Percutaneous mitral valve repair: A new treatment for mitral regurgitation

Abstract

Mitral valve disease affects more than 4 million people in the United States. The gold standard of treatment in these patients is surgical repair or replacement of the valve with a prosthesis. The MitraClip (Abbott Vascular, Menlo Park, CA) is a new technology, which offers an alternative to open surgical repair or replacement via a minimally invasive route. We present an evidence-based clinical update that provides an overview of this technology as it relates to managing patients with significant mitral regurgitation. This review article is particularly useful to noninterventional cardiologists and interventional cardiologists who will be managing patients with this novel technology in increased volumes over the next decade but who do not perform this procedure.

1. Introduction

Mitral valve disease is the second most common acquired valvular heart disease in adults. Severe mitral regurgitation (MR) is the most common manifestation of mitral valve disease in the developed world. MR affects more than 4 million Americans, or almost 10% of patients over the age of 75.¹ This epidemic is increasing in frequency as the population ages.²

MR is classified as either primary (degenerative) or secondary (functional). Primary MR from degenerative valve disease is due to a primary disruption of the mitral valve apparatus from either prolapsed or flail leaflets. Secondary MR on the other hand is due to remodeling of the left ventricle resulting in malcoaptation of the mitral leaflets.

Severe MR when untreated can lead to progressive dyspnea, left atrial dilation, permanent atrial fibrillation, left ventricular (LV) enlargement, and dysfunction leading to systolic and diastolic congestive heart failure.³ Severe MR has an annual mortality rate of up to 5% if untreated.⁴ Medical management alone may reduce symptoms but does not alter the natural history of the disease.³ The gold standard of treatment is surgical repair or replacement.² There are a substantial number of patients who are ineligible for mitral valve surgery because of prohibitive surgical risk, and for those patients, MitraClip (Abbott Vascular, Menlo Park, CA) is a new technology, which may offer an alternative treatment option.

2. Traditional treatment options

Mitral valve surgery is used to treat both primary and secondary MR. Surgery with mitral valve repair or replacement has been the standard of care in treating patients with primary MR. Patients with secondary MR are often treated medically, but surgical consideration is given if the patient requires another open heart procedure, such as coronary artery bypass grafting, or in some patients with progressive New York Heart Association (NYHA) class III and IV heart failure on optimal medical therapy. The decision to repair or replace is dependent on valve pathology and local surgical expertise. However, repair is favored over mitral valve replacement in order to preserve the native valve and sub-valvular apparatus.

Flail or billowing leaflets from prolapse are the most common pathologies amenable to resection or repair. With adequate operator experience, these techniques can result in reduced mortality, reduced risk of endocarditis, and can preclude the need for lifelong anticoagulation.5, 6, 7, 8, 9 Examples of such techniques include quadrangular and triangular resection, replacement of ruptured chordae with neo-chordae, placement of an edge-to-edge stitch to anchor the prolapsing leaflet cusp to the opposing stable cusp, and implantation of an annuloplasty ring. These techniques for primary mitral valve pathology have been successful. In those in whom repair is not feasible, mitral valve replacement can be performed with either a mechanical or bioprosthetic valve. A mechanical valve lasts longer than a tissue valve but has the disadvantage of lifelong anticoagulation.

Unlike primary MR, secondary MR remains a surgical challenge. The first approach to this problem has focused on annuloplasty – either done surgically or percutaneously. Significant efforts have focused on improving results for surgical mitral annuloplasty because undersized annuloplasty rings and lack of durability of surgical annular repair have remained the Achilles heel of this procedure. Newer adjustable annuloplasty rings, whose shape and size can be adjusted postimplantation, have been developed by MitraSolutions^® (MN, USA), DynaTek (MO, USA), and ValTech (Yehuda, Israel). This technological advance in mitral valve repair has spurred innovation toward the development of percutaneous annuloplasty therapies.

Numerous percutaneous annuloplasty techniques are being tested in clinical trials. The Carillon Mitral Contour System (Cardiac Dimensions, Inc., WA, USA) is currently under investigation in Europe. Alternative direct annuloplasty approaches have since emerged. A direct suture annuloplasty system has been developed by MitrAlign^® (MA, USA). This device uses a suture-pledget system to cinch the mitral annulus and reduce the mitral orifice area. Early results for this technique have been encouraging.¹⁰ Furthermore, Accucinch^® (CA, USA) has developed a similar technology but uses multiple anchors along the entire posterior annulus, which is also under early development.¹¹ Finally, the CardioBand^® system (Valtech Cardio, Yehuda, Isreal) uses a transseptal approach to deliver a flexible ring to the annulus via an automated suture technique. Animal models have demonstrated short-term success, and human studies are underway.¹²

A second approach to this problem of secondary MR focuses on the leaflets themselves. The MitraClip (Abbott Vascular, Menlo Park, CA) is a percutaneous technology that allows for minimally invasive repair of the mitral valve (Fig. 1). This technology is the focus of this review.

