Delegates at the 2018 Transcatheter Cardiovascular Therapeutics (TCT) meeting (21-25 September, San Diego, USA) broke into spontaneous applause after Gregg Stone (Columbia University Medical Center, Cardiovascular Research Foundation, New York, USA) reported that, according to the results of the COAPT trial, percutaneous edge-to-edge repair (MitraClip, Abbott) for the management of secondary mitral regurgitation significantly reduces the rate of heart failure hospitalisations at two years. Stone garnered further applause when he revealed MitraClip to reduce all-cause mortality.
The COAPT (Cardiovascular outcomes assessment of the MitraClip percutaneous therapy for heart failure patients with functional mitral regurgitation) trial was easily the most hotly anticipated trial of TCT. Just under a month before TCT, the MITRA-FR was presented at the 2018 European Society of Cardiology (ESC) Congress (25-29 August, Munich, Germany) and indicated that MitraClip for secondary mitral regurgitation did not provide a prognostic benefit. Prior to MITRA-FR, no data were available for the beneficial effect of MitraClip (for secondary mitral regurgitation) on hard outcomes (such as all-cause mortality). Therefore, many at TCT were eager to see if COAPT would confirm or refute the findings of MITRA-FR.
In COAPT, 614 patients with moderate-to-severe (3+) or severe secondary mitral regurgitation (4+) were randomised to receive MitraClip plus guideline-directed medical therapy (302) or guideline-directed medical therapy alone (312). According to Stone, a “key aspect” of the study was that a Central Eligibility Committee confirmed that enrolled patients met the eligibility criteria, “especially the use of maximally-tolerated guideline-directed medical therapy for heart failure”. He stated that enrolment of patients who were not receiving the maximal tolerated doses of therapy was deferred and these patients could be represented if suitable therapy had been instituted and the patient was still symptomatic. However, Stone revealed that none of the deferred patients came back. While admitting some of these patients died, he reported that others “did do better” after their medical therapy was revised and, thus, did not need to come back. This policy meant that there few major changes in heart failure medication during follow-up. By contrast, in line with real-world practice, the protocol of MITRA-FR allowed variable adjustment in heart failure medication after baseline.
The primary effectiveness endpoint of COAPT was the annualised rate of all heart failure hospitalisations through 24 months and the primary safety endpoint was freedom from device-related complications at 12 months (in MITRA-FR, the primary outcome was the rate of all-cause mortality and unplanned heart failure hospitalisations at 12 months). Stone reported that the primary effectiveness endpoint was significantly reduced in the MitraClip group at two years: 160 events vs. 283 for guideline-directed medical therapy alone group (p<0.01). Upon hearing this result, the audience burst into applause and Stone had to wait for them to stop clapping before revealing the number needed to treat with MitraClip to prevent one heart failure hospitalisation was 3. He added that the primary safety endpoint was also met: 96.6% freedom from device-related complications vs. a performance goal of 88% (p<0.001).
Further applause from the audience came when Stone announced that all 10 of the powered secondary endpoints were met. In particular, MitraClip was associated with a significant reduction in all-cause mortality at 24 months: 29.1% vs. 46.1% for guideline-directed medical therapy (p<0.01). Stone commented: “Mortality started to diverge after two years, suggesting the importance of a sustained durable relief of left ventricular overload.” In MITRA-FR, there were no significant differences between the MitraClip group and the medical therapy group at 12 months in the either the composite primary outcome of death and unplanned heart failure hospitalisation or in the secondary outcome of all-cause death.
Concluding, Stone said: “In patients with heart failure and moderate-to-severe or severe secondary mitral regurgitation who remained symptomatic despite maximally-tolerated guideline-directed medical therapy, transcatheter mitral leaflet approximation with the MitraClip was safe, provided durable reduction in mitral regurgitation, reduced the rate of heart failure hospitalisations, and improved survival, quality-of-life and functional capacity during 24-month follow-up. As such, the MitraClip is the first therapy shown to improve the prognosis of patients with heart failure by reducing secondary mitral regurgitation due to left ventricular dysfunction.”
He added that he and his coinvestigators felt that, potentially, there were “three principal reasons” as why the outcomes of COAPT and MITRA-FR were different. The first of these was that the patients enrolled in COAPT were different from those enrolled in MITRA-FR. Stone observed that patients in COAPT had, on average, more severe mitral regurgitation—mean baseline regurgitant orifice area (EROA) was 41±15mm3 vs. 31±10mm2 in MITRA-FR—while left ventricular end-diastolic volume was greater in MITRA-FR (135±35mL/m2 vs. 101±34mm in COAPT). The other two reasons were the aforementioned different approaches to guideline-directed medical therapy and different acute results (e.g. the rate of procedural complications were higher in MITRA-FR).
The discussion following Stone’s presentation focused on which patients with secondary mitral regurgitation would benefit the most from MitraClip, with the consensus being that both MITRA-FR and COAPT helped the community to better understand optimal patient selection for the procedure. Stone said: “The disparity between MITRA-FR and COAPT tells us that not all patients are going to benefit from a MitraClip. That if you treat patients whose ventricles are ‘too blown’ and who do not have severe mitral regurgitation, they are not going to benefit from MitraClip. In COAPT, we tried to select patients who were in the ‘sweet spot’ between having really severe heart failure but who were not so far gone that they would not benefit from reducing that aspect [i.e. regurgitation] of their overload status.”
The investigator of MITRA-FR Jean-Francois Obadia (Hôpital Cardiovasculaire, Louis Pradel, Chirurgie Cardio-Vasculaire et Transplantation Cardiaque, Lyon, France), who took part in the discussion, agreed with Stone that the disparity between the two studies provided useful information. He said: “I think it is the best scenario we could have. If they were both positive or both negative, that would have been the end of the story. But, the difference leads us to go deeper into the analysis of the results and to try to understand this complex disease,” adding that the studies say “what you should do [i.e. COAPT] and what you should not do [MITRA-FR]” in terms of patient selection.
Stone told Cardiovascular News: “For the MitraClip to be effective in heart failure, it is important that despite trying maximal doses of all heart failure medications and cardiac resynchronisation if indicated, the patient remains symptomatic and has severe secondary mitral regurgitation without excessive left ventricular dilatation. An expert operator must also be available who can successfully implant one or more clips without complications.”
COAPT was simultaneously published in the New England Journal of Medicine.