Key Points
Question
Does tricuspid transcatheter edge-to-edge repair (T-TEER) combined with optimized medical therapy (OMT) improve patient-reported outcome measures and clinical outcomes compared with OMT alone in patients with severe, symptomatic tricuspid regurgitation?
Findings
In a prospective, randomized (1:1) trial involving 300 patients with severe, symptomatic tricuspid regurgitation, treatment with T-TEER plus OMT vs OMT alone improved a composite score comprising patient-reported outcome measures and clinical events at 1 year.
Meaning
The addition of T-TEER to OMT reduces severity of tricuspid regurgitation and improves a composite outcomes score, driven by improved patient-reported outcome measures, in patients with severe, symptomatic tricuspid regurgitation.
Abstract
Importance
Correction of tricuspid regurgitation using tricuspid transcatheter edge-to-edge repair (T-TEER) in addition to guideline-directed optimized medical therapy (OMT) may improve clinical outcomes.
Objective
To evaluate the efficacy of T-TEER + OMT vs OMT alone in patients with severe, symptomatic tricuspid regurgitation.
Design, Setting, and Participants
Investigator-initiated, prospective, randomized (1:1) trial evaluating T-TEER + OMT vs OMT alone in adult patients with severe, symptomatic tricuspid regurgitation. The trial was conducted at 24 centers in France and Belgium (March 2021 to March 2023; latest follow-up in April 2024).
Intervention
Patients were randomized to T-TEER + OMT or OMT alone.
Main Outcomes and Measures
The primary outcome was a composite clinical end point at 1 year comprising change in New York Heart Association class, change in patient global assessment, or occurrence of major cardiovascular events. Tricuspid regurgitation severity was the first of 6 secondary outcomes analyzed in a hierarchical closed-testing procedure, including Kansas City Cardiomyopathy Questionnaire (KCCQ) score, patient global assessment, and a composite outcome of all-cause death, tricuspid valve surgery, KCCQ score improvement, or time to hospitalization for heart failure.
Results
Of 300 enrolled patients (mean age, 78 [SD, 6] years, 63.7% women), 152 were allocated to T-TEER + OMT and 148 to OMT alone. At 1 year, 109 patients (74.1%) in the T-TEER + OMT group had an improved composite score compared with 58 patients (40.6%) in the OMT-alone group. Massive or torrential tricuspid regurgitation was found in 6.8% of patients in the T-TEER + OMT group and in 53.5% of those in the OMT-alone group (P < .001). Mean overall KCCQ summary score at 1 year was 69.9 (SD, 25.5) for the T-TEER + OMT group and 55.4 (SD, 28.8) for the OMT-alone group (P < .001). The win ratio for the composite secondary outcome was 2.06 (95% CI, 1.38-3.08) (P < .001).
Conclusions and Relevance
T-TEER reduces tricuspid regurgitation severity and improves a composite score driven by improved patient-reported outcome measures in patients with severe, symptomatic tricuspid regurgitation.
Trial Registration
ClinicalTrials.gov Identifier: NCT04646811
This randomized clinical trial evaluates the efficacy of tricuspid transcatheter edge-to-edge repair plus guideline-directed optimized medical therapy (OMT) vs OMT alone for improving clinical outcomes in adult patients in with severe, symptomatic tricuspid regurgitation in France and Belgium.
