My Takeaways From TCT 2018: Sunglasses, Shadows, and the COAPT Eclipse
TCT 2018 will go down as the year that COAPT stole the spotlight. Flooding into its wake are explanations and questions as to what comes next.
SAN DIEGO, CA (UPDATED)—I felt a pang of sympathy for 26 of the 27 “late-breaking” studies presented this year at TCT. In the lead-up to the meeting, rumors were rampant that COAPT was “different” than MITRA-FR, but few of the people crowded into the TCT Main Arena on September 23 seemed to have anticipated the magnitude of the difference and just how much the MitraClip-treated patients would benefit. Other trialists presenting studies that day must have felt a bit like the movie producers for The Full Monty, Good Will Hunting, or L.A. Confidential—all nominated for Best Picture at the 1998 Academy Awards. Fine films, to be sure, but no match for Titanic, which swept the Oscars that year.
Near, far, wherever you are, you’ll likely have heard the results of COAPT. In more than 600 patients with heart failure and severe functional mitral regurgitation (MR), transcatheter mitral valve repair using the percutaneous clip procedure on top of guideline-directed medical therapy (GDMT) significantly reduced not only the primary endpoint of heart failure (HF) rehospitalizations by 47%, but also mortality at 2 years, by 38%, as compared with people treated with GDMT only.
The main results, the mortality finding, as well as results for the 10 other secondary endpoints—all statistically significant in favor of the MitraClip—produced whoops of excitement and spontaneous applause in the audience.
The last time I saw an audience respond with such unfettered excitement was my first year as a cardiology reporter, in 2001. That’s the year Marie-Claude Morice, MD (Cardiovascular European Research Center, Massy, France), unveiled results for RAVEL: the first randomized, double-blind trial of a drug-eluting stent. I don’t recall Morice being interrupted mid-presentation, but I do remember the packed, standing-room-only audience erupting into effusive applause the moment she finished. It was an unscripted, heartfelt reaction I thought I’d see repeated again and again covering this field, but I haven’t.
More than a decade and a half later, COAPT presenter and co-principal investigator (PI) Gregg Stone, MD (NewYork-Presbyterian/Columbia University Irving Medical Center, New York, NY), looked uncharacteristically awash at the audience reaction. Following the trial Q&A, Stone and co-PI Michael Mack, MD (The Heart Hospital Baylor, Plano, TX), actually reached for one another and embraced.
Mack has been a practicing cardiovascular surgeon for the better part of four decades. Speaking with TCTMD last week he said he’d never in his career seen such a response during a clinical trial presentation.
“That was pretty amazing, and I would say unprecedented,” he said. “Part of the reason was the anticipation of this trial was so great, because the trial took so long to complete, and then there was a negative trial being presented less than a month before. I think there was a lot of concern that this trial would be negative or only mildly positive. . . . When the trial was so dramatically positive, that led to the emotional response from the audience.”
An emotional response from the trialists, too, by the looks of things, but he downplayed this. “Obviously we were happy and surprised by the audience response,” Mack said. “It's been almost a 10-year journey. So to have the journey end this way . . . it’s an emotional moment, sure. Of course it's emotional.”
Reaction to COAPT
COAPT results eclipsed much of the other news coming out of TCT, produced a geyser of reactions, and generated widespread mainstream-media coverage. This included a dramatic spot on Dr. Oz last week where Stone himself was a guest and Mehmet Oz, MD—not everyone’s preferred poster boy for evidence-based therapies—managed to mention that he himself wrote the patent for the MitraClip. In fact, the patent written by Oz and others at Columbia University describing a beating heart, surgical edge-to-edge repair technique was acquired by Evalve, the company that developed and commercialized the MitraClip. Those claims were incorporated into Evalve's broader patent, company founder Fred St. Goar, MD, explained to TCTMD.
Late in the Dr. Oz segment, a patient treated with the device stepped on stage to speak energetically about her new lease on life.
