By Jeffrey Zimmet, MD, PhD
Associate Professor of Medicine, University of California, San Francisco; Director, Cardiac Catheterization Laboratory, San Francisco VA Medical Center
Dr. Zimmet reports no financial relationships relevant to this field of study.
SYNOPSIS: The first randomized trial of MitraClip for secondary mitral regurgitation showed no benefit over medical therapy.
SOURCE: Obadia JF, Messika-Zeitoun D, Leurent G, et al. Percutaneous repair or medical treatment for secondary mitral regurgitation.
N Engl J Med 2018; Aug 27. doi: 10.1056/NEJMoa1805374. [Epub ahead of print].
In 2013, the FDA approved the MitraClip device for the treatment of significant primary (also known as degenerative) mitral regurgitation (MR) in patients at high surgical risk. The approval was based in large part on the results of the 2011 EVEREST II trial. The authors of that trial randomized 279 MR patients 2:1 to percutaneous repair or to open surgery. Approximately 75% of the patients in this trial had primary MR, with secondary MR patients making up the remainder. Despite the relative lack of data on this population, most MitraClip procedures performed outside the United States involve cases of secondary MR. Subsequent prospective registries have suggested that these patients can benefit in terms of symptoms and functional capacity, but no dedicated randomized trials have been available until now.
The authors of the MITRA-FR trial randomized 307 patients with severe secondary MR to either MitraClip or to medical therapy. The primary outcome measure was a composite of all-cause mortality and unplanned heart failure hospitalization at 12 months. These were very sick patients; the trial inclusion criteria called for patients with left ventricular ejection fraction between 15% and 40%. A significant number fell into the lower end of that range.
Of the 152 patients assigned to receive the procedure, 14 did not experience a successful implant, either because the procedure was never attempted (eight patients) or because the procedure failed (six patients). Although the technique was effective in most cases in reducing MR in the short term (95% of patients in the MitraClip group showed an MR reduction of at least one grade. Seventy-five percent of those patients exhibited an MR grade of ≤ 1+ at the time of discharge after the procedure), the hard outcomes were disappointing. The composite primary outcome occurred in 83 patients in the intervention group and in 78 patients in the control group (odds ratio, 1.16; 95% confidence interval [CI], 0.73-1.84; P = 0.53). Death occurred in 24% of patients in the intervention group and in 22% of patients in the medical control group. The results were not different when viewed in a per-protocol analysis (according to whether patients actually received the device) vs. the intention-to-treat analysis.
Unfortunately, a substantial amount of follow-up data at one year were missing regarding echo, functional status, and quality of life outcomes (follow-up was 99% complete for the primary outcome). Regardless, analysis of the available data did not show significant improvements in New York Heart Association class, six-minute walk test, or global quality of life scores in the intervention group. Regarding procedural safety, 21 out of 144 patients in the intervention group experienced periprocedural complications. These included implant failure (4.2%), vascular complications or hemorrhage (3.5%), cardiogenic shock (2.8%), embolism and stroke (2.8%), and tamponade (1.4%).
The authors concluded that percutaneous mitral valve repair with MitraClip did not significantly alter rates of death and heart failure hospitalization at one year over medical therapy alone.
By definition, in secondary MR, the mitral leaflets and chordae are structurally normal. In such cases, MR occurs because of left ventricular and annular dilatation and associated functional abnormalities. It is worth repeating that these patients’ MR occurred because of a poor ventricle. Although severe, MR is associated with worse outcomes in these patients. Rectifying the MR does not change the underlying disease. In the MITRA-FR trial, improvements in MR following percutaneous mitral valve repair did not translate to improved hard outcomes. In fact, one could argue that because of the non-negligible rate of serious periprocedural complications, patients in the intervention group experienced net clinical harm from the procedure.
Close examination of the data from this trial leaves open the possibility that certain subgroups of patients may benefit. For example, the echo data indicate that the average patient in this trial exhibited truly severe left ventricular dilatation. One could argue many of these patients were beyond the point where a procedural intervention could be expected to produce benefits. The authors of the highly anticipated Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation (COAPT) trial, whose results are expected in the near future, chose to exclude patients with very low ejection fraction or very severe dilatation. Thus, the possibility of a different outcome remains.
In the meantime, the results of MITRA-FR demonstrate that patients with advanced heart failure and secondary MR will not benefit from the MitraClip procedure. It remains to be seen whether this will change procedural indications outside the United States and if the results of forthcoming trials will further alter this landscape.