Vagal stimulation advances for heart failure

LAS VEGAS – A novel device-based approach to the treatment of heart failure via vagal nerve stimulation resulted in improvements in objectively measurable cardiac function as well as in subjective heart failure symptoms in the ANTHEM-HF trial.

The improvements seen in ANTHEM-HF (Autonomic Neural Regulation Therapy to Enhance Myocardial Function in Heart Failure) were similar regardless of whether participants were randomized to stimulation of the left or right vagal nerve. That’s an important finding because left-sided vagal nerve stimulation (VNS) technology could readily be combined with implantable cardioverter-defibrillators and cardiac resynchronization therapy devices, which are routinely placed on the left side of the thorax, Dr. Inder S. Anand observed in presenting the study findings at the annual meeting of the Heart Failure Society of America.

[RW] Anthem-HF: Primary and secondary outcomes

“We believe that if this technology pans out and proves effective, it will be introduced into devices very easily. That’s the advantage of left-sided stimulation,” explained Dr. Anand, professor of medicine at the University of Minnesota, Minneapolis.

He was quick to add, however, that “There needs to be a lot more work before autonomic regulation therapy is ready for prime time.” That’s because ANTHEM-HF was a relatively small prospective study – just 60 patients – and it was uncontrolled and unblinded.

Left-sided VNS is a well-established treatment for epilepsy, with more than 100,000 patients having received devices in the last several decades. It’s also seeing increasing use in refractory depression.

The approach is still investigational for heart failure, where autonomic imbalance with increased sympathetic activity and decreased parasympathetic tone is associated with heart failure progression and worse clinical outcomes, the cardiologist explained.

In ANTHEM-HF, 60 patients on optimal medical therapy for heart failure with reduced ejection fraction were randomized to left- or right-sided implantation of the Cyberonics VNS device. Once activated, the VNS intensity was titrated over 10 weeks to the maximum tolerable current that remained below the threshold of heart rate change, side effects, and patient sensation. The chronic intermittent stimulation to the vagus nerve was delivered at 10 Hz, a 250 microsec pulse width, and an average stimulation current of 2.0 mA. The stimulation cycle was 14 seconds on, 66 seconds off.

Dr. Inder S. Anand of Minneapolis

The primary study endpoint was change in LVEF over the course of 6 months. From a baseline of 32.4% it improved significantly to 37.2%, which Dr. Anand deemed “very impressive” for just 6 months of therapy. The improvement was similar regardless of whether the VNS was left or right sided.

He said the study didn’t raise any safety concerns. The only serious treatment-related adverse event was a fatal perioperative embolic stroke in a recipient of a left-sided device.

The most common adverse events were hoarseness or other voice alterations, which occurred in 19 patients. Thirteen patients reported a new cough. These side effects mirror the experience in patients treated with the VNS device for epilepsy or depression.

Discussant Jagmeet P. Singh emphasized that “it’s important to interpret the ANTHEM-HF results with some degree of caution.” That’s because the usual variability within LVEF measurements can be in the 5% range, and the 4.8% improvement seen in this study wasn’t accompanied by a significant improvement in LV end systolic volume. Moreover, the improvements seen in secondary endpoints – 6-minute walk distance, NYHA class, and the Minnesota Living With Heart Failure qualify-of-life score – are all potentially open to bias since neither patients nor physicians were blinded.

Dr. Singh noted that the NECTAR-HF study, a blinded, sham-controlled clinical trial of VNS presented earlier at the annual congress of the European Society of Cardiology, was a negative study that showed no improvement in functional measures. While NECTAR-HF caused some skeptics to question the whole concept of VNS as a useful therapeutic strategy, the stimulation protocols used in NECTAR-HF and ANTHEM-HF were quite different, and it’s likely that the stimulation amplitude employed in NECTAR-HF wasn’t sufficient to affect the target subset of vagal nerve fibers, according to Dr. Singh, director of the cardiac resynchronization therapy program and the Holter laboratory at Massachusetts General Hospital, Boston.

He considers the ANTHEM-HF finding that left-sided VNS is comparable to right to be an important advance that “really moves the field forward.” Yet many critical questions about autonomic regulation therapy for heart failure remain unanswered. These include whether it truly is safe and effective, and if so, the optimal target dose and frequency of stimulation. Answers should be forthcoming from the ongoing INOVATE-HF study, a randomized, controlled, 650-patient study, sponsored by BioControl Medical. The trial features hard clinical endpoints and higher target-dose stimulation protocols than in prior studies.