J Thromb Thrombolysis DOI 10.1007/s11239-014-1067-4
Advances in interventional cardiology: MitraClip Said Alsidawi • Mohamed Effat • Tarek Helmy
Ó Springer Science+Business Media New York 2014
Abstract Severe mitral valve regurgitation is a serious condition with significant morbidity and mortality. It is not uncommon recently, to see patients with significant mitral valve regurgitation that are considered ‘‘non-surgical candidates’’ due to their comorbidities. MitraClip is a new percutaneous approach for treating mitral valve regurgitation which involves mechanical edge-to-edge coaptation of the mitral leaflets. In October of 2013, The US Food and Drug Administration (FDA) approved the MitraClip for patients with symptomatic degenerative mitral regurgitation deemed high risk for mitral-valve surgery. Several large clinical trials confirmed the safety and efficacy of MitraClip. We here discuss the growing role of MitraClip, the major clinical trials, the ongoing trials and the potential complications of the procedure. Keywords surgery
MitraClip Mitral regurgitation Mitral valve
Introduction Mitral valve (MR) regurgitation is a common valvular problem and the prevalence increases significantly with age. It is estimated that mitral regurgitation is present in 19 % of adults by a mean age of 54 years and in more than 80 % of people aged 80 years or more .
Common causes include mitral valve prolapse (myxomatous degeneration of the mitral valve), papillary muscle ischemia or infarction secondary to coronary artery disease, infective endocarditis, dilated cardiomyopathy (functional mitral regurgitation), degenerative valvular disease (associated with aging), rheumatic heart disease, ruptured chordae tendinae, radiation injury and many congenital disorders . Severe MR is a serious condition with significant morbidity and mortality. It causes a volume overload on the left ventricle leading to dilation and reduction in systolic function, and eventually clinical congestive heart failure. There is no effective medical management available at this time and surgical repair or replacement remain the most effective management strategy. As the patient population in the US ages, the incidence of comorbidities increases making surgery a more risky option in this cohort. In year 2000, the older population (aging 65 years or older) represented 12.9 % of the US population. This is expected to continue to rise and will be 19 % in year 2030 . It is not uncommon recently, to see patients with significant MR that are considered ‘‘nonsurgical candidates’’ due to their comorbidities. The field of interventional cardiology has made significant advances in providing alternatives for such patients and presented many therapeutic options that significantly improved not only the survival, but also the quality of life. MitraClip represents one of these breakthroughs in the treatment of severe mitral regurgitation and has been recently approved by the FDA in the United States.
All authors contributed equally to this work. S. Alsidawi (&) M. Effat T. Helmy Division of Cardiovascular Health and Disease, College of Medicine, University of Cincinnati, 231 Albert Sabine Way, Cincinnati, OH 45267, USA e-mail: [email protected]
Device and procedure description  MitraClip is a new percutaneous approach for treating MR which involves mechanical edge-to-edge coaptation of the
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Fig. 1 The MitraClip system
Fig. 3 MitraClip implant device
Fig. 2 Clip delivery system including the implant attached to the delivery catheter
mitral leaflets that is similar to the surgical technique developed by Ottavio Alfieri which involves suturing the mitral orifice into a double orifice valve with significant reduction or elimination of the regurgitation. Early developments of the percutaneous transcatheter device were attempted back in 1998, and the first in-human implant was done by Jose Condado in 2003 in Venezuela. The MitraClip device, which was designed to mimic an edge-to-edge repair, consists of a percutaneous transcatheter delivered
Fig. 4 MitraClip implant being placed through a trans-septal approach
through a trans-septal approach. The implant has two arms and two grippers which are used to grasp the opposing free edges of the anterior and posterior leaflet in order to improve leaflet coaptation and create a double-orifice valve (Figs. 1, 2, 3).
Advances in interventional cardiology
cardiologist. A surgical back up team should be available for any potential complications. The device is a cobalt chromium construction with polyester cover designed to promote tissue growth. It is MRI-compatible up to 3 T. After device deployment, it is recommended to give aspirin for 6 months and maybe clopidogrel for 1 month. Infective endocarditis prophylaxis is recommended.
MitraClip complications MitraClip complications are listed in Table 1.
