tctmd.com
In the list of “hot line” trials just released by the European Society of Cardiology (ESC) for its upcoming congress is one that many cardiologists may have all but forgotten they’d been waiting for.
RESHAPE-HF 2, still underway in Germany, was once widely anticipated as the crucial third trial for the MitraClip (Abbott) in functional mitral regurgitation (FMR) after two others delivered conflicting results. MITRA-FR, investigator initiated and conducted in France, found no difference in rates of all-cause death and unplanned rehospitalizations for heart failure at 12 months in patients randomized to a MitraClip versus best medical care. By contrast, COAPT, funded by Abbott and conducted in Canada and the United States, found that clip repair significantly reduced not only the primary endpoint of heart failure (HF) rehospitalization but also mortality at 2 years.
One observer, following COAPT’s enthusiastic reception at TCT 2018, told TCTMD he hoped the US Food and Drug Administration would hold off on extending MitraClip’s indication to FMR until RESHAPE-HF 2 was done.
That didn’t happen. The first device for transcatheter-edge-to-edge repair (TEER), as it came to be called, sailed through the FDA’s regulatory hoops within 6 months of COAPT’s release, gaining an indication for functional (secondary) MR. Soon after, guidelines in both the United States and Europe gave TEER a class 2a recommendation for patients with severe secondary MR, suitable anatomy, and persistent symptoms despite being treated with guideline-directed medical therapy.
Speaking with TCTMD last month, Stefan Anker, MD, PhD (Charité University, Berlin, Germany), the principal investigator for RESHAPE-HF 2, said he’s well aware that many have been hoping the German trial would help shed new light on old questions. Whether that proves to be the case awaits his ESC presentation, but Anker stressed that RESHAPE-HF 2 has enrolled a patient population quite distinct from those in MITRA-FR and COAPT. The baseline details for these patients were published late last month in the European Journal of Heart Failure.
As Anker and colleagues summarize in the paper, RESHAPE-HF 2 is comprised primarily of patients with moderate-to-severe FMR, defined as an effective regurgitant orifice area (EROA) of 0.25. COAPT and MITRA-FR, by contrast, recruited patients with severe FMR (EROAs of 0.40 and 0.31, respectively). Participants in all three trials are roughly similar with regard to age, comorbidities, use of cardiac resynchronization therapy, and LVEF, they add, but RESHAPE-HF 2 patients may have been “less sick” than those in the earlier studies, with lower mean NT-proBNP levels and better kidney function.
On the basis of MR severity, only a minority of RESHAPE-HF 2 patients overlap with those of the prior trials. Just 44% had an MR severity grade of 4+ (with 9% having an EROA > 40 mm2) compared with 41% in COAPT.
RESHAPE-HF 2 “represents the most contemporary cohort of patients for MitraClip and aims to extend the evidence for TEER to patients with less severe FMR,” the authors write. And notably, guidelines on both sides of the pond do not recommend TEER for patients with anything less than severe MR.
Welcome New Data
After the release of COAPT and MITRA-FR in 2018, Anker told TCTMD that he and his co-investigators were hoping to get grant support to resize their trial, something that did eventually happen. In last month’s interview, Anker said the study was “originally planned with a number of patients that was unrealistically small” to deliver a conclusive result, but that the grant renegotiation process delayed trial enrollment and follow-up by at least 2 years.
“In the end, the official number of patients recruited is 505, so we are very happy about this, really very happy,” he said. “Yes, it took long. . . . But now within 8 weeks, the world will see the results.”
Also of note, key trial endpoints have shifted. As investigators explain in a design and rationale paper, also published this spring, RESHAPE-HF 2 was originally designed to use a primary composite endpoint of total HF hospitalizations and CV death during 2 years of follow-up, similar to COAPT and MITRA-FR (although the latter was 1 year, not 2).
A blinded review in 2018, based on results in 355 RESHAPE-HF 2 patients, indicated not only that all-cause mortality rates were tracking lower than the other two trials, but also that follow-up needed to be extended, something that would prove difficult due to the consent forms initially signed by patients. The trial steering committee agreed in 2023 to extend recruitment, and earlier this year they agreed to extend the planned primary endpoint with two additional, separate primary endpoints. These were total HF hospitalizations at 24 months and change from baseline to 12 months in the KCCQ overall score. The trial would then employ a Hochberg procedure analysis plan, allowing for the trial to be positive with one, two, or three positive primary endpoint results based on different P-value cutoffs.
Acknowledging that changes to trial design tend to face some blowback in the academic cardiology circles, Anker said merely, “Let’s wait and see the results and then let's have that discussion.”
Commenting on the news that RESHAPE-HF 2 will at last be unveiled, Federico M. Asch, MD (MedStar Health Research Institute, Washington, DC), said that many physicians working in this space are interested to see these results, though not necessarily because they might settle lingering questions over which of the two earlier studies was better.
“I wouldn’t say that this is going to be untying the tie,” Asch said. “I don’t think this is going to say, ‘Oh, COAPT was right and MITRA-FR was wrong,’ or the other way around. These are just different studies. Whatever the results are, we will have to dig deep and understand how things may be similar or different, but each study has value on its own.”
A number of observational studies have hinted that TEER may have benefits in more moderate MR, Asch continued, pointing out that TAVI, too, was first approved in the “sickest” patients before moving into lower-risk, less-complex groups; results for the first TAVR trials in asymptomatic aortic stenosis are expected later this year.
In the case of TEER, Asch said, patients with moderate MR are only one group in whom studies are ongoing. Indeed, clip repair has also been studied in the context of bridge-to-transplantation, acute MR after MI or CV surgery, and hypertrophic cardiomyopathy, to name a few.
“There's many more questions to be answered, . . . and we are far from done with posing new questions and addressing new needs,” Asch said. “I think we’ve only cracked the shell.”