SAN DIEGO — After misfiring in a European trial just 3 weeks ago, the MitraClip roared back with substantial reductions in key clinical outcomes in patients with heart failure (HF) and moderate-to-severe or severe secondary mitral regurgitation (MR) in the COAPT trial.
Use of the MitraClip (Abbott) on top of guideline-directed medical therapy (GDMT) reduced the risk for HF hospitalizations within 24 months by 47% (35.8% vs 67.9%; hazard ratio [HR], 0.53; P < .001) vs GDMT alone, co-principal investigator Gregg W. Stone, MD, Columbia University Medical Center, New York City, reported to an outbreak of applause and cheers here at Transcatheter Cardiovascular Therapeutics (TCT) 2018.
The number needed to treat to prevent one HF hospitalization with MitraClip was 3.1.
The rate of freedom from device-related complications at 12 months — the primary safety outcome — was 96.6%, easily passing the 88.0% target (P < .001).
All 10 powered secondary outcomes, including death and quality of life, favored the MitraClip arm, Stone said to another round of applause. When the visibly moved Stone specified that the risk for all-cause death in this very sick cohort was cut by 38% (29.1% vs 46.1%; HR, 0.62; P < .001), with a number needed to treat of 6, the packed auditorium erupted again.
"As such, MitraClip is the first therapy shown to improve the prognosis of patients with heart failure by reducing secondary mitral regurgitation due to LV dysfunction," Stone concluded in the late-breaking session.
"The results are obviously important and very impactful, not only because of the relative improvement but because of the absolute improvements in a very-high-risk group that prior to this trial had really no therapeutic alternatives," he told theheart.org | Medscape Cardiology.
The recent MITRA-FR, the first randomized trial of percutaneous MR repair in this setting, reinforced that the MitraClip was safe but showed no effect on the primary composite outcome of unplanned HF hospitalizations or all-cause death, or its components, at 1 year.
"I'm shocked at the results, especially based on what was presented in MITRA-FRANCE," Vinod Thourani, MD, chair of cardiac surgery, MedStar Heart and Vascular Institute, Georgetown University School of Medicine, Washington, DC, told theheart.org | Medscape Cardiology. "There was, quite honestly, concern that if COAPT had negative results that this whole technology, which is being pushed into this space, would have an uphill battle."
One of the most important things, he said, is that MitraClip is a relatively safe procedure and that a significant number of these patients did not end up with more radical therapies, like heart transplantation or a ventricular assist device, down the road, within 2 years. In fact, the incidence or performance of these therapies was reduced by two thirds in patients treated with the MitraClip.
"Imagine if you carried this out to 5 years, the differences would be even more profound," Thourani said. "Quite honestly, I think this is just a big home run."
Nevertheless, the question many in the packed auditorium were asking is, How could the results be so different from MITRA-FR?
There are three principle reasons, suggested Stone. Most important, COAPT enrolled patients with substantially worse MR, with a mean effective regurgitant orifice area of 41 mm2 vs 31 mm2 in MITRA-FR. Ventricles in that trial, however, were severely dilated, with a mean left ventricular end-diastolic volume of 135 mL/m2 vs 101 mL/m2 in COAPT.
"As a result, COAPT had substantially greater volumetric MR in less-dilated ventricles, so the impact was greater," he said.
Second, MITRA-FR was a real-world trial and HF medications were allowed to fluctuate in both groups, whereas maximal GDMT had failed in all COAPT patients, so few changes could be made to benefit the control arm, Stone said.
Finally, acute results of the procedure, procedural complications, and durability of the MitraClip were somewhat better in COAPT.
Asked about the outcome difference, MITRA-FR principal investigator, Jean-François Obadia, MD, Louis Pradel Hospital, Bron Cedex, France, told theheart.org | Medscape Cardiology in an email that there is "definitely no contradiction. The populations are different. The two studies complete each other."
During the panel discussion of the results, however, Obadia also observed that "the selection criteria is very severe, very severe, and as a consequence the most enrolling center in COAPT had 46 patients in a period of close to 5 years…or less than one clip per month."
"So all your conclusions are true, but for a small part of our population."
HF specialist Stefan Anker, MD, PhD, Charité, Campus Virchow-Klinikum, Berlin, Germany, pointed out that the mortality was 23% in the control arm in MITRA-FR but 46% among COAPT controls.
"This is not the mortality we are seeing in the majority of patients getting clips in Europe, where big centers clip two to five patients per week, not per month," he said. "We need to know what's going on in milder-diseased patients."
Stone estimated that about 10% of all patients with HF would meet the COAPT criteria.
A total of 1576 patients with HF and MR were considered for enrollment between September 2012 and June 2017 at 89 centers in the United States and Canada. The presence of 3-plus to 4-plus secondary MR was confirmed by a central echocardiography core lab, and 665 eligible patients were then presented by local investigators to a central eligibility committee, consisting of at a minimum a heart failure specialist and expert mitral valve surgeon.
