Introduction

Mitral regurgitation (MR) secondary to dysfunction of the left ventricle (LV) has been termed secondary MR according to the 2014 American Heart Association (AHA) and American College of Cardiology (ACC) guideline for the management of patients with valvular heart disease.¹ According to the latest AHA statistics, secondary MR is present in 16,250 per million of the US population.^2,3 Based on the current population, it can be estimated that >5 million individuals may have secondary MR in the United States. With the aging population and growing incidence of heart failure (HF), the incidence and prevalence of secondary MR is predicted to increase further. It has been thought that secondary MR is a disease of the LV, and mechanical treatment of the mitral valve has not been shown to improve outcomes until recently. The Cardiothoracic Surgical Trials Network (CTSN) trial randomized 301 patients with moderate ischemic MR to coronary artery bypass graft surgery (CABG) alone or CABG plus mitral valve repair. The LV end-systolic volume index was similar in both groups at 1 and 2 years, leading to the conclusion that surgical mitral valve repair did not have any effect on cardiac geometry or LV reverse remodeling in patients with coronary artery disease and moderate MR. The amount of MR was less in the patients who underwent combined CABG and mitral valve repair, but this was associated with early increase in neurological events and supraventricular arrhythmias.⁴ Similarly, another CTSN trial comparing surgical mitral valve repair versus replacement in 251 patients with severe ischemic MR did not find a significant difference in the risk of death at 2 years (19.0% in the repair group vs. 23.2% in the replacement group). The LV end-systolic volume index decreased in both groups (-9.0 ml per square meter in repair group vs. -6.5 ml per square meter in replacement group). One of the important findings of this study was that 58.8% of the patients in the repair group had recurrence of moderate-severe MR compared with 3.8% in the replacement group.⁵ Because of these studies, the current guidelines give Class IIb indication to mitral valve surgery in symptomatic patients with severe secondary MR.1 Guideline-directed medical therapy is the only treatment with proven benefit in this population of HF with reduced ejection fraction (EF). In selected patients, cardiac resynchronization therapy (CRT) can also facilitate LV reverse remodeling and reduce associated secondary MR.⁶ However, no trial has compared surgical mitral valve intervention to medical therapy alone for secondary MR. Two recently presented randomized clinical trials, MITRA-FR (Percutaneous Repair With the MitraClip Device for Severe Functional/Secondary Mitral Regurgitation) and COAPT (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation), examined the impact of transcatheter mitral valve repair using MitraClip (Abbott; Abbott Park, IL) in addition to medical therapy compared with guideline-directed medical therapy alone in patients with secondary MR.

MITRA-FR

MITRA-FR was a multicenter, randomized, open-label controlled trial of MitraClip versus guideline-directed medical therapy in patients with secondary MR and HF with reduced EF (15-40%).⁷ Severe secondary MR was defined as an effective regurgitant orifice area (EROA) of >20 mm² or a regurgitant volume of >30 ml per beat. This clinical trial randomized 304 patients at 37 centers (each center had to perform at least 5 MitraClip procedures) in France. The mean age was 70.1 years, mean LVEF was 33%, mean LV end-diastolic volume index was 135 ml/m², EROA was 0.31 cm², regurgitant volume was 45 ml, and brain natriuretic peptide was 765-835 ng/L. Technical success at the time of procedure was achieved in 95.8% of the patients, and 14.6% patients with the implant had periprocedural complications. At discharge, 91.9% of the patients had ≤2+ MR. The primary outcome of death or unplanned HF hospitalizations at 1 year was similar in the MitraClip (54.6%) and medical therapy arms (51.3%) (odds ratio 1.16; 95% confidence interval [CI], 0.73-1.84). The rate of death was similar at 24.3% in the MitraClip arm compared with 22.4% in the control arm at 1 year. Echocardiographic data were missing in a large number of patients; therefore, the objective follow-up data are available only in a fraction of patients. Among the patients with available data (n = 97) in the MitraClip arm, ≤1+ MR was present in approximately 50% of the patients. In 60 patients (out of 152 initially enrolled) who underwent MitraClip, there was a 23.5 ml reduction in regurgitant volume, 0.15 cm² reduction in EROA. There were no significant changes in end-diastolic volume, end-diastolic diameter, end-systolic volume, end-systolic diameter, and EF in 89 patients with available data.⁷ This trial concluded that MitraClip in addition to guideline-directed medical therapy did not impact survival or HF hospitalization in patients with secondary MR.

