New England Journal of Medicine MARCH 04, 2023

Transcatheter Repair for Patients with Tricuspid Regurgitation (TRILUMINATE Pivotal)

Paul Sorajja, Brian Whisenant, Nadira Hamid, et al. (for the TRILUMINATE Pivotal Investigators)

Bottom Line

The TRILUMINATE Pivotal trial demonstrated that transcatheter edge-to-edge repair (TEER) using the TriClip system in patients with severe symptomatic tricuspid regurgitation significantly improves quality of life and reduces the rate of heart failure hospitalizations over two years, without a significant difference in all-cause mortality compared with medical therapy alone.

Key Findings

1. The primary hierarchical composite endpoint favored the TEER group over medical therapy (win ratio = 1.48; p = 0.02 at 1 year), driven primarily by substantial improvements in quality of life.

2. Patients receiving TEER showed significant improvements in the Kansas City Cardiomyopathy Questionnaire (KCCQ) score, with a 12.3-point increase compared with 0.6 points in the control group (p < 0.001) at 1 year.

3. Two-year follow-up data indicated a 28% relative risk reduction in the annualized rate of recurrent heart failure hospitalizations in the device group compared to the control group (hazard ratio 0.72, p = 0.02).

4. Tricuspid regurgitation reduction was durable, with 84% of patients in the device group achieving moderate or less tricuspid regurgitation severity at the 2-year follow-up.

5. There was no significant difference in all-cause mortality between the TEER and medical therapy groups through 2 years of follow-up.

Study Design

Design

RCT

Open-Label

Sample

350

Patients

Duration

2 yr

Median

Setting

Multicenter, International

Population Patients with symptomatic severe tricuspid regurgitation at intermediate or greater risk for surgery

Intervention Transcatheter edge-to-edge repair (TEER) with the TriClip device plus medical therapy

Comparator Medical therapy alone

Outcome Hierarchical composite of all-cause mortality, tricuspid valve surgery, hospitalization for heart failure, and improvement in quality of life (KCCQ)

Study Limitations

• The primary endpoint was subjective, relying heavily on quality-of-life assessment (KCCQ) in an open-label trial design, which may be susceptible to a placebo effect.

• A high rate of crossover from the control arm to the device arm after the 1-year follow-up complicates long-term comparative analysis.

• The study did not demonstrate a survival benefit, highlighting that the clinical impact remains focused on symptomatic improvement and reduced hospital burden rather than mortality reduction.

• The population was limited to those deemed at intermediate or greater surgical risk, restricting the generalizability of results to lower-risk patients.

Clinical Significance

The trial provides the first randomized evidence supporting the safety and efficacy of transcatheter tricuspid valve intervention. It establishes TEER as a viable therapeutic strategy for symptom relief and reduction of heart failure hospitalizations in a population where surgical options are high-risk and medical management is limited in efficacy.

Historical Context

Historically, severe tricuspid regurgitation was often treated conservatively with diuretics due to the prohibitively high morbidity and mortality associated with surgical intervention, leading it to be labeled the 'forgotten valve.' TRILUMINATE Pivotal represents the landmark first randomized trial to evaluate a transcatheter repair technology, mirroring the evolution seen previously with mitral TEER, and setting the stage for expanded transcatheter options in right-sided valvular disease.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

Explain the mechanical difference between functional (secondary) and degenerative (primary) tricuspid regurgitation (TR) and describe how the TriClip device physiologically addresses functional TR as seen in the TRILUMINATE population.

Key Response

Functional TR results from right ventricular (RV) and/or right atrial (RA) dilation that causes annular stretching and leaflet malcoaptation, whereas primary TR involves intrinsic leaflet damage (e.g., endocarditis, carcinoid). The TriClip system is a transcatheter edge-to-edge repair (TEER) device that clips the leaflets together (usually the septal and anterior leaflets) to create a tissue bridge, thereby reducing the regurgitant orifice area and improving coaptation even when the annulus is dilated.

Resident

A patient with severe symptomatic tricuspid regurgitation remains NYHA Class III despite optimal medical therapy. Based on the TRILUMINATE Pivotal trial, what are the expected benefits and limitations of proceeding with TEER compared to continuing medical therapy alone?

Key Response

According to the trial, the primary benefit of TEER is a significant improvement in quality of life (measured by the KCCQ score) and a reduction in TR severity (to moderate or less in 87% of patients). However, the trial did not demonstrate a statistically significant difference in all-cause mortality or the rate of heart failure hospitalizations at the one-year follow-up compared to the medical therapy group. Residents must realize the goal of this procedure is currently symptom palliation rather than survival extension.

Fellow

Discuss the clinical significance of the TRILUMINATE trial's categorization of TR severity (Severe, Massive, Torrential) and how the degree of residual TR post-TEER correlates with the trial's primary hierarchical endpoint.

