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Translational Pathway for Transcatheter Mitral and Tricuspid Valve Development

Clinical Evaluations – Methods


John Laschinger, MD


Michael Mack, MD

General Considerations

Mitral regurgitation (MR) is a seemingly simple problem (valve leaks) with complex etiology broadly divided into degenerative (a disease of the valve complex) and functional MR (a disease of the ventricle that effects the valve complex). As a result, a wide spectrum of transcatheter devices (trans-apical or trans-septal insertion) aimed at treating MR have been designed to affect hemodynamic changes ranging from those designed to correct MR by replacement of the valve to those designed to primarily reduce MR through repair of one or more of the individual components of the valve complex (three levels: annulus, leaflets, and chordae).

Trial designs for evaluation and possible approval of these devices will be tailored to:

— etiology of MR the device is intended to treat;

— the hemodynamic change the device is intended to affect;

— the stage of the disease with respect to underlying ventricular function;

— the presence of comorbidities; the availability of proven therapy for use as a comparator;

— whether the new device is intended as curative or palliative; and

— the identification of appropriate patient population(s) for testing.

In addition to these factors, a strong reliance on a “heart failure team” approach will be encouraged for all regulatory trials to assure uniform application of optimal heart failure treatment(s) and compliance pre- and post-intervention regardless of the device being studied, to assure all patients have received appropriate pre-procedure assessments of heart function and anatomic suitability for the proposed therapies, and to assure operator/interventional skills available at the individual test sites are appropriate for the device and control therapy being studied. Finally, since the mechanistic goals for these devices (i.e., MR correction vs. MR reduction) vary by design and may change over time due to progression of ventricular pathology and/or loss of mechanistic durability, rigorous core laboratory evaluation of appropriately timed imaging studies will be key components of any clinical or regulatory trial.

Choice of Comparator for MR Device Trials

For devices meant to treat MR, the choice of comparator is related primarily to the disease, the primary treatment effect of the device, and intended population of use (Figures 1 and 2). Other important considerations include the availability of standard of care therapy and the presence of an unmet clinical need. The underlying cause of MR (primary or degenerative vs. secondary or functional) is of primary importance.  For these broad categories, differences in etiology and pathology have led to varying availability of proven therapy to serve as a comparator. For patients early in the course of degenerative MR (prior to left ventricular dysfunction and with minimal symptoms), a well performed surgical repair that addresses all three levels of the valve complex and results in correction of MR is the gold standard therapy.  For patients later in the course of degenerative disease or for those with severe comorbidities, less effective treatments with regards to their ability to address the entire valve complex that result in significant reduction of MR may play a role – for example, using the MitraClip™ for inoperable degenerative MR – due to the less invasive and lower-risk nature of a percutaneous intervention. Additional considerations regarding choice of the patient population include operative risk status and timing in disease course, including the severity of resulting or underlying ventricular remodeling and dysfunction and the severity of symptoms.


Figure 1. Determining Control Therapy

In the setting of symptomatic moderate-to-severe mitral regurgitation (MR), various factors need to be considered when choosing appropriate comparators for clinical trials. These include not only the disease itself and the underlying mechanism of action, but the patient population, the conditions under which the device will be used, and the heart failure (HF) team involved. CAD = coronary artery disease; CRT = cardiac resynchronization therapy; GDMT = guideline-directed medical therapy; LVOT = left ventricular outflow tract; MV = mitral valve.

Figure 2. Example of a Decision Tree for Mitral Regurgitation Trials*

This example of a decision tree outlines possible comparator alternatives that can be used in mitral regurgitation (MR) trials for patients with symptomatic moderate-to-severe disease despite use of optimal guideline-directed medical therapy (GDMT). DMR = degenerative MR; EF = ejection fraction; FMR = functional MR; LVEDVI = left ventricular end-diastolic volume index. (Figure courtesy of the U.S. Food and Drug Administration.)

