On the Horizon

Percutaneous Mitral Valve Repair

Cath Lab Digest talks with Saibal Kar, MD, Director of Cardiovascular Intervention Research, Cedars-Sinai Heart Institute; Associate Professor, David Geffen School of Medicine, University of California, Los Angeles (UCLA), Los Angeles, California, about the MitraClip® device (Evalve, Inc., Menlo Park, California).
Cath Lab Digest talks with Saibal Kar, MD, Director of Cardiovascular Intervention Research, Cedars-Sinai Heart Institute; Associate Professor, David Geffen School of Medicine, University of California, Los Angeles (UCLA), Los Angeles, California, about the MitraClip® device (Evalve, Inc., Menlo Park, California).
What is mitral regurgitation? Mitral regurgitation (MR) is a condition that occurs when the mitral valve leaks when it should be closed (during contraction of the heart muscle). Mitral valve leakage commonly results from two different sets of problems. Degenerative MR refers to primary disease of the valve leaflets, the result of which may be leaflet flail, and leaflet billowing or prolapse. If one or more of the leaflets are flailing or prolapsing, you can have leakage through the valve. The second and more common type of problem is referred to as functional MR. With this condition, the mitral leaflets themselves appear structurally normal echocardiographically, but leakage occurs as a result of malcoaptation of the leaflets secondary to enlargement of the left ventricle, displacement of the papillary muscles or dilatation of the mitral annulus. Other causes of leakage include infection of the valve, leaflet erosion and rheumatic heart disease, but these are less common. How are MR patients normally treated? The treatment of MR depends on the severity. The severity of MR is graded echocardiographically from 1 to 4. Grade 3 or 4 MR is considered significant. Patients with grade 3 or 4 MR who are symptomatic or asymptomatic with evidence of ventricular dysfunction should be treated by either mitral valve repair or replacement surgery, if surgery is considered reasonable when weighing the risks and benefits to the patient. Mitral valve repair (rather than replacement), whenever possible is the preferred treatment. There are some centers that are performing minimally invasive cardiac surgery. Instead of doing a midline sternotomy, which means cutting the breastbone, the operation can be performed through the side of the chest, using a smaller incision, also referred to as a mini-thoracotomy. Open heart surgical repair or replacement, whether performed by a midline sternotomy or mini-thoracotomy, is associated with a small but definite risk of morbidity and mortality, even in low-risk patients. The mortality rate for isolated surgical mitral valve repair varies between 1 to 4%, depending on the patient’s clinical condition, and other concurrent illnesses. The major advantage of a minimally invasive surgical approach over the traditional midline approach is a slightly shorter recovery time, and a cosmetic advantage. Once surgery is complete, the valve function improves immediately. However, there is a recovery period from open heart surgery, which is about a week in the hospital and approximately six weeks for full recovery from the procedure. What is the double orifice surgical repair technique and how does the percutaneous mitral repair therapy with the MitraClip device make use of that technique? Ottavio Alfieri, an Italian surgeon, and his colleagues described a new surgical repair technique for patients with a complex anterior leaflet prolapse. The prolapsed segment of the anterior leaflet is sutured to the opposing portion of the middle scallop of the posterior leaflet, thereby stabilizing the prolapsed segment, effectively reducing the mitral leakage and leading to creation of a competent, double-orifice mitral valve. This operation, often referred to as the “Alfieri repair,” has been shown to be effective in selected patients with degenerative and functional MR. This simple and yet elegant surgical technique has been mimicked using a percutaneous technology by Evalve, Inc (Menlo Park, CA). The therapy is referred to as the MitraClip procedure, and it can be used to treat patients with both degenerative and functional MR. The MitraClip procedure is a percutaneous approach, creating a double orifice competent mitral valve by the application of the MitraClip in the middle of the valve. Instead of open heart surgery, requiring the heart to be stopped, the MitraClip procedure is performed in the catheterization laboratory on a beating heart. The patient is under general anesthesia, and the procedure is performed with the help of transesophageal echo and fluoroscopic imaging guidance. A special steerable guiding catheter is advanced via the femoral vein across the inter-atrial septum into the left atrium. A metal implant, the MitraClip device, which is attached to the end of a steerable clip delivery system, is advanced through the guide catheter and positioned in the left atrium at the location of the leak. The clip is oriented perpendicular to the line of mitral leaflet coaptation and then advanced across the valve