EVEREST II: Mitraclip Less Effective But Safer Than Surgery

April 06, 2011

April 5, 2011 (New Orleans, Louisiana) - Results from the EVEREST IItrial out to two years show that percutaneous repair of the mitral valve with the MitraClip (Abbott) device was significantly less effective at reducing mitral regurgitation than surgery, but the procedure was associated with superior safety and similar improvements in clinical outcomes [1].

Most commentators seem to agree that the clip will be used in those who are too high risk to undergo surgery--the older and sicker patients. But they are reserving judgment on the broader population until longer-term data become available.

The final one-year and some two-year results are published in the New England Journal of Medicine today to coincide with their presentation at the American College of Cardiology (ACC) 2011 Scientific Sessions.

The paper focuses on the intention-to-treat analysis, whereas when the results were first presented at last year's ACC meeting, they were reported primarily as a per-protocol analysis, with investigators concluding that the MitraClip was "noninferior" to surgery for the primary efficacy end point. That per-protocol analysis has been published in a supplementary appendix to the main paper.

In addition, at the ACC presentation today, Dr Ted Feldman (NorthShore University HealthSystem, Evanston Hospital, IL) reported two new analyses of the two-year results. The first--an intention-to-treat analysis-–showed results very similar to the one-year results. The second two-year analysis, described as a "comparison of treatment strategies," pitted the MitraClip, followed by surgery if the percutaneous approach was not successful, against surgery alone. This showed nonsignificant differences in the primary efficacy end point at both one and two years. Both analyses showed durability of the device between one and two years.

Feldman told heartwire that "in the intention-to-treat analysis, the benefit of surgery over the clip was entirely driven by patients in the clip group who needed subsequent surgery. We have shown that at one year, 80% of the clip patients do not need surgery; at two years, this is practically the same, at 78%. Almost all patients who had the clip but then needed surgery had surgery within six months. So if a patient gets the clip and gets to six months, they do fine. The odds of avoiding surgery are much better with the percutaneous procedure."

The odds of avoiding surgery are much better with the percutaneous procedure.

He added that "surgery is better at reducing mitral regurgitation. But both procedures reduced LV diastolic volume, and NYHA class heart failure is better at both one and two years with the clip. Irrespective of the mitral-regurgitation results, the left ventricle responds favorably to treatment with the clip. Symptomatically, patients do very well."

Is a Low Level of Regurgitation Acceptable?

But other experts were more cautious. One of these, Dr Robert Bonow (Northwestern University, Chicago, IL), told heartwire that "it looks as though the MitraClip might be an alternative strategy for reducing regurgitation in older people with lots of comorbidities who are not good candidates for surgery. With the two-year data we have just seen, I would say the clip is fine for an 80-year-old with heart failure, but a younger patient needs a 20-year fix, and we get this from surgery. We don’t know if we get this from the clip. Perhaps patients can tolerate low levels of regurgitation long term. Perhaps not."

Bonow added: "But I was pleased to see the stability of results between one and two years. I was concerned about regurgitation, but this seems to have stabilized now."

Cardiac surgeon Dr Steven Bolling (University of Michigan Cardiovascular Center, Ann Arbor), who was a panelist at the late-breaking session at which the latest EVEREST II results were presented, told heartwire that "there will be variable opinions about whether [the strategy of] clip first, then surgery is appropriate. It may be for a small subset of high-risk or CHF patients, but perhaps not for the vast majority, who are better served by surgery, which leaves them with substantially less mitral regurgitation."

Bolling added: "The trial suffers a little from awkward analyses--per protocol vs intention to treat, and the inclusion of both degenerative and functional [mitral regurgitation] patients. These are very different populations mixed together. But the main question for me is whether it is okay to have a level of 2+ regurgitation. Maybe it is. But as a surgeon, I wouldn't be happy to leave the operating room with this situation. I think we have to ask if the bar has been set too low."

Cochair of the session, interventionalist Dr Gregg Stone (Columbia University, New York), was more positive about the percutaneous approach. He told heartwire : "The most important lessons from the two-year EVEREST II data are that, by intention to treat, the MitraClip approach has an early safety advantage. It also has a 78% freedom from surgery at two years with similar mortality, and a sustained reduction in regurgitation and LV volumes, although not quite to the extent of surgery. And symptomatic patient benefit was at least as good with the MitraClip as with surgery. Overall, there clearly is a place for this device for selected patients with [mitral regurgitation]."

Feldman pointed out that that the discrepancy between the degree of mitral regurgitation and symptoms is puzzling. "While the degree of [mitral regurgitation] is worse with the clip, patients tend to feel better. We don't know the reasons for this. Perhaps we are not measuring [mitral regurgitation] correctly in the clip patients, or perhaps we have achieved a threshold of residual [mitral regurgitation] that is okay."

He acknowledged that patients at high risk during surgery are obviously the most attractive candidates for the clip and said this was in itself a large population. "There are as many patients out there with severe [mitral regurgitation] who cannot be referred for surgery as there are those referred for surgery."

Bolling further pointed out that regarding the improved safety results with the clip, the only difference was transfusions. "If we take those away, the two procedures are equally safe." But Stone countered: "It is well-established that transfusions increase morbidity/mortality down the line. We just haven't seen that yet in this trial."