Introduction
Patients with tricuspid regurgitation often experience poorer quality of life1 associated with reduced cardiac output and clinical manifestations of heart failure.2 Observational studies have repeatedly shown poor long-term survival in patients with severe tricuspid regurgitation.3,4 The quality-of-life benefits of treating tricuspid regurgitation with drugs, transcatheter devices, or cardiac surgery have not yet been elucidated, despite recent encouraging results, especially with devices.5,6,7,8 Owing to the natural history of tricuspid regurgitation,3,9 tricuspid valve surgery is rarely performed and is associated with in-hospital risks.10 Medical management is, therefore, the only option for many patients and is focused primarily on optimizing volume status.3
Tricuspid transcatheter edge-to-edge repair (T-TEER) has emerged as a safe and effective therapy for reducing tricuspid regurgitation.7,8,11 The first randomized clinical trial in this field, the Trial to Evaluate Cardiovascular Outcomes in Patients Treated with the Tricuspid Valve Repair System Pivotal (TRILUMINATE Pivotal), demonstrated that T-TEER, using the TriClip system (Abbott Structural), compared with medical treatment alone, reduced tricuspid regurgitation to moderate or less severe in 87% of patients and increased quality of life, measured using the Kansas City Cardiomyopathy Questionnaire (KCCQ), by a mean of 12.3 (SD, 1.8) points at 1 year.7 In patients with more complex anatomy, transcatheter tricuspid valve replacement may be considered.6,8 Even though the TriClip device, as well as one other transcatheter valve replacement system, is commercially available in the US and Europe, additional data are required to further explore and confirm the net clinical impact of T-TEER.12 Therefore, an investigator-initiated randomized clinical trial was conducted to evaluate T-TEER combined with optimized medical therapy (OMT) vs OMT alone in patients with severe, symptomatic tricuspid regurgitation.7
Methods
Trial Design
Tri.Fr was an investigator-initiated, prospective, randomized (1:1) trial evaluating the impact of T-TEER with the TriClip system plus OMT vs OMT alone in patients with severe, symptomatic tricuspid regurgitation. The study was conducted at 24 tertiary centers in France and Belgium between March 2021 and March 2023. The project was funded by the French Ministry of Health (PHRC-22-0104) and the trial protocol was approved by the National French Ethics Committee and has been published; the protocol and statistical analysis plan are also available in Supplement 1.13 All patients provided written informed consent for participation.
Investigational Device
T-TEER was performed with the TriClip Transcatheter Tricuspid Valve Repair System using a femoral approach under general anesthesia, with procedural guidance via transesophageal echocardiography.9 All 24 clinical centers had performed at least 10 T-TEER interventions before enrollment, and centers were selected according to their expertise in imaging and transcatheter valve interventions.
Patient Inclusion, Randomization, and Follow-Up
All patients with severe, symptomatic tricuspid regurgitation despite stable (≥30 days) guideline-directed OMT for heart failure were considered eligible if they were free from other cardiovascular conditions requiring intervention. Detailed inclusion and exclusion criteria have been reported elsewhere and are available in Supplement 1.13
Severity of tricuspid regurgitation and anatomical suitability for T-TEER were evaluated and confirmed by a central echocardiography laboratory (CoreLab, CIC 1414, University Hospital of Rennes, France) operating in an independent and blinded fashion. Tricuspid regurgitation was quantified using a multiparametric approach according to current guidelines and recommendations.14
A weekly meeting between the investigators and the eligibility committee (E.D., J.J., P.D.G., A.A., J.N.T.) was organized to validate every inclusion based on the patient’s medical history, symptoms, medical treatment, blood test results, 6-minute walk test (6MWT) distance, and right heart catheterization.
Randomization was performed through an automated, web-based system. A 1:1 permuted block randomization scheme was used with stratification according to clinical site and tricuspid regurgitation etiology (atrial, ventricular, or mixed).13 Patients randomized to the T-TEER + OMT group were required to undergo the procedure within 14 days. Clinical follow-up was conducted at 1, 6, and 12 months.13 Follow-up visits consisted of symptom assessment, 6MWT distance, and quality-of-life assessment using the KCCQ score.13
Trial Outcomes
The primary outcome was a composite clinical end point comprising change in New York Heart Association (NYHA) class (assessed by an independent observer at each visit), change in patient global assessment (PGA), or occurrence of major cardiovascular events assessed during a 12-month period after randomization (eFigure 1 in Supplement 2). This composite outcome was developed to evaluate new treatments for chronic heart failure by combining patient-reported outcome measures and major cardiovascular events (death or unplanned heart failure hospitalizations) into a single score.15,16 The score was a 3-level, ordered, categorical outcome, with each patient being classified as improved, unchanged, or worsened at each follow-up visit. A blinded committee adjudicated clinical events, and all analyses were performed using the adjudicated results. Patients were considered improved at the final 12-month visit if they experienced a favorable change in NYHA functional class (NYHA class at last visit – NYHA class at preinclusion visit <0) and/or if their PGA improved to less than 4 (mildly, moderately, or markedly improved) without experiencing any major adverse clinical events (eFigure 1 in Supplement 2). Patients were considered worsened if they experienced a major clinical event (death or unplanned heart failure hospitalization), if their NYHA class worsened (NYHA class at last visit – NYHA class at preinclusion visit >0) or if their PGA at the final visit was greater than 4 (slightly, moderately, or markedly worse). Patients were considered unchanged if they had an unchanged NYHA class or a PGA of 4 (unchanged) at last visit and experienced no major clinical events.
