MitraClip™ for secondary MR – the jury is still out

Take Home Messages
  • Secondary mitral valve regurgitation (MR) occurs as a result of coaptation failure secondary to alterations in left ventricle (LV) geometry and is associated with poor prognosis.
  • Surgical repair of secondary MR is currently mainly performed when concomitant revascularisation is indicated.
  • Percutaneous repair of MR is an alternative method that involves the use of a mechanical device called MitraClip™ (Abbott), that approximates the leaflets creating a doubleorifice.
  • Both the Cardiovascular Outcomes Assessment of MitraClip™ Percutaneous Therapy for Heart Failure Patients with Functional Mitral Regurgitation (COAPT), and the Percutaneous Repair with the MitraClip™ Device for Severe Functional/Secondary Mitral Regurgitation (MITRAFR) trial evaluated the use of MitraClip™ in treatment of secondary MR.
  • COAPT showed an impressive 32 % absolute reduction in heart failure hospitalisations and 17 % reduction in allcause mortality at 2 years, whilst the MITRA-FR showed no difference in outcomes (composite heart failure hospitalisation and all-cause mortality at 1 year) between those who received MitraClip™ alongside medical therapy and those who received medical therapy alone.
  • While the contradictory results created huge controversy and uncertainty in the role of MitraClip™ in secondary MR, optimal medical therapy should remain the mainstay.

Mitral valve regurgitation (MR) can be primary or secondary. In primary MR, one or more of the components of the mitral valve apparatus (i.e. valve annulus, leaflets, chordae tendineae and papillary muscles) are directly affected.1 In secondary MR (previously known as ‘functional’ MR), the valve leaflets and chordae are structurally normal, but changes in the left ventricle (LV) geometry results in malcoaptation and subsequent MR.1 Severe functional MR is an adverse prognostic marker associated with increased mortality risk in patients with heart failure and reduced LV systolic function despite optimal medical therapy (OMT), and independent of clinical and echocardiographic confounders and neurohumoral activation.2 In contrast to primary MR, intervention for secondary MR has not been shown to improve survival. There is also high chance of MR recurrence and significant operative mortality. Hence, surgery for secondary MR is not usually considered unless concomitant revascularisation is planned.1

Other than surgery, mitral valve regurgitation can be treated percutaneously with the use of MitraClip™ (Abbott, United States of America), a device that approximates the anterior and posterior mitral leaflets. Despite being less effective at reducing MR, percutaneous repair had been shown to be safer than conventional surgery, with similar improvements in clinical outcomes including LV size, New York Heart Association (NYHA) functional class and quality of life measures.3 The clinical efficacy and safety of MitraClip™ in addition to medical therapy versus medical therapy alone in patients with heart failure and severe secondary MR was evaluated in the Cardiovascular Outcomes Assessment of MitraClip™ Percutaneous Therapy for Heart Failure Patients with Functional Mitral Regurgitation (COAPT) and Percutaneous Repair with the MitraClip™ Device for Severe Functional/Secondary Mitral Regurgitation (MITRA-FR) trials. Announced just one month apart (MITRA-FR in August 2018 at the European Society of Cardiology Congress in Munich, COAPT in September 2018 at the Transcatheter Cardiovascular Therapeutics meeting in San Diego), the contradictory results created a whirlpool of controversy and debate about the role of MitraClip™ in secondary MR. In this editorial I will discuss both studies and explore the potential reasons for differences in outcomes.

The COAPT Trial

Study design

The COAPT trial was a randomised, controlled, open-label trial of transcatheter mitral-valve repair with the MitraClip™ device in patients with heart failure and moderate-to-severe or severe MR who remained symptomatic despite guideline-based OMT.4 A total of 614 patients at 78 sites in the United States of America and Canada were enrolled in the trial between December 2012 and June 2017. The trial was sponsored by Abbott. Enrolled patients had cardiomyopathy of ischaemic and nonischaemic aetiology, with ejection fraction (EF) of 20-50%, had moderate-to-severe (grade 3+) or severe (grade 4+) secondary MR and remained symptomatic despite maximal medical treatment (including cardiac resynchronisation therapy if appropriate) (see Table 1). Patients were randomised to receive transcatheter mitral-valve repair plus medical therapy (device group) or medical therapy alone (control group). The primary efficacy endpoint was all hospitalisations for heart failure within 24 months of follow-up. The primary safety endpoint was freedom from device-related complications at 12 months.


