2. Percutaneous Mitral Valve Repair for Patients With HF and Reduced Ejection Fraction and Severe Functional Mitral Regurgitation
Functional mitral regurgitation (FMR) secondary to left ventricular (LV) dysfunction and dilatation is an important contributor to the high mortality[3] observed in patients with HF and reduced ejection fraction (HFrEF). Observational studies and 1 previous randomized trial4 showed the potential benefits of surgical correction or percutaneous mitral valve repair (PMVR) for improving symptoms and promoting reverse remodelling. However, this has not been routinely recommended to date.[4]–[7] Such data have raised awareness regarding the importance of FMR on progression of HF and Although a number of technologies are in clinical development, edge-to-edge leaflet repair with the MitraClip system (Abbott Structural Heart) is currently the only Health Canada-approved device for PMVR. In a previous retrospective observational study mitral interventions (either transcatheter or surgical) were compared with conservative management.[8] Conservative management in patients with FMR was associated with a higher mortality compared with PMVR (hazard ratio [HR], 1.79; 95% confidence interval [CI], 1.34-2.39), with no significant mortality difference identified between the PMVR and surgical arms (HR, 0.86; 95% CI, 0.54-1.38). Of note, the death rate was numerically higher for patients treated with PMVR vs surgery (33% vs 23%), in keeping with the higher mean European System for Cardiac Operative Risk Evaluation (EuroSCORE) II observed in this group of patients (8.9 vs 4.7; P < 0.001). Because of the nonrandomized observational study design, these findings are not conclusive with respect to the role of PMVR in patients with HF and severe FMR. In 2018, 2 randomized controlled trials were published that compared the efficacy of PMVR using the MitraClip device (Abbott Structural Heart) in addition to guideline-directed medical therapy (GDMT) with GDMT alone in patients with FMR for whom mitral valve surgery was not deemed appropriate.[7],[8] These trials differed with respect to patient characteristics and outcome definitions. The Percutaneous Repair with the MitraClip device for Severe Functional/Secondary Mitral Regurgitation (MITRA-FR) 9 trial enrolled 304 patients with at least moderate-severe FMR (mean effective regurgitant orifice area of 31 mm2) and severe LV dilatation (indexed left ventricular end-diastolic volume of 135 37 mL/m2). PMVR did not provide a benefit in survival over GDMT alone (24.3% vs 22.4%; HR, 1.11; 95% CI, 0.69-1.77) or in the rate of unplanned hospitalization for HF (HHF; 48.7% vs 47.4%; HR, 1.13; 95% CI, 0.81-1.56) during the 1-year follow-up period. In contrast, the Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation (COAPT)[10] trial enrolled 614 patients after optimization of GDMT (only one-third of the screened patients were eventually randomized; Table 1) with longer (2-year) follow-up. Trial participants had higher brain natriuretic peptide (BNP) concentrations (mean, 1043 vs 800 ng/L), smaller indexed LV end-diastolic volume (101 34 mL/m2), and more severe FMR (mean effective regurgitant orifice area, effective regurgitant orifice area of 40.5 mm2 compared with the MITRA-FR population).[11],[12] Patients who received PMVR had lower all-cause mortality at 2 years compared with GDMT alone (29.1% vs 46.1%; HR, 0.62; 95% CI, 0.46-0.82; P < 0.001). PMVR also reduced the risk of HF hospitalizations (35.8% vs 67.9% per patient-year; HR, 0.53; 95% CI, 0.4-0.7; P < 0.001) and resulted in significant improvements in Kansas City Cardiomyopathy Questionnaire (KCCQ) quality of life scores and 6-minute walk distances. Taken together, these 2 trials suggest that PMVR has the potential to reduce mortality and HF hospitalization for selected patients with symptomatic moderate to severe or severe (3þ to 4þ) FMR despite optimal GDMT. For patients with moderate FMR or severely dilated left ventricles, the benefits, if any, remain unproven.