Secondary Outcomes
The secondary outcomes were tricuspid regurgitation grade (assessed at an independent echocardiographic core laboratory)14; quality of life assessed with the KCCQ score; PGA15; a hierarchical composite outcome including all-cause death or tricuspid valve surgery, time to heart failure hospitalization, and improvement of 15 points or greater in KCCQ score assessed 12 months after randomization; major cardiovascular events (myocardial infarction, unstable angina, revascularization, stroke, cardiovascular death, or heart failure hospitalization); and cardiovascular death.
Statistical Analysis
Given an ordinal, 3-level primary outcome, we calculated that 300 patients would provide 90% power to demonstrate that T-TEER + OMT is superior to OMT alone, with a 1-sided α level of .025 and the following assumptions: proportions of improved (0.15 in the T-TEER + OMT group; 0.05 in the OMT-alone group), unchanged (0.5 in the T-TEER + OMT group; 0.45 in the OMT-alone group), or worsened (0.35 in the T-TEER + OMT group; 0.5 in the OMT-alone group).
Efficacy analyses were performed in the intention-to-treat cohort and are presented by treatment group. Continuous variables are presented as means (standard deviations) (for normally distributed variables) or medians (25th-75th) for nonnormal distributions. Discrete variables are summarized as frequencies with percentages.
The primary outcome was tested using a Wilcoxon linear-rank test. Treatment effect was estimated through the probability of a better composite score rank for a randomly selected participant from the T-TEER + OMT group and compared with a randomly selected participant from the OMT-alone group, along with a 95% confidence interval. To evaluate the effect of tricuspid regurgitation mechanism (atrial dilatation vs leaflet tethering vs mixed etiology) on the response to T-TEER, a prespecified subgroup analysis according to tricuspid regurgitation mechanism was performed.
Secondary outcome analysis followed a predefined hierarchical hypothesis-testing strategy to adjust for multiplicity. According to this strategy, the statistical significance of each secondary outcome could be investigated only if the previous outcome was significant (2-tailed P < .05). The statistical-hierarchy testing order was (1) tricuspid regurgitation grade; (2) quality-of-life KCCQ score; (3) PGA; (4) composite secondary end point including all-cause death or tricuspid valve surgery, time to heart failure hospitalization, and improvement of 15 points or more in KCCQ score assessed 12 months after randomization; (5) major cardiovascular events; and (6) cardiovascular death.
Secondary outcomes 1 and 3 were tested using a Wilcoxon linear rank test. Secondary outcome 2 was tested using analysis of covariance. For secondary outcome 4, the treatment effect was expressed as the win ratio using the Finkelstein and Schoenfeld unmatched pair approach.17 The win ratio is a method for reporting composite outcomes that prioritizes the more clinically important event. Additional details are provided in Supplement 2. Secondary outcomes 5 and 6 were tested using the log-rank test. All analyses were performed using SAS version 9.4 (SAS Institute). All P values were 2-tailed unless explicitly stated.
Results
Trial Population
Between March 18, 2021, and March 13, 2023 (last follow-up April 2024), 300 patients from 24 centers in France and Belgium were enrolled in the randomized phase of the trial; 152 patients were assigned to T-TEER + OMT and 148 to OMT alone. The CONSORT diagram is provided in Figure 1.
Figure 1. Recruitment, Randomization, and Follow-Up in a Trial of Transcatheter Edge-to-Edge Repair for Severe Isolated Tricuspid Regurgitation.
OMT indicates optimized medical therapy; and T-TEER, tricuspid transcatheter edge-to-edge repair.
aThree patients withdrew consent and 1 died.
bPatients withdrew consent early or were lost to follow-up.
