Assessing Efficacy of the MitraClip: Echocardiographic Outcomes
Editor's Note: This Expert Analysis is part of a series presenting perspectives on major ACC.19 trials. Please follow this link for the companion articles.
Patients with heart failure and secondary (functional) mitral regurgitation (MR) constitute a significant source of morbidity and mortality in cardiac surgery, with a subset of patients with ejection fractions lower than 20% and 3+ or greater MR at even higher risk of clinical decompensation. From a surgical perspective, it has been long understood that secondary MR is a left ventricular problem and that successful surgical outcomes depend on sound medical management of associated left ventricular failure preoperatively with guideline-directed medical therapy and electrophysiologic support with biventricular pacing for appropriate patients. Percutaneous edge-to-edge mitral valve repair using the MitraClip has progressively gained traction with FDA approval in 2013 for patients with primary MR at prohibitive surgical risk and added approval for heart failure (HF) plus secondary MR in March 2019. These approvals have largely been due to landmark trials like COAPT (Cardiovascular outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients with Functional Mitral Regurgitation) conducted in the US and Canadian, and the MITRA-FR trial (Percutaneous Repair with the MitraClip Device for Severe Functional/Secondary Mitral Regurgitation) conducted in France. The COAPT study has redefined the role of percutaneous transcatheter MV repair.
Published in 2018, COAPT was a randomized, open label, multicenter (614 patients, 78 centers) trial that enrolled patients with heart failure and moderate-to-severe (>3+) secondary MR despite maximally tolerated guideline directed medical therapy (GDMT). These patients were randomized 1:1 to GDMT alone or maximally tolerated GDMT plus MitraClip. The results were striking in that patients who received the MitraClip plus GDMT (device group) had a significantly lower composite rate of all-cause mortality or HF hospitalization than those on GDMT alone (device 45.7% vs. control 67.9%; HR 0.57 [95% CI 0.45-0.71], p < 0.01; NNT (24 months) = 4.5 [95% CI 3.3-7.2]). In addition, all other secondary endpoints were statistically significant in favor of the device group. The rationale for the echo sub study was in part driven by the need to assess the echocardiographic grading criteria for MR in the COAPT trial, pre and post device implant. All patients had TTE at baseline and through 24 months of follow up and all echo analyses were performed at an independent core lab using standardized ACC/ASE guidelines. Other key objectives of the sub-study were to delineate the echocardiographic characteristics of the COAPT population, evaluate serial echocardiographic outcomes and identify echocardiographic predictors of outcomes for both responders and non-responders to the MitraClip. As study investigators have mentioned, clarifying the echo grading criteria is important given the differences between the American and European guidelines. All COAPT patients had LVEFs between 20-50% and left ventricular end-systolic volume <70mm in addition to secondary MR amenable to percutaneous edge-to-edge repair. Most patients (N = 570, 85.7%) had an effective regurgitant orifice area (EROA) of > 0.3 cm2 or pulmonary vein systolic flow reversal. 10.5% of study patients (N = 70) had an EROA 0.2 cm2 to < 0.3 cm2 with one of three additional criteria (regurgitant volume > 45ml, regurgitant fraction > 40% and vena contracta width > 0.5cm. 25 patients (3.8%) had EROA either not measured or less than 0.2 cm2.
HF hospitalization and overall mortality benefit from MitraClip was noted across all echocardiographic subgroups, regardless of degree of LV dysfunction, dimensions, pulmonary hypertension or TR/MR severity. The composite of all-cause mortality or first HF hospitalization was significantly lower at virtually all levels of baseline left ventricular ejection fraction (LVEF <30%, device 45.8% vs. control 77.6%, HR 0.46 [95% CI 0.33-0.64]; LVEF ≥30%, device 44.1% vs. control 60.5%, HR 0.61 [95% CI 0.44-0.85]; LVEF ≤40%, device 43.8% vs. control 71.8%, HR 0.50 [95% CI 0.39-0.65]; LVEF >40%, device 49.7% vs. control 53.5%, HR 0.70 [95% CI 0.39-1.23]). Notably, MR severity improved in both groups at all time points through year 2, results were however significantly better in the device group (p < 0.001) with less than 7% having grade 3+ or 4+ regurgitation at all time points. Improvement was also significantly better in the device group at 1 year (improved by ≥2 grades, device 84.1% vs. control 15.9% (p < 0.0001). Improvement by MitraClip was seen in all MR criteria (p < 0.0001).