COAPT

COAPT was a multicenter, controlled, parallel-group, open-label trial of MitraClip versus medical therapy in patients with moderate-severe or severe secondary MR.⁸ The patients were symptomatic despite maximally tolerated guideline-directed medical therapy, which was assessed by a HF specialist. Key exclusion criteria were EF <20%, LV end-systolic diameter ≥70 mm, ACC/AHA stage D HF, hemodynamic instability requiring inotropic support or mechanical heart assistance, evidence of right-sided congestive HF with echocardiographic evidence of moderate or severe right ventricular dysfunction, and estimated pulmonary artery systolic pressure >70 mmHg, unless active vasodilator therapy was able to reduce the pulmonary vascular resistance to <4.5 Wood Units with v wave less than twice the mean of the pulmonary capillary wedge pressure. A total of 614 patients was enrolled, which was higher than the initial target of 420 patients because of higher-than-expected mortality rate in both arms.⁹ Mean age was 72 years, mean Society of Thoracic Surgeons score was 7.8-8.5, mean LVEF was 31%, mean LV end-diastolic volume index was 101 ml/m², EROA was 0.41 cm², LV end-systolic dimension was 6.2 cm, right ventricular systolic pressure was 44 mmHg, and brain natriuretic peptide was 1014 ng/L. MitraClip was implanted in 98% of the patients with whom it was attempted, with the mean number of 1.7 clips. Device-related complications at 12 months were noted in 3.4% patients. The primary endpoint of annualized HF hospitalizations was significantly reduced in the MitraClip arm (35.8%) compared with control arm (67.9%) (hazard ratio 0.53; 95% CI, 0.40-0.70). The rate of all-cause mortality was also significantly lower in the MitraClip arm (29.1%) compared with control arm (46.1%) (hazard ratio 0.62; 95% CI, 0.46-0.82). The number needed to treat to reduce 1 HF hospitalization at 2 years was 3.1 and to reduce 1 death was 5.9. All secondary endpoints, including MR grade ≤2+ at 1 year, all-cause mortality at 1 year, change in Kansas City Cardiomyopathy Questionnaire score, change in 6-minute walk distance, New York Heart Association Class I or II at 1 year, change in LV end-diastolic volume, and all-cause mortality at 2 years, were significantly lower in the MitraClip arm. At 30 days, 72.2% of the patients had ≤1+ MR, and 93.8% had ≤2+ MR. At 1 year (n = 210), 68.6% had ≤1+ MR, and 94.8% had ≤2+ MR. At 2 years follow-up (n = 114), 76.3% had ≤1+ MR, and 99.1% had ≤2+ MR. The number assessed decreased overtime because of high mortality rate. These results suggest that most of the patients surviving at 2 years had ≤2+ MR, indicating the importance of mechanical reduction of regurgitation in patients with secondary MR. LV end-diastolic volume reduced by 1.1 ml over a period of 1 year in the MitraClip arm compared with an increase of 18.6 ml in the control arm. Although MitraClip did not result in LV reverse remodeling, it prevented the LV from further enlargement.⁸ In conclusion, this clinical trial showed that transcatheter mitral valve repair using MitraClip in addition to guideline-directed medical therapy was superior to guideline-directed medical therapy alone in patients with secondary MR.

Discrepancies/Proportionate and Disproportionate MR

Until early 2018, guideline-directed medical therapy and CRT were the only evidence-based therapies for patients with HF with reduced EF and secondary MR. The recent presentation of two clinical trials, MITRA-FR⁷ and COAPT⁸ has changed our understanding of secondary MR. The two trials had conflicting results, with MITRA-FR showing no benefit of MitraClip versus medical therapy and COAPT reporting significantly reduced mortality and HF hospitalizations with MitraClip versus medical therapy alone. Some of the discrepancies in the results can be explained by the baseline characteristics and results of these trials, as detailed below:

