Results of a sham-controlled randomized trial of an indirect mitral annuloplasty system showed significant reductions in functional mitral regurgitation (FMR) after 1 year of follow-up in patients with heart failure and secondary mitral regurgitation.
In an intention-to-treat analysis, the mean change in regurgitant volume at 1 year among 55 patients who received the Carillon mitral contour system device (Cardiac Dimensions; Sydney, Australia) was –7.1 mL, a reduction of 22%, compared with an increase of 3.3 mL (8%) in patients who underwent a sham procedure (P = .03), reported Horst Sievert, MD, CardioVascular Center, Frankfurt, Germany.
REDUCE FMR was positive despite significant challenges and the investigators" fears that it would flop, Sievert said here at Transcatheter Cardiovascular Therapeutics 2018.
Challenges included the unexpected finding that nearly one-third of patients in the intention-to-treat analysis had only mild (grade 1) regurgitation on baseline echocardiogram, and that nearly half of all patients had New York Heart Association (NYHA) class II heart failure. So the patient population had less severe disease than that seen in most other heart failure trials.
This wasn"t intended; it happened because patients were not screened by the core lab before they were enrolled into the trial, but the end of the trial was positive, which means despite including patients with less severe MR, still we saw an effect, which is actually a good thing to see," Sievert said.
He noted that the ongoing CARILLON US Food and Drug Administration pivotal randomized trial of the device is sham-controlled, includes echo prescreening of patients for mitral regurgitation severity, and is adequately powered for a hierarchical end point that includes key clinical end points.
The Carillon mitral contour system is an indirect annuloplasty device that consists of a wire with a distal anchor for placement in the great cardiac vein and a proximal anchor for placement in the coronary sinus. A transjugular delivery system is used for insertion.
Sievert presented results from an intention-to-treat analysis that included all randomized patients regardless of implantation status, an as-treated analysis of all patients with device implants at the end of the procedure, and a per-protocol analysis that included as-treated patients and others who met inclusion and exclusion criteria.
Patients could be included if they had dilated ischemic or nonischemic cardiomyopathy, moderate to severe FMR (defined as 2+, 3+, or 4+), NYHA class II, III, or IV heart failure, left ventricular ejection fraction (LVEF) of 50% or less (with the proviso that patients with LVEF from 40% to 50% must have MR 3+ or 4+ and NYHA class III or IV), a left ventricular end diastolic diameter (LVEDD) larger than 55 mm or an LVEDD/body surface area larger than 3.0 cm/m2, and had been on stable heart failure medication for at least 3 months.
Reasons for exclusion were hospitalization in the previous 3 months for myocardial infarction, coronary artery bypass graft surgery, or unstable angina; hospitalization in the previous 30 days for coronary angioplasty or stent placement; expectation that the patient would require any cardiac surgery within 1 year; the presence of a coronary artery stent in the implant target zone; severe mitral annual calcification; or significant organic mitral valve pathology.
Of the 120 patients randomized, 59 in the treatment group who received the device and 11 who did not for various technical reasons were available for 1-year follow-up. In the sham group, 24 patients were available for follow-up at 1 year.
For the procedure, all patients were heavily sedated, blindfolded, given noise canceling headphones, underwent coronary sinus angiogram for study eligibility, and then were randomized to receive the device or the sham procedure (an angiogram).
The echo core lab was blinded to patient randomization status and to the time of the echoes. Patients completed questionnaires about blinding at each follow-up visit, and 96% of the time they indicated that they were unsure about the treatment assignment, Sievert noted. Assessors were blinded to patient randomization throughout the 1-year follow-up assessment.
As noted, the trial met its primary end point of a reduction in mean regurgitant volume at 1 year, with an absolute difference of 10.4 mL between the device and sham groups.
The device was also significantly better in a predefined secondary analysis of change in regurgitant volume at 1 year in the as-treated analysis, which excluded the 14 patients who did not receive the device. In this analysis, mean volume decreased by 7.5 mL among 45 patients in the device group, but increased by 3.3 mL in the 13 patients in the sham group.
The per-protocol analysis showed a trend favoring the device, but the difference did not reach statistical significance (P = .06) because of the smaller sample size, Sievert said.
For the secondary end point of changes in left ventricular end diastolic and systolic volumes, the investigators observed volume reductions at both 6 and 12 months in the device group, and volume increases at 6 months with further increases at 12 months in the sham group.
Although there were no significant between-group differences in either recurrent heart failure hospitalizations, rate of total heart failure admissions per patient year, or days alive without heart-failure-related hospitalization at 1 year in the as-treated analysis, the rate of recurrent hospitalizations for heart failure in the device group was about half that of the sham group, and patients who received the device had 29 more days alive without a heart-failure-related hospitalization, Sievert noted.
There were no device-related deaths, cardiac perforations, device embolism, or surgery or percutaneous coronary interventions related to the device, and no late myocardial infarctions in the device group.
The rates of major adverse events at 1 year were 16.1% in the device group and 18.2% in the sham group.
After presentation of the REDUCE FMR data, discussant Scott Lim, MD, University of Virginia Medical Center, Charlottesville, said that he thinks the device is not quite ready for the major leagues.
"I do think one of the interesting points is that every site thought they were enrolling patients with severe functional MR," he said.
Moderator Martin B. Leon, MD, New York-Presbyterian/Columbia University Medical Center, New York City, commented that "if you want to do a study on quantitative MR, good luck, because the quality of the echoes, the ability to measure quantitative MR is extremely difficult because the drop-out is remarkable."
At a briefing prior to the presentation, discussant Michael J. Mack, MD, Baylor Health Care System, Plano, Texas, noted that "in this trial, the difference was due to both positive left ventricular remodeling in the treatment arm and continued progression in the sham control arm."
Ori Ben-Yehuda, MD, Cardiovascular Research Foundation, New York City, who moderated the briefing, said in an interview with theheart.org | Medscape Cardiology that the study data, although preliminary, are very important.
"The fact that they are able, with what is a very safe approach, to reduce functional mitral regurgitation, and that they"re showing some remodeling, is very encouraging, so kudos to them," he said.