At the ESC Heart Failure Congress, Some COAPT Converts—and Some Pushback

ATHENS, Greece—Heart failure experts gathered here at the European Society of Cardiology 2019 Heart Failure (ESC HF) Congress saw several new COAPT analyses and seemed at least partly reassured that the MitraClip might help a subset of their patients. But still under dispute is the degree to which mitigating mitral regurgitation (MR) with a clip will really help a patient for whom heart failure is his or her primary problem and whether the rollout of the procedure is proceeding appropriately.

One strong message that seemed to strike a chord with conference-goers was that secondary MR is first and foremost a heart failure disease and that heart failure specialists need to retain control of how and when their patients are treated.

New COAPT Insights

As reported by TCTMD, William T. Abraham, MD (Ohio State University, Columbus), presented a new COAPT subanalysis looking at baseline BNP/NT-proBNP levels showing MitraClip (Abbott) to be of benefit regardless of biomarker levels at the time of enrollment. Also at ESC HF, JoAnn Lindenfeld, MD (Vanderbilt Heart and Vascular Institute, Nashville, TN), presented a different subgroup analysis, this one trying to tease out COAPT patients who were more similar to the MITRA-FR trial population. Parsing the numbers in this way might help explain the differences between these two trial results, she noted.

The oft-repeated hypothesis is that MITRA-FR-like patients with a smaller effective regurgitant orifice area (EROA)—that is, less severe MR—and a larger ventricle would derive limited clinical benefit associated with the MR reduction afforded by clip therapy.

In this new analysis, the primary endpoint of all-cause mortality or HF hospitalizations at 24 months in COAPT was not significantly different in patients with an EROA of < 0.30 cm2 and a left ventricular end-diastolic volume index (LVEDVi) > 96 mL/m2 randomized to the MitraClip as compared with guideline-directed medical therapy (GDMT). By contrast, patients with either an EROA of > 0.30 cm2 or a LVEDVi < 96 mL/m2 derived a significant benefit from MitraClip implantation over meds alone.

Both groups, however, showed an improvement in quality of life at 12 months.

“In a MITRA-FR-like subgroup of COAPT patients, there was no improvement in heart failure hospitalizations and all-cause mortality at 12 months, although quality of life and 6-minute walk test improved,” Lindenfeld said. By 24 months, though, “there was a trend for improved heart failure hospitalizations and all-cause mortality,” she added.

All-Cause Mortality or HF Hospitalization at 24 Months

Pushing for More Data

Piotr Ponikowski, MD, PhD (Wroclaw Medical University, Poland)—during a session entitled “Functional Mitral Regurgitation: The Road Ahead”—spoke passionately about his concerns over how fast MitraClip had been taken up in certain parts of Europe. He gave the example of German centers that are implanting hundreds of clips per year. If the correct criteria were being used to determine who would really benefit from a clip, he mused, this would mean that thousands of patients would have had to have been referred and screened, a scenario he implied was unlikely.

Elaborating to TCTMD after his talk, Ponikowski noted that his center is participating in RESHAPE-HF 2, a trial that’s actually enrolling patients with more moderate degrees of mitral regurgitation who are “less sick, with better ventricles” but are optimized on medical therapy and cardiac resynchronization therapy as needed.

“We are one of the most efficiently recruiting centers for RESHAPE-HF 2, and I can only say that it is really not so easy to find so many patients,” he said. “My major concern is that we are receiving a lot of referrals for MitraClip. However, if we follow the guidelines, which clearly say to optimize the treatment first and make sure that the patient receives what he or she needs to receive according to the ESC guidelines for heart failure with reduced ejection fraction, and after a couple of weeks you are seeing the severity of mitral regurgitation improve, then 50% to 60% of these patients disappear. I’m not saying the ventricle is shrinking, but they are getting less symptomatic and they are getting less mitral regurgitation.”

Nathan Mewton, MD, PhD (Hôpital Cardiovasculaire Louis Pradel, Lyon, France), the senior author on the published MITRA-FR paper, also remains unconvinced by COAPT. Speaking in multiple sessions during the congress, Mewton reminded his audience that all of the COAPT presentations made at meetings over the last 6 months, such as the BNP/NT-proBNP and EROA/LVEDVi snapshots released at ESC HF, would likely not even make the cut for publication in a high-impact journal. Many included small patient subsets and amount to little more than “shaking down the trial and looking at the crumbs,” according to Mewton.

