EDITORIAL

Transcatheter Therapy for Tricuspid Regurgitation — First Act

Mathias Orban, Steffen Massberg

N Engl J Med 2023; 388:1902-1903
DOI: 10.1056/NEJMe2302457

Severe tricuspid regurgitation is associated with impaired quality of life and poor survival.¹ The condition is managed medically with diuretic agents; surgery is of limited use, since many patients have a variety of coexisting conditions that increase surgical risk. Current U.S. and European society guidelines recommend tricuspid-valve surgery primarily in conjunction with left heart surgery or in symptomatic patients with severe tricuspid regurgitation and right ventricular dilatation who do not have severe right ventricular dysfunction.^2,3 Whether the available treatment options improve the prognosis of patients with severe isolated tricuspid regurgitation has not been addressed specifically in randomized trials. As a result, large numbers of patients with severe tricuspid regurgitation are undertreated.⁴

Isolated severe tricuspid regurgitation has become a therapeutic target for percutaneous approaches, especially for high-risk patients in whom tricuspid regurgitation persists despite treatment of the underlying cause (e.g., left heart disease). Tricuspid transcatheter edge-to-edge repair (TEER) has been the most widely investigated intervention for severe isolated tricuspid regurgitation.⁵ Retrospective registry studies and prospective single-group studies have shown that tricuspid TEER reduces tricuspid regurgitation, alleviates symptoms, reduces neurohumoral activation, and induces reverse remodeling of the right heart.⁶ However, a head-to-head comparison with medical management has been limited to retrospective propensity-matched studies.⁷

The Trial to Evaluate Cardiovascular Outcomes in Patients Treated with the Tricuspid Valve Repair System Pivotal (TRILUMINATE Pivotal), the results of which are presented by Sorajja and colleagues in this issue of the Journal, is a randomized evaluation of the safety and effectiveness of tricuspid TEER as compared with medical therapy alone.⁸ The results for the primary end point of the trial — a hierarchical composite that included death from any cause or tricuspid valve surgery, hospitalization for heart failure, and an improvement in quality of life as assessed with a structured questionnaire — favored tricuspid TEER over medical therapy alone at 1 year after randomization (win ratio, 1.48; 95% confidence interval, 1.06 to 2.13). This finding was driven by an improvement in quality of life, a major therapeutic goal for patients with severe symptomatic tricuspid regurgitation. Although bias cannot be ruled out because of the open-label design, the finding of improved quality of life is consistent with previous, nonrandomized studies of tricuspid TEER.⁶ The extent of reduction in tricuspid regurgitation was also correlated with improvements in quality-of-life scores in the TEER group. There were important additional findings: TEER was safe in vulnerable patients, and the procedure was effective — 87.0% of the patients in the TEER group had moderate or less tricuspid regurgitation at 30 days, as compared with only 4.8% of the patients in the control group. These results were stable at 1 year.

Contrary to expectations, the trial did not show differences in the incidence of death or hospitalization for heart failure at 1 year. This suggests that tricuspid regurgitation is a phenotypic manifestation of the coexisting conditions in affected patients and that its correction has no effect on prognosis, which is determined by the underlying diseases. Conversely, the results may also indicate that patient selection in the trial did not allow for detection of differences between the groups. Thus, several important aspects must be considered when interpreting the findings of this trial.

First, the enrolled patients were less severely ill than those in previous studies.^6,9 This observation is supported by the higher percentage of patients in New York Heart Association class II, as well as by the low percentage of patients who had been hospitalized for heart failure in the year preceding randomization. The level of health in this trial population may be explained by the fact that the trial excluded patients who were receiving dialysis or who had severe pulmonary hypertension, which could represent up to 50% of the patients treated with tricuspid TEER in previous registries.⁹ The patients enrolled in TRILUMINATE Pivotal also had a mean left ventricular ejection fraction of 59%. This implies that patients with heart failure with reduced ejection fraction, a major cause of secondary tricuspid regurgitation, were underrepresented in the trial. Therefore, death and hospitalization for heart failure occurred less frequently than had been predicted when the trial was designed. It remains unknown whether a population with a higher-risk profile and associated higher event rates would derive a prognostic benefit from tricuspid TEER as compared with medical therapy alone.

Second, catheter-based treatment of the tricuspid valve is highly demanding because of the complex and variable anatomy as well as the challenges in echocardiographic visualization. Against this background, the percentages of patients with single-leaflet device attachment (7%) or severe or greater residual tricuspid regurgitation at 30 days (13%) in the TEER group are not surprising. Randomized clinical trials of transcatheter tricuspid-valve replacement, a procedure that typically results in complete abolition of tricuspid regurgitation, may clarify whether complete reduction of tricuspid regurgitation translates into an improvement of prognosis.

Third, this trial was conducted during the Covid-19 pandemic, which may have had an effect on the incidence of hospitalization for heart failure; a preference for outpatient care over inpatient care during the pandemic could have affected rehospitalization rates.¹⁰ Fourth, there was a greater reduction in the daily diuretic dose in the TEER group. Thus, it is not known whether a more stringent continuation of diuretics in the TEER group would have resulted in fewer hospitalizations for heart failure during follow-up. Fifth, the follow-up period of 1 year might have been too short to detect effects of tricuspid TEER on mortality or on hospitalizations for heart failure in this patient population. Other trials of tricuspid TEER are under way (TRICI-HF [ClinicalTrials.gov number, NCT04634266. opens in new tab] and TRI-FR [NCT04646811. opens in new tab]); with sufficient follow-up, the combined results of these trials may inform us about the potential prognostic effects of tricuspid TEER in general and about the subgroups of patients that derive the greatest benefit from this procedure.

TRILUMINATE Pivotal is an important first step in establishing tricuspid TEER as a new treatment strategy for patients with severe tricuspid regurgitation, but more studies are needed to identify the patient population that will benefit most from this new catheter-based treatment option.