Speaking with TCTMD, Saibal Kar, MD (Cedars-Sinai Medical Center, Los Angeles, CA), pointed out that Oz’s comments regarding the patent were exaggerated, noting that others had similar ideas and were involved in the patent, not to mention it was Ottavio Alfieri and colleagues who first came up with the “Alfieri stitch.” Kar did, however, agree that the patient featured on the show was an accurate reflection of the kind of improvements he saw among some of the people he treated in COAPT, and he was the biggest enroller in the trial. While not all patients do this well, he said, this particular person was emblematic of the types of dramatic improvements seen among the best responders in the trial.
Attention is turning now to what happens next.
“If the device is approved by the Food and Drug Administration [FDA] for treatment of severe heart failure, as expected, then insurers, including Medicare, most likely will cover it,” reporter Gina Kolata wrote in the New York Times.
To the world out there, including the FDA, you have one positive trial and one negative trial, so what do you do? Michael Mack
These next steps, however, are the source of much discussion. Sanjay Kaul, MD (Cedars-Sinai Medical Center, Los Angeles, CA), speaking with TCTMD during TCT 2018, urged the FDA to wait for the results of RESHAPE HF 2.
Stone, however, believes the FDA should move swiftly to approve expanded MitraClip indications based on what is known so far, a point he stressed in a presentation during an FDA Town Hall Meeting at TCT 2018. Specifically, he pointed to the groups that he believes stand out in post hoc analyses as those who will and won’t benefit.
“The only subgroup from COAPT we’ve found that did not benefit was those with a small amount of MR (EROA < 30 mm2) and a large LV (greater than the median of 96 mL/m2),” he told TCTMD in an email. “MITRA-FR enrolled many such patients, whereas COAPT enrolled few.”
To be exact: 52% of patients in MITRA-FR had an EROA of < 30 mm2 as compared with 14% in COAPT. “This is likely one of the main reasons why MITRA-FR failed, and we now have confirmation from COAPT,” Stone said. “Patients won’t benefit if they have a small amount of volumetric MR from a very large LV—the relative proportion of MR and its contribution to the volume overload state is just not large enough such that correcting it makes a clinically significant difference.”
The Elephant in the Room
Mack, speaking with TCTMD, called MITRA-FR “the elephant in the room,” adding that it will be up to the FDA to decide whether or not the analyses are persuasive.
“I think we've been able to figure out who are the nonresponders and why MITRA-FR was not positive: that’s for trialists to sift through the weeds and compare,” he said. “But to the world out there, including the FDA, you have one positive trial and one negative trial, so what do you do? Do you convene an FDA expert panel to help the FDA dissect through the results? . . . I have no idea whether there will be an FDA panel or not, but I do think the FDA set a high bar here for this trial, which was one reason it was so difficult to enroll, and you can't ignore the fact that the trial was so positive.”
Beyond an FDA decision is Centers for Medicare & Medicaid Services (CMS) coverage, he noted, predicting that the process of reopening a national coverage determination (NCD) for MitraClip, following an FDA decision would likely last “9 months to a year.”
Mack, asked whether he thinks the extraordinarily positive COAPT results will lead to more off-label use before an FDA decision, acknowledged that this was a very real possibility, but said paying for it is a different matter. In the past, some physicians have gotten around the functional MR reimbursement issue by diagnosing a patient with “mixed MR”—documenting enough degenerative MR to allow for the coverage of a clip procedure.
“The FDA doesn't tell you how to practice medicine and there is room for off-label use, and we're seeing it already in the TVT Registry,” Mack noted, pointing out that 15% of MitraClip use in the US has been for functional MR. “The jeopardy that people have is committing Medicare fraud,” he continued. The MitraClip for now “is approved for reimbursement for a very specific indication, which is high-risk degenerative MR, so every hospital and hospital system and operator has different degrees of appetite for risk in terms of Medicare reimbursement, with some being extremely compliant and some not worried so much about it.”
Then there’s the questions of what guideline writing committee members should do: should they wait for the third study, RESHAPE HF 2, reputed to be nearing completion, or move faster, to help patients who meet the COAPT inclusion criteria?