“These are only subanalyses and should be taken as hypothesis-generating for new trials and nothing else,” he said.

Mewton also pointed to COAPT data that, in his mind, need more clarification. The first issue involves the inconsistent reporting of stroke volumes in the trial, a concern raised in a recent letter to the editor at the New England Journal of Medicine. The other deals with the significantly better optimization of GDMT—specifically renin-angiotensin system blockers and beta-blockade—among the MitraClip-treated patients, a discrepancy he found in a supplementary table for the published trial. Future subanalysis presentations might want to address these two points, he observed.

Mewton took the “con” side in an ESC HF debate arguing for versus against the use of MitraClip in patients with severe functional MR. During his provocative introduction, he likened the field of cardiology to the members of a football team (soccer, for North Americans). “Here we have all kinds of different specialties and they all are working towards getting patients towards better status and better survival,” he said.

In this analogy, the heart failure specialists are the midfielders, Mewton explained. “They are not doing things with their hands, but they are using their brains to distribute the goals. Then you have the strikers, which are the interventional cardiologists.” The interventionalists “want to score a goal with whatever they have in their fingers,” be that a stent, an atrial septal defect/patent foramen ovale occluder, a TAVR device, a left atrial appendage occluder, or a percutaneous mitral valve, he continued. “And what I discovered is that they need a lot of brains to do that perfectly.”

But their “goal,” Mewton said, is to score principally by using devices, not drugs, such as the mainstay medications of heart failure care that have unequivocally proven their efficacy in terms of their impact on survival. “Don’t get me wrong here: we need good interventional cardiologists, they are vital to our team, but we must send them good patients.”

Otherwise, “this is what happens,” he said, showing a slide tracking the explosion of MitraClip therapy in Germany, which since 2012 has risen from 1,000 patients per year to 5,600 in 2016.

In my opinion, percutaneous mitral valve repairs are not useful in most heart failure patients with secondary mitral regurgitation. Nathan Mewton

“And you could argue whether those MitraClips are useful,” Mewton said. “In my opinion, percutaneous mitral valve repairs are not useful in most heart failure patients with secondary mitral regurgitation.”

Speaking second, Konstantinos Spargias, MD (Hygeia Hospital, Athens, Greece), who took the pro-MitraClip side in the debate, called for a truce. “I’m not in a confrontational mode,” he said as he wrapped up his presentation. “We just had one trial that is extremely positive and another that is neutral—it’s not negative. And if we draw the same distance between the two trials and continue acting like nothing has changed, then many patients will lose their lives while we’re waiting for more convincing data. And the data we are waiting for is just data to more properly select the timing and the correct patient population for this treatment,” he said.

Learning and Moving On

At the outset of the MitraClip debate, just 20% of the audience said they agreed with the use of the MitraClip in patients with heart failure and severe functional MR while 80% were against its use. By the end of the session, however, those numbers were substantially reversed, with 53% of voters saying they’d been persuaded by the evidence in favor of clipping and 47% saying they remained unconvinced.

Speaking with TCTMD on day 3 of the meeting, Lindenfeld said she, too, had sensed a shift there. “I think people have been impressed by the consistency of the data in COAPT, and I think some of their fears have been allayed that only one out of three patients screened in COAPT were randomized, so they’ve seen how rigorously we controlled the medical therapy,” she observed.

Acknowledging that some of her peers remain unpersuaded, she shrugged it off by saying: “I think that’s good, because we still have a lot to learn about who exactly the right person is [for this device]. But the more people I talk to here, the more I think people once they see the COAPT data laid out and the potential differences between the trials—and as we explore more and more the reasons for those differences—are more and more convinced.”

Mewton, for his part, stressed to TCTMD that he believed the MitraClip “might be efficient to reduce mitral regurgitation. And it’s quite a safe procedure, so from the perspective of safety it’s a good device and it [speaks to] the progress of more and more intervention without chest surgery opening. That’s an advance.”