Key Response

TRILUMINATE highlighted that the traditional 'severe' category was insufficient, as many patients had 'massive' or 'torrential' TR. The trial showed that while TEER effectively reduced TR by at least one grade in nearly all patients, the clinical 'win' was largely driven by the KCCQ (Quality of Life) component. For fellows, it is critical to note that while technical success is high, the correlation between hemodynamic reduction in TR and hard clinical outcomes like RV remodeling or long-term mortality is still being elucidated.

Attending

The TRILUMINATE trial utilized an open-label design where the primary endpoint was driven by the KCCQ score. How should this influence your shared decision-making process when discussing TEER with a high-surgical-risk patient who is concerned about the 'placebo effect' of the procedure?

Key Response

Attending-level practice requires acknowledging that in unblinded trials, subjective endpoints like KCCQ are highly susceptible to the placebo effect (as seen in the contrast between the ORBITA sham-controlled trial and other open-label trials). Clinicians should frame the procedure as an effective tool for symptom relief and TR grade reduction, but maintain transparency that 'hard' benefits like longevity have not been proven, especially when compared to the rigorous standards of sham-controlled device trials.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

Analyze the impact of using the Finkelstein–Schoenfeld hierarchical composite endpoint (Win Ratio) in the TRILUMINATE trial. How does this statistical approach handle the competing risks of death and quality-of-life improvements compared to a standard Cox proportional hazards model?

Key Response

The Win Ratio is a hierarchical method that first compares the 'hardest' outcomes (death) between pairs, then proceeds to the next outcome (hospitalization), and finally to 'softer' outcomes (KCCQ change). This allows the study to be powered for a composite even when mortality is low. However, a researcher must critique the fact that if mortality is balanced between groups, the 'win' is almost entirely determined by the KCCQ, which may overweight a subjective metric in the overall trial result.

Journal Editor

As a peer reviewer, how would you address the discrepancy between the significant TR grade reduction (a surrogate) and the lack of difference in the heart failure hospitalization rate in TRILUMINATE, and what threats to internal validity does the lack of a sham control group pose for this NEJM publication?

Key Response

Editors look for 'biological plausibility' and 'internal validity.' The concern is that if the physiological reduction of TR (the surrogate) was truly 'disease-modifying,' we should expect to see a signal in heart failure hospitalizations or NT-proBNP levels. The lack of a sham control means the KCCQ improvement (the trial's primary driver) cannot be definitively decoupled from the psychological effect of intervention, which is a significant limitation for a high-impact surgical/device trial.

Guideline Committee

The 2020 ACC/AHA Valvular Heart Disease guidelines previously listed transcatheter tricuspid intervention as a Class 2b recommendation for highly selected patients. Based on TRILUMINATE, what level of evidence (LOE) and Class of Recommendation (COR) changes would you propose, and how does the lack of mortality benefit affect these considerations?

Key Response

While TRILUMINATE provides 'Level B-R' (Randomized) evidence, the lack of mortality or hospitalization benefits makes a Class 1 recommendation unlikely. The committee might consider an upgrade to Class 2a for symptomatic patients who are high surgical risk, similar to the evolution of mitral TEER. However, the guidelines currently emphasize that surgery is preferred for primary TR (Class 1) and secondary TR at the time of left-sided surgery (Class 1), so TEER remains a niche for 'isolated' secondary TR in patients not suitable for surgery.

Clinical Landscape

Noteworthy Related Trials

2011

EVEREST II Trial

n = 279 · NEJM

Tested

Transcatheter mitral valve repair using the MitraClip device

Population

Patients with moderate-to-severe or severe mitral regurgitation

Comparator

Surgical mitral valve repair or replacement

Endpoint

Composite of freedom from death, surgery for MV dysfunction, and grade 3+ or 4+ MR

Key result: The study demonstrated that the transcatheter device was safer than traditional surgery, although surgery was more effective at reducing mitral regurgitation.

2018

COAPT Trial

n = 614 · NEJM

Tested

Transcatheter edge-to-edge mitral valve repair (TEER)

Population

Patients with symptomatic heart failure and moderate-to-severe secondary mitral regurgitation

Comparator

Guideline-directed medical therapy alone

Endpoint

All hospitalizations for heart failure within 24 months

Key result: TEER significantly reduced the rate of heart failure hospitalizations and improved quality of life compared to medical therapy alone in patients with secondary mitral regurgitation.

2022

TREAT-TR Trial

n = 285 · JACC

Tested

Transcatheter tricuspid valve repair using the Edwards PASCAL system

Population

Patients with symptomatic severe tricuspid regurgitation

Comparator

Medical management

Endpoint

Reduction in tricuspid regurgitation grade and clinical improvement

Key result: The PASCAL system demonstrated a significant reduction in tricuspid regurgitation severity and improvements in functional status at 1 year.

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