Unmet Clinical Needs

Michael Mack, MD

Primary mitral regurgitation (MR) is defined as intrinsic mitral valve pathology that has caused valve incompetence leading to left ventricular (LV) volume overload. This is a mechanical problem for which the only effective solution is mechanical restoration of mitral competence. The gold standard for the treatment of severe MR is surgical mitral valve repair because repair has better short- and long-term outcomes than mitral valve replacement (MVR), including lower operative mortality and fewer long-term complications (1).

However, many patients with severe primary MR are elderly or have multiple comorbidities or both, making them too high risk for cardiac surgery. In such patients, the MitraClip™ has been approved for use in the United States. This device is deployed percutaneously by transseptal puncture, gaining access to the mitral valve. The leaflets are grasped in their centers and brought together to form a mitral repair in the form of a “bowtie.” The device and the procedure to place it have an excellent safety record (2). Furthermore, implantation success has improved dramatically as operators have developed progressively greater experience with the procedure. In mid-term results, post “clip” MR has not translated into progressive worsening of MR (2,3). It should be noted that the MitraClip requires considerable time and skill for implantation. Thus, one unmet need would be a more easily percutaneously  implantable device. Additionally, there are patients who are at very high risk for surgery but whose valve anatomy makes it difficult or impossible to deploy the “clip.”  For such patients a procedure less invasive than standard surgery — i.e., either trans-apical or percutaneous mitral valve replacement — could be helpful. A large number of such valves are currently in various phases of development and some could meet the needs of this small group of difficult-to-treat patients.

Finally, while mid-term results of the MitraClip have been excellent, long-term results are not yet available. If recurrent severe MR occurred late after “clip” deployment, the patients in whom it recurred would likely be elderly and poor surgical candidates. It is unlikely that a percutaneous valve could be deployed in the midst of the mitral leaflets tethered by the “clip.” Thus, an alternative therapy is needed. Percutaneous placement of artificial chordae tendineae might be a possible solution where the leaflet segments responsible for MR could be pulled into coaptation by the newly placed artificial chordae.

Secondary MR is termed secondary because it is caused by LV damage and the subsequent chamber remodeling that follows it, rather than due to an abnormality of the mitral valve itself. The real unmet need in treating secondary MR is a therapy that would correct the underlying LV damage. Currently no such therapy exists and, until it does, therapy is aimed at treating the underlying heart failure attendant to LV dysfunction. Thus, aggressive medical therapy including diuretics, beta blockade, and interruption of the various components of the renin-angiotensin-aldosterone system are indicated.

However, many patients remain symptomatic despite optimal medical therapy and thus additional therapeutic options are needed. Unlike the treatment of primary MR, neither surgical repair nor mitral valve replacement has been shown to be superior to medical management alone. However, a recently well-performed randomized trial known as COAPT (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients with Functional Mitral Regurgitation) found the MitraClip superior to aggressive medical therapy, both in improved mortality and reduction in rehospitalization for heart failure (4).  If this superiority is confirmed, MitraClip would become the new gold standard.  As with primary MR, one unmet need would be mitral valve treatment that would restore valve competence in patients unsuitable for clip placement.

The management of tricuspid regurgitation (TR) is problematic because little evidence-based data exist and those that are available are often contradictory. Thus, the single most important unmet need in this arena is studies that would clarify when therapy is needed and what that therapy should be.

Primary TR is relatively rare and is caused by trauma or infective endocarditis. Surgical valve replacement or repair has been the mainstay of therapy in such cases when severe TR has led to symptomatic right ventricular (RV) failure.

However, most TR is secondary to RV pressure or volume overload caused by LV failure or by lung disease. For secondary TR, the foundation of treatment is medical therapy of the underlying conditions that caused it. In some cases, the causal agent is left-sided valvular heart disease necessitating surgery.  It is standard practice to repair or replace the tricuspid valve during left-sided surgery if severe TR is present preoperatively. Open to debate is the intraoperative management of less than severe TR (5). In such cases, the spectrum of how to address the tricuspid valve  is broad (6,7).  In some cases, mild-to-moderate TR is left untreated with the expectation that relief of left-sided hemodynamic overload will in turn decrease RV load, reducing TR. In others, tricuspid annuloplasty is performed even when there is no TR if the tricuspid annulus is exceptionally large.

With this uncertainty, it is not surprising that some patients continue to have TR postoperatively and in other patients, TR is paradoxically even worse after surgery than before (7). Thus, the patient who has had a successful left-side operation may now suffer from heart failure due to TR.  Unfortunately, the risk of reoperations in such patients can be unexpectedly high, necessitating a less invasive approach to correcting severe TR. This is the major unmet need in this group of patients and a variety of percutaneous solutions are under investigation. Clearly a percutaneous method of reducing TR would have wide application in patients with TR following cardiac surgery and would also be welcomed in cases of symptomatic TR when surgery is not contemplated.