Mean age was 78 (SD, 6) years (range, 50-93), and 63.7% were women (Table 1). A total of 285 patients (95.0%) had atrial fibrillation and 208 (69.3%) had arterial hypertension. Thirty-two patients (10.7%) had undergone previous aortic valve intervention and 41 (13.6%) had undergone mitral intervention. Heart failure hospitalization had occurred in 121 patients (40.3%) in the year before inclusion. Forty-four patients (14.7%) had an implantable cardiac device. On echocardiography at baseline, median left ventricular ejection fraction was 57% (25th-75th, 50%-64%) and median cardiac output was 4.0 L/min (25th-75th, 3.2-4.9). Tricuspid regurgitation was quantified as massive (4+) in 189 patients (63%) and torrential (5+) in 84 patients (28%). Baseline characteristics were well balanced between groups (Table 1; eTables 1-5 in Supplement 2). Information on medication use is provided in eTables 1 and 4 in Supplement 2.
Table 1. Characteristics of the Patients at Baseline.
| Characteristic | No. (%) | |
|---|---|---|
| T-TEER+OMT (n = 152) | OMT alone (n = 148) | |
| Sex | ||
| Female | 98 (65.5) | 93 (62.8) |
| Male | 54 (34.5) | 55 (37.2) |
| Age, mean (SD), y | 78.3 (6.4) | 78.7 (6.4) |
| Body mass index, median (IQR)a | 25.2 (22.4-28.7) | 25.0 (22.8-28.9) |
| NYHA functional classb | ||
| II | 93 (61.2) | 77 (52.0) |
| III-IV | 59 (38.9) | 68 (45.9) |
| Past history | ||
| Atrial fibrillation | 143 (94.1) | 142 (95.9) |
| Atrial arrhythmia on ECG | 113 (74.3) | 120 (81.1) |
| Hypertension | 106 (69.7) | 102 (68.9) |
| Dyslipidemia | 67 (44.1) | 56 (37.8) |
| Prior (<1 y) heart failure hospitalization | 55 (36.2) | 66 (44.6) |
| Stroke or transient ischemic attack | 22 (14.5) | 22 (14.9) |
| Diabetes | 22 (14.5) | 26 (17.6) |
| Peripheral vascular disease | 18 (11.8) | 10 (6.8) |
| Paced rhythm on ECG | 11 (7.2) | 10 (6.8) |
| Chronic obstructive pulmonary disease | 9 (5.9) | 11 (7.4) |
| Prior ST-segment elevation myocardial infarction | 8 (5.3) | 6 (4.0) |
| Cardiac interventions | ||
| Prior percutaneous coronary intervention | 28 (18.4) | 18 (12.2) |
| Permanent pacemaker (including CRT/ICD) | 21 (13.8) | 23 (15.5) |
| Severe mitral failure | 21 (13.8) | 22 (14.9) |
| Any prior intervention | 17 (11.2) | 16 (10.8) |
| Surgical mitral valve repair | 6 (3.9) | 9 (6.1) |
| Percutaneous mitral valve repair | 13 (8.5) | 13 (8.8) |
| Any prior aortic intervention | 18 (11.8) | 14 (9.5) |
| Coronary artery bypass graft | 12 (7.9) | 8 (5.4) |
| Other baseline measures | ||
| Right heart catheterization | ||
| Systolic PAP, mm Hg | ||
| Median (IQR) | 35.0 (28.0-42.0) | 35.5 (29.0-43.0) |
| Mean (SD) | 22.2 (6.4) | 22.6 (6.7) |
| Mean right atrial pressure, mean (SD), mm Hg | 8.93 (4.3) | 10.0 (5.5) |
| Six-min walk test distance, mean (SD), m | 302 (104) | 309 (112) |
| KCCQ overall summary score, mean (SD)c | 54.0 (23.4) | 54.0 (25.0) |
| NT-pro BNP, median (IQR), pg/mL | 1504 (837-2552) | 1778 (993-2511) |
| Glomerular filtration rate <30 mL/min/1.73 m2 | 13 (8.55) | 6 (4.05) |
| Baseline medications | ||
| Loop diuretic | 145 (95.4) | 143 (96.6) |
| β-Blocker | 107 (70.4) | 110 (74.3) |
| Mineralocorticoid receptor antagonist | 70 (46.0) | 80 (54.0) |
| ACE inhibitor or ARB or sacubitril/valsartan | 56 (36.8) | 60 (40.5) |
| Thiazide, No. (%) | 14 (9.21) | 17 (11.5) |
Abbreviations: ACE, angiotensin-converting enzyme; ARB, angiotensin 2 receptor blocker; CRT, cardiac resynchronization therapy; ECG, electrocardiogram; ICD, implantable cardioverter-defibrillator; KCCQ, Kansas City Cardiomyopathy Questionnaire; NT-pro BNP, N-terminal pro-brain natriuretic peptide; NYHA, New York Heart Association; OMT, optimized medical therapy; PAP, pulmonary artery pressure; T-TEER, tricuspid transcatheter edge-to-edge repair.