Valve Replacement vs Repair

Bonow highlighted another concern--the fact that several of the MitraClip patients who went on to have surgery actually underwent valve replacement rather than repair. "Of those who went on to have surgery, half got a mitral-valve replacement, which means inserting manmade material, the need for anticoagulation and higher risks downstream. But these patients had originally been selected for the trial because they were ideal candidates for repair. My concern here is that perhaps the clip could have damaged the valve so that it is no longer suitable for repair and has to be replaced." He added: "You have to remember that only one in seven patients were candidates for EVEREST in the beginning. Then, the clip is not successful in almost one-quarter of them. And half of these get replacement rather than repair when they undergo subsequent surgery."

The Intention-to-Treat One–Year Results

The EVEREST II trial randomized 279 patients with moderately severe or severe (grade 3+ or grade 4+) mitral regurgitation in a 2:1 ratio to undergo either percutaneous or surgical repair of the mitral valve.

The primary composite end point of freedom from death, from surgery for mitral-valve dysfunction, and from grade 3+ or 4+ mitral regurgitation at 12 months was significantly better in the surgery group.

Primary Efficacy End Point and Individual Components at 12 Months

End point Percutaneous repair, n=181 (%) Surgical repair, n=89 (%) p
Freedom from death, mitral-valve surgery, and grade 3+ or 4+ mitral regurgitation 55 73 0.007
Freedom from death 6 6 1.00
Freedom from surgery for mitral-valve dysfunction 20 2 0.001
Freedom from grade 3+ or 4+ mitral regurgitation 21 20 1.00

The primary safety end point of adverse events at 30 days was significantly reduced in the MitraClip group, but this was primarily accounted for by a reduction in blood transfusions.

Primary Safety Results at 30 Days

End point Percutaneous repair (%) Surgical repair (%) p
Any major adverse event 15 48 <0.001
Any major event excluding transfusion 5 10 0.23
Transfusion of >2 units of blood 13 45 <0.001

In the published paper, the authors report that during 12 months of follow-up, 37 of 178 patients (41%) in the MitraClip group underwent mitral-valve surgery. The reasons for surgery were no percutaneous implantation of a device (17 patients), mitral regurgitation of grade 3+ or 4+ after device implantation (17 patients), and symptoms (three patients). In seven cases, leaflet or chordae tears were noted during surgery.

Secondary efficacy end points at 12 months showed improvements in left ventricular size, NYHA functional class, and quality-of-life measures compared with baseline in both groups, but surgery was associated with a transient decrease in quality of life at 30 days, which the authors attribute to the invasiveness of surgery.

The authors note that "although percutaneous treatment did not reduce mitral regurgitation below grade 3+ in 23% of patients, among those who had improved mitral regurgitation after the procedure, the improvement remained at 12 and 24 months for a majority. Measures of efficacy remained durable through 24 months of follow-up, and 78% of patients remained free from mitral-valve surgery."

They point out that subgroup analysis identified age of at least 70 years and functional mitral regurgitation as subgroups in which surgery was not as effective as percutaneous treatment; there was a similar trend in the subgroup with reduced left ventricular function.

In an accompanying editorial [2], Drs Catherine Otto and Edward Verrier (University of Washington School of Medicine, Seattle) say that the EVEREST II authors are to be commended for conducting a rigorous clinical trial, but they express concern that, at 12 months, substantial residual regurgitation (grade 2+ or more) was present in 46% of patients in the percutaneous-treatment group, compared with 17% in the surgical group. They write: "This modest reduction in regurgitant severity might be associated with favorable short-term and midterm outcomes, but surgical series suggest that residual mitral regurgitation predicts adverse long-term clinical outcomes."

Two-Year Results: Intention to Treat Analysis

Two-year results showed much the same outcomes as the one-year results.

Primary Efficacy End Point and Individual Components at Two Years

End point Percutaneous repair, n=172 (%) Surgical repair, n= 83 (%) p
Freedom from death, mitral valve surgery, and grade 3+ or grade 4+ mitral regurgitation 51.7 66.3 <0.001
Freedom from death 11.0 10.8 >0.999
Freedom from surgery for mitral-valve dysfunction 22.1 3.6 <0.001
Freedom from grade 3+ or grade 4+ mitral regurgitation 19.8 21.7 0.84

 

On the different analyses presented, Dr Sanjay Kaul (Cedars Sinai Medical Center, Los Angeles, CA) commented heartwire : "The only important one is the intention to treat, which is the one the New England Journal of Medicine quite rightly insisted on. This clearly shows that the clip is not as effective as surgery." He added: "As clinicians we should not advocate new therapies because they are safer but ineffective. They have to be effective first. And the clip is not effective compared with surgery. However, it will be used in some patients--those not suitable for surgery."

Feldman told heartwire that ultimately the decision of which strategy to go with will be made on an individual basis. "The MitraClip will be an option if the valve anatomy is suitable, and the most powerful reason to consider the clip would be for patients at higher risks during surgery. Looking at subgroups, it appears that the clip may be better for older patients, those with functional rather than degenerative mitral regurgitation, and for patients with left ventricular dysfunction." He added: "This is a first-in-class catheter-based strategy for mitral regurgitation. It is a very big step."

He noted that successful placement of the clip was increasing as operators became more experienced with it. "In the randomized study, we were seeing procedure success rates of around 85%. But now in the postrandomization study, we are achieving success rates of around 95%. We are clearly getting better at doing this."

Feldman has served as an advisor or consultant for Abbott and Edwards and has received grants for clinical research from Abbott and Edwards.

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