Fig. 5 MitraClip device after placement in the mitral position
The patient is prepared in a similar fashion as for an open surgical mitral valve procedure. The right femoral vein and left femoral artery (or right radial artery) and vein or the right internal jugular veins are cannulated for hemodynamic assessment and monitoring. From the right femoral venous puncture, a TEE guided trans-septal puncture of the septum is performed. A 24-Fr steerable guiding catheter is advanced through the trans-septal route through which the steerable clip delivery system with the MitraClip attached at the distal end is delivered (Figs. 4, 5). This allows the introduction of the clip delivery system into the left atrium. The MitraClip is advanced under echocardiographic and fluoroscopic guidance into the left ventricle and withdrawn with the arms opened to allow capture of both leaflets with the grippers and arms. Once adequate leaflet insertion is confirmed, the MitraClip can then be tightened to assess efficacy and once deemed adequate, the MitraClip is released. More than one MitraClip can be used in one patient to get the desired results, caution is exercised and post deployment transmitral gradient is assessed to avoid the occurrence of iatrogenic mitral valve stenosis. The procedure is performed with full anticoagulation with a target activated clotting time (ACT) close to 250. Currently, the procedure is being performed under general anesthesia with the presence of an echocardiographer, a cardiac anesthesiologist in addition to the interventional
After being in development for more than a decade, The MitraClip device was approved by the CE Mark for commercial use in Europe in 2008 and is recommended by the European Society of Cardiology (ESC) for use in patients with symptomatic severe MR who are determined to be inoperable or at high surgical risk by an experienced heart team involving a cardiologist and a cardiac surgeon and who have a life expectancy [1 year. Currently, the device has a class IIB recommendation by the ESC. When first approved, only 4–5 procedures were being done a month in Europe. This number continues to increase, with up to 280 procedure or more being performed a month now for a total of at least 5,000 procedures thus far . In 2011, the device got approval in Australia. In October of 2013, The US Food and Drug Administration (FDA) approved the MitraClip for patients with symptomatic degenerative mitral regurgitation deemed high risk for mitral-valve surgery. The FDA approval follows the recommendations of the advisory committee, which voted 5 to 3 in March 2013 that the efficacy of the MitraClip exceeded the risks in patients with a prohibitive risk for surgery. The FDA stated that ‘‘The MitraClip Delivery System is indicated for the percutaneous reduction of significant symptomatic MR (MR C3?) in patients refractory to optimal medical therapy with at least a 1-year life expectancy and suitable anatomic criteria who have been determined by an experienced mitral valve surgeon or other members of a heart failure/heart team to be at excessive risk for open mitral valve surgery and in whom existing comorbidities would not preclude the expected benefit from correction of the MR.’’ . What will happen after FDA approval? After approval by the FDA in the United States, we expect a quick increase in the number of procedures using
S. Alsidawi et al. Table 1 Complications of MitraClip Study
Complication rate (%)
Death not related to MitraClip
Prolonged ventilation [48 h
Bleeding requiring transfusion
EVEREST II HRR and REALISM HR at 12 months
ACCESS-Europe (1 year)
TRAMI (pre- and postdischarge)
Two clips required
Inability to reduce MR
Need for mitral valve surgery
Major vascular complications
ASD requiring intervention
New onset atrial fibrillation
Currently, Abbott Vascular represents the only manufacturer of the device for which the FDA gave approval. Abbott also continues to sponsor clinical trials of the MitraClip therapy to further assess the device role in the United States and Europe.
Need for resuscitation
Bleeding Total death
Need for repeat procedure
Need for surgery for failure
Who will perform the procedure?
Major vascular complications
MitraClip in centers with experienced interventional cardiologists. Based on the European experience, the number of MitraClip procedure performed in the United States will
increase monthly as more interventional cardiologists become familiar and experienced with it. To ensure safety and efficacy, the FDA initiated the MitraClip Post Approval Study (PAS). The purpose of the MitraClip PAS is to collect data on the MitraClip device when used by a broad group of physicians in a commercial use setting. These data will be used to confirm the long-term safety and effectiveness of the MitraClip device, confirm that the MitraClip device can be used safely by implanting physicians with varying levels of experience and identify any low-frequency or unanticipated MitraClip device-related adverse events that may occur in a commercial setting. The study will be composed of two separate arms corresponding to functional MR (FMR) patients and degenerative MR patients (DMR). Enrollment in the DMR arm will begin upon market approval of the MitraClip System in the US. Enrollment in the FMR arm will commence after the COAPT trial (see below) is fully enrolled. Abbott Vascular will work in collaboration with Society of Thoracic Surgeons (STS) and American College of Cardiology (ACC) societies to conduct this post-approval study.
