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Terminated trials can still produce important data. Although the sponsor prematurely stopped the ANTHEM-HFrEF trial of vagal nerve stimulation for heart failure, the investigators published their analysis of the partial results in JACC, raising questions about what happens when trials are cut short.

ANTHEM was a pivotal trial designed to evaluate LivaNova’s VITARIA vagal nerve stimulation device, which was granted breakthrough designation by the FDA, for the treatment of heart failure with reduced ejection fraction (HFrEF). It had a flexible trial design with interim analyses planned after randomization of 400 patients and again after a randomization of a subsequent 100 patients, up to the planned trial size of 1000.

After the 500-patient interim analysis, the independent Data Safety and Monitoring Committee recommended that the trial continue, but LivaNova conducted its own analysis and concluded the data “did not demonstrate a sufficiently strong positive impact on functional or mortality endpoints, and that it was unlikely that the continuation of the study would demonstrate such an impact.”

In the wake of its premature termination, ANTHEM’s primary endpoint of improving time to cardiovascular death or heart failure hospitalization was neutral but underpowered, leaving investigators working to preserve the trial’s value.

With the partial analysis, they were able to demonstrate the feasibility of the trial and safety of the device, and unlike earlier studies they showed vagal nerve stimulation could achieve and sustain autonomic engagement.

“Importantly, the approach taken after premature trial termination underscores the investigators’ need to fulfill their scientific and ethical responsibilities to preserve trial integrity and transparency, while maximizing the knowledge to be gained, particularly out of respect for the patients who volunteered to participate,” the authors wrote in JACC.

The early end of the trial was a blow not only for the patients and investigators but also for the study of vagal nerve stimulation for heart failure in general, according to Kushal T. Kadakia, MD, MSc, a resident physician at Massachusetts General Hospital in Boston and a deputy associate editor at JACC.

“It was disheartening to the field of heart failure research because there has been controversy about these devices, and having a definitive trial would have put that clinical question to rest and avoid further duplication or redundancy of resources,” he said.

Kadakia praised the investigators for persevering and publishing the results despite the premature termination of the trial.

“It’s important to ensure studies like this are not lost to patients or clinicians,” he said. “When people honor the medical system by choosing to engage with research it’s important that we allow that to come to fruition.”

He feels especially bad for the patients who took part in the trial and had a device implanted into their body.

“It’s not clear whether it was communicated to these patients the possibility that the trial could be stopped early, and what the provisions are for follow-up, whether the device should be removed and what other care should be provided, particularly because there’s now uncertainty about its benefits,” he said.

The FDA should also tighten its rules around the breakthrough device program to ensure sponsors given the flexibility of novel trial designs do not abuse the spirit of that agreement, Kadakia noted. About 150 devices granted breakthrough designation have achieved premarket authorization so far, and around 1000 more are in the pipeline.

“When they provide these breakthrough designations to sponsors, they should define the criteria that would allow for early termination so that these abrupt discontinuations don’t happen,” he said.

Kadakia reported having no relevant financial relationships.

Brian Owens is a freelance journalist based in New Brunswick, Canada.