MitraClip in the US: As Coverage Update Looms, Some Questions for REPAIR MR

The Centers for Medicare & Medicaid Services (CMS) is widely expected to show some love for functional mitral valve disease on February 14, 2020. That’s when CMS is due to release its updated proposal for covering transcatheter mitral valve (MV) repair, which, for now, means the MitraClip (Abbott)—the only US Food and Drug Administration-approved device for MV repair.

That proposed decision memo, which has been in the works since last August, will drop nearly a year after the FDA approved the expanded indication for the device, permitting its use in functional mitral regurgitation (MR) patients with a similar profile to patients enrolled in the COAPT trial.

But just how the MitraClip has been used in the United States since the expanded approval is unclear, even as a new clinical trial gets underway looking to boost use in degenerative disease.

Michael Mack, MD (Baylor Scott and White Heart Hospital, Plano, TX), the co-principal investigator for COAPT, which paved the way for the expanded indication, said he thinks uptake has been relatively slow in the US so far, due not only to the still-pending CMS coverage decision, but also the lack of buy-in from heart failure specialists.

“I run the service line for a healthcare system that's got four MitraClip programs and we have not seen a huge uptick,” he told TCTMD. “I think the message [from COAPT] still has not resonated with the heart failure community. Advanced heart failure specialists are mainly treating with drugs and when drugs don't work, it's transplant or [a left ventricular assist device].”

COAPT was the wildly positive trial, published in 2018, showing that the MitraClip in a highly selected group of patients could halve heart failure hospitalizations at 2 years as compared with guideline-directed medical therapy. But the stark difference in outcomes between COAPT and the MITRA-FR trial in France produced months of debate and uncertainty in the cardiology community. The FDA’s updated indications for use ultimately drew heavily on COAPT criteria, specifying that the patient with functional MR should have moderate-to-severe MR (≥ grade 3) as well as a left ventricular ejection fraction ≥ 20% and ≤ 50%, as well as a left ventricular end-systolic dimension ≤ 70 mm, with persistent symptoms despite maximally tolerated guideline-directed medical therapy (GDMT) as determined by a multidisciplinary heart team.

Choosing the Right Patients

The 16 months since COAPT was published have seen a flurry of studies trying to identify the ideal functional MR patient who would benefit from a clip. These include a deep dive into COAPT echo criteria, new theories of proportionate and disproportionate MR, and the relative importance of MR etiology. In the past month alone, new journal articles have tried to flesh out how patient age, body weight, and renal function can influence the likelihood of MitraClip success.

Gilbert Tang, MD (Mount Sinai Health System, New York, NY), has previously highlighted the fact that quantitative echocardiography in MR is dynamic, making it all the more challenging for referring centers to decide whether a given patient is a suitable candidate.

I think the message [from COAPT] still has not resonated with the heart failure community. Michael Mack

“There are some quantitative measurements that you need to make, that we know can be subject to error,” Tang said. “Even though community echocardiographers can generate a report, we typically like to do our own report to make sure that the numbers are consistent in terms of MR severity, looking at different ways to quantify that, [including] the ejection fraction and the LV dimensions. And then we have a team discussion with the heart failure cardiologist.”

Prior to the expanded FDA indication, some physicians already convinced of the benefit of MitraClip in functional MR and hoping to use the clip in this setting sometimes relied on a diagnosis of “mixed MR” such that a patient with mostly functional MR but some degree of degenerative MR could still be eligible for clip therapy. For example, said Mack, “There are patients who have functional MR and a severely tethered posterior leaflet and that is interpreted by some, I believe incorrectly, as what's called mixed disease or having a degenerative component. So I do think there is some off-label use going on, but it is not huge.”

Tang says his center has seen an increase in referrals for MitraClip, with specialists even sending patients outside of the COAPT inclusion criteria, but who have no other options and, in the mind of the referring cardiologist, have “disproportionate MR” and therefore might benefit.

 “On the one hand, I think there is certainly the risk of indication creep and over-expansion of the therapy without oversight, but at the same time, the fact that the COAPT trial was so successful has got the heart failure community to be more engaged and to feel that there may be patients who might benefit who are outside the criteria,” Tang said. “Because MitraClip is relatively safe and they feel that the mitral regurgitation is the culprit of the heart failure symptoms despite being on maximally tolerated GDMT, they want to see if they would benefit from this therapy and in fact many of them have. And I think the heart failure community has been pleasantly surprised.”

Saibal Kar, MD (Los Robles Hospital and Medical Center, Thousand Oaks, CA and Bakersfield Heart Hospital, CA), who reminded TCTMD that he was the single biggest enroller for COAPT, says he’s seen a steady increase in MitraClip use, not just at his own institutions, but at centers across the US. “I personally go to many conferences, and I proctor and teach around the country, and I’ve seen a continuous increase in adoption among referring physicians who are sending patients to me personally as well as a continuous increase in interest around the country, both among cardiologists and cardiovascular surgeons.” He believes the lack of national coverage by CMS remains the key barrier to wider use.

A New Trial Launched

A new randomized clinical trial of the MitraClip has also received FDA approval to move ahead at 60 US sites. Abbott made the announcement earlier this month that REPAIR MR will compare the MitraClip versus surgery in 500 patients with severe, degenerative MR at intermediate risk for surgical repair. Kar and Patrick McCarthy, MD (Northwestern Medicine, Chicago, IL), are the principal investigators.