Fig. 1.

Industrial illustration of the MitraClip (Abbott Vascular, Menlo Park, CA) device.

In addition to surgical and percutaneous intervention, a third viable option for secondary MR patients is optimal medical management of heart failure. The MitraClip repair system is being compared to optimal medical management, in addition to biventricular pacing in a randomized control trial that is currently enrolling patients, known as the Clinical Outcomes Assessment of the MitraClip Percutaneous Therapy for Extremely High-Surgical-Risk Patients (COAPT) trial for functional MR patients with NYHA class III and IV heart failure. The results of this trial will alter the treatment paradigm for this very sick cohort of patients.¹³

3. Overview of technology

The MitraClip (Abbott Vascular, Menlo Park, CA) applies the concept of the Alfieri procedure, which is an “edge-to-edge” surgical technique that creates a double orifice mitral valve by fixing the cusps of the anterior and posterior mitral leaflets together using a double stitch at the point of maximal regurgitation.¹⁴ The MitraClip is the first and only device currently available for percutaneous treatment of MR. The Food and Drug Administration (FDA) approved its use commercially in 2013 for cases of degenerative MR in patients with prohibitive surgical risk for open surgical repair or replacement.¹⁵ The MitraClip is being investigated for functional MR as part of an Investigational Device Exemption (IDE) Trial, COAPT, which is actively recruiting patients at the time this review paper is being written.

The MitraClip procedure is performed by the heart-team comprising of an interventional cardiologist experienced in managing patients with mitral valve disease, a cardiac surgeon experienced in mitral valve surgery, a cardiac anesthesiologist, an echocardiographer, catheterization laboratory technicians, nurses, and industry proctors who are trained in the coordinated delivery and care of this complex therapy. A cardiac surgeon may be the implanting physician or may be present in the event a complication occurs. The procedure is performed in the cardiac catheterization laboratory or Hybrid Operating Room (OR) under general anesthesia with Transesophageal Echocardiogram (TEE) guidance. TEE is used to guide transseptal access, steering and orientation of the clip delivery system and clip toward the mitral valve, and grasping of the leaflets to confirm placement of the device on the anterior and posterior leaflets of the mitral valve (Fig. 2). Assessment of residual MR after clip deployment is complex. Pulmonary vein flow pattern, color Doppler assessment, systolic blood pressure, and mean left atrial pressure before and after clip deployments are all considered in the decision-making. Placement of a second clip is frequently necessary and the mitral valve area and mean gradients are evaluated prior to placement of a second clip. Due to number of steps involved in the procedure, the implanting physician needs to have undergone extensive training on deployment of this device.

Fig. 2.

3D echocardiographic image of the MitraClip (Abbott Vascular, Menlo Park, CA) placed within the mitral valve.

Patients are typically recovered in the catheterization lab recovery room or postanesthetic care unit. They are then transferred to a telemetry floor until they are stable enough for discharge. The median length of stay, after a MitraClip procedure, is 2.4 days.¹⁶ One of the tremendous advantages of this procedure is how well it is tolerated even in patients with severe LV dysfunction and elevated left atrial filling pressures. The short recovery times and length of hospitalization position this device favorably when compared to mitral valve repair or replacement in the high and extreme surgical risk group of patients.

After this procedure, these patients are prescribed dual antiplatelet therapy (DAPT) for a minimum of 6 months. In addition, they need infective endocarditis prophylaxis prior to dental or urologic procedures for 6 months. Anticoagulation with warfarin or Xa inhibitors is resumed if the patient was treated with these medications for other conditions like atrial fibrillation or thrombo-embolic venous disease.

4. Indications for use and desired outcomes

FDA approval was first sought in 2010, for treating degenerative and functional MR in high-risk surgical and inoperable patients. This was denied although the indication was ultimately narrowed to include only high-risk and inoperable patients with degenerative MR. Since there was an unmet clinical need in this subgroup of patients, FDA approval was granted in 2013.

Treatment for symptomatic functional MR with guideline-directed medical therapy and cardiac resynchronization therapy improves symptoms and long-term outcomes.¹⁷ Most of the commercial experience till date in functional MR patients is from Europe, since Conformité Européenne (CE) mark was granted 5 years prior to FDA approval.

