By Jeffrey Zimmet, MD, PhD
Associate Professor of Medicine, University of California, San Francisco; Director, Cardiac Catheterization Laboratory, San Francisco VA Medical Center
Dr. Zimmet reports no financial relationships relevant to this field of study.
SYNOPSIS: The largest trial to date of MitraClip in highly selected patients with congestive heart failure and functional mitral regurgitation revealed significant reductions in heart failure hospitalization and two-year mortality.
SOURCE: Stone GW, Lindenfeld J, Abraham WT, et al. Transcatheter mitral-valve repair in patients with heart failure. N Engl J Med 2018; Sep 23. doi: 10.1056/NEJMoa1806640. [Epub ahead of print].
Recently, the MITRA-FR trial revealed no apparent benefit to percutaneous edge-to-edge repair for functional mitral regurgitation in patients with heart failure. However, the authors of the Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation (COAPT) trial just reported a seemingly opposite result. What accounts for such a dramatically different result?
COAPT was a large randomized, controlled, open-label trial that compared transcatheter edge-to-edge mitral leaflet repair with guideline-directed medical therapy alone in patients with heart failure and at least moderate-to-severe mitral regurgitation (MR). This was a rigorously directed trial in which all screened patients had imaging confirmed by an echocardiography core lab before inclusion. A central committee evaluated each patient for eligibility prior to enrollment.
Patients who were not on maximally tolerated medical therapy were sent back for further management. Patients included in the trial had advanced heart failure with a mean ejection fraction (EF) of 31% and either a heart failure hospitalization in the preceding 12 months or an elevated brain natriuretic peptide level. By design, patients with disease deemed too severe to benefit were excluded, including patients with EF < 20% and those with severe left ventricular (LV) dilatation.
Over a period of nearly five years, 614 patients at 78 centers were enrolled, with 302 randomized to the device group and 312 to control. Enrollees were, on average, 72 years of age. Approximately two-thirds were men. The etiology of cardiomyopathy was ischemic in 61% of patients and nonischemic in 39%. Among the device group, 95% had a device successfully implanted. Of these, more than 95% scored grade 2+ or lower MR at the time of hospital discharge. Device-related complications occurred in only 3.4% of patients.
The annualized rate of heart failure hospitalizations was 35.8% per patient-year in the device group vs. 67.9% per patient-year in the control group (hazard ratio, 0.53; 95% confidence interval, 0.40-0.70; P < 0.001), resulting in a number needed to treat of 3.1 to prevent one hospitalization in 24 months. While mortality at one year was not significantly different between the two groups, all-cause death at two years was significantly lower in the device group (29.1% vs. 46.1%).
Among the prespecified secondary endpoints that showed significant improvements in the device group were MR grade of 2+ or lower at 12 months, New York Heart Association functional class of I or II at 12 months, change in quality of life score, and change in six-minute walk test.
The authors concluded that transcatheter mitral repair with the MitraClip system in heart failure patients with moderate-to-severe functional MR resulted in lower rates of heart failure hospitalization and all-cause mortality at two years vs. medical therapy alone.
Much has been made of the apparent contradiction represented by the strikingly positive results of COAPT in the face of the recent negative results of MITRA FR. Some have suggested that a tiebreaker of sorts is needed (a third trial of percutaneous mitral repair in functional MR is in the works [RESHAPE-HF]). A tiebreaker is not necessary; however, more data may very well help narrow the population of patients most likely to benefit from this procedure. Although the patients in MITRA-FR and COAPT appear very similar, closer examination shows that COAPT patients overall had a greater degree of MR (mean effective regurgitant orifice area, 41 in COAPT vs. 31 in MITRA) but lesser ventricular dilatation (mean LV end-diastolic volume index, 101 in COAPT vs. 135 in MITRA). Simply put, COAPT included patients who were more likely to benefit from MR reduction and excluded patients who were too far gone to benefit. Concurrently, stricter operator procedure volume requirements in COAPT resulted in better overall procedure results (a greater degree of MR reduction with a lower procedural complication rate vs. MITRA-FR). Also, the reduction in MR was relatively durable in COAPT. At one year, 95% of procedure patients had maintained a MR of grade 2 or lower. The positive results in COAPT track with the ability of the procedure to reduce MR, which meets basic tenets of plausibility.
The COAPT results have been met with great enthusiasm in the interventional cardiology community. However, cardiologists should be careful extrapolating these results to the real world. Heart failure patients with MR are common; on the other hand, patients who fit the strict COAPT criteria were much harder to find. Sick enough, but not too sick; continued MR despite exquisite management by heart failure specialists; grading of MR confirmed by a central core lab; exclusion of a host of comorbidities, including oxygen-requiring COPD and severe pulmonary hypertension. Even the highest-enrolling center in COAPT enrolled less than one patient per month, on average.
It is highly likely this procedure will be applied to patients who do not fit the COAPT entry criteria. Before referring patients, look first to their medical management. Optimize them in every way, then reassess carefully by echocardiography. We already know what happens when this technology is applied to patients with congestive heart failure and functional MR who do not fit these criteria and who are not optimized on medical therapy. For this, we need only look to the negative MITRA FR trial for the answer.