Calculated as weight in kilograms divided by square of height in meters.
Patients classified as NYHA functional class II have slight limitation of physical activity and are comfortable at rest. Ordinary physical activity results in fatigue, palpitation, shortness of breath, or chest pain. Those classified as functional class III have marked limitation of physical activity but are comfortable at rest, while those in class IV have symptoms at rest and any physical activity causes further discomfort.
Overall summary score is calculated as the mean of the physical limitation score (6 items), total symptom score (calculated as the mean of the symptom frequency score [4 items] and symptom burden score [3 items]), quality of life score (3 items), and social limitation score (4 items). The KCCQ has a score range of 0 to 100 (scores of 0-24 indicate very poor to poor quality of life; 25-49, poor to fair; 50-74, fair to good; and 75-100, good to very good).
Procedural Outcomes
Four patients allocated to T-TEER + OMT did not receive the device: 3 withdrew before the inclusion visit and 1 had a stroke just before the intervention. Among the 148 patients who underwent T-TEER, the device was successfully implanted in 144 patients (97.3%); 123 (83.1%) had 2 or more clips deployed (eTables 6 and 7 in Supplement 2). Median time from device insertion to removal was 75 min (25th-75th, 55-100). Median length of stay in the hospital was 3 days (25th-75th, 2-6). One patient (0.67%) died within 30 days of the procedure.
Primary Outcome
At 1 year, 290 patients were assessed for the primary outcome (Table 2). In the T-TEER + OMT group, 109 patients (74.1%) were improved, 8 (5.5%) were unchanged, and 31 (20.4%) had worsened. In the OMT-alone group, 58 (40.6%) were improved, 16 (12.1%) were unchanged, and 71 (47.5%) had worsened (P < .001). Rates of improvement in the clinical composite score were higher in the T-TEER + OMT group than in the OMT-alone group (74.1% vs 40.6%, respectively), driven primarily by improvement in NYHA class and PGA (eTable 8 in Supplement 2). eFigure 2 in Supplement 2 shows the distribution of the clinical composite score at 1-year follow-up. No statistically significant differences in rates of cardiovascular hospitalization or cardiovascular death were observed.
Table 2. Primary and Secondary End Points.
