Gaithersburg, MD - The CorCap ventricular support device from Acorn Cardiovascular (St Paul, MN), a polyester mesh covering for a failing heart intended to stem myocardial remodeling and dilatation, failed to earn a market-approval recommendation from a US Food and Drug Administration advisory panel. Virtually all members saw the device as promising but also noted important weaknesses in the sole randomized study on which the CorCap's premarket approval application (PMA) was primarily based. But with nine panel members voting against, four others said the CorCap should at least be available to surgeons and patients anyway.

According to Dr John C Somberg (American Institute of Therapeutics, Lake Forest, IL), the CorCap had seemed like a "novel idea" and "an essentially low-tech intervention that might benefit congestive heart failure." But he echoed most other members of the the Circulatory System Devices advisory panel whose vote carried the day in noting "disturbing" aspects of Acorn's submitted data that forced him to vote against approval. "The device is very promising. I hope we see a randomized controlled trial that proves me wrong and demonstrates clear efficacy."

But Dr Jeffrey Borer (Weill Medical College, New York, NY), who voted for approval, said, "Based on the data that were presented to us, in a circumscribed population for whom a clear medical need exists, the clinical benefit was sufficiently demonstrated."

Also among the minority, Dr Thomas B Ferguson (Washington University, St Louis, MO) said, "There are compelling reasons to have the device out there in its present form and to do a very careful postmarket study, because this device is needed."

The basis for the PMA was the multicenter Acorn Pivotal Trial, which randomized patients with HF of predominantly NYHA class 3 to receive or not receive the CorCap on top of optimal medication [1]. Those receiving the device, which required a midline sternotomy, showed a significant advantage (p=0.024) for the study's controversial primary end point, a composite of mortality, need for subsequent surgeries indicated for the treatment of HF, or change in NYHA class.

The exclusion criteria included hypertrophic cardiomyopathy or past, concomitant, or planned coronary bypass surgery, so the trial overwhelmingly consisted of patients with idiopathic HF. Panelist Dr Robert Califf (Duke University, Durham, NC), who voted for approval of the device, observed that the resulting group was atypical of the US population with HF.

But the panel's ultimate decision stemmed largely from perceived weaknesses in the trial's methods and interpretation, including the nature of the primary end point, how it was met in the trial, and how it stacked up against risk. The array of complicating issues forced the panel's discussions into what Califf, an international expert on clinical-trial design, referred to as a "quagmire."

The CorCap ventricular support device

Dr Eugene H Blackstone (Cleveland Clinic, OH) said, "I'm having a lot of trouble with the primary end point." The first two components represent events, while the third is a continuous variable, he noted. "I have probably analyzed more cardiac surgery data than anyone in the room and probably more than anyone in the world. I would have no idea how to do an analysis that combines this kind of information."

Also voting against approval, Dr Clyde Yancy (University of Texas Southwestern Medical Center, Dallas) said it was "odd" that the primary end point didn't include hospitalization. "It is a standard that we previously held other devices to . . . even if the intervention itself required a hospitalization."

Somberg, in addition, pointed out that despite showing a significant benefit collectively, results for all three components of the primary end point were suspect. No difference in mortality emerged in the trial. And while significantly more control patients required additional cardiac surgeries in the unblinded trial, that was probably driven by "conscious or unconscious" bias on the part of the surgeons who could have been tilted away from choosing surgery in patients bearing the device. The FDA had presented extensive evidence that the difficulty and therefore risk of further cardiac surgeries is dramatically enhanced in patients with the CorCap.

Moreover, more than half of the data on change in NYHA class were missing, forcing the investigators to fill in huge gaps using established statistical techniques. In fact, more than 40% of data for all three end-point components had to be imputed.

"To me, a trial rides on its primary end point," said Califf. "I'm a rabid advocate of imputation of missing data, but I've never been involved in imputing more than half the data for a key end point."

Most of the panel members seemed to look forward to further clinical trials exploring the CorCap in hope it will show a solid benefit in patients with HF who don't respond to optimal drug therapy.

According to Dr G Michael Felker (Duke University, Durham, NC), who was not on the panel, the device's risk/benefit profile would look more attractive if it could be put in place using nonsternotomy techniques like those used for minimally invasive bypass surgery. "I'm sure someone is working on it," he said to heartwire.

Primary end point,* CorCap randomized-trial outcomes as presented to the advisory panel

Outcome	CorCap	Control	OR (95% CI)	p
Overall population, data imputed	n=147	n=146	1.73 (1.07-2.79)	0.024
Improved (%)	37.7	27.3
No change (%)	25.1	27.7
Worsened (%)	37.2	45.1
Subgroup with complete data	n=93	n=98	1.84 (0.94-3.59)	0.07
Improved (%)	30.1	18.4
No change (%)	18.3	22.5
Worsened (%)	51.6	59.2