MITRA-FR: No Benefit of MitraClip in Functional MR

MUNICH, Germany (UPDATED)—In a setback to the field of transcatheter interventions for mitral valve disease, one of three hotly anticipated trials has failed to find a benefit of the MitraClip (Abbott) on top of best medical care in functional mitral regurgitation (MR).

“Despite its apparent safety and efficacy, the MitraClip does not carry any benefit in terms of hard clinical outcome, deaths or rehospitalization,” Jean-François Obadia, MD (Hôpital Cardiovasculaire Louis Pradel, Bron, France), said during his Hot Line presentation at the European Society of Cardiology Congress 2018 here today. “More randomized studies are necessary to define a possible subgroup of patients who could benefit from MV repair.”

Physicians reacting to the results used words like “disappointing,” but pointed to the fact that two other trials are still in the works: COAPT, which will be presented at the TCT meeting next month, and RESHAPE-HF, another European trial rumored to be nearing completion.

The MitraClip is approved for the treatment of primary mitral regurgitation in both Europe and North America based primarily on trials focused on patients with degenerative MR. European guidelines offering a class IIb, level of evidence C, recommendation for secondary MR patients who remain symptomatic despite optimal medical management. New trial data have been eagerly awaited in the hopes of informing treatment decisions in patients with functional MR, which already makes up a hefty proportion of MitraClip use in countries where the device is reimbursed.

MITRA-FR: Key Findings

More than 450 patients were screened for MITRA-FR, but 304 were ultimately consented and randomized: 152 to the MitraClip and 152 to best medical care. After exclusions in both arms, 109 patients were ultimately treated with the clip and 137 with medical therapy.

During the procedure, five patients experienced vascular complications requiring surgery or blood transfusion, two patients developed cardiac emboli, and two had cardiac tamponade. No patients died, and no patients required urgent conversion to surgery. Just under half of the patients were treated with one clip, 45% of patients received two clips, and 9% of patients required three or more clips.

At 12 months, there was no difference in the primary composite endpoint of all-cause death and unplanned rehospitalizations for heart failure: 54.6% in the intervention group and 51.3% in the control group (OR 1.16; 95% 0.73-1.84).

Thirty-seven patients (24.3%) in the MitraClip group and 34 (22.4%) in the medical therapy group died over follow-up (OR 1.11; 95% CI: 0.69-1.77). Similarly, 48.7% and 47.4% of patients in the clip and medical groups, respectively, had an unplanned hospitalization (OR 1.13; 95% CI 0.81-1.56).

A range of prespecified analyses examining the findings according to patient age, NYHA class, presence of comorbidities and, importantly, baseline LVEF and baseline MR orifice size found no significant benefits of clip coaptation.

“The cause of the poor prognosis is more the underlying cardiomyopathy than the MR, which is mainly a marker of severity of our heart failure patients,” Obadia concluded. “Despite the fact that we have been effective in reducing the regurgitation, this has had absolutely no consequence in reducing the primary composite endpoint.”

During the discussion following a morning press conference, Kurt Huber, MD (Sigmund Freud University Medical School, Vienna, Austria), asked about symptom relief, pointing out that large MitraClip registries have pointed to significant relief of symptoms with clip placement, with the degree of symptom relief typically tracking with the improvement in regurgitation grade.

Obadia, in response, conceded that MITRA-FR was not focused on symptom relief, but that the trial did mirror the findings of prior registries. “The technique is safe, we decrease the regurgitation, and we also improve the patient (symptoms) after 1 year,” he said—something that is “exactly the same as the registries.”

“The problem for the registries is that they have no control group," he noted. "And if you look at the control group [in MITRA-FR], because of the high quality of the medical treatment, they are also improved. This is why we require randomized data; we cannot rely on registries.”

One explanation for the neutral outcomes may be the high quality of medical care in MITRA-FR, Obadia noted. “This study is also an encouragement to treat the patients better with medical treatment.”

There’s Sick, and Then There’s Sick

Prior observational studies have suggested that the vast majority of clip procedures currently being performed are being done for functional MR. Asked by TCTMD whether the MITRA-FR results should curb device use in patients with secondary MR, Obadia demurred.

“Before this study, we had absolutely no answer and we used the clip very liberally,” he acknowledged. “This probably was one extreme and with one prospective study, which is important, we cannot go from one extreme to another, or to stop [altogether]. What I would suggest is that we should be more restrictive in the indication, but since I cannot exclude that in some subgroup of patients the clip would be useful, I think it is important to keep the door open.”

Stephan Windecker, MD (Bern University Hospital, Switzerland), also commenting on the findings for TCTMD, pointed out that MITRA-FR enrolled some of the sickest patients to date, with 1-year mortality and rehospitalizations in the trial being “higher than in any registry that has been published to date.”