But the trial, listed as not-yet-recruiting on ClinicalTrials.gov, is already stirring controversy, both Tang and Mack told TCTMD. For one thing, said Tang, there are concerns that trialists will struggle to select patients who are truly intermediate risk, since patients at low risk for surgery with degenerative MR do very well with surgical repair, where long-term durability is well established. “Based on the inclusion criteria [for REPAIR MR], I would say that these patients would actually more likely be low risk than intermediate risk, given the surgical mortality of elective mitral repair is so low,” Tang said. At the best mitral referral centers today, he noted, actual mortality rates are even lower than the predicted STS mortality scores.

I think the heart failure community has been pleasantly surprised. Gilbert Tang

Mack, likewise, is concerned about patient selection as well as the choice of primary endpoint in REPAIR MR—survival free of stroke and any cardiovascular hospitalization at 2 years. “You operate or intervene with MitraClip on patients with severe or mitral regurgitation in order to fix the mitral regurgitation and there's no part of the [REPAIR MR] primary endpoint that has anything to do with correcting the mitral regurgitation,” Mack said. “Stroke, to me, is an irrelevant endpoint” in this setting, while cardiovascular hospitalizations “is a heart failure endpoint, and patients with degenerative MR don’t have heart failure.”

Mack emphasized that he is “totally for the expansion of the MitraClip into intermediate-surgical-risk patients,” but is concerned both that intermediate risk is not well defined in the trial and that the endpoint is flawed. “I realize they were trying to come up with something that was fair and reasonable, but to me having a primary endpoint that does not include death and does not include degree of residual MR is somewhat lacking. . . . I don’t think it’s a stretch to say there will be no difference in stroke and rehospitalization at 2 years, therefore MitraClip will be noninferior to surgery in intermediate-surgical-risk patients. If that stays the endpoint there is no reason to do the trial. We already know the answer.”

The trial sponsor, he noted, has been very responsive to feedback from the surgical community and he predicts that the design of the trial may yet change. The recent hullabaloo over the choice of endpoint definitions in the EXCEL trial, also sponsored by Abbott, is a plausible reason for the sponsor’s sensitivity here and the desire for consensus at the outset, Mack noted. “This trial design, including inclusion criteria and endpoints, will have heightened scrutiny because of the EXCEL effect,” he predicted.

Kar said that there are ongoing conversations about the trial design but that he does not think there will be any changes to the trial’s primary endpoint at this time, although the secondary endpoints are still up for discussion. He defended the trial’s enrollment criteria, insisting that it is truly an intermediate-risk cohort, most notably because it is focused on older patients. All patients entering the trial need sign-off by a surgeon and need to be 75 years or older, or if younger than 75, need to have an STS score of 2% or greater or other comorbidities that would represent an impediment to surgery. It is targeting the patients who, he stressed, are turned away for surgical repair.

“It is a carefully designed trial and very-low-risk patients will not be included,” he insisted.

Moreover, the endpoints are clinical endpoints similar to those chosen for the intermediate- and low-risk trials for TAVR, which did not have echocardiographic outcomes as a primary endpoint. “The endpoint needs to be a clinically meaningful endpoint. If you have mild MR but no increase in heart failure hospitalization, no increase in stroke, and no subsequent death, what difference does it make to you as a patient? And if you end up needing to go for surgery for 2+ MR that will be captured as a rehospitalization.”

What’s more, the trial will not only exclude rehospitalizations within the first 30 days, which might have biased the results against surgery, Kar said, but will continue to follow patients out to 5 years to capture late differences.

Time Will Tell

Contacted by TCTMD, Abbott spokesperson Mary Kokkinen said the company has “no formal statement regarding any speculation about the [REPAIR MR] endpoint.”

[REPAIR MR] is a carefully designed trial and very-low-risk patients will not be included. Saibal Kar

Also asked for specific numbers on MitraClip use in the United States since the expanded FDA approval, Kokkinen said only that the MitraClip has had “double-digit growth in the past year,” but that she wasn’t able to provide “detailed breakouts” for the US.

Abbott’s March 2019 press release announcing the expanded FDA approval for MitraClip noted that 80,000 devices had been sold worldwide. Their January 2020 announcement about the launch of REPAIR MR said that sales have now surpassed 100,000.

Doing the math, Mack estimated that 50% of the MitraClip market is in the US, meaning that 10,000 MitraClips were implanted in the US in 2019. To put that in perspective, he continued, “there were probably 75,000 TAVR procedures in the US last year.”

His best guess? The MitraClip market is not as big as people originally thought. “Everybody had a feeling that [potential MitraClip patients were] sitting in heart failure clinics: I'm still not so sure that that's true,” Mack said. “There were all those market projections all the way along about the huge untreated population, but I've been skeptical.”

Certainly the MitraClip rollout was never going to match that of TAVR, he added. “It's never going to have the rapidity of adoption, it's never going to have the growth rate, even though people feel that the people with [functional] disease is a larger population. Part of the reason is that it's harder to diagnose and it's a technically more difficult procedure to perform than TAVR is and it's harder to get good results. So I think that people who think that this is TAVR redux, déjà vu all over again—that's not going to happen. The expectations of the rate of clinical adoption have to be much more measured and nuanced compared to TAVR.”

Referrals for tricuspid disease, on the other hand, are a different story. “We're actually seeing tricuspid referrals expand much more rapidly than mitral,” Mack added. “I think that's a bigger market than anybody anticipated.”