1. Grade of regurgitation in the inclusion criteria. The mean EROA was 0.31 cm² in MITRA-FR compared with 0.41 cm² in COAPT. Based on the current AHA/ACC valve guidelines, patients included in MITRA-FR had moderate secondary MR. The results of these trials suggest that transcatheter mitral valve repair with MitraClip may be beneficial only in patients with severe secondary MR defined as EROA >0.40 cm².
2. Baseline LV size. Mean indexed LV end-diastolic volume was 135 ml/m² in MITRA-FR compared with 101 ml/m² in COAPT. The LVs were significantly larger in MITRA-FR patients, which may reflect advanced HF and cardiomyopathy. A sub-analysis of COAPT in patients with an EROA ≤0.3 cm² and LV end-diastolic volume index >96 ml/m² found no difference in HF hospitalizations at 1 year in patients receiving Mitraclip compared with control group. This suggests that markedly dilated LVs may not benefit from MitraClip. Further analysis from these trials may help elucidate the sub-group of patients with minimal or no benefit.
3. Involvement of HF team. MITRA-FR allowed adjustment of medications by the investigators, whereas COAPT mandated highest doses of guideline-directed medical therapy and CRT (if indicated) with involvement of HF specialists in the trial adjudication committee and at the enrolling centers.
4. Success in MR reduction. At 12 months, 83% of the patients in MITRA-FR had ≤2+ MR compared with 95% of the patients in COAPT. With the noted differences in results in both the trials, it is possible that successful and sustained reduction in the grade of MR to ≤2+ is important in achieving optimal outcomes with MitraClip.

These discrepancies have been elegantly explained by Grayburn et al.¹⁰ recently, where the authors introduced the concept of proportionate and disproportionate MR. The authors proposed that a mitral valve intervention such as MitraClip would be beneficial in patients who have disproportionate MR relative to the LV size (i.e., if the MR is greater [higher EROA] than is expected from a dilated LV); then MitraClip or other similar therapies to reduce MR may improve outcomes. The average patient in MITRA-FR was in the proportionate MR category because the study included sicker patients with more dilated LVs and less MR. On the other hand, an average patient in COAPT was in the disproportionate category, suggesting anticipated benefit from an intervention.

Implications of These Data

COAPT provides strong evidence that reduction of MR in patients with secondary MR reduced mortality and HF hospitalizations. Even in the device arm, 29.1% of the patients died at 2 years, and the annualized rate of all hospitalizations for HF was 35.8% per patient-year, reflecting that this was a very sick group of patients in need of close follow-up. COAPT took a long time to enroll patients because of its strict inclusion criteria. The patients included in MITRA-FR may not have benefited from mitral valve intervention because the disease process was too advanced. Although there is no trial comparing surgical mitral valve intervention to medical therapy in severe secondary MR, the data from the CTSN trial⁵ shows that a downsized annuloplasty ring in patients with severe secondary MR was associated with a recurrence of moderate or severe MR in 58.8% of the patients at 2 years compared with 22.8% in COAPT.

A few caveats that should be considered when applying COAPT and MITRA-FR results in the real world:

1. These trials demonstrated the importance of the involvement of HF in the heart valve team for optimization of HF including CRT.
2. COAPT included experienced operators with a technical success of >95% reduction in MR grade to ≤2+; these results may not be reproducible in a real-world setting.
3. When considering who these results apply to, it is important to remember that COAPT excluded the following patients: EF <20%, LV end-systolic diameter ≥70 mm, ACC/AHA stage D HF, hemodynamic instability requiring inotropic support or mechanical heart assistance, evidence of right-sided congestive HF with echocardiographic evidence of moderate or severe right ventricular dysfunction, estimated pulmonary artery systolic pressure >70 mmHg.
4. Close follow-up for optimization of medications and volume status after the procedure is important.
5. Early identification of secondary MR and early referral to the valve/structural team, before the LV is too dilated or the patient is hospitalized requiring inotropic support, is optimal; if patients are evaluated too late in their disease course, the benefit of MitraClip may lessen.

Implications for Ongoing Trials and Clinical Practice

The encouraging results of COAPT provide a significant boost to the ongoing trials of transcatheter mitral valve therapies. COAPT showed for the first time that treating MR in patients with cardiomyopathies results in reduction in HF hospitalization and all-cause mortality. With this, there will likely be an increase in referrals for secondary MR, providing a boost to the ongoing trials. It is unknown if replacing the mitral valve (either surgically or with a transcatheter approach)—and potentially eliminating MR—would yield similar/better/worse results in secondary MR. Another question is if MitraClip should become the control group in these trials instead of guideline-directed medical therapy or surgery. It will be important to know what percentages of patients in COAPT or MITRA-FR were excluded because of anatomical reasons because some patients would be ineligible for MitraClip because of their anatomy. In addition, the results of the ongoing RESHAPE-HF (A Randomized Study of the MitraClip Device in Heart Failure Patients With Clinically Significant Functional Mitral Regurgitation) randomized clinical trial of MitraClip versus guideline-directed medical therapy will provide additional information.¹¹