“I don’t think we should wait,” COAPT heart failure co-PI William T. Abraham, MD (Ohio State University, Columbus), told me, pointing out that the RESHAPE HF 2 population is different, again, from the patients in COAPT and MITRA-FR. “I think these trials will all be complementary . . . but for now I would like to see our guidelines evolve to recommend the MitraClip in the COAPT population.”
JoAnn Lindenfeld, MD (Vanderbilt Heart and Vascular Institute, Nashville, TN), the other heart failure co-PI, chimed in, adding, “Especially when you see the mortality in the control population, that tells you we can’t wait.”
Contacted by TCTMD, principal investigator Stefan Anker, PhD (Charité University, Berlin, Germany), confirmed that mortality rates in RESHAPE HF 2 are indeed lower than in both COAPT and MITRA-FR, hinting at a different population. Investigators are also considering resizing the trial, if they can get grant support. “These efforts are ongoing,” he said in an email. “Once this is sorted, we will make public statements about it.”
Finally, there’s the implications for up-and-coming mitral therapies still in development or early testing. Both Stone and Mack believe the MitraClip must now be the comparator arm for future therapies. “Ongoing and future trials investigating surgical and transcatheter mitral valve repair and replacement techniques and devices in HF patients with secondary MR who meet these criteria, in my opinion, must include the MitraClip as an active control arm,” Stone said in his Town Hall presentation. “I don’t know how you could ethically proceed without that.”
COAPT, MITRA-FR Comparisons
Other explanations have been floated as to why COAPT and MITRA-FR came out so different.
COAPT investigators insist that the degree of maximal GDMT in the trial was critically important: patients in this trial had to be truly out of medical options at the time they were randomized to receive the clip, as determined with close consultation with HF experts. MITRA-FR, by contrast, was designed as a pragmatic trial and rates of drug use and titration during the course of the trial was not tracked although adherence to guidelines was urged.
Another potential explanation, voiced by Stone and others at TCT 2018, is that investigators participating in the North American trial may have been more experienced than those in France. Asked about this by TCTMD, MITRA-FR PI Jean-François Obadia, MD (Hôpital Cardiovasculaire Louis Pradel, Bron, France), called these remarks “unfair,” reminding TCTMD that France has an international reputation for leading in the field in valve interventions, from Alain Carpentier to Alain Cribier. He also pointed out that the trial roll-in period required a minimum experience of three patients in COAPT and five patients for MITRA-FR; moreover, the mean number of enrolled patients per center was 1.4 and 2.6, respectively.
That said, technical success and outcomes between trials paint a different picture, as Stone posited in his FDA presentation. Procedural complications were nearly twice as high in MITRA-FR than in COAPT (14.6% vs 8.5%), and residual MR class ≥ 3+ was higher post-clip for MITRA-FR compared with COAPT, both acutely (9% vs 5%) and at 12 months (17% vs 5%).
Finally, observers not involved in either trial have pointed to differences in trial design and oversight. The principle funder for MITRA-FR was the French Ministry of Health and Research National Program, with Abbott Vascular providing devices as well as support for investigators’ meetings. MITRA-FR was overseen by Hospices Civils de Lyon, a public academic institution, which assumed overall responsibility for the trial. According to the published paper in the New England Journal of Medicine, the Clinical Investigation Center of Lyon, an academic research organization, conducted and coordinated the trial and also collected the trial data, with all of the analyses performed by the statistical department at Hospices Civils de Lyon.
COAPT was sponsored by Abbott. Again, as documented by the published paper (also in the NEJM), the trial was designed by the principal investigators and the sponsor, with the PIs having unrestricted access to the data, writing the manuscript, and vouching for the accuracy and completeness of the data and analyses and for the fidelity of the trial to the protocol. The sponsor participated in site selection, site management, and data analysis.
Mack, asked whether the closer involvement of the sponsor in COAPT helps explain why it was positive and MITRA-FR was not, was adamant: “I've heard this criticism already and I feel exactly the opposite.”