After confirmation that all eligibility criteria were met — especially failure of GDMT and treatment with cardiac resynchronization therapy (CRT) or revascularization when necessary — 302 patients were randomly assigned to MitraClip plus GDMT and 312 to GDMT alone.
Their mean age was 72 years, three fourths were at high risk for surgery, and the mean Society of Thoracic Surgeons risk score was 7.8 in the device arm and 8.5 in the control arm.
MitraClip implantation was attempted in 293 patients, and of these, it was successfully implanted in 98% (mean 1.7 clips per patient).
Importantly, every prespecified subgroup had relative consistent reductions with the MitraClip in HF rehospitalizations, death, or the composite, Stone said.
Also, quality-of life scores on the Kansas City Cardiomyopathy Questionnaire improved by 12.5 points in the device group at 12 months, with a 5-point increase clinically significant, while becoming worse over time in the control group.
Panelist Stephan Windecker, MD, Bern University Hospital, Switzerland, who reviewed MITRA-FR when it was presented last month, called the COAPT results "conclusive."
"The size of the treatment effect in terms of mortality and repeat revascularization is beyond any doubt," he said. "To put the results in perspective, if we look at other device therapies in heart failure, these results excelled those achieved with CRT both in terms of repeat revascularization as well as mortality."
Speaking with theheart.org | Medscape Cardiology, Windecker said the larger sample size and longer follow-up may have played a role in the differing results but that the results also highlight the critical role of heart team evaluation in secondary MR.
"I think what comes out for me is that patient selection is very important for the heart team, that you are really certain these patients have secondary mitral regurgitation and failed medical therapy," he said. "And secondly, that you have expert operators, with a lot of experience and a track record performing these procedures."
Stone sounded a similar note when interviewed. "What this shows is that a heart team assessment, which not only included interventional cardiologists, cardiac surgeons, but, importantly, heart failure doctors, is critical to the success of the management of these patients," he said. "Rarely have we had studies where it includes all three disciplines, and what this study highlights to me is that we really need all three disciplines to have successful outcomes."
In a press conference, Jeffrey Popma, MD, Beth Israel Deaconess Medical Center, Boston, Massachusetts, called COAPT "breathtaking."
"I looked at these results and the first time I saw them, it just knocks you off your chair. This was a very difficult trial to perform, but the results are just spectacular."
Co-principal investigator Michael Mack, MD, Heart Hospital Baylor, Plano, Texas, described the trial as the most difficult but also the most positive he has been involved in. "This is seminal in this field."
The investigators have been in communication with the US Food and Drug Administration (FDA), Stone told reporters, adding, "I believe the FDA should act on these data."
With one positive and one negative trial, however, Sanjay Kaul, MD, Cedars-Sinai Medical Center, Los Angeles, California, countered that the FDA should wait for results from the forthcoming RESHAPE-HF2 trial before expanding the MitraClip indication.
MitraClip gained initial approval in the United States in late 2013 for patients with symptomatic degenerative mitral regurgitation considered at high risk for mitral valve surgery. The third-generation MitraClip device was approved this July.
As to how the COAPT results will affect the guidelines for functional MR, Mack told attendees after the formal presentation that "One randomized trial is clearly going to change the guidelines, and you would say probably to a 2A indication; one will probably not change it to a 1A."
Session co-moderator and coauthor of the 2017 American Heart Association/American College of Cardiology focused update on the management of valvular heart disease, Robert O. Bonow, MD, Northwestern University, Chicago, Illinois, said that the guideline committee will likely be quickly convened to review the analyses but agreed the results will have to be balanced against the RESHAPE trial.
The study was funded by Abbott. Stone reports grant from Abbott to the Cardiovascular Research Foundation during the conduct of the study; receiving personal fees from Claret, Ablative Solutions, Matrizyme, Miracor, Neovasc, V-Wave, Shockwave, Valfix, TherOx, Reva, Vascular Dynamics, Robocath, HeartFlow, Gore; and other renumeration from the MedFocus family of funds, Ancora, Cagent, Qool Therapeutics, Aria, Caliber, SpectraWave, and the Biostar family of funds. His employer, Columbia University, also receives royalties from Abbott for sale of the MitraClip. Thourani is an advisor to Edwards Lifesciences, Boston Scientific, Abbott, and Gore Vascular. Windecker reported receiving research grants from Epic and being involved in studies related to MitraClip. Bonow reports no relevant disclosures.
N Engl J Med. Published online September 23, 2018. Full text
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Cite this: COAPT Stuns, Resurrects MitraClip in HF With Mitral Regurgitation - Medscape - Sep 23, 2018.