| End point | T-TEER + OMT (n = 152) | OMT alone (n = 148) | Absolute difference (95% CI) | Effect estimate (95% CI) | P value |
|---|---|---|---|---|---|
| Primary | |||||
| Clinical Composite Score, No. (%)a | |||||
| Improved | 109 (74.1) | 58 (40.6) | |||
| Unchanged | 8 (5.44) | 17 (11.9) | −0.34 (−0.44 to −0.23)b | 0.67 (0.61 to 0.72)c | <.001 |
| Worse | 30 (20.4) | 68 (47.6) | −0.27 (−0.38 to −0.17)b | ||
| Missing, No. | 5 | 5 | |||
| Secondary (listed in hierarchical order) | |||||
| TR grade at 1 y, No. (%) | |||||
| <2+ | 104 (78.3) | 14 (11.0) | |||
| 3+ | 20 (15.0) | 45 (35.4) | |||
| 4+ | 5 (3.76) | 49 (38.6) | 0.73 (0.68 to 0.78)c | <.001 | |
| 5+ | 4 (3.01) | 19 (15.0) | |||
| Absolute change in KCCQ score from baseline to 1 y, mean (SD), pointsd | 15.9 (30.1) | 0.40 (25.7) | 14.5 (27.2) | <.001 | |
| PGA at 1 y, No. (%)e | |||||
| Improved | 100 (74.6) | 51 (39.5) | |||
| Unchanged | 19 (14.2) | 36 (27.9) | 0.21 (0.12 to 0.31)b | 0.68 (0.63 to 0.74)c | <.001 |
| Worse | 15 (11.2) | 42 (32.6) | 0.35 (0.24 to 0.46)b | ||
| Hierarchical composite end point of time to death or tricuspid valve surgery, or heart failure hospitalizations, and improvement of ≥15 points in KCCQ score at 1 yf | 2.06 (1.38 to 3.08)g | <.001 | |||
| Won per end point of time to death, No. | 1192 | 709 | |||
| Won per end point of time to tricuspid valve surgery, No. | 149 | 133 | |||
| Won per end point of heart failure hospitalization, No. | 2680 | 1787 | |||
| Won per end point of KCCQ improvement at 1 y, No. | 5264 | 1875 | |||
| Pair of patients tied, No. | 8707 | ||||
| Kaplan-Meier estimate of percentage of patients free from MACEs through 1 yh | 84.4 | 80.1 | 0.78 (0.45 to 1.36)i | .38 | |
| Kaplan-Meier estimate of percentage of patients free from cardiovascular death at 1 y | 96.6 | 94.2 | 0.60 (0.20 to 1.84)i | .37 | |
Abbreviations: KCCQ, Kansas City Cardiomyopathy Questionnaire; MACE, major adverse cardiovascular event; NYHA, New York Heart Association; OMT, optimized medical therapy; PGA, patient global assessment; T-TEER, tricuspid transcatheter edge-to-edge repair.
Clinical composite score combines changes in the NYHA class, or PGA and occurrence of major cardiovascular events assessed during the 12-month period after randomization. It is eventually a 3-level ordered categorical end point, each randomized patient being classified as improved, unchanged, or worse, depending on the clinical response during the trial and the clinical status at the end of the trial.
Cumulative risk difference across levels of end points.
Probability of a better rank for a randomly selected participant from the T-TEER + OMT strategy vs OMT-alone strategy. P value is from a Wilcoxon linear rank test.
The KCCQ has a score range of 0 to 100; scores of 0 to 24 indicate very poor to poor quality of life; 25 to 49, poor to fair; 50 to 74, fair to good; and 75 to 100. Patients who experienced an adjudicated cardiovascular death or underwent tricuspid valve surgery prior to completing the 12 months follow-up were analyzed, but their KCCQ score (overall summary score) at 1 year was imputed as zero point. P value is from an analysis of covariance test.
Original 7-level result was shrunk into a 3-level result: “improved,” “unchanged,” or “worse.” Patients who experienced an adjudicated cardiovascular death or underwent tricuspid valve surgery prior to completing the 12-month follow-up were analyzed, but their PGA score was imputed as 7 points (“worse”).
The number of wins in each group is provided after all possible pairs were formed (total of 148 × 152 = 22 496 pairs).
Win ratio, using the unmatched pair approach.
For major cardiovascular events (myocardial infarction [or unstable angina or revascularization], or stroke, or cardiovascular death, or hospitalization for heart failure).
Hazard ratio (Cox proportional hazard model). P value is from a log-rank test.
Secondary Efficacy Outcomes
The rate of massive (or greater) tricuspid regurgitation was greater in the OMT-alone group than in the T-TEER + OMT group (68 patients [53.5%] vs 9 [6.8%]). The probability of a better rank for a randomly selected participant from the T-TEER + OMT group vs the OMT-alone group was 0.73 (95% CI, 0.68-0.78; P < .001). The distribution of tricuspid regurgitation grade over time is shown in eFigure 3 in Supplement 2.
The KCCQ overall summary score was available in 272 patients (90.7%) at baseline and in 248 (82.7%) at 1 year. Estimated least-square means were 69.9 (standard error mean, 25.5) in the T-TEER + OMT group and 55.5 (standard error mean, 28.8) in the OMT group (P < .001) (Table 2). eFigure 4 in Supplement 2 shows the change in KCCQ score over time. Absolute difference between the groups at 1 year was 14.5 (SD, 27.2) points (P < .001) (Figure 2 and Figure 3).
