COMMENTARY

COAPT Hits Sweet Spot of MitraClip Efficacy for Secondary MR

Can It Be Replicated?

Interviewer: John M. Mandrola, MD; Interviewee: Robert W. Yeh, MD, MBA

Disclosures

September 25, 2018

John M. Mandrola, MD. Hi, everyone. This is John Mandrola for theheart.org | Medscape Cardiology, and I'm here at the TCT [Transcatheter Cardiovascular Therapeutics] meeting just hours after the COAPT trial[1] was presented. I'm with Bobby Yeh, from Beth Israel Deaconess Medical Center. Bobby is known for being a voice of reason on social media. Thanks for joining us.

Robert W. Yeh, MD, MBA: Thanks for inviting me.

Mandrola: Give us your general impressions of COAPT.

Yeh: I'm still digesting all of the information, but as a first impression—boy; those were impressive results. They were not the results I was expecting. Caring for patients who have dilated ventricles and significant functional mitral regurgitation (MR), I thought these patients can't get better so I was expecting a negative trial, especially after the previous trial (MITRA-FR) that was recently published was negative.[2]

This one was across-the-board positive, which was a real surprise to me, and I congratulate the investigators for pulling off a really successful trial.

Mandrola: What did you think of the plausibility of MR being reduced and being associated with positive outcomes? It's pretty good, isn't it?

Yeh: It's great, and we have to dive more deeply to try to understand mechanistically why this happened. In some trials we never know why, mechanistically, it shows what it shows, but the consistency of the findings in COAPT in the various subgroups and the consistency across all of the different endpoints make one believe that it's internally valid for the population that they enrolled.

Dr Stone[1] made some important points, and one to take away is that these in general were not the sickest ventricles; and the patients had highly significant MR even after very optimized medical therapy. The trial managed to find this sweet spot of patients who are sick but not too sick to benefit.

Mandrola: Well, that's the perfect segue to ask how one trial from France can be completely negative and this trial can look as good as antibiotics and clean water. It's just shocking.

Yeh: It makes one want to figure out a mechanism behind it. The investigators put forward some potentially plausible explanations for that: Maybe the patients in MITRA-FR had ventricles that were a little more dilated and had less MR; maybe the proceduralists did not have quite the same expertise as in the COAPT trial. There was a litany of differences between the trials, but I'd love to see a pooled analysis to see who truly benefits.

We've had discussions on Twitter about the fact that clinical trials often don't identify the subgroups that are most likely to benefit and those not likely to benefit from a therapy. Sometimes that's not in the interest of those who run the trials. But here we have one population who looked like they benefited and another who didn't. Wouldn't it be great if we could figure out exactly who it is that benefited the most? That would help clinicians because they're the ones who are going to have to make these decisions on a daily basis.

Mandrola: Do you think there's a sweet spot? That's the explanation; what's your feeling about that clinically?

Yeh: With conditions like this and many others where people get ill and then decline, I think there is a sweet spot where you can intervene early enough to impact outcomes but not too early that you're grabbing people who might do fine anyway, and not too late that they're irrecoverable. But whether we can identify that has been the challenge. It's part of the reason why we try so hard when we interview patients in the clinic, because we're trying to find that sweet spot of benefit versus futility versus potential harm.

The remarkable thing about the trial is that it appears that they managed to do that and they did it through the unusual and intensive way they screened these patients. They were rigorously reviewed by the sites, then they were reviewed centrally with central adjudication of the echocardiography data to confirm that these really were the types of patients they thought would benefit. That rigor showed up in the results of the trial.

Mandrola: Now we're going to have a third trial (RESHAPE-HF2). Do you think we have to wait for that as a tiebreaker or should regulators and clinicians move forward with these findings?

Yeh: It depends a bit on what we mean by "move forward." If clinicians were able to find the types of patients that were enrolled in COAPT in their clinics, I'm confident that such patients might benefit on average from treatment [with the MitraClip]. I'm not as confident that it's easily replicable by rank-and-file clinicians who see such patients.

We need to understand the special sauce of how these patients were identified in COAPT to make it generalizable to the clinical community and to also make regulators understand which patients will potentially benefit. I don't think it's in anyone's interest to unleash a procedure among patients who might not benefit, and we already have a negative trial to know that that's possible. We have the example of MITRA-FR—that we can easily identify the wrong patients—so let's try to home in on the ones who will benefit.

Mandrola: It's going to be tricky in a real-world situation to reconcile these conflicting trials.

Yeh: I think you're right, and I leave that to the real clinical experts who do these procedures a lot. Hopefully they'll be able to undertake that task.

Mandrola: Well, thanks so much for being with us today.

Yeh: Thanks, John.

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