What is the role of MitraClip percutaneous therapy for patients with symptomatic heart failure and secondary mitral valve regurgitation?

In patients with advanced heart failure, dilatation of the left ventricular chamber often occurs. This causes the mitral valve apparatus to “stretch,” and leads to impaired coaption of the mitral valve leaflets. Secondary mitral regurgitation follows and increases the severity of volume overload. This process is strongly associated with decreased quality of life, increased rate of hospitalization for heart failure, and shortened survival. Good adherence to guideline directed medical therapy and cardiac resynchronization improves outcomes, but these patients still have poor outcomes with high rates of rehospitalization. While surgical management of primary/degenerative mitral regurgitation (MR) is a proven management strategy, surgical intervention on secondary MR has not shown to improve outcomes. Improvement in percutaneous interventions have allowed for experimentation with percutaneous mitral valve repair. The EVEREST II trial showed this strategy was safe, but not as effective when compared to surgical repair. However, this study overwhelmingly recruited patients with primary MR (73% of the study population). When a subgroup that included only secondary MR patients was analyzed, the outcomes were comparable between surgery and Mitraclip. Because of this, further trials were conceived to investigate the role of MitraClip in patients with symptomatic HFrEF and moderate to severe secondary MR.

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By the end of this post, you should have a basic understanding of a few of these trials and how you might counsel Mr. Mitral. 

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The Trials

• COAPT (2018)
• MITRA-FR (2018)

COAPT (2018)

In patients with HFrEF and moderate-severe secondary MR, percutaneous mitral valve repair reduced heart failure hospitalizations at 24 months when compared to medical therapy alone.

Population (N = 614)

• Adults with moderate to severe secondary MR, reduced ejection fraction heart failure, and NYHA II-IV symptoms
• On goal directed medical therapy
• With at least one hospitalization in the last year

Intervention

• MitraClip + GDMT (N = 302)
• GDMT alone (N = 312)

Outcomes

• Significantly less heart failure hospitalizations at 24 months in the MitraClip group (35.8% per pt year vs. 67.9% per pt year)
• Freedom from device-related complications at 12 months in the MitraClip group was very high (96.6%)
• Significantly more patients with grade 2+ mitral regurgitation or less at 12 months in MitraClip group (secondary outcome)
• Quality of life (based on KCCQ score), distance on 6-minute walk test, NYHA functional class maintained at I or II, and change in LV end-diastolic volume from baseline were all significantly better in the device group compared to control at 12 months (secondary outcomes)

Criticisms

• Open-label design allowing for bias, however this was partially mitigated by an independent adjudication committee blinded to treatment assignment that verified outcomes
• Limited followup of only 2 years  
• Authors were tied to industry, including Abbott (MitraClip company)
• There were some differences in GDMT in the two groups
  • More patients in the device group were optimized with an ACEi
  • More patients in the device group were on a P2Y12 inhibitor at 30 days
  • More patients in the device group were on a beta blocker at 1 year
• MITRA-FR had conflicting results

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MITRA-FR (2018)

The encouraging results of COAPT were not replicated in this smaller and shorter trial done exclusively in France – differences in baseline valvular and ventricular characteristics may be to blame.

Population N = 304

• Adults with moderate to severe secondary MR, reduced ejection fraction heart failure, and NYHA II-IV symptoms
• On goal directed medical therapy
• With at least one hospitalization in the last year.

Intervention

• MitraClip + GDMT (N = 152)
• GDMT alone (N = 152)

Outcomes

• No significant difference in composite of all-cause mortality or unplanned hospitalization for heart failure at 12 months between MitraClip and GDMT (54.6% vs. 51.3%)
• No significant difference in death from any cause, cardiovascular death, unplanned hospitalization for heart failure at 12 months and major CV events at 12 months (secondary outcomes)

Criticism

• The patients enrolled in this trial had less severe MR and more dilated left ventricles than in COAPT
• Open-label design allowing for bias; however, unlike COAPT  there was no independent adjudication committee blinded to treatment assignment
• Limited follow up of 12 months for primary outcome
• There was higher incidence of residual MR class ≥3+ immediately post op (9% v 5%) and at 12 months (17% v 5%), which may partially explain the lack of clinical benefit
• Authors did not keep track of GDMT used throughout the study