Despite delays in FDA approval, the only pivotal, randomized control trial performed with this device was done in the USA – the EVEREST 2 clinical trial. In this study, the MitraClip (Abbott Vascular, Menlo Park, CA) was randomized in 2:1 fashion with mitral valve surgery in 279 patients.¹⁸ These included patients with both degenerative and functional MR. The primary outcome was freedom from death, surgery for mitral valve dysfunction, or severe MR. Results of the EVEREST 2 trial are summarized below (Table 1).

Table 1.

Results from the EVEREST 2 trial.

Patient population

• 279 patients with severe MR who were candidates for mitral valve surgery.

Efficacy

• Surgical repair decreased MR more than MitraClip (Abbott Vascular)®. In 12-month follow-up, 20% of MitraClip patients required surgery for mitral valve dysfunction versus 2% in the surgical arm.

• Both groups had improvements in MR, left ventricular indices, heart failure functional class (NYHA), and quality of life, although degree of MR reduction and LV indices were decreased more in the surgical group.

• When MitraClip reduced MR to ≤2 plus, the repair was durable at 5 years.

Safety

• Major adverse events in 15% of MitraClip cohort versus 48% of surgical cohort.

• Most of the adverse events were blood transfusion, but prolonged intubation was also significantly higher in the surgical arm.

MR, mitral regurgitation; NYHA, New York Heart Association.

The majority of additional data have emerged through various registries. ACCESS-EU is a postmarket registry of MitraClip patients. A retrospective evaluation of 567 patients in this registry was performed.¹⁹ Several key differences were found in the real-world application of the MitraClip device compared to the EVEREST 2 trial. In the ACCESS-EU registry, the patients tended to be older and had higher surgical risk than those evaluated in the EVEREST 2 trial. The anatomic characteristics of the mitral valve did not meet inclusion criteria of the EVEREST 2 trial in a substantial number of patients and the majority of patients had functional MR. Nonetheless, even in this very sick cohort, clinical outcomes with the MitraClip demonstrated excellent improvements in MR reduction, NYHA heart failure classification, patient quality of life, and 6-min-walk test results.¹⁹ In a subgroup analysis of the EVEREST 2 trial, MitraClip was equivalent to surgery in older patients (≥70 years) and those with functional MR.³ Although the MitraClip does not have an indication for functional MR in the USA, it is interesting that preliminary data from registries, such as ACCESS-EU, have already begun to suggest benefit with this device in this subgroup.

5. Patient selection

Currently patients deemed suitable for the MitraClip (Abbott Vascular, Menlo Park, CA) procedure must be at prohibitive risk for open heart surgery, determined by the heart-team. Prohibitive surgical risk is frequently due to one of the following reasons:

• (1)30-day Society of Thoracic Surgeons (STS) predicted operative mortality risk score of ≥8% for mitral valve replacement or ≥6% for mitral valve repair.
• (2)Porcelain aorta or extensively calcified ascending aorta.
• (3)Frailty (assessed by in-person cardiac surgeon consultation).
• (4)Hostile mediastinum.
• (5)Severe liver disease/cirrhosis (MELD Score >12).
• (6)Severe pulmonary hypertension (systolic pulmonary artery pressure >2/3 systemic pressure).
• (7)Right ventricular dysfunction with severe tricuspid regurgitation, chemotherapy for malignancy, major bleeding diathesis, immobility, AIDS, severe dementia, internal mammary artery at high risk of injury.

In addition to assessing for these surgical risk factors, there are specific anatomic criteria that must also be met:

• –Coaptation length ≥2 mm.
• –Coaptation depth <11 mm.

For flail leaflets:

• –Flail gap ≤10 mm.
• –Arm length (coaptation length) ≤15 mm.

MitraClip has the potential to be used in patients outside this selective cohort. The results of the COAPT trial may alter the treatment paradigm for this group of patients with functional MR that are currently excluded from commercial use.

6. Complications and long-term outcomes

The risks are remarkably low for the MitraClip (Abbott Vascular, Menlo Park, CA) procedure in comparison to open repair and are generally well tolerated. No cardiopulmonary bypass is necessary for this procedure. Even in the pivotal EVEREST 2 clinical trial, major adverse events of death and major stroke were similar in both arms of the study.3, 16 Patients in the surgical arm had a higher need for blood transfusion and longer mechanical ventilation times than patients in the MitraClip arm. New onset atrial fibrillation and acute renal failure incidence were higher in the MitraClip group.

