MITRA-FR at 2 Years: Still No Benefit of MitraClip Over Meds

PARIS, France—Even after following patients for another 12 months, MITRA-FR investigators have the same answer they did 1 year ago: percutaneous repair of functional mitral regurgitation (MR) using the MitraClip (Abbott) is no better than medical care in decreasing the risk of all-cause death or unplanned heart failure hospitalizations.

“These 24-month results of the MITRA-FR trial confirm that the addition of a percutaneous clip to medical treatment did not decrease the rate of death or unplanned hospitalization,” lead investigator Jean-François Obadia, MD (Civil Hospices of Lyon, France), said here at the European Society of Cardiology Congress 2019.

Results were published simultaneously in the European Journal of Heart Failure.

The 2-year findings came as no surprise to Gregg Stone, MD (Cardiovascular Research Foundation, New York, NY), who called them “fairly predictable based on the 1-year results. I would have been somewhat surprised if the 2-year results had become positive, although in COAPT, the mortality difference did not emerge until 2 years.”

It’s almost 1 year to the day since Obadia presented the 12-month results from the French MITRA-FR trial, prompting rabid speculation as to whether the somewhat larger COAPT trial, led by Stone and Michael Mack, MD (The Heart Hospital Baylor, Plano, TX), due out within weeks, would also come up short. When unveiled at TCT 2018, COAPT showed a near-halving of the risk of HF hospitalizations at 2 years. In the ensuing months, the extent to which these two trials both complement and contradict one another has been the source of endless speculation and debate, with the different trial durations being a key discussion point.

Today, some questions—but not all—were finally answered. As Obadia showed here, 24-month rates of the composite primary outcome all-cause mortality or unplanned heart failure hospitalization were similar in both groups: 64.2% for the MitraClip patients and 68.6% for those managed medically, a nonsignificant difference.

Secondary outcomes, including death from any cause, cardiovascular death, unplanned hospitalizations for heart failure, and MACE numerically favored the clip group but did not significantly differ.

MITRA-FR 24-Month Outcomes: Intention to Treat

Obadia and colleagues also conducted a new, post-hoc analysis intended to more closely mirror the way events were tallied in COAPT, which used a repeat-event analysis for HF hospitalizations as compared with the time-to-first-event approach used in MITRA-FR.

In this exploratory analysis looking at the cumulative incidence of hospitalizations for heart failure patients over the course of MITRA-FR, the investigators showed that event curves started to separate at 1 year and continued to diverge out to 24 months, with a nonsignificant trend toward more hospitalizations occurring in the medically managed patients.

But the pattern, Obadia acknowledged, implies that “the results today are not completely neutral. We were surprised by this.” That said, this was not a prespecified analysis and should not be overinterpreted, he cautioned.

Next Steps, New Questions

MITRA-FR and COAPT investigators are now planning a combined, patient-level meta-analysis that they hope will help them drill down into echocardiographic and other factors to identify who will benefit most from a percutaneous clip. This will take some time, Obadia told TCTMD, since French patients need to be reconsented in order to have their information pooled with an American data set.

The MITRA-FR investigators also plan to follow their patients out to 5 years to see if the signal of diverging outcomes continues. Of note, said Obadia, it won’t be possible to pool longer-term data with COAPT, since patients in the US trial initially randomized to optimal medical therapy are now permitted to cross over to percutaneous clip therapy. In MITRA-FR, said Obadia, patients will not be permitted to undergo MitraClip therapy until the 5-year mark has passed.

Discussing this with TCTMD after a morning press conference, Obadia bristled at the idea that this was in any way unfair for the MITRA-FR patients, since in this study patients did not benefit. “Why would we apply the lesson of another trial to the decisions for our patients?” he said.

Not a Simple Story

By Obadia’s count, MITRA-FR and COAPT have been cited more than 200 times in the medical literature since their release last year; fully 17 editorials have been published trying to explain why the trials reached different conclusions, he said during a morning press conference.

Twelve months after his initial presentation, Obadia seemed at least partially convinced that differences between the patients enrolled, as well as the different definitions of severe MR in France versus the United States that were used in the trials, are among the reasons for the conflicting results from COAPT and MITRA-FR. But, he continued, the interpretation of these two studies is “probably more complex than what has been said in all those editorials.”

For Stone, there are a range of possible explanations for the different results. “With the types of patients that were enrolled in MITRA-FR, with the procedural and long-term results that they obtained, with the way that heart failure medications were used as background therapy (which were allowed to fluctuate differently between the two groups), there were certainly no differences between MitraClip therapy and conservative care,” he said. “But if you take a COAPT population with more severe MR, less severely dilated left ventricles, who are failing truly maximized guideline-directed medical therapy and they still are symptomatic and you have operators who get excellent procedural results, then [the MitraClip] had a striking benefit beyond any statistical shadow of a doubt.”

Rebecca Hahn, MD (NewYork-Presbyterian/Columbia University Irving Medical Center, New York, NY), characterizing MITRA-FR as “impeccably designed and very well randomized,” reviewed many of the purported differences between the two trial populations. But instead of dwelling on the differences, Hahn proposed that the patient groups may actually be “more concordant than previously thought.”

Reiterating a point alluded to by Stone, Hahn noted that medical therapy in MITRA-FR was uptitrated during the course of the trial, such that patients may have been “optimized” at around the 1-year mark. This might help explain the apparent divergence in the HF hospitalization analysis, she hypothesized.

“The additional benefit of mitral repair in all patients with optimal, aggressive medical therapy still needs to be proven,” she concluded. “I applaud the two groups of investigators for wanting to answer those questions.”

Mariell Jessup, MD, chief science/medical officer of the American Heart Association, commenting on the results for TCTMD, said that the heart failure community is still struggling with the disparate results and echoed the sentiment that the “MitraClip story” in functional MR “is not a simple one.” Jessup is hopeful the patient-level meta-analysis promised by Obadia will offer insights on what matters for clip success—be it the degree of regurgitation, the amount of left ventricular dilation, or the specific heart failure etiology—and what medical therapies need to be optimized in advance.

Jessup said she is reassured that both Stone and Obadia are emphasizing the need for medical therapies to be fully optimized before a percutaneous approach is considered and for all decisions be made by a multidisciplinary team. In the presence of so many outstanding questions about these two trials, centers will continue consider all of the options open to patients and the expertise on hand, she observed.

Uptake in the US in the wake of the Food and Drug Administration’s decision to expand the indication for the MitraClip to include functional MR has been “cautious,” she said, “so far.”