Percutaneous Mitral Valve Repair With MitraClip System
Percutaneous Mitral Valve Repair With MitraClip System
The MitraClip system was first introduced in 2004 as a percutaneous intervention for MR. Inspired by Alfieri's edge-to-edge repair techniques, MitraClip involves deployment of an implant that approximates the anterior and posterior MV leaflets, resulting in a double-orifice MV that minimises regurgitation. The EVEREST I and II trials have demonstrated device safety and lower complication rates for patients treated with MitraClip, although open surgery was deemed significantly more efficacious at 12 and 24 months. Recent CE approval by the European Union in 2008 has increased clinical application of MitraClip, particularly in Europe.
It is hypothesised that MitraClip would have maximum benefit in patients with severe symptomatic MR, defined as grade 3+ and 4+ MR on echocardiography and NYHA functional class III–IV, who are at a high risk of surgical morbidity and mortality. The minimally invasive nature of MitraClip has been shown to significantly reduce blood loss, as well as demonstrate acute procedural success. In high risk patients, for whom conventional surgery is not suitable, MitraClip has shown significant promise and efficacy, as demonstrated in the present analysis.
EuroSCORE, a measure of surgical mortality, was used in all but one study in the present review, and reported surgical mortality values ranged from 12–41%. Recent evidence indicates that EuroSCORE overestimates mortality in MV surgery and the true value is closer to 0.55 × EuroSCORE. The MitraClip is considered safe in this high risk patient group even when taking into account the potential recalibration of this score. In the present analysis, weighted mean procedural mortality was 3.3% (range 0–7.8%). Despite the high risk patient cohort, this is comparable to the results from analysis of 32 699 MV repair patients in the STS Adult Cardiac Database, which reported unadjusted repair mortality of 1.8% and 3.7% in NYHA class III and IV patients, respectively. While 12 month mortality ranged from 10–25%, this may partly be reflective of the advanced state of disease in the present study population.
Importantly, echocardiographic findings show significant postoperative improvements, with acute procedural success ranging from 72–100%, and a reduction of preoperative grade 3+ and 4+ MR to ≤grade 2+ in 73–100% of patients. All studies showed measurable improvement on echocardiography. While larger studies have the resources to evaluate determinants of interventional success independently, such as echocardiographic findings, potential bias may exist when investigators from institutional studies self-assess these outcomes.
A recent pooled analysis of 351 high surgical risk patients in the EVEREST II High Risk Registry and the REALISM Continued Access Study demonstrated an implantation success of 96%. Eighty-six per cent of surviving patients experienced MR reduction to ≤2+ with significant reduction in LV volume at 12 months, and 'durable' MR reduction at 24 months. In addition, 83% of patients were classified as NYHA class I/II at 12 months, with improvements in physical and mental components according to the SF-36 quality of life questionnaire. This study was presented recently at the 62nd Annual Scientific Session of the American College of Cardiology in San Francisco and detailed data were not available to be included in the present systematic review. ACCESS-EU is another recent multicentre study, which demonstrated 89% freedom from death at 6 months; freedom from MR >2+ was 80%, freedom from MV surgery was 97%, 70% of patients were in NYHA class I/II, and there was a mean improvement of 66 m in the 6 min walk test distance. Preliminary freedom from death at 12 months was 85%. This study was presented at the 61st Annual Scientific Session of the American College of Cardiology in Chicago. As only preliminary data were available, the study was not included in the present systemic review. In addition, during the preparation of this review, results from the German TRAMI Registry were published. This study demonstrated non-severe MR post-successful placement of clips in 95% of patients. Hospital mortality was reported at 3% while 66% of patients were classified as NYHA class I/II at follow-up (median length 3 months).
The voluminous research of short term outcomes of MitraClip implants underlines the infancy of this device, and draws attention to the limited understanding of long term outcomes. It is not known whether subsequent MR surgery after device implantation, which occurs in up to 22% of patients, affects outcomes or survival. Durability of the device is also not known beyond 3 years. Furthermore, the majority of existing trials, in particular the EVEREST series, are performed in high volume tertiary care centres, therefore limiting the universal generalisability of results. Higher powered studies are required to investigate differences in outcomes stratified by aetiology (functional versus degenerative).