“The principal investigators were the ones that called the trial design, everybody was blinded all the way through it, [and] the findings and the manuscript were all written by the principal investigators of the trial,” Mack stressed. “I would actually say that industry-sponsored trials are actually better run than government-funded trials because the budget is so much greater. You have core labs, event adjudication, research monitors, and you have FDA oversight with all this, so I would argue it’s actually a more robust situation. I know that that's a hard sell out there, to say that there's no industry influence, but there was no industry influence here at all.”
Without getting into the dollar amounts, Mack estimated that the amount of money spent in the conduct of COAPT compared with MITRA-FR “was a factor greater than fifty” and said this inevitably led to a more rigorous study.
Moreover, the FDA had “major input,” he pointed out, “which is the reason the trial was as robust as it was and randomized against medical therapy—that was all the sponsor and the FDA negotiating what would it take for the FDA to approve the device.”
Considering the severity of a population I have taken in charge for so many years, I am still questioning myself. Their results are flabbergasting and so unexpected, almost too good to be true. What else could I say? Jean-François Obadia
Also asked whether he thought the role of the sponsor had any kind of influence, Obadia reiterated a point he’s made before, namely that he believes the two different trial populations explain the different study results. Together, the two trials tell operators who should receive the clip and who shouldn’t. “I still stick to this analysis because I respect my colleagues and, in particular, Gregg Stone and Michael Mack, who have probably been very accurate in the selection of their patients,” Obadia commented. “Having said that, and considering the severity of a population I have taken in charge for so many years, I am still questioning myself. Their results are flabbergasting and so unexpected, almost too good to be true. What else could I say?”
Mack spoke to this point as well, emphasizing that the MITRA-FR trial “is more like real-world practice” while COAPT, given how carefully patients were selected for the trial, may be less “generalizable.”
“I'm concerned that in the real-world, GDMT won't be as robust as it was in COAPT,” Mack said. “The operators won't be as experienced as those in COAPT, so it's unlikely that you're going to be able to reproduce the results of COAPT in the real world."
I’d hate for readers to leave this blog without remembering the TCT 2018 runners-up—the many excellent and important trials that were relegated to COAPT’s shadow. These, in many cases, are also studies representing innovation, years of work, and the courage of patients who agreed to be enrolled in experiments without any guarantee of personal benefit.
- TALENT was the first randomized trial of an Indian-made stent versus the best-in-class Xience stent (Abbott) conducted in Europe.
- IMPERIAL, also a first, was a randomized, head-to-head comparison of two drug-eluting stents in patients with femoropopliteal disease.
- MAIN-COMPARE and SYNTAXES offered new insights into the relative strengths and weaknesses of PCI and CABG for the revascularization of coronary artery disease over long-term follow-up.
- ULTIMATE, conducted in China, compared clinical outcomes among patients undergoing stent implantation with IVUS guidance versus standard angiography.
- CorMiCa, another first of its kind study, was a randomized, sham-controlled trial of invasive tests to distinguish noncardiac chest pain from microvascular angina or vasospastic angina.
Many, many other stories, slides, and video can be found on TCTMD’s conference page. I hope you’ll take the time to check out everything else that got short shrift in the long shadows cast while COAPT hogged the stage.
I can also summon one other memory from RAVEL’s presentation so long ago. When the applause for Morice died down, one of the session chairs, Wim J. Van der Giessen, MD (Thoraxcenter, Rotterdam, the Netherlands), cautioned that even for such a promising therapy as the world’s first drug-eluting stent, future obstacles are hard to predict. “I'm quite sure we will have at least one unique sirolimus-associated adverse event," he prophesized. "I hope it will be mild."
Five years after RAVEL’s debut, the DES “firestorm” swept the cardiology community, fueled by longer-term data showing that first-generation DES were associated with a higher risk of stent thrombosis and death than bare-metal stents. The sparks eventually died down, but the years in between were a period of sober soul-searching and explosive innovation. Back in 2001, session co-chair Karl R. Karsch, MD (Bristol Heart Institute, England), was more prescient than he could have realized when he said: “There is light at the end of the tunnel [but] don't put on your sunglasses too soon."