Figure 2. KCCQ Summary Score Over Time and Magnitude of Reduction in Tricuspid Regurgitation.
Reduction in tricuspid regurgitation is the delay in the echo grading of the tricuspid regurgitation vs the Kansas City Cardiomyopathy Questionnaire (KCCQ) score. The KCCQ has a score range of 0 to 100; scores of 0 to 24 indicate very poor to poor quality of life; 25 to 49, poor to fair; 50 to 74, fair to good; and 75 to 100, good to very good. Boxes indicate IQR (25th-75th); horizontal lines within boxes, median; whiskers, smallest and largest values within 1.5 times the IQR; dots outside the whiskers, outliers.
Figure 3. Change in KCCQ Overall Summary Score Over Time.
The Kansas City Cardiomyopathy Questionnaire (KCCQ) has a score range of 0 to 100; scores of 0 to 24 indicate very poor to poor quality of life; 25 to 49, poor to fair; 50 to 74, fair to good; and 75 to 100, good to very good. Boxes indicate IQR (25th-75th); horizontal lines within boxes, median; whiskers, smallest and largest values within 1.5 times the IQR; dots outside the whiskers, outliers. OMT indicates optimized medical therapy; and T-TEER, tricuspid transcatheter edge-to-edge repair.
One hundred patients (74.6%) in the T-TEER + OMT group had an improved PGA, compared with 51 patients (39.5%) in the OMT-alone group (Table 2). The probability of a better rank for a randomly selected participant from the T-TEER + OMT strategy was 0.68 (95% CI, 0.63-0.74) (P < .001). eFigure 5 in Supplement 2 shows the distribution of PGA (3-level result) at 1 year.
Major cardiovascular events occurred in 23 patients (15.1%) in the T-TEER + OMT group and 28 patients (18.9%) in the OMT-alone group (eFigures 6 and 7 in Supplement 2). Eight patients (0.1%) died and 20 (13.5%) were hospitalized in the OMT-alone group compared with 5 (0.03%) and 15 (0.1%), respectively, in the T-TEER + OMT group (Figure 4).
Figure 4. Survival Curves for Patients in the T-TEER + OMT Group and the OMT-Alone Group.
OMT indicates optimized medical therapy; and T-TEER, tricuspid transcatheter edge-to-edge repair.
Additional Outcomes and Safety
NYHA functional class is displayed in eFigure 8 in Supplement 2. The T-TEER + OMT group experienced greater increases in 6MWT distance (from 302 [SD, 104] to 333 [SD, 120] m, mean +10%) than the OMT-alone group (from 309 [SD, 112] to 302 [SD, 116] m, mean +2%). The increase occurred as soon as the 6-week follow-up visit and remained stable thereafter (eTable 9 in Supplement 2).
Adjudicated adverse events are shown in eTable 10 in Supplement 2. Procedural data and major adverse events for the T-TEER + OMT group are displayed in eTables 4 and 11 in Supplement 2. The T-TEER procedure displayed a good safety profile, with 8 (5.2%) single-leaflet device attachments and a 30-day major adverse event rate of 0.7%.
eTable 12 in Supplement 2 shows the association between residual tricuspid regurgitation at 1 year in the T-TEER + OMT group and the composite score, NYHA class evolution, PGA, and absolute changes in KCCQ score and 6MWT distance over time.