There are several limitations associated with the existing literature that complicates the present review. First, all but three studies in the present analysis combined both functional and degenerative valvular pathologies. Functional MR has been shown to be amenable to medical treatment, which may obviate the need for percutaneous surgical intervention, particularly in high risk patients. Secondly, the infancy of MitraClip results in a paucity of data on patient prognostication. Indeed, inclusion and exclusion patient selection and the definition of high risk varied significantly between the included studies, thereby confounding analysis. Finally, the available literature on high surgical risk patients is of low quality, with the majority either registry or observational studies. However, the US-based COAPT RCT, which will compare MitraClip intervention against standard medical treatment in high surgical risk patients, has recently started patient recruitment. Results from this study, as well as from the European RESHAPE-HF trial (which similarly compares MitraClip intervention with optimal medical care), will help better define the role of MitraClip in the management of MR. Investigators in future trials need to be blinded to the intervention when evaluating procedural success, as predisposition to the favourability of MitraClip may confound accurate assessment of the device, therefore overestimating success rates.
Recent guidelines from the European Society of Cardiology and the European Association for Cardio-Thoracic Surgery recommends percutaneous mitral clip procedures in high surgical risk patients to be considered by a multidisciplinary team. The absence of comparative studies and the absence of mid to long term data of this intervention in the present systematic review mandates a formal team approach to patient selection and outcome analysis. The inclusion and exclusion criteria of the EVEREST trial provide some indication of the limits of this new technology. Closely examining the variations in leaflet and annular pathology contributing to MR and differential effectiveness of the available medical, percutaneous and surgical interventions in varying pathologies is important in optimising the treatment pathway.
Despite high acute procedural success rates after MitraClip implantation, almost one quarter of patients remain highly symptomatic (NYHA III/IV) at 1 year follow-up. It remains unclear which clinical or procedural characteristics are predictive of such a poor clinical response. This observation should be subject to further research. Before further convincing evidence becomes available, the use of MitraClip implantation should be considered only within the boundaries of clinical trials with special arrangements for clinical governance, consent, and audit or research. MitraClip interventions should only take place in centres with appropriate cardiothoracic surgical support to manage the potential intraoperative complications. It is likely that progressive development of technology, familiarity with techniques, and better understanding of appropriate criteria for patient selection will continue to refine the indications for this procedure.
Discussion
The MitraClip system was first introduced in 2004 as a percutaneous intervention for MR. Inspired by Alfieri's edge-to-edge repair techniques, MitraClip involves deployment of an implant that approximates the anterior and posterior MV leaflets, resulting in a double-orifice MV that minimises regurgitation. The EVEREST I and II trials have demonstrated device safety and lower complication rates for patients treated with MitraClip, although open surgery was deemed significantly more efficacious at 12 and 24 months. Recent CE approval by the European Union in 2008 has increased clinical application of MitraClip, particularly in Europe.
It is hypothesised that MitraClip would have maximum benefit in patients with severe symptomatic MR, defined as grade 3+ and 4+ MR on echocardiography and NYHA functional class III–IV, who are at a high risk of surgical morbidity and mortality. The minimally invasive nature of MitraClip has been shown to significantly reduce blood loss, as well as demonstrate acute procedural success. In high risk patients, for whom conventional surgery is not suitable, MitraClip has shown significant promise and efficacy, as demonstrated in the present analysis.
EuroSCORE, a measure of surgical mortality, was used in all but one study in the present review, and reported surgical mortality values ranged from 12–41%. Recent evidence indicates that EuroSCORE overestimates mortality in MV surgery and the true value is closer to 0.55 × EuroSCORE. The MitraClip is considered safe in this high risk patient group even when taking into account the potential recalibration of this score. In the present analysis, weighted mean procedural mortality was 3.3% (range 0–7.8%). Despite the high risk patient cohort, this is comparable to the results from analysis of 32 699 MV repair patients in the STS Adult Cardiac Database, which reported unadjusted repair mortality of 1.8% and 3.7% in NYHA class III and IV patients, respectively. While 12 month mortality ranged from 10–25%, this may partly be reflective of the advanced state of disease in the present study population.
Importantly, echocardiographic findings show significant postoperative improvements, with acute procedural success ranging from 72–100%, and a reduction of preoperative grade 3+ and 4+ MR to ≤grade 2+ in 73–100% of patients. All studies showed measurable improvement on echocardiography. While larger studies have the resources to evaluate determinants of interventional success independently, such as echocardiographic findings, potential bias may exist when investigators from institutional studies self-assess these outcomes.