The FDA along with Abbott Vascular proposed training requirements for physicians to be able to perform the MitraClip Procedure. The MitraClip team should include multi-disciplinary physician teams made up of at minimum an interventional cardiologist, a cardiac surgeon who has completed at least 25 mitral valve surgeries in the prior year, an echocardiographer and a cardiac anesthesiologist. Abbott Vascular proposes to specify training requirements based on the level of physician experience with the MitraClip procedure and structural heart interventions. Experience level will correspond to the degree of training that will be required to achieve certification as a skilled MitraClip device user: 1.
Level 1 physician operator: defined as an operator with no prior experience implanting the MitraClip device or with no current experience (within the past 6 months).
Advances in interventional cardiology Table 2 Major published trials Study name
Number of patients
Number of centers
Majority of MR etiology
Summary of findings
Reduction of severe MR to 2? or less achieved in 70.9 % of patients. There was a sustained freedom (66 % of the patients) from the combined endpoint of death, need for surgery, or recurrent MR after 1 year in the initial patient cohort. This trial completed its 5-year follow-up with consistent, durable results
EVEREST II (RCT)
At 1 year, MitraClip was safer with only 9.6 % of MitraClip patients having major adverse events compared with 57 % of surgical patients. At 4 years, the rate of the composite endpoint of freedom from death, surgery, or 3? or 4? MR was not statistically different between the MitraClip group and the surgical group. Surgery for mitral valve dysfunction, however, occurred more in the MitraClip group. Most importantly, there was significant durability of the MitraClip device
88 % of patients improved by at least one MR grade from baseline to 12 months, 53 % improved by two or more grades, and 16 % improved by three or more grades. 71.4 % of patients were NYHA class I or II at 12 months By 12-month, 6-min walk test results had improved and quality of life had improved
MitraClip in ESHF (EF \25 %) registry
Procedural success was achieved in 94 % of patients, with grade III present in 93 % of patients at baseline yet only 6 % post-intervention. The peri-procedural complication rate was low, with only minor bleedings as the most significant event. In-hospital and post-discharge mortality was low
Severity of MR was reduced in all successfully treated patients and 92 % were discharged with MR B2?. Thirty-day mortality was 6 %; cumulative survival at 6 months was 81.2 %. At 6 months, MR B2? was present in 87 % of patients, and 72 % of patients were in NYHA functional class I or II. 6-min walk distance improved significantly, and significant reductions in LV volumes indicative of reverse LV remodeling were noted
ESHF end stage heart failure, DMR degenerative mitral regurgitation, FMR functional mitral regurgitation
Level 1 operators will be required to complete a minimum initial number (5 in a 90 day period) of MitraClip device training cases as a primary operator. Level 1 operators must complete a minimum of 1 case per month going forward. Level 2 physician operator: defined as an operator who has prior experience implanting the MitraClip device. Level 2 operators will require training based on the final approved device labeling prior to commercial use of the MitraClip device, and they will be required to complete a minimum of two cases per month as primary operator.
A minimum of two MitraClip procedures per month is the recommended caseload. If no MitraClip device implant cases are performed for 90 days, then Abbott Vascular will provide mandatory retraining to the operators and staff in
order to ensure that they maintain procedural expertise. All surgeons in the multi-disciplinary team will have a minimum clinical experience of 25 mitral valve repair experience in the prior year, and will also undergo formal training to the MitraClip explant procedures.
