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- ↵⁎Reprint requests and correspondence:
Dr. Zoltan G. Turi, Cooper University Hospital, One Cooper Plaza D-427, Camden, New Jersey 08103
The past 2 years have seen the culmination of a number of important pivotal trials in percutaneous structural heart disease intervention, including PARTNER A and B (Placement of AoRTic TraNscathetER Valve Trial), EVEREST II (Endovascular Valve Edge-in-Edge REpair STudy), CLOSURE I, and PROTECT AF (Embolic Protection of Patients in Atrial Fibrillation Trial), all attempting to provide a high-level evidence base for selected patients with aortic stenosis, mitral regurgitation (MR), patent foramen ovale, and atrial fibrillation, respectively. In general, these studies have yielded more nuanced results than their predecessor registries and have dampened some of the enthusiasm within the cardiology community for their major innovations. The outcomes did not produce undisputed winners. The EVEREST II (1), a randomized, controlled 2:1 comparison of the MitraClip device and mitral valve surgery, did show a safety benefit (primarily transfusion rate) with less impressive early efficacy outcomes than surgery, but only PARTNER B (2) has been deemed a clear “winner” by most, comparing percutaneous aortic valve replacement with conservative therapy resulted in better functional class and lower mortality, albeit at a higher risk of stroke and vascular complications. PARTNER B, like the EVEREST High Risk Study (3) in this issue of the Journal, was an investigation of patients judged too sick for surgery, but the former was a randomized, controlled trial, whereas this study has the limitations of a registry and uses a highly problematic “comparator” group.
Among the therapeutic options for severe MR, medical therapy is largely palliative, directed at controlling symptoms and manifestations of heart failure (4). Surgical intervention is well tolerated in a population judged by surgeons to be at acceptable risk; a number of registries and retrospective analyses have provided evidence consistent with the superiority of surgery over medical therapy, of mitral valve repair over replacement, and, where replacement has been needed, of preservation of the subvalvular apparatus. However, in patients at high surgical risk due to multiple comorbidities, the mandate for surgery is less compelling (5). Moreover, until the EVEREST II trial randomized patients to medical therapy versus percutaneous mitral valve repair, the evidence base was remarkably lacking in high-level clinical trials studying the outcomes of any intervention for severe MR, surgical or percutaneous (6). Unfortunately, the clinician with a high-risk patient still does not have a solid evidence base with which to choose between medical therapy and surgery, given substantial peri- and postoperative morbidity and mortality (7) in this population.
In this context, the MitraClip procedure brings a potentially important third approach for selected high-risk patients. Its predicate surgical method, the edge-to-edge Alfieri repair (8) predominantly includes concomitant ring placement. There is a relatively small evidence base examining isolated Alfieri repair without annuloplasty (9); the omission of annuloplasty has been shown to create greater mechanical stress on the edge-approximating stitch, the likelihood of “accelerated failure of the repair,” and a higher rate of need for reoperation (10). While the method and extent of leaflet approximation with the percutaneous and surgical techniques may not be identical, the lack of a high-level evidence base comparing the isolated Alfieri procedure with standard mitral valve repair limits our ability to anticipate the effectiveness of the MitraClip approach.
With regard to the study by Whitlow et al. (3) in this issue of the Journal, the authors address the outcomes in a patient population that was judged too high risk for the EVEREST II. We believe that this is a very important study with substantial caveats. First, a major weakness is the inadequacy of the “comparator” group. More than 50% were screen failures and did not meet anatomic criteria, noninvasive data were not read by the core laboratory, a number did not have eligibility assessed by transesophageal echocardiography, patients were selected retrospectively and included only a subset of those eligible, the sample size was small, events were not adjudicated by the clinical events committee, and no information is provided on patient management or any other outcomes parameter except survival.
Second, although the patients in both groups were high risk, the nature of the high risk needs to be emphasized. This was not a study of patients with dilated cardiomyopathy and poor left ventricular function: the mean ejection fraction was 55%, only slightly lower than the 60% in EVEREST II. Rather, this was a study of patients with comorbidities. Compared with the EVEREST II population, there was older age and greater presence of concomitant coronary artery disease, chronic obstructive pulmonary disease, diabetes, previous myocardial infarction, atrial fibrillation, previous cardiovascular surgery, previous percutaneous coronary intervention, and New York Heart Association functional class III or IV. However, more than one third of the patients did not meet the threshold of a Society of Thoracic Surgeons score of ≥12, and their risk assessment was augmented by a less rigorous “up assignment.” This does speak to known concerns about the applicability of the Society of Thoracic Surgeons scoring system; PARTNER B added a similar set of high-risk parameters to identify patients who were inoperable (2).