A recent pooled analysis of 351 high surgical risk patients in the EVEREST II High Risk Registry and the REALISM Continued Access Study demonstrated an implantation success of 96%. Eighty-six per cent of surviving patients experienced MR reduction to ≤2+ with significant reduction in LV volume at 12 months, and 'durable' MR reduction at 24 months. In addition, 83% of patients were classified as NYHA class I/II at 12 months, with improvements in physical and mental components according to the SF-36 quality of life questionnaire. This study was presented recently at the 62nd Annual Scientific Session of the American College of Cardiology in San Francisco and detailed data were not available to be included in the present systematic review. ACCESS-EU is another recent multicentre study, which demonstrated 89% freedom from death at 6 months; freedom from MR >2+ was 80%, freedom from MV surgery was 97%, 70% of patients were in NYHA class I/II, and there was a mean improvement of 66 m in the 6 min walk test distance. Preliminary freedom from death at 12 months was 85%. This study was presented at the 61st Annual Scientific Session of the American College of Cardiology in Chicago. As only preliminary data were available, the study was not included in the present systemic review. In addition, during the preparation of this review, results from the German TRAMI Registry were published. This study demonstrated non-severe MR post-successful placement of clips in 95% of patients. Hospital mortality was reported at 3% while 66% of patients were classified as NYHA class I/II at follow-up (median length 3 months).
The voluminous research of short term outcomes of MitraClip implants underlines the infancy of this device, and draws attention to the limited understanding of long term outcomes. It is not known whether subsequent MR surgery after device implantation, which occurs in up to 22% of patients, affects outcomes or survival. Durability of the device is also not known beyond 3 years. Furthermore, the majority of existing trials, in particular the EVEREST series, are performed in high volume tertiary care centres, therefore limiting the universal generalisability of results. Higher powered studies are required to investigate differences in outcomes stratified by aetiology (functional versus degenerative).
There are several limitations associated with the existing literature that complicates the present review. First, all but three studies in the present analysis combined both functional and degenerative valvular pathologies. Functional MR has been shown to be amenable to medical treatment, which may obviate the need for percutaneous surgical intervention, particularly in high risk patients. Secondly, the infancy of MitraClip results in a paucity of data on patient prognostication. Indeed, inclusion and exclusion patient selection and the definition of high risk varied significantly between the included studies, thereby confounding analysis. Finally, the available literature on high surgical risk patients is of low quality, with the majority either registry or observational studies. However, the US-based COAPT RCT, which will compare MitraClip intervention against standard medical treatment in high surgical risk patients, has recently started patient recruitment. Results from this study, as well as from the European RESHAPE-HF trial (which similarly compares MitraClip intervention with optimal medical care), will help better define the role of MitraClip in the management of MR. Investigators in future trials need to be blinded to the intervention when evaluating procedural success, as predisposition to the favourability of MitraClip may confound accurate assessment of the device, therefore overestimating success rates.
Recent guidelines from the European Society of Cardiology and the European Association for Cardio-Thoracic Surgery recommends percutaneous mitral clip procedures in high surgical risk patients to be considered by a multidisciplinary team. The absence of comparative studies and the absence of mid to long term data of this intervention in the present systematic review mandates a formal team approach to patient selection and outcome analysis. The inclusion and exclusion criteria of the EVEREST trial provide some indication of the limits of this new technology. Closely examining the variations in leaflet and annular pathology contributing to MR and differential effectiveness of the available medical, percutaneous and surgical interventions in varying pathologies is important in optimising the treatment pathway.
Despite high acute procedural success rates after MitraClip implantation, almost one quarter of patients remain highly symptomatic (NYHA III/IV) at 1 year follow-up. It remains unclear which clinical or procedural characteristics are predictive of such a poor clinical response. This observation should be subject to further research. Before further convincing evidence becomes available, the use of MitraClip implantation should be considered only within the boundaries of clinical trials with special arrangements for clinical governance, consent, and audit or research. MitraClip interventions should only take place in centres with appropriate cardiothoracic surgical support to manage the potential intraoperative complications. It is likely that progressive development of technology, familiarity with techniques, and better understanding of appropriate criteria for patient selection will continue to refine the indications for this procedure.
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