The trial concluded that in patients with symptomatic heart failure despite OMT, and moderate-to-severe or severe secondary MR,
percutaneous mitral valve repair resulted in a 32.1% absolute reduction in the rate of hospitalisation for heart failure at 24 months of follow up when compared with medical therapy alone (hazard ratio (HR) 0.53, 95 % confidence interval (CI) 0.4-0.7; p<0.001) (see Table 2). The outcome was also positive for the 10 prespecified secondary end points, and which included all-cause mortality within 24 months, quality of life (as assessed by the Kansas City Cardiomyopathy Questionnaire and New York Heart Association (NYHA) functional class), functional capacity (as measured by the 6- minute walk test), mitral regurgitation and left ventricular remodelling (as measured by mitral regurgitation grade and left ventricular end-diastolic volume), death from any cause at 12 months, death or hospitalisation for heart failure within 24 months, all hospitalisation for any cause within 24 months and freedom from death from any cause, stroke, myocardial infarction, and non-selective cardiovascular surgery for device related complications at 30 days.

With regards to device success in reducing MR at the time of discharge: the MR grade was 1+ or lower in 214 patients (82.3%), 2+ in 33 patients (12.7%), 3+ in 9 patients (3.5%), and 4+ in 4 patients (1.5%). At twelve months MR grade was 2+ or lower in 199 (out of 210) patients (94.8%).

The MITRA-FR Trial
Study design

The MITRA-FR Trial was a multicentre (all centres were in France), randomised controlled, open- label, phase 3 trial.5 A total of 452 patients were enrolled in the trial between December 2013 and March 2017. Enrolled patients had chronic heart failure symptoms (assessed by NYHA class II, III, or IV), left ventricular EF between 15% and 40%, and severe secondary mitral regurgitation. (see Table 1). Patients were then randomised to receive percutaneous mitral-valve repair in addition to medical therapy or to receive medical therapy alone. The primary efficacy outcome was a composite of death from any cause or unplanned hospitalisation for heart failure at 12 months. The study was funded by the French Ministry of Health and Research National Program. Besides providing the trial device, Abbott Vascular, the manufacturer of the device, also provided support for investigators’ meetings, and proctored the procedures during device implantation.

Table 1. Baseline characteristics for COAPT and MITRA-FR trials
Age, years71.7±11.870.1±10.1
Male sex %66.678.9
NYHA II, %42.736.8
NYHA III, %5153.9
NYHA IV, %69.2
NT pro-BNP, ng/L5174.3±6566.63407 (1948-6790)
Effective regurgitant orifice area, mm24131±10
Left ventricular EF, %31.3±9.133.3±6.5
Data expressed as mean±standard deviation, median (interquartile range) or percentages. EF ejection fraction, NT pro-BNP N terminal pro-B-type natriuretic peptide, NYHA New York Health Association.


At 12 months, there was no statistical difference in the rate of death or unplanned hospitalisation for heart failure between patients with severe secondary MR who underwent percutaneous mitral-valve repair in addition to receiving medical therapy and those who received medical therapy alone (see Table 2). There was no statistically significant difference in the incidence of any of the prespecified secondary outcomes at 12 months, and which included all-cause death, unplanned hospitalisation for heart failure, death from cardiovascular causes, and survival free from major adverse cardiovascular events.

In the intervention group, 14 out of 152 patients had no study device implanted: implantation was either not attempted (8 patients) or failed (6 patients). In the 144 patients in whom implantation was attempted, 21 had periprocedural complications. At the time of discharge from the hospital, 123 patients in the intervention group had assessments for the severity of mitral regurgitation. Of these, 113 patients (91.9%) had reduction of mitral regurgitation to 2+ (mild to moderate) or lower, and 93 patients (75.6%) had reduction to 0+ (none or trace) to 1+ (mild). At 12 months, the echocardiographic data were missing for many of the patients in the MITRA-FR trial, but at least 48 out of 152 patients in the intervention group had residual MR of grade 2+ or higher.