Experience with other valves The use of MitraClip device in tricuspid valve regurgitation was first attempted in 2011 in a patient with congenitally corrected transposition of great arteries . Few centers tried this approach but long term follow-ups are lacking. Challenges for emerging percutaneous approaches to the tricuspid valve include the lack of convenient adjacent structures for device placement and the relatively low-flow
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state in the right heart, which may promote thrombus formation. The coronary sinus ostium, atrioventricular node, and inferior vena cava are adjacent structures that must not be covered by any potential therapeutic devices. The presence of preexisting trans-tricuspid pacemaker or defibrillator leads will require unique percutaneous solutions .
Clinical trials in the US: (Table 2) Endovascular Valve Edge-to-Edge Repair Study or EVEREST study I and II represent the land mark trials in the United States that drove the FDA approval of the device. EVEREST I , was a single-arm registry of 55 patients designed to evaluate the safety and efficacy of the MitraClip device. This prospective, multicenter experience with MitraClip therapy demonstrated that (89 %) of the patients had successful deployment of the device with reduction of severe MR to 2? or less achieved in 70.9 % of patients at discharge. In addition, there was a sustained freedom (66 % of the patients) from the combined endpoint of death, need for surgery, or recurrent MR in a substantial proportion of patients after 1 year in the initial patient cohort. Annular diameter was stable through 12 months, indicating absence of further annular dilation. This trial completed its 5-year follow-up with consistent, durable results. This cohort also experienced improved symptoms, indicating that clinical benefit was associated with the achieved MR reduction. EVEREST II  EVEREST II Randomized Controlled Trial is a prospective, multi-center, randomized study of the MitraClip System in the treatment of MR, randomizing patients to MitraClip or mitral valve surgery. EVEREST II trial randomized 279 patients to MitraClip versus surgery in a (2:1) fashion who had an indication for mitral valve surgery. The results of the randomized trial supported the early nonrandomized safety signals, with only 9.6 % of MitraClip patients having major adverse events compared with 57 % of surgical patients. Adverse events were driven in both groups by transfusion, but the need for transfusion was more than six times more common in the surgical group (53.2 vs. 8.8 %). Death (2.5 %), re-operation (1.3 %), stroke (2.5 %) and urgent/emergent surgery (5.1 %) only happened in the surgical group. The safety endpoint was thus met. For efficacy, the EVEREST II randomized trial designed the end point to be non-inferior with a 31 % margin. The rate of the primary efficacy end point (freedom from death, from surgery for mitral valve dysfunction, and from grade
3? or 4? MR at 12 months) was lower in the MitraClip group compared with the surgery group (55 vs. 73 %; p = 0.007), which indicates that MitraClip was found to be inferior to surgery for the studied population because the lower bound of the 95 % CI for the treatment effect exceeded the prespecified delta. Thus, from 1 year follow-up of patients in the EVEREST II trial, MR reduction by the MitraClip was not sufficient for patients who are candidates for surgery. 4-Year follow-up of the EVEREST II trial was recently published  showing that the rate of the composite endpoint of freedom from death, surgery, or 3? or 4? MR in the intention-to-treat population was not statistically different between the MitraClip group and the surgical group. Same was noted for the degree of MR and death between the two groups. Surgery for mitral valve dysfunction, however, occurred in 20.4 % in the MitraClip group versus 2.2 % in the surgical group (p \ 0.001) at 1 year and 24.8 versus 5.5 % (p \ 0.001) at 4 years. Most importantly, there was significant durability of the MitraClip device. There was no device embolization, device fracture, erosion or migration. The EVEREST II High Risk Registry (HRR) study is a prospective multi-center study of the MitraClip System for the treatment of MR in high surgical risk patients. Enrollment in the RCT and HRR is closed. A continued access prospective, multi-center study (REALISM) of the MitraClip System in a surgical population (non-high risk arm) and a high surgical risk population (high risk arm) is ongoing. Enrollment in the non-high risk arm of REALISM is closed. Enrollment in the high risk arm of REALISM is ongoing. High risk patients were defined by the EVEREST II high risk registry as: 1. 2.
Calculated STS score C12 % or Surgeon investigator–determined patient risk for mortality C12 % owing to the presence of at least one of the following: Porcelain aorta or mobile ascending aortic atheroma, post-radiation mediastinum, previous mediastinitis, functional mitral regurgitation with ejection fraction \40 %, age [75 years with ejection fraction \40 %, prior reoperation with patent grafts, C2 prior chest surgeries, hepatic cirrhosis, C3 of the following STS high-risk factors, creatinine [2.5 mg/dL, prior chest surgery, age[75 years, ejection fraction\35 %
European experience: (Table 2) About 50 centers in Europe have been using the technique since September 2008, and 2 years later, 1,000 procedures were performed. The rate of implants in Europe is accelerating on a monthly basis.
