Following months of speculation and hours of testimony, the Circulatory System Devices panel of the US Food and Drug Administration (FDA) voted overwhelmingly to recommend approval of the Sapien transcatheter heart valve to treat certain inoperable patients with severe aortic stenosis.

The panel, which met July 20, 2011, voted 7 to 3 that the device demonstrated reasonable assurances of safety; 9 to 1 that the device demonstrated reasonable assurances of efficacy; and 9 to 0 (with 1 member abstaining) ultimately in favor of approval, that the benefits of the valve outweighed the risks.

In a telephone interview with TCTMD, acting panel chair Richard L. Page, MD, of the University of Wisconsin (Madison, WI), said although the recommendation for approval of the Sapien device is for a relatively narrow population, “this is groundbreaking in the evolution of these devices as treatment options and in the evolution of the collaboration between cardiothoracic surgeons and interventionalists.”

Definition Changes Raise Questions

Edwards Lifesciences (Irvine, CA) is seeking to market 2 sizes of the valve, a 23-mm device and a 26-mm device, plus the delivery system.

In briefing documents released prior to the panel meeting, FDA reviewers said the Sapien transcatheter heart valve was associated with "an impressive reduction of mortality . . . relative to the heterogeneous control group.”

The premarket approval (PMA) application was based on results from Cohort B of the PARTNER (Placement of AoRtic Transcatheter Valves) trial. Originally published in the October 21, 2010, issue of the New England Journal of Medicine, PARTNER randomized 358 patients who had severe aortic stenosis and cardiac symptoms but were ineligible for surgery to undergo TAVI or receive standard therapy.

Overall, there was a relative risk reduction in all-cause mortality of 46% with TAVI compared with medical therapy. The trial also found a cardiovascular mortality risk reduction of 61% compared with patients receiving optimal medical care, including balloon valvuloplasty. Risk of a composite endpoint of death or repeat hospitalization also was lower in TAVI-treated patients, although the risk of stroke and vascular complications was higher.

The FDA briefing documents indicated that a change had been made to the adverse event definitions by the company after the study was completed and unblinded, which resulted in some discussion by FDA panel members prior to the final vote. In the company submission, the word “stroke” was changed to “major stroke” in the composite endpoint of major adverse cardiovascular and cerebrovascular events. FDA’s review encompassed all strokes.

“Neurological adverse events remain an important safety consideration for this device and impact the overall risk-benefit profile of the Sapien transcatheter heart valve,” said the FDA in its review documents distributed to the panel. Specifically, the 30-day stroke rate for the published PARTNER trial was 5% in TAVI-treated patients and 1.1% in the medical therapy group. But the panel considered the original trial definitions of stroke—7.3% for the Sapien and 1.7% for the control group.

Societies Stress Need for Collaboration, Training

The day-long session included oral and written testimony from a number of medical groups including the Society of Thoracic Surgeons (STS), the American College of Cardiology (ACC), and the Society for Cardiovascular Angiography and Interventions (SCAI), all of which stressed the need for collaboration between surgeons and interventionalists when deciding which patients are appropriate for the valve, and the need for implementing the necessary training to perform the procedure.

The STS and ACC also proposed expanding their existing national databases to include all patients treated with TAVI.

“The FDA panel’s recommendation further reinforces the value of TAVI for inoperable patients,” commented SCAI president Christopher J. White, MD, of the Ochsner Heart and Vascular Institute (New Orleans, LA). “For more than 30 years, advances in interventional cardiology have helped improve survival for patients with heart disease. TAVI is an important advancement, and as this treatment expands in the United States, it will be important for cardiology societies to work together to establish standards and training to ensure the procedure is used as safely as possible.”

Ralph Brindis, MD, MPH, of the Oakland Kaiser Medical Center (Oakland, CA), and immediate past president of ACC, added that he was “hopeful that the societies can manage the training necessary” to perform the procedure.

Focus on Neurological Events, Need for Follow-up

The panel also discussed neurological adverse events at length.

“Sapien is certainly effective, but we need to educate patients and physicians about the real stroke risk,” said panel member Valluvan Jeevanandam, MD, of the University of Chicago Medical Center (Chicago, IL).

That concern also was echoed by other members of the panel, including neurologist David C. Good, MD, of the Milton S. Hershey Medical Center (Hershey, PA), who said the patient brochure needs major revisions. “Stroke danger is not emphasized enough,” he said.

Ultimately, given that 20% more patients were alive 1 year after receiving the Sapien device compared with standard therapy, the panel determined that the benefits outweighed the risks.

Another point of considerable discussion involved a proposed post-marketing study, which the panel said would require the same rigor as the PARTNER trial. The proposed study would include 75 of the 200 original PARTNER sites that are likely to begin offering TAVI.

A separate PMA has been filed by Edwards Lifesciences seeking approval to market the valve for use in high-risk surgical patients based on the favorable results of PARTNER’s Cohort A.

Related Stories:

• SOURCE Registry Data Published: TAVI Stays Strong at 1 Year
• NEJM Letters Take on PARTNER Trial
• PARTNER: All-Cause, CV Mortality Lower in Patients Treated with TAVI vs. Standard Therapy at 1 Year