Both the COAPT and the MITRA-FR trials evaluated the use of MitraClip™ in addition to optimised medical therapy in patients with symptomatic heart failure and severe secondary mitral regurgitation. Both were randomised controlled and well powered studies. The COAPT trial was very positive showing a dramatically lower rate of hospitalisation for heart failure (relative risk reduction of 47 %) and lower all-cause mortality in the treatment group within 24 months of follow up compared to medical therapy alone. The MITR-FR trial was surprisingly neutral and outcomes did not differ significantly between the two groups in the trial. Both trials had their limitations. They were both open label trials, which can generally allow for bias in the assessment of outcomes. Both were conducted around the same time, and hence the same classes of medications were available for use in accordance with the contemporary guidelines at the time (The COAPT trial followed the American College of Cardiology/ American Heart Association (ACC/AHA) guidelines, while the MITRA-FR trial followed the European Society of Cardiology (ESC) guidelines). But unfortunately, the MITRA-FR trial authors did not provide data on the individual classes of drugs used during the trial period,5 making it difficult to verify whether any alterations in the regime of medical therapy used may have been a confounder explaining the difference in outcomes between the two trials.

Table 2. Comparison of outcomes in the COAPT and MITRA-FR trials
Study characteristic  
Number of patients, n614307
Follow up, monthsMedian 22.7 (IQR 12.4-24.0)12
Successful implantation, %9896
Primary efficacy outcomeAll hospitalisation for heart failureComposite of all-cause death and unplanned hospitalisation for heart failure
Primary safety outcomeFreedom from device complications at 12 monthsPrespecified serious adverse eventsa
AnalysisIntention to treatIntention to treat
Efficacy endpoints
Composite of all-cause death and unplanned hospitalisation for heart failure-54.6 v 51.3
OR 1.16 (0.73-1.84); p=0.53
All hospitalisations for heart failure 24
months, % per patient year
35.8 v 67.9
HR 0.53 (0.4-0.7); p<0.001
Unplanned hospitalisation for heart
failure, %
-48.7 v 47.4
HR 1.13 (0.81-1.56)
All-cause deaths at 12 months, %19.1 v 23.2
HR 0.81 (0.57-1.15)
24.3 v 22.4
HR 1.11 (0.69-1.77)
All-cause deaths at 24 months, %29.1 v 46.1
HR 0.62 (0.46-0.82)
Safety endpoints
Freedom from device complications at 12 months, %96.6-
Serious adverse events, %-82.2 v 79.6
Periprocedural complications, %-14.6
Other significant outcomes
Functional status, quality of life, echocardiographicImproved KCCQ score, higher proportion of patients with NYHA class I-II, prevention of deterioration in 6 minute walk test or adverse remodelling (LVED volume)Significant missing data at follow-up therefore no analysis performed
Efficacy and safety data displayed as % intervention v control with HR or OR (95 % CI). a including ischaemic or haemorrhagic stroke, MI, need for RRT, periprocedural complications, bleeding at 1 year. CI confidence interval, HR hazard ratio, IQR interquartile range, KCCQ Kansas City cardiomyopathy questionnaire, LVED left ventricular end diastolic, MI myocardial infarction, NYHA New York health association, OR odds ratio, RRT renal replacement therapy..

With regards to patients’ characteristics: the trials were conducted in different parts of the world, butthe age and gender of patients were comparable in both studies. The echocardiographic data suggested that patients in the COAPT trial had more severe MR with a mean effective regurgitant orifice area of 41mm2, compared to 31mm2 in the MITRA-FR trial which may be considered closer to the moderate range. Furthermore patients in the COAPT trial had higher baseline NT pro-BNP level, suggesting that patients in the COAPT trial may have worse heart failure /heart failure substrate at baseline, despite comparable NYHA classes. This is supported by the secondary outcome data where patients in the COAPT trial randomised to OMT alone showed a significant deterioration in symptoms, adverse LV remodelling and exercise capacity which was not seen in the MitraClip™ group. One important factor contributing to the divergent results was the duration of follow up. In the COAPT trial patients were followed up for 2 years after MitraClip™ implantation, whilst in the MITRA-FR patients were followed up for 1 year. All-cause death at 1 year were similar between the two groups in the COAPT trial, suggesting that the potential mortality benefit seen occurred after 1 year.