[9] Some have suggested that the lack of demonstrable benefit with PMVR in the MITRA-FR trial might have been attributable to the extent of LV dilatation and negative remodelling in the context of less severe FMR and the absence of forced medical GDMT optimization. Conversely, in the COAPT trial,[10] intervention occurred earlier in the course of the disease process, with optimized GDMT having already been in place (Table 1). A third randomized controlled trial of GDMT vs PMVR therapy, a European study, A Randomized Study of the MitraClip Device in Heart Failure Patients With Clinically Significant Functional Mitral Regurgitation (RESHAPE-HF 2, NCT02444338) is currently enrolling patients with results expected by the end of 2021. Finally, a trial designed to evaluate the potential benefits of early transcatheter intervention in HFrEF patients with less severely dilated left ventricles and moderate FMR, the Evaluation of Outcomes of Transcatheter Mitral Valve Repair for the Treatment of Low Ejection Fraction and Moderate Functional Mitral Valve Regurgitation in Heart Failure (EVOLVE-HF; NCT03705312) trial, is currently under way. These trials might further refine our understanding of optimal patient selection and timing for intervention. Neither the COAPT nor the MITRA-FR trials included a surgical arm. Whether surgery or PMVR results in similar clinical benefit in patients with FMR is being addressed in the Multicenter, Randomized, Controlled Study to Assess Mitral Valve Reconstruction for Advanced Insufficiency of Functional or Ischemic Origin (MATTERHORN) randomized trial (NCT02371512) including 210 participants, with the study completed in December 2019.
Recommendation
1. We recommend that maximally tolerated GDMT, including cardiac resynchronization therapy and revascularization where appropriate, be implemented before consideration of PMVR for patients with HFrEF and severe FMR (Strong Recommendation, High-Quality Evidence).
2. We suggest that patients with symptomatic HF (HFrEF) despite maximal GDMT and severe mitral regurgitation be evaluated for PMVR (Weak Recommendation, Moderate-Quality Evidence).
3. We recommend that a multidisciplinary dedicated heart team (including interventionalists, cardiac surgeons, imaging specialists, and HF specialists) perform the evaluation and care of potential candidates for PMVR (Strong Recommendation, Low-Quality Evidence).
Values and Preferences
These recommendations emphasize optimization of all other established therapies for HFrEF and FMR before consideration of PMVR. They also highlight the role of optimizing GDMT (because this has been clearly associated with improved outcomes)[13] vs reduction in FMR severity per se. The use of multidisciplinary teams reflects the approach taken in the clinical trials to ensure excellent evaluation, care, and follow-up associated with PMVR.
Practical Tip
Caution should be used when treating FMR in patients with HFrEF because the encouraging results from the COAPT trial[10] must be considered in the context of new medical treatments that were not frequently incorporated into clinical practice when the trial was performed (sacubitril-valsartan, ivabradine),[14] as well as treatments currently under study in patients with HFrEF.
The identification of candidates with HFrEF and FMR most likely to benefit from the PMVR procedure might be informed by the characteristics of patients enrolled in the COAPT and MITRA-FR studies (Table 1). Patients with severe LV dilatation (typically LV end diastolic dimension > 70 mm) and less than severe mitral regurgitation might be poor candidates for MitraClip (Abbott Structural Heart).
Patients with FMR should first receive maximally tolerated GDMT, including pharmacological and nonpharmacological HF therapies (eg, cardiac resynchronization therapy where applicable) for a reasonable minimum period of time (eg, 3 months), before PMVR is considered.
– Patients considered for PMVR should be referred to centres with:
– Experience in the evaluation of patients with advanced HF;
– High volumes of patients with valve disease managed medically and surgically;
– High likelihood of achieving the volume of PMVR (eg, 2-4 per month) required for developing and maintaining competence in well selected patients.[15],[16]
References
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2. Grade Working Group. The Grading of Recommendations Assessment, Development and Evaluation (GRADE). 2016. Available at: www. gradeworkinggroup.org. Accessed February 16, 2016.
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