into the left ventricle. The MitraClip device is used to grasp the leaflets, and then the clip is closed to create a competent double orifice valve. If suboptimal results are achieved in the initial attempt, the clip can be re-opened, the leaflets released, the clip repositioned and the mitral leaflets can be re-grasped at the desired location. This procedure has all the attributes of a minimally invasive percutaneous procedure. The access is via the femoral vein, the procedure is done on a beating heart, and the clip itself is repositionable and removable prior to clip deployment. How do you determine if the MitraClip device is properly placed? Through the use of transesophageal echo (TEE), which is the reason the patient is under general anesthesia. We use both fluoro and TEE to image the device and heart structures, but TEE is the primary imaging tool. With fluoro, the leaflets cannot be seen; only the catheters and clip can be visualized. With TEE, we confirm that the leaflets are well grasped and inserted into the clip. The reduction in MR, which is the other important aspect of proper clip placement, is also assessed using TEE. Once the procedure is successfully performed, the patient is woken up from general anesthesia. Hemostasis of the femoral venous puncture site in the groin is achieved by simple manual compression or a temporary subcutaneous figure-of-8 suture. Patients are typically discharged within 48 hours. Can you tell us about the EVEREST (Endovascular Valve Edge-to-Edge REpair Study) trial series? The MitraClip procedure has been evaluated in a series of studies called the EVEREST I, EVEREST II and REALISM trials. EVEREST I was the pilot study that evaluated the feasibility of the MitraClip procedure for patients with significant MR. The pilot study successfully demonstrated the feasibility of the MitraClip procedure in selected MR patients. All echocardiograms were evaluated in a core lab. Following the pilot study, the FDA approved the pivotal EVEREST II clinical trial comparing percutaneous mitral repair with the MitraClip device to mitral valve surgery. The trial completed enrollment in September 2008. In this study, 279 eligible patients were prospectively randomized to either the MitraClip procedure or mitral valve surgery in a 2:1 ratio, and are currently undergoing clinical and echocardiographic follow up. The trial is a prospective, core lab evaluated, event-monitored trial. In addition to the randomized study arm, there was a registry arm called the EVEREST II High Risk Registry, in which 78 high surgical risk patients were treated with the MitraClip device. Patients were considered high risk if the estimated mortality was calculated to be ≥ 12% using the STS (Society of Thoracic Surgery) calculator, or were considered to be high risk based on the study surgeons’ estimate, based on certain pre-specified morbidities. The High-Risk Registry completed enrollment in January of 2008 and one-year follow up is available. Data from this registry was presented at the May 2009 EuroPCR meeting in Barcelona, Spain. Following enrollment completion of the EVEREST trials, patients are being treated in a continued access registry called REALISM. Both high and lower risk patients with significant MR are treated with the MitraClip procedure in this registry. Just over 70 patients to date have undergone the procedure in the ongoing REALISM study. What did the High-Risk Registry data tell us about the MitraClip therapy? The registry sought to evaluate the ability of the MitraClip system to improve the clinical status of high surgical risk patients for the correction of significant MR. This study has a very important value, because it is the high surgical risk patients who have the greatest need for an alternative procedure. These patients have very few options. The primary safety endpoint of the registry was 30-day mortality. The secondary safety endpoint was 30-day major adverse events. The primary major effectiveness endpoint was at 12 months, looking at reduction of MR, freedom from death, functional class, function of the left ventricle and re-hospitalization for congestive heart failure. What we found was very impressive. If these 78 patients underwent surgery, it was estimated that their 30-day mortality would be 18.2%. The actual 30-day mortality with percutaneous repair in these patients was 7.7% (statistically significant). At 30 days there were 6 deaths, and, one patient had a stroke, one patient had renal failure and 11 patients needed 2 units of blood. So overall, the therapy appears quite safe. There also were no procedural deaths, which is very important. Very few percutaneous valve technologies have achieved this. In addition, we showed that, efficacy-wise, about 82% of patients at 30 days had MR of 2+ or less which was sustained to one year. Most patients demonstrated an improvement in symptomatic status by 30 days with continued improvement to one year. Can you discuss the improvements in left ventricular (LV) function found in EVEREST? When MR and the volume overload to the ventricle are reduced, the ventricle may also reduce in size. This reduction observed