Even after the US Food and Drug Administration (FDA) published a negative assessment of mitral valve repair with the MitraClip device for patients with moderate to severe mitral regurgitation (MR) earlier this week, the FDA’s Circulatory Systems Device Panel voted March 20, 2013, narrowly in favor of the novel technology on the basis of safety.

The MitraClip system (Abbott Vascular, Santa Clara, CA) involves a clip that is inserted into the mitral valve via percutaneous femoral venous transseptal access. The device is then aligned above the valve in order to secure the mitral leaflets, creating a bridge that supports durability of repair and may limit dilatation of the annulus.

The panel voted 8 to 0 supporting the device’s safety but narrowly against the system’s effectiveness by a 5 to 4 margin, with the tie-breaking vote coming from the panel chair. In the end, the advisory committee decided the benefits of the device outweigh the risks for use in this patient group by a 5 to 3 vote.

Committee Criticizes Prior Evidence

The most recent MitraClip data that the panel considered came from the EVEREST II trial, which randomized 279 patients with moderate-to-severe or severe MR (3+ or 4+) and anatomical criteria suitable for endovascular repair to percutaneous treatment with the MitraClip system (n = 184) or surgical repair or replacement (n = 95). One- and 2-year findings indicated that the primary efficacy endpoint of freedom from death, mitral valve surgery or reoperation, or MR grade 3+ or 4+ favored surgery. However, MitraClip therapy was safer and resulted in improvements in quality of life and New York Heart Association (NYHA) functional class that were as good as or better than surgery.

Additionally, the EVEREST II High-Risk Registry enrolled symptomatic patients (MR 3+ or 4+) who were not candidates for surgery (n = 78). For comparison, the researchers retrospectively identified a group of MR patients (≥ 3+) with the same predicted surgical mortality rate who were screened but did not enroll in the registry or were not anatomically eligible for MitraClip device placement and received standard therapy (n = 36).

At 30 days, mortality in the high-risk registry was lower than the protocol-predicted rate and trended lower than that predicted by the Society of Thoracic Surgeons risk calculator. In addition, MitraClip patients showed improvement over baseline in MR grade ≤ 2+, NYHA functional class, quality of life, LV parameters, and congestive heart failure hospitalizations.

Agency Weighs in Early

The FDA’s executive summary released prior to yesterday’s panel meeting took issue with the EVEREST II trial, stating that the data “did not demonstrate an appropriate benefit-risk profile when compared to standard mitral valve surgery in a selected mitral valve patient population.” While the trial showed a higher adverse event rate in the surgery group and also met the primary efficacy endpoint, the FDA said the efficacy results were “highly questionable” and not enough evidence to move forward toward approval.

In particular, the FDA prefers a primary efficacy endpoint that defined clinical success using MR grade >1+ as the cutoff rather than MR >2+, something that the agency says it informed the EVEREST II investigators of before the trial even began.

Furthermore, the FDA said the data from the EVEREST II High-Risk Registry “are not easily interpretable,” adding that the lack of an appropriate comparator group, poorly defined inclusion and exclusion criteria, a wide range of surgeon experience, and a heterogeneous patient population with regard to MR etiology hindered the study and its results.

The executive summary outlined the FDA’s plans to work with Abbott on a recently begun study, COAPT. The RESHAPE-HF trial is also underway in Europe.

“FDA firmly believes that the currently enrolling COAPT and European trials are well-designed trials that will help to answer the many important questions posed by the very limited data analyses presented in this [premarket approval] and the mitral regurgitation literature. Therefore, FDA recommends that the MitraClip [clip delivery system] continue to remain available to this vulnerable patient population as an investigational device so that Abbott Vascular can conduct the COAPT and European trials in an optimal manner.”

MitraClip the Only Option

In a telephone interview with TCTMD, Ted Feldman, MD, of Evanston Hospital (Evanston, IL) expressed support for the positive vote, especially after the FDA review. “I think that the fundamental issues were whether the focus was more on methods or more on results,” said Dr. Feldman, who attended the advisory panel meeting. “The FDA review focused entirely on the methods while the presentation from Abbott and certainly the commentary, including commentary from patients and several surgeons, all focused on the safety and the unmet need for high-risk patients.”

What swayed the vote, he suggested was “recognition that the procedure has the very first safety profile, that the demonstration of efficacy is strong enough, and that this group of patients has no options other than living with the disease or MitraClip.”

The FDA will make its final approval decision in the next few months, and “nobody can predict [what the decision will be] any more than they could predict the way things went yesterday,” Dr. Feldman said. Regardless, he added, information from COAPT will provide “more information over the next several years irrespective of what FDA offers in terms of a final decision.”

Related Stories:

• EVEREST II Registry Looks at MitraClip in High-Risk Patients
• EVEREST II: Two-Year Outcomes Show Positive, Negative Aspects of MitraClip
• EVEREST: Clip Device Reduces Mitral Regurgitation with Few Adverse Events