A systematic review by Vakil et al. demonstrated that MR reduction was significantly improved with the MitraClip device with an incidence of moderate to severe MR reduced to 14.7% of patients.²⁰ The long-term benefit is still unknown for patients with functional MR. Furthermore, MR has been found to be reduced from severe to mild with MitraClip in the vast majority of patients. In addition, it is known from previous studies on surgical repair of MR that there is a higher mortality rate with residual MR of greater than mild severity.¹³ Therefore, all efforts are made to obtain this result, even if it requires implanting multiple clips to achieve this.

Early on in the experience, only one clip was used during a case reflecting lower rates of improvement of symptoms, NYHA functional class and MR reduction. However, currently 38% of cases receive two clips and 3% receive greater than two clips.²¹ There is no data yet on what the outcomes are for patients receiving single versus multiple clips. Like with any new technology, but more so with a device as complex, such as this, there is a steep learning curve, and that with more experience outcomes, will continue to improve.

Surgical options after placement of a MitraClip are preserved. Also, the need for subsequent mitral valve repair happens to be associated with single leaflet detachment and the risk is highest in the first 6 months after placement of the clip. The other measures of efficacy assessed for the MitraClip in the pivotal trial were LV size, NYHA functional class, and quality of life. LV dimensions, including end-diastolic and end-systolic volumes, were significantly reduced in both groups at 12 months when compared to baseline. At 12 months, a NYHA functional class III or IV was noted in 2% of the percutaneous repair group as compared to 13% in the surgery group; these numbers continued to decline or were maintained at 4 years.²¹ The perceived quality of life also improved in both groups, but was in favor of the MitraClip arm at 30 days as compared to surgery due to the additional morbidity and invasiveness of surgical repair.

All patients receiving the clip commercially are entered into a nationwide STS database so that national outcomes can be tracked and data collected on the current patterns of use.

7. Obstacles and barriers to widespread adoption

The major barrier to widespread adoption of this technology is the careful and limited roll of this technology in the USA. The MitraClip (Abbott Vascular, Menlo Park, CA) is currently available in 75 centers in the United States due to technical requirements that need to be in place at the facilities offering this technology. One of the major obstacles is the existence of a functioning “heart-team,” so that appropriate screening and patient selection occurs. The SCAI/AATS/ACC/STS have endorsed an expert consensus document outlining the institutional and operator requirements necessary for the safe conduct of this procedure.²² Also, each center needs a skilled echocardiographer with 2D and 3D imaging skills for optimal screening of patients and intraprocedural guidance.

Another barrier to widespread adoption is the lack of adequate coverage for this therapy by the Centers of Medicare and Medicaid Services. Based on data from the EVEREST 2 trial, the MitraClip is a cost-effective technology when compared to surgical repair. Including hospital admission, follow-up hospital stays, postsurgical care during the first 12 months, when compared to surgical repair, the MitraClip reduced health care costs by $2200 per person.²³ In terms of quality-adjusted life years (QALY) in the EVEREST 2 study with high-risk patients, the quality of life increased and the cost of maintenance decreased from year 2 to year 10.²⁴

In the primary modified intention-to-treat EVEREST 2 population, the MitraClip strategy resulted in a small gain in QALY through 12 months, modestly reducing costs per patient, making MitraClip economically dominant.²³ Threshold analysis shows that MitraClip would be cost effective at a limit of $54,000 per QALY gained at $26,200.²³

8. Conclusion

With all new technologies, it is important that not only the hospital staff, including catheterization lab nurses and technicians, registered nurses, anesthesiologists, but also the primary care providers are fully engaged and understand the new device. When there is an overall understanding of the new technology and its role in the armamentarium in heart failure management by all providers caring for the subset of patients with heart failure who have significant MR, readmission and clinical outcomes for these patients can be improved.

In terms of MR, the first-line therapy for all patients is still mitral valve surgery. It has been the gold standard, and when done by qualified and experienced surgeons, it has great outcomes. Surgical repair of the mitral valve has been shown to improve survival and prevent the development of heart failure.² However, there are certain populations of patients that are not candidates for this procedure; for these patients, the MitraClip (Abbott Vascular, Menlo Park, CA) is an ideal alternative.

In summary, the MitraClip is a sophisticated new technology for treating MR. It is a highly complex system, but it has shown promising results in reducing MR and the burden of heart failure. The MitraClip has shown that percutaneous intervention is safe with a high procedural success rate and a low procedural complication rate. Future studies will look at MitraClip versus medical management in high-risk groups with functional MR. Currently, it cannot replace surgical repair, but it is an option for patients that cannot have surgery. Ultimately, it may be replaced by transcatheter mitral valve replacement but that technology is at least a decade away from approval.

Conflicts of interest

The authors have none to declare.