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The Bottom Line

The 2018 COAPT trial provides robust evidence that in patients with HFrEF, moderate to severe secondary MR, and symptoms refractory to aggressive medical therapy, percutaneous valve repair improves outcomes. The 2018 MITRA-FR trial did not show improved outcomes with this procedure. However, the patients in MITRA-FR had less severe valve hemodynamics and were not as clearly “refractory” to medical treatment prior to enrollment. Based on this data, the FDA approved MitraClip for the treatment of secondary moderate-severe or severe MR despite optimal guideline-directed medical therapy. 

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Expert’s Opinion

Marcella Calfon Press, MD, PhD, FACC

Assistant Professor, UCLA Interventional Cardiology
Co-Director, UCLA Barbra Streisand Women’s Heart Health Program

The role of MitraClip in the management of mitral regurgitation has evolved tremendously since the initial landmark EVEREST II trial in 2011. That trial showed that MitraClip was less effective in reducing MR compared with surgery. However, in patients where a greater than 2+ reduction in MR was seen, MitraClip was associated with a superior safety profile and similar improvements in clinical outcomes. Notably, the EVEREST trial enrolled patients with predominantly primary/degenerative MR who were eligible for surgery. That trial led to the initial FDA approval for MitraClip and ACC/AHA 2014 Guideline recommendations that stated it should be considered in patients with primary/degenerative MR who were at prohibitive surgical risk.

The COAPT and MITRA-FR trials asked the question of whether MitraClip was also beneficial in patients with secondary/functional MR. The two trials were published in the same edition of the New England Journal of Medicine, but the results were very different – COAPT showed a dramatic reduction in its primary endpoint, while MITRA-FR did not. Why were there such dramatic differences between these two contemporary trials?  Firstly, COAPT appears to have more effectively selected patients that were truly optimized on medical therapy. They did this by having a run-in period where CHF meds were titrated to the maximum tolerated doses, and patients were subsequently excluded if their symptoms abated or if the degree of mitral regurgitation decreased significantly. Secondly, the two studies had dissimilar echocardiogram parameters. COAPT’s patients had less advanced left ventricular dilatation and more severe mitral valve regurgitation than MITRA-FR’s patients. This suggests that the patients enrolled in the COAPT trial had heart failure symptoms and mitral regurgitation that were truly refractory to medical therapy. Ultimately, it was COAPT that led to the updated FDA approval and updated ACC/AHA Guidelines, which expanded the indication for MitraClip to include patients with secondary/functional MR and ongoing symptoms despite appropriate medical and device therapies.

My clinical take on this: Over the past several years, my practice has shifted to reflect these updated recommendations. I am now using MitraClip in patients with symptomatic primary MR who are not surgical candidates and in patients with secondary/functional MR who remain symptomatic despite goal directed medical and device therapies. Patients benefit significantly with this intervention. They see improvement in heart failure class and reduction in heart failure admissions. The limitations of MitraClip are both anatomical and clinical. From an anatomical standpoint, the success is often related to the presence of severe calcification, high baseline gradients, small orifice area or the presence of a large cleft.  Applying MitraClip therapy to the appropriate patient is key as the benefit is limited to those who have failed medical and device therapies. Though select patients with advanced NYHA Class 4b or who are in shock (excluded from COAPT trial) may benefit, there is limited data in this patient population and a multidisciplinary approach with the advanced heart failure team is critical.

The newly realized benefits of MitraClip therapy have permanently impacted the management of MR in the current era. It is currently the only FDA approved transcatheter therapy for the mitral valve. However, the future of percutaneous mitral valve intervention is rife with possibility. Future developments in annulopasty and replacement are sure to create exciting opportunities to apply new technologies to this important valve. The challenge of the future will be determining which technology best fits each valve and each patient.

I am a proctor for the MitraClip procedure with Abbott. No other conflicts of interest to declare. 

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