Randomised trials are needed to evaluate the safety and effectiveness of transcatheter mitral valve replacement (TMVR) against current standard of care therapies such as transcatheter edge-to-edge repair (TEER). This is according to lead author Jason Rogers (University of California Davis Medical Center in Sacramento, USA) and colleagues, writing in an opinion paper published in JACC: Cardiovascular Interventions. This consensus document summarises the recommendations of key opinion leaders from interventional cardiology, cardiac surgery, and heart failure specialties.
TMVR is a rapidly evolving therapy for the treatment of symptomatic mitral regurgitation (MR) and mitral stenosis (MS), Rogers et al note, adding that numerous TMVR devices are currently under investigation.
A major potential benefit of the technique, the authors suggest, is the predictable, complete elimination of MR, which is less certain with TEER. This benefit needs to be evaluated against its risks, Rogers and colleagues suggest, including the relative procedural invasiveness, need for anticoagulation, and long-term structural valve deterioration.
“The design of clinical trials for novel TMVR devices must take into account the complexity and heterogenous nature of mitral valve pathologies and available treatment options,” Rogers and colleagues write, adding that although there can be benefits associated with complete MR elimination from valve replacement versus valve repair, “the risks of valve replacement must be weighed against other available therapies”.
For transcatheter technologies targeted to patients with primary MR, they write, randomised trials must be considered against surgical mitral valve repair for surgical candidates or TEER for patients who are at high risk for surgical mortality. For transcatheter technologies targeted to patients with severe secondary MR, randomised clinical trials may be considered against guideline-directed medical therapy, TEER, or surgery depending on patient anatomy or surgical candidacy.
Single-arm trials for patients with an unmet clinical need—for example those with severe mitral annular calcification or with primary MR who are not candidates for surgery or TEER— may be considered but are most meaningful if performed within an overall construct that includes a randomised trial to best interpret the safety and effectiveness of novel first-in-class transcatheter devices against the standard of care, Rogers et al write.
Considering appropriate endpoints for any such trials, the paper’s authors write: “Depending upon the trial’s objectives, primary, secondary, and descriptive endpoints may be chosen from the options provided within the Mitral Valve Academic Research Consortium documents. As patients with untreated MR are at high risk for mortality and progressive heart failure symptomatology, the primary endpoint for TMVR trials should include endpoints that are related to heart failure (i.e. mortality and/or heart failure hospitalisations).”
Quality of life may be considered as a component of a composite primary endpoint depending upon the trial’s intent, but should not be used in isolation, Rogers and colleagues write. Furthermore, trials with TEER as a control group could be designed to demonstrate either superiority or non-inferiority depending upon the device features, and results from such trials could be used to define anatomies for which TMVR may be more suitable than TEER and vice versa.
Secondary endpoints should include those pertaining to safety, for example a composite of major adverse events, stroke, bleeding, myocardial infarction, device effectiveness (MR severity), measures of success (technical success, device success, patient success), left ventricular (LV) dimensions (LV end-diastolic and end-systolic volumes), quality of life (Kansas City Cardiomyopathy Questionnaire score), and functional capacity (six-minute walk distance, New York Heart Association [NYHA] functional class).
The paper’s authors acknowledge that there are challenges to the execution of a randomised controlled trial with current-generation TMVR technologies. They note that the clinical community may be reluctant to randomise patients because of competing commercially approved therapies (TEER), the current requirement for transapical access, and the anatomic restrictions limiting TMVR candidacy including left ventricular outflow tract obstruction and mitral annular sizing. In addition, TEER technology continues to advance and there is improving operator experience with TEER, “both of which have been shown to lead to greater effectiveness and better safety”.
These issues are addressable, Rogers and colleagues note, with study oversight and should not cause abandonment of randomised trials for the evaluation of TMVR technologies, as single-arm only trials “have major limitations”. Importantly, TEER suitability for randomized trials of TMVR vs. TEER should be confirmed by an independent review by a panel of TEER experts.
In their concluding remarks, Rogers et al write that “with emerging data on mitral therapies, stand-alone single-arm trials for novel TMVR therapies using performance goals as the sole basis for evidence generation have limitations and are most powerful when complemented with a concurrent randomised controlled trial to minimise patient selection bias and maximise study validity against standard of care in a broad population”.
They add that establishing clear indications on the basis of high-quality scientific evidence could be expected to reduce off-label use of approved therapies. “Perhaps most important,” they conclude, “without such comparative data from randomised controlled trials, we will lack a comprehensive understanding of the roles of various therapies for patients with MR”.