in prior EVEREST investigations was recently confirmed in the EVEREST High-Risk Registry, where there was a significant reduction of both the LV end diastolic volumes and systolic volumes at one-year follow up. There was also an increase in the forward stroke volume, i.e. the forward flow into the aorta, in these patients at 12 months. In addition to these LV volumetric changes, there was also a reduction in the mitral annular dimension. The mitral valve consists of two leaflets attached to the annulus. Patients with severe MR develop dilatation of the ventricle and often, dilatation of the annulus, resulting in worsening of MR. Surgeons often correct this by placing a mitral annular ring. There was, therefore, some skepticism about the long-term outcome of the MitraClip device, which does not incorporate usage of a mitral annular ring. Yet this study indicates that there was a concomitant reduction of annular size following percutaneous valve repair. This unique observation has very important clinical implications. There was some discussion about the native tissue. Is this related? No. The ring is basically the annulus. The native tissue means the actual leaflet tissue. The data has shown that no major damage to the leaflets occurs. Some patients have had mitral valve surgery up to 5 years later. The clip was removed and the valve could be successfully repaired, confirming there is no significant damage to the native tissue when a MitraClip device is implanted. Would potential leaflet damage be affected by the number of times the MitraClip device was repositioned? It’s unlikely, because it doesn’t stitch the leaflets, it clips them. If there was a stitch, the leaflets would have holes. But this is a clip, so the damage that takes place to the leaflet over time does not appear to be significant. The High-Risk Registry clearly shows durability out to 12 months. We also have data from the preliminary cohort of the first 107 non-randomized patients, which consist of the 55 feasibility study patients and 52 roll-in patients, and even in this early patient experience, the MitraClip device has shown to be durable. Of the 74% of patients who achieved acute procedural success (defined as MR of 2+ or less on a pre-discharge echo), approximately 94% are free from death up to 2 years and 83% are free from mitral valve surgery at 2 years. So even in the initial EVEREST cohort, we see evidence of durability. We assume that there will be similar results beyond the reported 12 months in the High-Risk Registry as well. What are the potential complications of this procedure? Sometimes there can be a development of pericardial effusion as a complication of transseptal catheterization. There is a low rate of partial clip detachment, where the clip remains attached to one instead of both leaflets, which is a rare complication. It usually presents with the symptom of worsening MR, and patients can be treated by surgery, where the clip can be removed and the patient can undergo surgical repair or replacement. There’s been no case of clip embolization. What about the learning curve for this procedure? This is a very important question that I am asked often. There are several basic skill sets that the physician should have. It’s a team effort between the interventional cardiologist or cardiac surgeon, echocardiographer and anesthesiologist. A very good echocardiographer is essential, as well as a valve interventionalist who understands three-dimensional structures of the heart and echocardiography. Traditional interventionalists understand angiography and fluoro very well, but are not that familiar with echo. So the ideal interventionalist should be a person who is very familiar with echo. What about procedure time? It has gradually come down. Very early on, the average was around 3 to 4 hours and now it is at or below 2 hours. I tend to take a little longer, even though I’ve done the most procedures in the U.S. I like to take my time on each procedure interval in order to ensure that the leaflets are properly inserted in the clip and the MR is appropriately reduced. If the initial result with a single clip is not satisfactory, then I add another clip. The FDA allows placement of two clips. How often do you put in two clips? In my own experience, I’ve put two clips in about 40% of patients; I think the general experience is around 35%. A second clip is placed if there is suboptimal reduction of MR following the first clip. What are the plans for announcing data this fall? We are planning to show the EVEREST II High-Risk Registry data that focus on clinical outcomes and ventricular function. Data will continue to be collected. Regarding the EVEREST II randomized study, data will probably be presented early next year. Based on the initial data, the MitraClip therapy was granted full CE mark approval in Europe. What’s impressive is that in Europe they have already done over 120 cases in a short span of time. This is only at 14 centers, and there are additional centers that will soon be using the system. It shows a very rapid acceptance of this new technology in Europe. Dr. Kar can be contacted at karsk@cshs.org