Assessing Safety

Since test and control therapies will have different safety concerns, it is important that the safety endpoints used to evaluate the test and control therapy be balanced. The variations in both procedural and device safety risks posed by drug, surgical, or transcatheter therapy and their timing must be accounted for in the design of any study.  When used as a composite, important procedural or device related adverse events must be balanced to avoid designs unfairly favoring one therapy over another whenever possible. Additionally, all adverse events related to procedural safety or device safety specific to the assigned treatment must also be carefully evaluated and adjudicated appropriately. Important device safety concerns include those related to access (e.g., vascular, apical, septal, open surgical, etc.), anchor points (e.g., tissue disruption, device misplacement, embolism, etc.), durability (e.g., malfunction, fracture, thrombosis, etc.), damage or interaction with surrounding tissues (e.g., mitral apparatus, coronary compression, etc), infection, paravalvular leak, hemolysis, and unplanned additional devices and need for emergent unplanned intervention or surgery.

Assessment of Effectiveness

Determining the proper endpoint for device effectiveness depends on the etiology of MR, the hemodynamic goals of the device (correction vs. reduction of MR), the available comparative therapies, the timing of treatment in the course of the disease, and the incidence and effects of residual MR or MR recurrence. Typical endpoints reflective of improvements in survival and reduction in heart failure events may need to be supplemented by effectiveness endpoints designed to assess the occurrence and durability of symptom palliation or measurable improvements in function or quality of life (Figure 3).


Figure 3. Effectiveness Outcomes Important to Patients

Device or treatment efficacy may mean different things to different patients, particularly when disease severity is considered. For example, for minimally symptomatic patients who are not experiencing concerns regarding daily functions, increased survival will likely be a more critical outcome whereas patients with more severe disease are likely to be focused on the quality, rather than length, of life before them. GDMT = guideline-directed medical therapy; HF = heart failure.

Whatever benefits are observed, they should be durable and associated with continued expected performance of the test/control devices or therapies.  Patient-centered composite endpoints (Table 1) may be useful in characterizing the totality of benefits for each patient and treatment group (1). Also helpful is the documentation of supportive secondary endpoints such as favorable trends in biomarkers, measured improvements in ventricular volume or function, or prevention of deterioration in ventricular function or volume that are associated with continued expected device hemodynamic performance.


Table 1.  Patient-centered Benefit/Risk Composites

Statistical and Benefit-Risk Assessment

The final regulatory assessment is based on a statistical assessment of the prespecified endpoints for safety and effectiveness and the overall assessment of all available data (i.e., the totality of the data) needed to facilitate sound scientific and clinical judgment regarding benefits versus the risks of the test device (2). This assessment is necessarily impacted by the availability, safety and effectiveness, and benefits and risks of other accepted therapies (Figure 4). For a meaningful benefit-risk assessment, unmet clinical need and patient preferences must be taken into account.


Figure 4. Benefit-Risk Determination Considerations

The goal of a clinical evaluation is to find acceptable alternatives to current of standard of care (SOC), meaning that the therapy being evaluated would demonstrate at least noninferiority but preferably superiority in efficacy or safety or both than the SOC. Clinicians need to always keep in mind there is a threshold at which risk outweighs benefit and an alternative becomes riskier or more invasive with no increase in benefit to the patient. No matter whether the patient/clinician preference is to sacrifice benefit to reduce risk or add risk for increased benefit, the scenario should not cross the threshold where the risk or invasiveness of the device being tested harms the patient.


  1. Stone GW, Adams DH, Abraham WT, et al. Clinical Trial Design Principles and Endpoint Definitions for Transcatheter Mitral Valve Repair and Replacement: Part 2: Endpoint Definitions: A Consensus Document From the Mitral Valve Academic Research Consortium. J Am Coll Cardiol. 2015;66:308-21.
  2. Evans SR, Follmann D. Using Outcomes to Analyze Patients Rather than Patients to Analyze Outcomes: A Step toward Pragmatism in Benefit:risk Evaluation. Stat Biopharm Res. 2016;8:386-93.
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