Last year, the first two randomised controlled trials (RCT) looking at percutaneous edge-to-edge repair (MitraClip, Abbott) for the management of functional mitral regurgitation (MR) were published. MITRA-FR was presented at the 2018 European Society of Cardiology (ESC) Congress (25-29 Aug, Munich Germany), and showed no prognostic benefit for MitraClip over medical therapy for functional mitral regurgitation. In contrast, the COAPT (Cardiovascular outcomes assessment of the MitraClip percutaneous therapy for heart failure patients with functional mitral regurgitation) trial, presented at the 2018 Transcatheter Cardiovascular Therapeutics (TCT) meeting (21-25 Sept, San Diego, California), showed significant benefit in favour of MitraClip over medical therapy for all endpoints, including heart failure hospitalisation and mortality. Omar Chehab discusses the differences between the two randomised trials, and examines the implications for the future management of functional mitral regurgitation.
An obvious difference between the two trials is in their design—COAPT enrolled roughly double the number of patients of MITRA-FR (614 vs. 304), at twice as many sites (78 vs. 37), and follow-up in COAPT was 24 months, compared to 12 months in MITRA-FR.
But perhaps the most likely explanation for the difference in outcomes of the two trials lies in patient selection. COAPT applied stricter inclusion criteria, allowing patients with a left ventricular ejection fraction (LVEF) between 20 and 50%, and left ventricular end systolic diameter of ≤70mm. MITRA-FR included patients with a left ventricular ejection fraction of 15–40%, with no limit set on left ventricular (LV) size. The criteria for significant mitral regurgitation were also different. COAPT included patients with an effective orifice area (EROA) of ≥30 mm2 and a regurgitant volume (RV) of ≥45ml/beat. MITRA-FR included patients with an effective orifice area of ≥20mm2 and a regurgitant volume of ≥30ml/beat. And, unlike MITRA-FR, COAPT did not include patients with untreated significant coronary artery disease (CAD) and patients with significant pulmonary hypertension or right ventricular impairment.
When comparing the patient cohorts, the mean effective orifice area and left ventricular end-diastolic volume (LVEDV) in COAPT was 41mm2 and 101mL/m2, respectively, compared to 31mm2 and 135mL/m2 in MITRA-FR. Hence, COAPT patients had more mitral regurgitation and less left ventricular dilatation than those in MITRA-FR. Therefore, it is possible that the MITRA-FR patients had worse outcomes because the proportion of mitral regurgitation severity to left ventricular function/dimension tipped the balance towards cardiomyopathy being the prognosis-defining issue, rather than the severity of the mitral regurgitation.
Another distinction between the two trials was the uptitration of optimal medical therapy (OMT). The MITRA-FR patients were very well medicated in terms of prognostic heart failure treatment, at least matching COAPT when it came to the percentage of patients on angiotensin inhibitors, beta blockers, and mineralocorticoids; 10–12% of MITRA-FR patients were on an angiotensin/neprilysin inhibitor compared to 3–4% of patients in COAPT. In MITRA-FR, the adjustment of medication mimicked real world practice, and took place gradually after trial enrolment. Whereas a central eligibility committee determined whether a patient was already on maximal tolerated optimal medical therapy before enrolment in COAPT, and very little adjustment occurred during follow-up.
In terms of procedure safety and durability, the complication rate in COAPT was 8.5% compared to 14.6% in MITRA-FR. The short-term mitral regurgitation reduction with MitraClip was comparable in both trials—this reduction was maintained in COAPT at 12 months (94.8 % of patients had ≤grade two mitral regurgitation). In MITRA-FR, some echo data were missing, but from available information at least 48 patients in the intervention group had ≥grade two mitral regurgitation at 12 months, out of the 138 MitraClip patients.
Finally, follow-up in MITRA-FR was 12 months compared to 24 months in COAPT. A point raised in the discussion that followed the presentation of the COAPT results was that the mortality benefit was observed predominantly >one year after treatment, which favours the trial with the longer follow-up duration.
What are the implications for the management of secondary mitral regurgitation? The fact that we have had two trials with differing designs and outcomes is useful, and many regard them as complementary rather than contradictory. MITRA-FR patients and outcomes more likely reflect real world practice, whereas COAPT has demonstrated that, in the right patient, MitraClip can have significant and lasting prognostic benefit on top of optimal medical therapy.
COAPT brings into question the notion that mitral regurgitation in the diseased ventricle is a mere bystander and that the prognosis is entirely driven by cardiomyopathy. The marked improvement in survival seen in COAPT patients suggests that mitral regurgitation has an added pathophysiological role in left ventricular deterioration. Interestingly, the subgroup in COAPT that did not benefit from MitraClip were the 10% of patients with an effective orifice area <30mm2 and a left ventricular end-diastolic volume greater than the median. Going forward, it would be helpful to better understand the pathophysiological relationship between mitral regurgitation and the cardiomyopathy, and at what point treating mitral regurgitation can lead to positive remodelling and prognostic benefit.
These trials support the value of guideline-directed optimal medical therapy, resynchronisation therapy, and revascularisation where indicated. Crucially, what COAPT and MITRA-FR tell us is that timely intervention in significant mitral regurgitation can have a substantial additive benefit for a sick patient cohort who currently have a poor prognosis and high hospitalisation rate—ideally, before the pendulum swings away from the mitral regurgitation and towards the cardiomyopathy as the dominant prognosis-defining issue. We await the results of RESHAPE-HF2, the third randomised controlled trial of MitraClip in secondary mitral regurgitation, to see what this will add to the debate.
Omar Chehab is at Guy’s and St Thomas’ NHS Foundation Trust, London, UK.