St. Jude Medical's RESPECT Trial for PFO Closure Presented at TCT

October 25, 2012—St. Jude Medical, Inc. (St. Paul, MN) announced that results from its RESPECT trial were presented during a late-breaking trial session at the TCT 2012: Transcatheter Cardiovascular Therapeutics conference in Miami, Florida, by John D. Carroll, MD, of the University of Colorado.

According to St. Jude Medical, the data from RESPECT, which is evaluating the company's Amplatzer patent foramen ovale (PFO) occluder in the prevention of recurrent cryptogenic stroke, shows that the primary analysis was not statistically significant but trended towards superiority, while additional analyses demonstrated superiority. Stroke risk reduction was observed across the totality of analyses with rates ranging from 46.6% to 72.7%.

“The patient population affected by cryptogenic stroke tends to be relatively young and healthy,” commented Dr. Carroll. “PFO closure with the Amplatzer PFO occluder is potentially a novel prevention strategy that may be superior to medications alone. Stroke is a devastating disease and we now have compelling evidence that shows a 46% to 72% risk reduction in recurrent strokes, which is meaningful for this otherwise healthy patient population with a long life expectancy.”

St. Jude Medical stated that the RESPECT trial is a prospective, one-to-one randomized, event-driven study that began in 2003 and enrolled 980 patients at 69 centers across the United States and Canada. All patients in the study experienced a stroke, confirmed by magnetic resonance imaging, which was ruled cryptogenic before participating in the trial.

Participants were randomly assigned to one of two groups. One group received the Amplatzer PFO occluder and medical management, and the other group was treated using the current medical management standard of care alone, which consists of receiving medicine to prevent clots and potentially decrease the risk of another stroke.

Enrollment was stopped when 25 primary events (stroke and all-cause mortality) occurred. All patients were monitored at 1 month, 6 months, 12 months, 18 months, 24 months, and annually thereafter. Patients enrolled in the trial will continue to be followed until a regulatory decision is made by the US Food and Drug Administration (FDA).

St. Jude noted in its announcement that the RESPECT trial's design assumed that both randomization and patient follow-up would be equal between the two arms for the duration of the study. During the trial, a difference in lost-to-follow-up patients between the two arms was observed and therefore, the raw count analysis (the intended primary endpoint analysis) was unduly biased. As a result, AGA Medical Corporation (Plymouth, MN) disclosed to the FDA this unequal bias while still blinded to the primary endpoint data and reiterated that final analysis would include three additional, protocol-specified analyses. AGA Medical, which developed the Amplatzer device and initiated the RESPECT trial, was acquired by St. Jude Medical in October 2010.

The protocol-specified analyses performed on the data included the raw count analysis and three Kaplan Meier (time-to-event) analyses.

In the intent-to-treat raw count analysis, there was a 46.6% risk reduction of stroke in favor of the device (P = .131). However, patients were counted to the arm they were randomized to, regardless of receiving treatment; this assumes a similar study population was maintained in each arm. But because the populations are different, this analysis is no longer valid.

In the intent-to-treat Kaplan Meier analysis, there was a 50.8% risk reduction of stroke in favor of the device (P = .089). The Kaplan Meier analysis adjusts for any drop out differential between study arms to more accurately compare the two outcomes over time. Patients were included based on the arm they were randomized to, regardless of receiving treatment.

In the per-protocol analysis, there was a 63.4% risk reduction of stroke in favor of the device (P = .034). The per-protocol analysis evaluated patients according to whether the study treatment protocol was followed (eg, inclusion/exclusion criteria, medical management protocol, etc.)

In the as-treated analysis, there was a 72.7% risk reduction of stroke in favor of the device (P = .007). The as-treated analysis evaluated patients according to whether they actually received the treatment (eg, device or medical therapy only).

“More than a third of these patients are likely to have another stroke over their lifetime. If we can cut that number in half, we're making a significant difference in the lives of patients and their families,” commented Jeffrey L. Saver, MD, of the University of California at Los Angeles, in the company's press release. “The totality of results from the RESPECT trial provides evidence that device therapy has clinically meaningful benefits for patients with a PFO and cryptogenic stroke who are at risk for recurrent stroke.”

In a comment to Cardiac Interventions Today, Ted E. Feldman, MD, said, “Many people want a winner and a loser in this situation and have that be the end of the story—almost nothing in medicine is like that. These data shed more light on the subject and are consistent with nonrandomized data in several thousands of patients, which is reassuring. The statistical negativity of the top line primary endpoint doesn't change the fact that even with this very small event rate, when you look at the patients who were actually treated, there appears to be a benefit. A subgroup analysis that shows best outcomes in patients with large shunts and septal aneurysms is also consistent with what we know to date and is confirmatory. The ‘glass half full' perspective is that there is as much or more data than we have for many other complex issues that we have to make decisions about, and this will help greatly with informing individual patients. Another take home point is that the safety data are very strong; this is a safe procedure and the outcomes are certainly not worse than medical therapy.”