“Usually patients we include in randomized controlled trials have lower morbidity and lower mortality, and this is a randomized controlled trial where that is not the case. So, I do believe that event rate is largely driven by the underlying cardiomyopathy. Does that mean we shouldn’t treat any patient? No, I don’t think that is the conclusion. I think in that very extreme patient risk population, we don’t have an indication that it affects prognosis, but I think there still remains the role for the heart team to decide in those very sick patients who remain symptomatic, despite optimal medical therapy, which direction to go: medical treatment, MitraClip, or potentially an LVAD device or transplant.”

Windecker also pointed to the fact that “the secondary endpoint assessment is rather incomplete.  In other words, we don’t have a good understanding of the disconnect between reduction in MR and its impact on symptomology—there is a lot of missing data.”

Huber, also speaking with TCTMD, had a different take on the “sickness” of the patients, pointing out that MITRA-FR enrolled patients who were eligible for optimal medical therapy or MitraClip, whereas physicians weighing the use of the MitraClip are typically considering it for use in patients who are already maxed out on medical therapy and ineligible for surgery.

“We have patients with severe, reduced left ventricular function and secondary MR and they have a lot of symptoms and these patients are already on optimal medical therapy to the extent they can tolerate,” he said. “I think these patients still should get the device.”

Both Windecker and Huber also stressed that prognosis is not the most important issue for many of the patients being assessed for MitraClip, with Huber noting that many have a life expectancy of under 3 years. For these patients, said Huber, improved quality of life is more important than prognosis.

Also commenting on the study for TCTMD, Ted Feldman, MD (Evanston Hospital, Chicago, IL) said, “Of course, it’s disappointing to see a randomized trial of such an important therapy that is negative. That said, the big takeaway that I have from this effort is that it’s probably underpowered. We saw a large number of patients in the ITT randomized group who didn’t make it in to treatment in both arms, a lot of crossovers in both directions, and the trial was powered at 80% if everyone made it through follow-up. So I think it doesn’t mean it’s the end of the story. There’s some concern that this was a beta error, that there’s a treatment effect that may not be seen. We will get a second look with COAPT at TCT, and we’ll get a third look with RESHAPE HF, which is now, I understand, nearing completion of enrollment.”

COAPT co-principal investigator, Gregg W. Stone, MD (NewYork-Presbyterian/Columbia University Irving Medical Center, New York, NY), also offered some caveats. “The results of MITRA-FR are surprising,” he told TCTMD via email. “Patients did feel better (NYHA class) with the MitraClip, but the hard endpoints were not improved. While the reasons for the lack of improvement are uncertain, some possibilities include enrollment of too many patients with only moderate (2+) MR; uncertain differences in medical therapy between the groups; relative lack of operator experience; follow-up [that was] too short; and too few patients with not enough power. Many of these issues will be addressed in the upcoming COAPT Trial.”

Like others, Feldman also pointed to the difficulty of understanding how much up-titration of medication over the course of the trial may have affected the study results. The low ejection fractions of patients in the study also deserve notice, he added, pointing out that mean EF was much lower than that of patients typically treated today and included in published registries.

Saibal Kar,MD (Cedars-Sinai Medical Center, Los Angeles, CA), who told TCTMD he was the highest enroller in COAPT, said he has some concerns about the level of operator experience in MITRA-FR, pointing to the 48 patients who had significant residual MR at 1 year. “This suboptimal reduction of MR is not consistent with more contemporary MitraClip data,” he said.

In a follow-up email, Kar added: “This was a small study with only 1-year follow up, with lots of important secondary endpoint data missing, like quality of life, 6-minute walk, and even echo data.” Most importantly, he continued, MITRA-FR offered a hint that patients with more severe MR (effective regurgitant orifice area > 40 mm²) did better with clip coaptation than did patients with less severe MR.

“This is similar to coronary artery disease,” Kar observed. “When you stent less severe stenosis, there is no benefit over medical treatment.”

The release of the MITRA-FR results in the main arena today appeared to dampen the enthusiasm of audience members polled about their MitraClip use. Surveyed prior to the presentation, 36% of responders said that they “frequently” consider the MitraClip to reduce symptoms and/or mortality in patients with mitral regurgitation and heart failure with reduced ejection fraction, while 53% responded that they use the technology selectively.

Polled again following Obadia’s presentation, 57% percent of responders said they would still consider percutaneous valve repair in nonsurgical patients in the setting of severe symptoms, while 42% said “there is no sufficient evidence to ever use percutaneous mitral valve repair.”