The investigators identified three key echocardiographic predictors of poor outcomes in patients treated with GDMT alone: MR severity (effective regurgitant orifice area by Proximal Isovelocity Surface Area, or PISA), baseline LVEF and tricuspid regurgitation. RVSP was the only predictor of adverse outcomes in patients who received the MitraClip and GDMT.
One of the key take home messages of this analysis was that in the evaluation process for patients requiring percutaneous edge-to-edge repair, it is arguably important to duplicate echocardiographic criteria used in the sub-study to replicate its results in real-world populations. This is a significant study because it did show that MitraClip did provide benefits in terms of survival and heart failure hospitalization in all echocardiographic subgroups, regardless of degree of LV (left ventricular) dysfunction, LV dimensions, pulmonary hypertension, severity of tricuspid regurgitation or individual mitral regurgitation parameters. It is important, however, to also remember that the clinical end-point used in the binary analysis by the sub-study (24-month all-cause mortality or first HF hospitalization) was not the same as the primary efficacy endpoint of the COAPT trial (all heart failure hospitalizations over 24 months). With this endpoint however, the sub-study investigators have demonstrated that 67.4% of control patients died or had a first HF hospitalization within 2 years as compared to 45.4% of MitraClip treated patients. This is sobering data and suggests that there is much more work to be done, not just in mortality reduction for both groups but also that none of the sub-study's echocardiographic criteria/measurements proved to be clinically meaningful as baseline predictors of response to percutaneous edge-to edge transcatheter approximation.
What is also becoming much more evident given the data from the COAPT echo sub study is that echocardiography is going to play an increasingly important role in the future for the management of patients with both primary and secondary MR requiring transcatheter interventions. In the real-world setting, given the clinical equipoise regarding baseline echocardiographic factors that determine success versus non responders to MitraClip, more prospective and registry data will increase clarity.
- COAPT: Presented by Dr. Federico M. Asch at the American College of Cardiology Annual Scientific Session (ACC 2019), New Orleans, LA, March 17, 2019.
- Stone GW, Lindenfeld JA, Abraham WT, et al. Transcatheter mitral-valve repair in patients with heart failure. N Engl J Med 2018;379:2307-18.
- Nishimura RA, Bonow RO. Percutaneous repair of secondary mitral regurgitation—a tale of two trials. N Engl J Med 2018;379:2374-6.
Keywords: Acute Coronary Syndrome, Acute Kidney Injury, Aneurysm, Dissecting, Aortic Aneurysm, Aorta, Aortic Valve Insufficiency, Aortic Valve, Aortic Valve Stenosis, Arrhythmias, Cardiac, Arterial Pressure, Atherosclerosis, Atrial Appendage, Atrial Fibrillation, Bicuspid, Biomarkers, Cardiac Surgical Procedures, Constriction, Pathologic, Constriction, Pathologic, Conversion to Open Surgery, Coronary Artery Bypass, Coronary Disease, Creatinine, Diagnosis, Differential, Disease-Free Survival, Dilatation, Echocardiography, Endovascular Procedures, Factor VII, Follow-Up Studies, Heart Defects, Congenital, Heart Transplantation, Heart Failure, Heart Valve Diseases, Heart Valve Prosthesis, Heart-Assist Devices, Hemodynamics, Hemorrhage, Hospital Mortality, Hospitalization, Hypertension, Hypertension, Pulmonary, Length of Stay, Liver Diseases, Mitral Valve, Mitral Valve Stenosis, Mitral Valve Insufficiency, Pacemaker, Artificial, Patient Selection, Percutaneous Coronary Intervention, Prospective Studies, Pulmonary Disease, Chronic Obstructive, Pulmonary Embolism, Pulmonary Veins, Pulsatile Flow, Quality Improvement, Quality of Life, Referral and Consultation, Registries, Reoperation, Renal Insufficiency, Research Personnel, Respiratory Insufficiency, Risk Factors, Smoking, Sodium, Spinal Cord Ischemia, Stroke, Stroke Volume, Surgeons, Surgical Instruments, Thrombosis, Tomography, X-Ray Computed, Transcatheter Aortic Valve Replacement, Treatment Outcome, Tricuspid Valve Insufficiency, Ventricular Dysfunction, Left, ACC Annual Scientific Session, ACC19
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