If we draw the same distance between the two trials and continue acting like nothing has changed, then many patients will lose their lives while we’re waiting for more convincing data. Konstantinos Spargias

But for Mewton, the key thing to remember is that mitral regurgitation in heart failure patients is a disease of the left ventricle. “I’m a little concerned about the fact of reducing heart failure, which is a primary disease, to being a mitral regurgitation problem—it’s not as simple as that. So it’s very important to remind all physicians that you should first treat patients with medical therapy . . . and probably select those patients that are closer to the primary MR profile, which are the smaller ventricles and bigger regurgitation,” he advised.

A similar reminder was delivered by Frank Ruschitzka, MD (University Heart Center, Zurich, Switzerland), who spoke during a number of the mitral regurgitation sessions by urging the audience to dispense with the idea of “functional” MR and instead prioritize the term “secondary MR” to make it crystal clear to physicians in other specialties that heart failure is the primary disease.

“We cannot leave it to industry to tell us what to do, and we can’t leave it to the interventionalists only. Secondary heart failure is a disease of the left ventricle, so a heart failure specialist has to be in charge,” he stressed.

Ruschitzka also offered conference attendees a sneak peek at a soon-to-be-published joint position paper from the European Heart Failure Association in partnership with the European Association of Percutaneous Cardiovascular Interventions, the European Heart Rhythm Association, and the European Association of Cardiovascular Imaging. This, he said, is the first time that he could remember that such a multisociety document had been convened with heart failure experts taking the helm.

I think we all agree that we need more data, but what COAPT said to us is that this is a viable option for therapy and now we need to figure out how to optimize it, but staying strictly within the COAPT criteria. JoAnn Lindenfeld

The document will provide an algorithm for managing patients with heart failure and secondary MR, starting with recommendations for heart team members at centers undertaking MitraClip implantations. This should include a heart failure specialist, a CV imager, an interventional cardiologist with expertise in transcatheter mitral valve repair, a cardiac electrophysiologist, a cardiac surgeon with experience in mitral valve surgery, cardiac support, and transplantation, and, ideally, a heart failure nurse.

“For the first time, we all sat together under the leadership of heart failure specialists,” Ruschitzka said. “That’s a sea change. Who would have thought a few years ago that for an interventional therapy, a heart failure doctor would be leading the multidisciplinary team? This team should evaluate and optimize guideline-directed medical therapy . . . and we need to discuss who will benefit or not. We need to look for suitable valve morphology and not go for too big ventricles, and probably go for more severe MR and then you may—but only then—consider a transcatheter treatment option.”

And as a final point, he added, “stay away from futile interventions. This is the algorithm we are recommending, and it is now under review.”

Lindenfeld, speaking in the same panel discussion, said that an American College of Cardiology/American Heart Association guideline on the same topic “will be out any day now,” a key difference in the US document being that the inclusion of the surgeon on the team will be optional.

But Lindenfeld also took the opportunity to remind attendees that the MitraClip remains an option for a limited number of patients, and said they have a duty to make sure their patients are appropriately treated. Her hospital has had 40 patients referred for the MitraClip since COAPT came out, she said. “Only four were adequately medically managed at the time we saw them and of the remaining 36, 24 had their mitral regurgitation reduced to less than 2+ with optimal medical therapy.”

She continued: “I think we all agree that we need more data, but what COAPT said to us is that this is a viable option for therapy and now we need to figure out how to optimize it, but staying strictly within the COAPT criteria. You stay there, which excludes the patients with the very large ventricles, I think we can say they will benefit.”

Meanwhile, there is still the contribution expected from the RESHAPE-HF 2 trial. Primary investigator Stefan Anker, MD (Charité – Universitätsmedizin Berlin, Germany), was also prominent in many of the mitral regurgitation sessions here but remained tight-lipped when asked for an update on the trial. “What I said at TCT last year is that the mortality in RESHAPE-HF 2 is lower than both COAPT and MITRA-FR,” he told TCTMD. “We have recruited patients in moderate-to-severe functional mitral regurgitation, so we might need longer follow-up.”

Anker’s unofficial prediction is that follow-up in RESHAPE-HF 2 will need to be 2 to 3 years to acquire enough events for the primary analysis—an estimate echoed by Ponikowski.

Anker also stressed that RESHAPE-HF 2 will not be “a tiebreaker” for COAPT and MITRA-FR but rather “a third population.”