they had a mean 1.3 mL/kg per min advantage in peak VO2 compared with controls, which is better than that seen in the controlled trials of cardiac resynchronization therapy. These are the type of patients to be enrolled in the pivotal trial now being planned, according to the cardiologist.

Discussant Clyde W. Yancy, president-elect of the American Heart Association, observed that new therapies with novel mechanisms of action are desperately needed in the field of heart failure, and said he is pleased that further studies of CCM are planned. But he sounded a note of caution.

“This is a very provocative study, but by the same token there is something about CCM that bespeaks of an inotropic effect, so we have to continue to be very thoughtful and circumspect and follow up larger populations for a longer period of time,” said Dr. Yancy, medical director of the Baylor Heart and Vascular Institute, Dallas.

Dr. Abraham has received research grants and consulting fees from Impulse Dynamics, sponsor of FIT-HF-5.