COAPT at 3 Years: MitraClip Benefits Persist, Crossovers Profit

Patrice Wendling

September 30, 2019

SAN FRANCISCO — New 3-year data from the COAPT trial show persistent benefits from mitral valve repair using the MitraClip (Abbott) and that patients initially assigned guideline-directed medical therapy (GDMT) who underwent repair after a 2 year delay achieve similar gains.

The trial scored a major victory last year when it reported — just weeks after the negative MITRA-FR trial — that MitraClip repair on top of GDMT improved survival, reduced heart failure (HF) hospitalizations, and resulted in better quality of life than GDMT alone at 2 years.

Michael Mack

At 3 years, the difference in the primary effectiveness end point is "even more pronounced," with HF hospitalizations reduced 51% with the MitraClip (hazard ratio [HR], 0.49; 95% CI, 0.37 - 0.63) and the number needed to treat (NNT) down from 3.2 to 3.0, Michael Mack, MD, Baylor Scott and White Heart Hospital, Plano, Texas, said in a late-breaking clinical trial session here at Transcatheter Cardiovascular Therapeutics 2019.

Freedom from device-related complications, the primary safety end point, held constant after the first 30 days, at four events, in the intention-to-treat analysis.

For the end point of all-cause mortality or HF hospitalization used in MITRA-FR, Kaplan-Meier estimates for the MitraClip and GDMT diverged from 44.5% and 66.6%, respectively, at 2 years to 58.8% and 88.1%, respectively, at 3 years (HR, 0.48; 95% CI, 0.39 - 0.59). The NNT fell from 4.5 to 3.4, he said.

Crossover Patients

A second analysis focused on the patients who crossed over to MitraClip repair, which was allowed at 24 months but is not an option in MITRA-FR until the final follow-up at 5 years. Of the 312 GDMT-only patients, five ultimately crossed over before 24 months and 53 did so between 24 and 36 months.

Among these 58 patients, 13.8% were hospitalized for HF within 12 months, a rate comparable to those originally assigned to the MitraClip, Mack said.

However, all-cause mortality, at 18.2%, was not different from those who continued on medical therapy, but was comparable to patients originally assigned to the MitraClip.

"We only saw the mortality benefit of MitraClip starting at 12 months afterward, so it's not surprising we don't see a mortality benefit yet," he said "Again, this is reflected in the multivariate predictors, which do not show significance with MitraClip" (HR, 0.89; P = .79).

During a discussion of the results, session comoderator Stuart J. Pocock, PhD, London School of Hygiene and Tropical Medicine, said: "It's fascinating to see, even though the crossovers are a select group, that they behave very similarly to those who were randomized at time zero in terms of event rates. I think that is a reassurance."

Mack, however, pointed out that only 38% of patients crossed over and a significant number (124) died before they had the opportunity to cross over, so "in all likelihood there is some selection bias.

"If you get it, yes, you have results comparable initially, but this is a select group and I think needs to be interpreted cautiously with that in mind."

A Bit Too Late?

Several panelists commented on the high mortality rate, which overall reached 42.8% with MitraClip and 55.5% with GDMT alone at 3 years, and the implications this has on the treatment of mitral valve disease and future trial design.

"We identified a group of patients who, even with significant improvement in the COAPT study as we can see here, are still dying and still coming back to the hospital. So the question is: Is all of this already a little bit too late?" Nir Uriel, MD, University of Chicago, said.

"I think that this calls for a very aggressive approach in mitral regurgitation patients," he said.

Michael A. Borger, MD, PhD, head of cardiac surgery at the Leipzig Heart Center, Germany, said the results are "very, very impressive" and confirm the European experience, but that patient selection remains an issue.

"You have the best characterized MitraClip patient population probably in the world right now. Can you identify those patients who either die or do not have a quality-of- life benefit?" he asked.

In response, Mack highlighted the concept put forth by Milton Packer, MD, and Paul Grayburn, MD, that distinguishing MR as proportionate or disproportionate to the degree of left ventricular dilatation can help guide the selection of optimal treatment for patients with MR.

"I think that is an interesting concept because we've been consistently saying all the way along you need to fail medical therapy and Dr Packer is convinced he can identify those patients, right out of the gate, with disproportionate MR who are not going to respond to medical therapy," Mack said.

Additional analyses are planned on the crossover patients, but it may be that some were too sick to undergo MitraClip repair, others may have been doing well on GMDT, and some may have been unaware that crossover was an option for them, he added. Notably, 85 of the GDMT-only patients chose not to crossover and 169 were ineligible because of death, transplantation, left ventricular assist device implantation, or study withdrawal.

Inappropriate Patients

Speaking to theheart.org | Medscape Cardiology, Borger said one of the big questions is whether the very positive COAPT data will result in the MitraClip potentially being applied in inappropriate patient populations.

"We have to try to figure out a way, probably not just through medical education but possibly also financially, to ensure that people are applying this in the correct patient population," he said. "So tying it to reimbursement, for example, I know is being discussed; that the patients are being screened to make sure they are meeting the criteria for COAPT rather than applying it for all patients with MR."

Borger said he wasn't surprised by the mortality rate in COAPT because once patients develop significant myocardial fibrosis, which was likely the case for patients in the analysis, mortality is much higher than what would be seen in the baseline population.

"The results are impressive and I caution against overapplication to patients who don't meet the inclusion criteria," he said. "But the reality is that it's probably going to be, nonetheless, implanted in a lot of patients who do not meet the inclusion criteria. That's just the reality of medicine."

Comoderator Juan Granada, MD, executive director and chief innovation officer at the CRF Skirball Center for Innovation, New York City, said extensive imaging and functional work is ongoing to differentiate patients with MR who will and will not benefit from earlier MitraClip repair and that this is "perhaps the most important question right now in this field."

The COAPT and MITRA-FR data already provide some insights into risk stratification and patient selection, such as moderate to more-severe disease, more MR, and bigger MR jets, he said.

"I think COAPT is already showing a population that we know could benefit and we can expand on that and go earlier," Granada said.

COAPT was funded by Abbott. Mack disclosed being coprincipal investigator for the PARTNER 3 trial, funded by Edwards Lifesciences; study chair of the Apollo trial, funded by Medtronic; and a consultant for Gore. Borger reported speaker honoraria and consultant fees to his institution from Edwards Lifesciences, Medtronic, Abbott, and CryoLife. Granada reported having no relevant conflicts of interest.

Transcatheter Cardiovascular Therapeutics (TCT) 2019. Presented September 28, 2019.

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