Another important factor to consider was the success of device implantation. In the COAPT trial there were low rates of residual MR post device implantation, suggesting high immediate implantation success. This was consistent at 12 months suggesting a degree of durability of the procedure. Unfortunately much of the echocardiographic data was missing in the MITRAFR trial making comparisons difficult. Furthermore, neither studies reported operator volumes prior to randomisation which were likely to be relatively low. The number of patients enrolled in the COAPT trial was approximately double that of the MITRAFR
therefore it is possible that the MITRA-FR outcomes may reflect the learning curve associated with operator experience, and results may continue to improve in line with accumulating operator volumes.

Documentation of heart failure medications in the COAPT trial was thorough; the authors reported class of medication at baseline, 30 days, one year and at two years follow up. While angiotensin converting enzyme inhibitors, angiotensin receptor blockers and neprilysin inhibitor (ARNI) use was comparable at 30 days, these drugs were used significantly more in the intervention group compared to the control group at one and two years follow up. Furthermore, the rate of ARNI use was tripled by one year. The use of this particular class of medication in patients with heart failure and reduced EF was not only shown to be effective at reducing cardiovascular death and heart failure hospitalisation,6 but was also found to have a huge impact on cardiac reverse remodelling reducing LV diameter and volume;7 changes which are incriminated in the development of secondary MR. A similar trend was seen with the use of beta blockers when comparing 30 days and one year data. These observations suggest the favourable outcomes evident in the interventional arm of the COAPT trial may be in part due to better OMT.


Both the COAPT and the MITRA-FR trials evaluated the use of MitraClip™ in secondary MR. The results were conflicting, with the COAPT study showing a highly favourable outcome (significant reductions in hospitalisations and all-cause mortality at 24 months) while the MITRA-FR study showed no benefit in addition to medical therapy. The exact reasons as to why this was the case remain unclear but may relate to: patient selection (better outcomes in more severe MR); longer follow up (better outcomes seen at 2 years follow up compared to 1 year); operator experience (outcomes improve in line with operator volume); and effect of prognostic medications (better outcomes with better OMT). There is obviously a concern as to how the results of these studies will be interpreted and implemented in the real world. The role of MitraClip™ in the treatment of secondary MR is likely to cause controversy. Whilst the data of the COAPT trial appear more robust compared to the MITRA-FR where some crucial data were missing, the positive outcome seen in the COAPT trial may in fact be driven by optimised medical therapy.



  1. Baumgartner H, Falk V, Bax J, et al. 2017 ESC/EACTS Guide-lines for the management of valvular heart disease. Eur Heart J 2017;38:2739–91.
  2. Goliasch G, Bartko PE, Pavo N, et al. Refining the prognostic impact of functional mitral regurgitation in chronic heart failure. Eur Heart J 2018;39:39-46.
  3. Feldman T, Foster E, Glower DD, et al. Percutaneous repair or surgery for mitral regurgitation. N Engl J Med 2011;364:1395-406.
  4. Stone GW, Lindenfeld J, Abraham WT, et al. Transcatheter Mitral-Valve Repair in Patients with Heart Failure. N Engl J Med 2018; 379:2307-2318.
  5. 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.
  6. McMurray JJ, Packer M, Desai AS, , et al. Angiotensin–Neprilysin Inhibition versus Enalapril in Heart Failure. N Engl J Med 2014; 371:993-1004.
  7. Wang Y, Zhou R, Lu C, et al. Effects of the Angiotensin-Receptor Neprilysin Inhibitor on Cardiac Reverse Remodeling: Meta-Analysis. J Am Heart Assoc 2019;8:e012272.