Vagus Nerve Stimulation Fails to Improve Clinical Outcomes in Chronic Heart Failure
CHICAGO, IL—Stimulating the vagus nerve appears to be safe and well tolerated but, compared with optimal medical therapy alone, it does not lessen the rate of a composite of all-cause death or events related to worsening heart failure in patients with chronic NYHA class III heart failure and reduced ejection fraction, results of the randomized INOVATE-HF trial show.
The intervention led to significant improvements in the secondary outcomes of exercise capacity, NYHA class, and quality of life, but the influence of the placebo effect cannot be excluded because both patients and physicians were aware of treatment assignment, according to Michael Gold, MD, PhD (Medical University of South Carolina, Charleston), who reported the findings at the American College of Cardiology 2016 Scientific Sessions here. The results were published simultaneously online in the Journal of the American College of Cardiology.
“I think it’s certainly time to go back to the drawing board,” Gold said after his presentation, adding that future research will focus on the optimal way to perform stimulation of the vagus nerve and on the search for subgroups of patients who might derive a greater benefit from the treatment.
There is evidence that such an approach could work. Preclinical studies have shown that vagus nerve stimulation boosts cardiac function and reduces mortality and inflammation in animals, and a nonrandomized pilot study of the technology used in the current trial—the CardioFit system (BioControl Medical; Yehud, Israel)—demonstrated improvements in quality of life and LV function.
The CardioFit system consists of a pulse generator implanted in the right infraclavicular space, a cuff-like stimulation lead that attaches to the vagus nerve on the right side of the neck, and a standard transvenous lead inserted into the right ventricle to monitor changes in heart rate. The device is designed to address the autonomic imbalance seen in heart failure by enhancing parasympathetic activity.
The potential clinical impact of that was evaluated in the unblinded INOVATE-HF trial, which was conducted at 85 centers in the United States, Europe, and Israel and included 707 patients with NYHA class III heart failure, an LVEF of 40% or less, and an LV end-diastolic diameter of 50 to 80 mm. They were randomized to device implantation plus medical therapy or medical therapy alone.
At the second interim analysis, the data and safety monitoring board recommended stopping the trial due to futility, and it was closed on December 15, 2015.
The primary efficacy endpoint was a composite of all-cause death or events attributed to worsening heart failure. Through a mean follow-up of 16 months, the rate was 30.3% in the device arm and 25.8% in the control arm (HR 1.14; 95% CI 0.86-1.53).
Although there were benefits seen in patients implanted with the device on some secondary outcomes, there was no positive impact on echocardiographic parameters, including ejection fraction and LV end-systolic volume index.
Freedom from procedure- or system-related complications through 90 days—one of the coprimary safety endpoints—was observed in 90.6% of patients in the device arm, exceeding the goal of 75%. There was no difference between trial arms in all-cause mortality or all-cause complications through 1 year, the other coprimary safety endpoint.
Still Room to Move Forward
That evidence of safety is important, according to Clyde Yancy, MD (Northwestern University Feinberg School of Medicine, Chicago, IL). Commenting on the study for TCTMD, he said that “the fact that it was proven to be safe is very reassuring, because it means we have an opportunity to keep moving.”
There are questions about whether the approach used in the trial is the right way of stimulating the vagus nerve and whether targeting a different patient population would yield different results, and those areas are worth additional research, said Yancy, a past president of the American Heart Association.
“I don’t think we should say this is the end of anything,” he said, pointing out that the demonstration of safety means “it was an informative trial and not necessarily a negative trial.”
He noted that in addition to the CardioFit system there are several device-based strategies under investigation for improving heart failure outcomes and said that it will be difficult for those technologies to demonstrate added benefit on top of evidence-based drug therapies.
“We have to recognize that the bar is very high when guideline-directed medical therapy is broadly and appropriately implemented,” Yancy said.
Sham Control Essential
As research continues in this area, the experience from renal denervation studies cannot be dismissed, Yancy said, alluding to the demonstrated importance of having a sham control when evaluating new devices. “You can almost make the argument now that it’s not ethical to avoid a sham arm, because you’re subjecting patients to the belief that an intervention that may or may not have benefit on them has a benefit simply because of the placebo effect,” he said.
Because of the unblinded nature of INOVATE-HF, one cannot put too much stock in the benefits seen on secondary outcomes, especially when considering the definitively negative primary outcome, he said.
Gold acknowledged that limitation in his presentation but said that it would not be possible to do a sham-controlled study for device therapies meant to be used over the long-term.
His coauthor Randall Starling, MD (Cleveland Clinic, OH), also pointed out that patients can feel when the vagus nerve is being stimulated and that the treatment can affect their voices, making it very difficult to perform a blinded study.
- Gold MR, Van Veldhuisen DJ, Hauptman PJ, et al. Vagus nerve stimulation for the treatment of heart failure: the INOVATE-HF trial. J Am Coll Cardiol. 2016;Epub ahead of print.
- The study was sponsored by BioControl Medical.
- Gold and Starling report serving as consultants to BioControl Medical.