The outcomes are somewhat nuanced in this study as well. There was relatively high procedure-related mortality for a percutaneous approach (8%). MR graded 2+ or higher was 46% through hospital discharge and 69% at 1 year. Both are high; in EVEREST II, MR grade of ≥2+ was 46% at 1 year (17% after surgery). Only 44% had a ≥2 grade reduction in MR, whereas 19% had no change or a 1-grade increase. A somewhat more optimistic perspective comes from looking at severe MR only; there was an 87% reduction to less severe over 12 months, overall left ventricular dimensions appeared to improve, and New York Heart Association functional class decreased to I or II in 71% of those who were III or IV at baseline. However, interpretation of these follow-up data can be misleading; the reader needs to take into consideration the importance of the de facto censoring of 31% of the patients (including the 24% who died before 1-year follow-up). Thus, comparisons, such as shown in Figure 2 of Whitlow et al. (3), can result in the reader overinterpreting the benefits of MitraClip in this patient population. Unfortunately, only mortality data are provided for the comparator group, and we believe that its weaknesses make the mortality benefit shown in Figure 3 uncertain.
What are the take-home lessons from the study by Whitlow et al. (3)? First, although a subset of patients who had MitraClip placement appeared to have encouraging results, we are concerned that this study not result in denying the benefits of mitral valve repair to patients who in fact could undergo successful surgery. In our experience, excellent surgical results can be obtained in many patients judged at high risk on the basis of cardiomyopathy rather than comorbidities (11). Even with regard to the population studied in this high-risk registry, with high risk primarily defined by comorbidities, we are concerned that patients have a full exploration of the risks and benefits of mitral valve repair, and second the point made by Otto and Verrier (12) that patients being considered for our expanding therapeutic options should be screened by a noninterventional valve disease specialist, interventional cardiologist, and cardiac surgeon; we would add that the latter 2 should be experienced in structural heart disease interventions and high-risk mitral valve surgery, respectively.
Second, without PARTNER A– and B–like prospective, randomized enrollment to MitraClip versus medical therapy for patients who are high risk (A) and truly inoperable (B), the benefits of MitraClip therapy in these patients will remain uncertain. It will be important to consider what constitutes high risk and inoperable: multiple comorbidities or dilated cardiomyopathy (or both). Among patients with a dilated left ventricle and annulus, it will also be essential to define a subset of patients for whom the MitraClip will be anatomically suitable. Because of the heterogeneity of mitral valve insufficiency (much more so than, for example, aortic stenosis), this is a subset of patients with severe MR, although this registry did include patients with both functional and degenerative regurgitation. Many such patients are currently offered only the limited benefits of conservative, primarily medical, therapy (13). These randomized studies should include a well-defined therapeutic strategy and detailed outcome analyses for both groups. We do believe that some of the concerns expressed regarding the results of EVEREST II would apply to a lesser degree in these trials. The long-term durability of MitraClip placement may be less important in a population with comorbidities that make 5-year survival less likely, even with successful treatment of MR; in the inoperable groups, the relatively high crossover rate to surgery in EVEREST II would presumably not occur. Therefore, any secondary benefit seen in an intention-to-treat analysis would be less likely to confound a randomized trial.
Until then, we do not believe that the results of the current registry can be extrapolated readily to routine adoption of the MitraClip for high-risk patients. However, every cardiologist follows patients who are disabled with or dying of this disease, with limited survival and without a suitable alternative to medical therapy. The preliminary results of the EVEREST High Risk Registry suggest that the percutaneous approach has a reasonable enough risk-to-benefit ratio that it should continue to be available, albeit only if performed under investigational protocols by operators skilled at transseptal puncture and working in institutions with extensive experience in percutaneous structural heart interventions (14) as well as a proven track record with mitral valve repair in at least moderate-risk patients.
Dr. Turi receives grant support from Abbott Vascular and St. Jude Medical for research unrelated to valvular heart disease and consults for St. Jude Medical. Dr. Rosenbloom serves as consultant for St. Jude Medical and Edwards Lifesciences.
↵⁎ Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
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