Advances in interventional cardiology
Access-Europe registry:  This is the largest registry in Europe with the goal is to provide a post marketing real-world data on the safety and efficacy of MitraClip. The current report includes data on 567 patients with functional or DMR enrolled between April 2009 and 2011 at 14 European centers. The majority of patients (84.9 %) were New York Heart Association (NYHA) functional class III or IV. Most had FMR (77 %). MR was symptomatic or asymptomatic moderate-to-severe (3?) or severe (4?). MitraClip was successfully implanted in all but two patients (99.6 %). The procedure improved MR severity versus baseline, such that nearly 80 % of patients had MR severity of 2? or less at 12 months. Overall, 88 % of patients improved by at least one MR grade from baseline to 12 months, 53 % improved by two or more grades, and 16 % improved by three or more grades. Additionally, 71.4 % of patients were NYHA class I or II at 12 months. A total of 6.3 % of patients required mitral valve surgery within 12 months post-procedure. Single leaflet device attachment occurred in 27 patients (4.8 %); ten underwent a second MitraClip procedure, 11 had no additional treatment, six underwent surgery, and one had additional MitraClip devices implanted during the index procedure. No cases of device embolization were reported. By 12-month follow-up, 6-min walk test results had improved by 59.5 ± 112.4 m versus baseline (p \ 0.0001) and quality of life as measured by responses to the Minnesota Living with Heart Failure Questionnaire had improved by 13.5 ± 20.5 points (p \ 0.0001). Despite the limitations, this registry showed that in this patient population, the MitraClip procedure is safe, with low rates of hospital mortality and adverse events. MitraClip therapy in patients with end-stage systolic heart failure:  Another European registry to assess the feasibility, shortterm durability and clinical outcomes of MitraClip therapy for mitral regurgitation (MR) in patients with end-stage heart failure and a severely reduced left ventricular (LV) ejection fraction (\25 %). 50 patients were included with at least grade 3? MR. procedural success rate of 94 %. Severity of MR was reduced in all successfully treated patients and 44 (92 %) were discharged with MR B2?. Thirty-day mortality was 6 %; cumulative survival at 6 months was 81.2 %. At 6 months, MR B2? was present in 27 (87 %) of 31 patients, and 23 (72 %) of 32 patients were in NYHA functional class I or II. Six-minute walk distance improved significantly, and significant reductions in LV volumes indicative of reverse LV remodeling were noted.
TRAMI (Initial results from the German trans-catheter mitral valve interventions) registry:  This registry evaluated the acute results of MitraClip implantation. 486 patients [median age 75 (interquartile range 70–80) years; 200 women (41 %)] were enrolled in the registry (309 retrospectively and 177 prospectively). with 481 patients (99 %) having undergone percutaneous edge-toedge therapy for MR using the MitraClip. At baseline, 93 % of patients were in New York Heart Association (NYHA) functional class III or IV and 71 % of patients had a left ventricular ejection fraction (LVEF) B50 %. Twothirds of patients presented with FMR. Procedural success was achieved in 94 % of patients, with grade III present in 93 % of patients at baseline yet only 6 % post-intervention. Retrospective patients were followed for a median of 183 days, prospective patients for a median of 44 days. The peri-procedural complication rate was low, with only minor bleedings as the most significant event. In-hospital and post-discharge mortality was 2.5 and 12.5 %, respectively suggesting that MitraClip is a reasonable option in high risk surgical patients.