This is a rapidly evolving field, and there is much to learn about the pathophysiology of secondary MR and the impacts of different interventions to reduce or eliminate MR. The COAPT results provide great encouragement to the field and these ongoing efforts insofar because we now have compelling data that secondary MR is not simply a marker of a bad prognosis. On top of guideline-directed medical therapy, fixing MR can improve patient outcomes. Based on the COAPT results, the US Food and Drug Administration approved MitraClip on March 14, 2019, for treatment of secondary moderate-severe or severe MR despite optimal guideline-directed medical therapy.¹² The next 5-10 years will be an exciting adventure that will likely result in very different treatment paradigms than we have had for the treatment of secondary (and primary) MR to date.

References

1. Nishimura RA, Otto CM, Bonow RO, et al. 2014 AHA/ACC guideline for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2014;63:e57-185.
2. de Marchena E, Badiye A, Robalino G, et al. Respective prevalence of the different carpentier classes of mitral regurgitation: a stepping stone for future therapeutic research and development. J Card Surg 2011;26:385-92.
3. Benjamin EJ, Virani SS, Callaway CW, et al. Heart Disease and Stroke Statistics-2018 Update: A Report From the American Heart Association. Circulation 2018;137:e67-e492.
4. Michler RE, Smith PK, Parides MK, et al. Two-Year Outcomes of Surgical Treatment of Moderate Ischemic Mitral Regurgitation. N Engl J Med 2016;374:1932-41.
5. Goldstein D, Moskowitz AJ, Gelijns AC, et al. Two-Year Outcomes of Surgical Treatment of Severe Ischemic Mitral Regurgitation. N Engl J Med 2016;374:344-53.
6. van Bommel RJ, Marsan NA, Delgado V, et al. Cardiac resynchronization therapy as a therapeutic option in patients with moderate-severe functional mitral regurgitation and high operative risk. Circulation 2011;124:912-9.
7. Obadia JF, Messika-Zeitoun D, Leurent G, et al. Percutaneous Repair or Medical Treatment for Secondary Mitral Regurgitation. N Engl J Med 2018;379:2297-306.
8. Stone GW, Lindenfeld J, Abraham WT, et al. Transcatheter Mitral-Valve Repair in Patients with Heart Failure. N Engl J Med 2018;379:2307-18.
9. Mack MJ, Abraham WT, Lindenfeld J, et al. Cardiovascular Outcomes Assessment of the MitraClip in Patients with Heart Failure and Secondary Mitral Regurgitation: Design and rationale of the COAPT trial. Am Heart J 2018;205:1-11.
10. Grayburn PA, Sannino A, Packer M. Proportionate and Disproportionate Functional Mitral Regurgitation: A New Conceptual Framework That Reconciles the Results of the MITRA-FR and COAPT Trials. JACC Cardiovasc Imaging 2019;12:353-62.
11. A Randomized Study of the MitraClip Device in Heart Failure Patients With Clinically Significant Functional Mitral Regurgitation (RESHAPE-HF) (ClinicalTrials.gov website). 2019. Available at: https://clinicaltrials.gov/ct2/show/NCT01772108. Accessed February 15, 2019.
12. A Clinical Evaluation of the Safety and Effectiveness of the MitraClip System in the Treatment of Clinically Significant Functional Mitral Regurgitation (Reshape-HF2) (ClinicalTrials.gov website). 2019. Available at: https://clinicaltrials.gov/ct2/show/NCT02444338?recrs=a&cond=mitraclip&draw=2&rank=11. Accessed February 15, 2019.

Keywords: Heart Valve Diseases, Mitral Valve, Mitral Valve Insufficiency, Ventricular Dysfunction, Left, Natriuretic Peptide, Brain, Pulmonary Wedge Pressure, Coronary Artery Disease, Cardiac Resynchronization Therapy, Ventricular Dysfunction, Right, American Heart Association, Heart Ventricles, Stroke Volume, Blood Pressure, Pulmonary Artery, Echocardiography, Coronary Artery Bypass, Heart Failure, Cardiac Surgical Procedures, Vasodilator Agents, Vascular Resistance, Arrhythmias, Cardiac, Outcome Assessment, Health Care, Cardiomyopathies

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