Is COAPT Designed to Fail? Experts Debate Treatment Timing in Severe Functional MR
Some experts fear the trial’s enrollment criteria, requiring prior HF hospitalizations and severe MR, may mean a clip is too little, too late.
WASHINGTON, DC—After a 6-year wait, the full results of the COAPT trial are eagerly expected later this year, but experts in the field are already questioning whether the study is asking the right question when it comes to the treatment of patients with functional mitral regurgitation (MR).
In a session devoted to mitral valve disease at CRT 2018 here, Francesco Maisano, MD (University Hospital, Zurich, Switzerland), reviewed the current status and future directions for percutaneous treatment of MR. And he posed a question to experts keeping a close watch on this field: were the patients included in COAPT too far gone to show any treatment benefit?
“Even a parachute doesn’t work if you open it too late,” said Maisano.
The COAPT study investigators randomized patients with class 3 or greater functional MR and symptomatic heart failure to receive either MitraClip (Abbott Vascular) or optimal medical therapy. The primary efficacy endpoint is recurrent heart failure hospitalization, and the primary composite safety endpoint includes a number of possible complications.
To be included in the study, however, patients were required to have had least one hospitalization for heart failure in the past 12 months and to have been adequately treated per applicable standards for coronary artery disease, left ventricular dysfunction, MR, or heart failure. Such therapy includes cardiac resynchronization therapy (CRT), revascularization, and/or optimal medical therapy.
“COAPT—who knows what will happen, but it is designed to fail,” said Maisano. “You’re applying the therapy like [a left ventricular assist device]. This is a patient who has not responded to CRT, who has not responded to medical therapy, and who comes back several times [to the hospital].” At the end, when the patient still has severe MR and has not responded to any therapy, only then are physicians trying the MitraClip, he added.
Michael Mack, MD (The Heart Hospital Baylor, Plano, TX), one of COAPT’s principal investigators, tentatively agreed with the assessment, but stressed the study, which is expected to be presented at TCT 2018 in September, will provide important answers.
“I think the answer is kinda, sorta, maybe,” said Mack, when asked if COAPT might have included patients too sick to show a treatment benefit of percutaneous mitral valve repair. “But the important thing is that it is the first clear randomized trial that will give some answers. It will be nice if it’s positive, but if it’s not, if it doesn’t meet its primary endpoint, there is going to be a wealth of data to sort through to find the signal of benefit, to find those patients who will benefit from the mechanical interruption of severe MR. In a way, I think it’s going to be a positive trial, but in retrospect, a lot of people do agree that the bar was set too high and it may be too late [for intervention].”
Given that, Mack said several centers have initiated “COAPT-lite” studies, essentially loosening the entry criteria to include healthier patients in those trials.
Steven Goldstein, MD (MedStar Washington Hospital Center, DC), who also participated in the panel discussion, said that anywhere between 30% to 50% of patients with dilated or ischemic cardiomyopathy and MR who are given a “full-court press” with medical therapy show clinical improvement. For this reason, he suggested, there is a need for better risk stratification before patients are randomized into interventional trials so that physicians are treating only those with the potential for improvement.
In addition to COAPT, other studies testing the MitraClip in patients with severe functional MR are also underway. The multicenter MITRA-FR study, which includes approximately 288 patients with severe MR randomized to optimal medical therapy or treatment with the MitraClip procedure, is expected to be presented later this year, likely at the 2018 European Society of Cardiology Congress. The German MATTERHORN study is comparing MitraClip to valve repair/replacement surgery in approximately 210 patients with moderate-to-severe MR.
Is It Crazy to Intervene in Moderate MR?
During the mitral valve intervention session, Molly Szerlip, MD (The Heart Hospital Baylor), pointed out that functional MR is a disease of an abnormal left ventricle, not an abnormal mitral valve, and this has important implications for patient prognosis. Although she opened her presentation with a rhetorical question—“Are we crazy to intervene in moderate MR?”—Szerlip said the data suggest the answer is: maybe not.
For example, she highlighted a recent meta-analysis, one that included 45,900 subjects with functional (secondary) MR, showing that even mild secondary MR was associated with adverse outcomes in patients with ischemic or idiopathic cardiomyopathies. In that analysis, higher grades of functional MR were associated with worse left ventricular dysfunction.
“We know that the hemodynamic effects of MR augment the effects of the ejection fraction,” said Szerlip. “Maybe we’re treating functional MR once the [left ventricle] has already become irreversibly damaged. Maybe catching functional MR before it becomes severe, and before the LVEF is reduced, will be the [secret] to better outcomes.”
Marvin Eng, MD (Henry Ford Hospital, Detroit, MI), said there are approximately 16,000 cases of functional MR per 1,000,000 individuals. Like others, he noted prognosis is dependent on MR severity, with more severe MR linked with increased hospitalizations for heart failure and mortality. “When you catch patients in the early phase of the disease, with class 1 or 2 symptoms, they do better over the long term,” said Eng.
Steven Bolling, MD (University of Michigan, Ann Arbor), who chaired the session along with Ted Feldman, MD (NorthShore University HealthSystem, Evanston, IL), said that surgically intervening on “patients further upstream”—that is, when MR is still moderate—comes with significantly higher “emotional and biological burdens.” With percutaneous mitral valve repair, maybe physicians can pull the parachute ripcord earlier, suggested Bolling.
During the session, Feldman noted there have been discussions about whether or not it might be better to treat moderate functional MR before the ventricle is too badly damaged. However, one of the objections to studying moderate MR is that a very large number of patients would be needed in randomized trials to show a difference in clinical outcomes.
Szerlip agreed. “I think you’re going to need a lot of patients to be able to show a difference in moderate MR,” she said. “It’s a problem.” An additional problem is identifying patients accurately, she said, noting there is much variability and subjectivity in quantifying MR, particularly moderate MR.
At present, the American Heart Association/American College of Cardiology guidelines do not recommend intervening in patients with moderate functional/secondary MR, even in the setting of concomitant CABG or aortic-valve surgery. In patients with degenerative/primary MR, use of MitraClip, the only US Food and Drug Administration-approved percutaneous mitral valve repair device, “may be considered” for symptomatic patients with severe regurgitation who have a prohibitive risk for surgery.
MitraClip is not approved in the United States for functional MR—that regulatory decision hangs on COAPT. In Europe, percutaneous edge-to-edge repair is a class IIb indication (level of evidence C) in highly selected patients with functional MR.
Mitral Valve Basics. Presented at: CRT 2018. March 4, 2018. Washington, DC.
- Maisano reports consulting for receiving research support from, and/or holding stock in 4tech, Abbott, Bioventrix, Direct Flow, Edwards, Medtronic, Mitraltech, Perifect, TSP Medical, and Xeltis.
- Mack reports serving as the co-principal investigator of COAPT, receiving material support from Medtronic and Edwards Lifesciences, and serving on the executive committee of the PARTNER and APOLLO trials.
- Szerlip reports serving on the speaker’s bureau for Medtronic and Edwards Lifesciences.
- Bolling reports material support from Edwards Lifesciences.
- Feldman reports consulting for Abbott, Boston Scientific, and Edwards Lifesciences.
- Goldstein and Eng report no relevant conflicts of interest.