Conclusions from the current published literature Both EVEREST I & II trials confirmed the safety of the device in the acute and the chronic settings. Procedural complications were rare and, most importantly, the device has proven significant durability. MitraClip was much safer than mitral valve surgery mainly secondary to the decrease in the need for post-operative transfusion in addition to the other surgical complications. This is an important finding, as most patient that are selected to undergo a MitraClip device are elderlies and have significant comorbidities and choosing the safest approach in these patient is warranted. In regards to efficacy and clinical success, at 1 year, clinical success was higher in the surgically treated group compared with the mitral clip arm. At 2 years, intention-totreat analysis revealed that the primary composite endpoints were still significantly better in the surgery group compared with the MitraClip group. More than 15 % of patients in the device arm subsequently underwent mitral valve surgery due to persistent severe MR at 2 year follow-up. At 4-year follow up, the differences between the two groups in terms of clinical success started to narrow with no significant difference in the degree of residual MR along with continued preferable outcomes and durability of the MitraClip device and improved left ventricular remodeling and volumes. However, the need for repeated mitral valve surgery still showed significant advantage to the surgical arm.
S. Alsidawi et al. Table 3 Ongoing clinical trials Trial
MR etiology targeted
Composite of death (all-cause), stroke, worsening kidney dysfunction, permanent left ventricular assist device (LVAD) implant, or heart transplant Primary effectiveness endpoint for 12 months Recurrent heart failure (HF) hospitalizations
Hierarchical composite of allcause mortality and recurrent heart failure hospitalizations
permanent left ventricular assist device (LVAD) implant, or heart transplant. This study is estimated to be completed in 2019. A randomized study of the MitraClip device in heart failure patients with clinically significant functional mitral regurgitation (RESHAPE-HF) (Table 3) is the second large randomized trial being conducted currently mainly in Europe. Hypothesis: This trial is a randomized study of the MitraClip device in heart failure patients with clinically significant functional mitral regurgitation. A hierarchical composite of all-cause mortality and recurrent heart failure hospitalizations is hypothesized to occur at a lower rate with the use of the MitraClip device in addition to optimal standard medical therapy compared to optimal standard of care therapy alone.
FMR functional mitral valve regurgitation
The experience with MitraClip in Europe has shown a steep learning curve with high success rate and significant improvement in both clinical and echocardiographic profiles. EVEREST trial showed lower procedural success compared to European reports. The patients’ characteristics were significantly different between these reports however. EVEREST mainly enrolled patients with DMR with a DMR/FMR ratio of 75/25 % approximately, while most of the European studies mainly included patients with FMR who tend to be sicker with lower EF and higher surgical risks. These are important differences to keep in mind when comparing outcomes of different studies.
Ongoing trials As mentioned above, the enrollment in the high risk arm of the EVEREST REALISM trial is still ongoing. Two large multi-center randomized controlled trials are now being conducted to address some of the unanswered questions in the EVEREST trials. The first is the Clinical Outcomes Assessment of the MitraClip Percutaneous Therapy for High Surgical Risk Patients (COAPT) (Table 3) Trial which is a phase 3 trial that aims to confirm the safety and effectiveness of the MitraClip System for the treatment of moderate-to-severe or severe FMR in high surgical risk subjects. This study was requested by the FDA to compare the MitraClip device to no treatment in high surgical risk patients, as the EVEREST trial randomized patients who were candidates for surgery. In this study many specified primary and secondary outcomes are being studies. Primary safety endpoint for 12 months: Composite of death (all-cause), stroke, worsening kidney dysfunction,
Conclusion Mitral valve surgery is the gold standard treatment for mitral regurgitation. However, we continue to encounter many cases and on a daily basis where patients are not candidates for surgery for many reasons. There are reports that less than 30 % of elderly patients with significant MR actually end up getting a surgical repair or replacement. MitraClip represents an attractive option for such patients. Acute, as well as chronic, safety has been well documented by multiple trials and durability was also proven by the EVEREST trial. The efficacy of the MitraClip device in the 4-year followup from the EVEREST II trial was approaching the surgical efficacy except for the higher chances of needing reoperation in the device arm. The experience in Europe has shown a steep learning curve and the outcomes of the procedure will continue to improve in the US after receiving FDA approval and the widespread use of the device. The results of the COAPT and the RESHAPE studies will likely address most of the remaining controversies and shed more light on who would benefit most from this procedure. As above, It is critical that a multi-specialty team including an interventional cardiologist, a cardiac surgeon, a cardiac anesthesiologist and an echocardiographer be involved in the care of these patients pre- and post-operatively.
Conflict of interest
No conflict of interest to disclose.
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