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The EVEREST trials: A new option for treatment of mitral regurgitation?
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The recent data from the EVEREST II trial have given us a peek at the options that percutaneous repair of mitral regurgitation might offer.
The combined EVEREST data were generated from three registries and the randomized EVEREST II trial itself. This resulted in a wide range of clinical experience from patients undergoing treatment using the MitraClip (Abbott) device — 115 in the nonrandomized EVEREST I feasibility and “run-in” patients in EVEREST II; 78 patients in the nonrandomized “high-risk” registry; and 279 patients in the EVEREST II trial. It is important to note that about 20% of patients treated with the MitraClip had a “functional” component of mitral regurgitation (MR), and thus conclusions as to strict applicability of MitraClip therapy because of the inclusion criteria in EVEREST II are likely not justified.
The interest that EVEREST II generated was heightened because of its design. The 2:1 randomization scheme between MitraClip therapy and mitral surgery (repair or replacement) was straightforward, but the follow-up mandated echocardiographic core lab and clinical follow-up at baseline, 30 days, six months and one year. The surgeons and interventionalists had their feet held to the fire.
Not surprisingly, the demographics of the two groups were similar, except that the MitraClip group arguably had a higher incidence of congestive HF (91% vs. 78%), whereas the surgical group had more patients with peripheral vascular disease (12% vs. 7%). On balance, the groups seemed pretty evenly matched in the randomization process. The primary endpoints per protocol were for safety (superiority hypothesis) and effectiveness (noninferiority hypothesis) of the MitraClip vs. surgery. The former was defined by a list of elements that included death, stroke, MI, sepsis and elements of urgent/emergent cardiac surgery (possibly favoring the surgical group) and transfusion of >2 units of blood. At first glance, the last element might seem to favor the MitraClip group, since approach to the mitral valve was through venous access rather than a thoracotomy, but one cannot argue that transfusion is benign and does not belong on the list. Effectiveness was judged on clinical success, defined at the onset of the trial as a combination of freedom from death, mitral valve surgery and MR >2+ (as judged by the core lab).
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Perhaps the big surprise in the outcome of this study was the wide difference in the safety outcome. The results of EVEREST I (the feasibility study) and the nonrandomized portions of EVEREST II had shown a remarkably low incidence of serious outcome events with the MitraClip. The results of the randomized trial supported these 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. Thus, the safety superiority endpoint of MitraClip therapy was easily met.
The efficacy endpoints were pretty much as expected. Looking at the EVEREST I and nonrandomized data provided the insight that reduction of MR to 0 by use of the MitraClip was rarely done. In contrast, surgical therapy had always been expected to produce at the very least 1+ or less MR. Did that happen? Well, sort of. At one year, 76% of the surgical group had 1+ or no residual MR, but almost half of those had mitral valve replacement — not repair. In contrast, only 36% of MitraClip patients had 1+ MR. Moving the bar up also showed that surgery does well: 81.5% of MitraClip patients had 2+ or less MR at one year. Surgical therapy increased that number to 97%. Thus, the trial definition of clinical success rate at 12 months occurred in 72% of MitraClip patients and in 88% of patients in the surgical group. With this difference, noninferiority for effectiveness was also met.
What do these outcomes mean to physicians caring for patients with MR? For me, the proof of the pudding lies in what happened to patients’ NYHA functional class and, perhaps more importantly, what happened to their ventricular function after repair. At one year, the MitraClip and surgical groups had good NYHA functional outcomes: 98% of the MitraClip patients were in NYHA Class I/II, as were 88% of patients in the surgical group. Not only did patients feel better, but both groups had significant reductions in left ventricular end diastolic volumes and dimensions and also in LV diastolic volumes. That means that reduction of MR to 2+ or less, regardless of the therapeutic method used, seemed to be enough to reverse LV dysfunction — at least at one year. Perhaps the long-held assumption that the reduction of MR to 0 or 1+ is mandatory for the improvement outcomes is, in fact, not correct. If those outcomes can be reached with greater safety, MitraClip therapy becomes an option for many patients who otherwise might have surgery.
This conclusion is wrapped in a number of “ifs.” The conclusion holds if the outcomes continue to show noninferiority during the next year or two of follow-up; if the MitraClip continues to maintain the same reduction of MR; if surgical outcomes continue to be as good as they are at one year; and if LV function continues to improve in patients treated with the MitraClip. For now, and for many selected patients in the short term, the results of the EVEREST study show us that there is another option on the table. A new dialogue can begin.
For more information:
- Feldman T. J Am Coll Cardiol. 2005;46:2134–2140.
- Feldman T. LBCT I. Presented at: American College of Cardiology 59th Annual Scientific Sessions; March 14-16, 2009; Atlanta.
Peter C. Block, MD, is a Professor of Medicine and Cardiology at Emory University and Director of the Clinical Trials Office at Emory University Hospital in Atlanta. Block is also Co-section Editor of the Vascular Medicine and Intervention section of Cardiology Today.