Discussion
The randomized Tri.Fr trial demonstrates that T-TEER + OMT reduces tricuspid regurgitation severity and improves clinical outcomes, driven by improved PROMs (NYHA class and PGA) in patients with severe, symptomatic tricuspid regurgitation. The clinical composite outcome improved in 74.1% of the T-TEER + OMT group vs 40.6% of the OMT-alone group. Occurrence of death or heart failure hospitalization did not significantly differ between groups, even if absolute numbers favored the T-TEER + OMT strategy. Improvement in quality of life was sustained at 1 year and was consistent between parameters (NYHA class, PGA, and KCCQ score), confirming that T-TEER + OMT vs OMT alone resulted in a substantial improvement in health status in patients with severe, symptomatic tricuspid regurgitation. The safety of the procedure was confirmed, with a very low rate of intrahospital adverse events (8.0%), including a single-leaflet device attachment rate of 5.2%, which compares favorably with other reports.7,11,18
The study population comprised relatively symptomatic patients with impaired baseline quality of life (mean KCCQ score, 54.0 [SD, 24.1]; 42.4% with NYHA class III or IV symptoms at baseline) and with a high proportion of heart failure hospitalizations (40.3%) in the previous year. Patients with highly advanced disease (ie, severe kidney insufficiency, advanced cardiorenal syndrome, pulmonary artery systolic pressure >60 mm Hg, liver failure, and history of cardiac decompensation with ascites) and those with unsuitable anatomy for T-TEER (leaflet gap ≥10 mm) were excluded to ensure procedure safety and appropriate tricuspid regurgitation reduction, as well as to prevent futility.8 Patients had a preinclusion hospitalization rate similar to that in the observational, prospective postmarketing BRIGHT registry or the prospective TRISCEND I single-group study (tricuspid valve replacement), while the baseline KCCQ score was higher and closer to that described in the TRILUMINATE Pivotal trial.6,7,18 In comparison with these studies, fewer patients had advanced heart failure symptoms (42.3% with NYHA class III or IV in Tri.Fr vs 60% to 80% in other studies).6,7,11
While the prognostic impact of a tricuspid regurgitation diagnosis is now well recognized, the effect of its correction (as well as appropriate patient selection for correction) is still the matter of debate.19 One-year cardiovascular death and hospitalization rates were lower in this cohort than in previous registries.20 One-year mortality in the TRILUMINATE cohort was 8.6%,7 compared with 3.4% in the present study, resulting in lack of power to detect any difference in hard outcomes at 1 year.21 However, in contrast to TRILUMINATE, the numerically lower clinical event rates observed in the T-TEER + OMT group contributed to the statistical treatment effect demonstrated in the current study. As previously observed, a clear link between quality-of-life improvement and tricuspid regurgitation reduction was confirmed. The clinical improvement observed in 40.6% of the patients in the OMT-alone group may be explained by OMT intensification around study inclusion and follow-up but with no statistically significant effect on tricuspid regurgitation severity (89.5% of the patients still had severe or greater tricuspid regurgitation at 12 months vs 23.5% in the T-TEER + OMT group). In addition, particular efforts were dedicated to maintain and monitor medical treatment in patients undergoing T-TEER + OMT (30.8% of the patients received >125 mg/d of furosemide).
The absolute difference in KCCQ score between the 2 strategies was 14.5 (SD, 3.45), representing a moderate-to-large clinical benefit in favor of T-TEER + OMT, exceeding that observed in most heart failure drug trials.1,7 However, the open-label design, without a sham control group, may mitigate this finding, even if consistency was observed between parameters assessed at various points in time, including objective improvement of the 6MWT distance (mean improvement, 2.0 [SD, 42] m in the OMT-alone group vs 10 [SD, 34] m in the T-TEER + OMT group).22,23 Considering the same predefined outcome as in the TRILUMINATE trial (hierarchical composite including all-cause of death or tricuspid valve surgery, time to heart failure hospitalization, and an improvement of ≥15 points in quality of life [KCCQ]), and an at least similar effect size of T-TEER at 1 year was observed (win ratio, 1.48 compared with medical treatment [95% CI, 1.06-2.13]; P = .02 in TRILUMINATE7 vs 2.06 [95% CI, 1.38-3.08]; P < .001 in Tri.Fr). Protocol-mandated longer-term follow-up at 2 and 5 years will further inform on the occurrence of cardiovascular events13 and will allow the analysis of cardiovascular hospitalization and cardiovascular and global death at these time points.13
Limitations
Several limitations must be acknowledged. First, Tri.Fr is an investigator-initiated study supported by a limited grant. Second, the patient population was selected based on clinical characteristics and an anatomy deemed suitable for T-TEER, which may limit the generalizability of the findings. Third, Tri.Fr was designed as an open-label study without a sham control, which may impair the interpretability of changes in patient-reported outcome measures. Fourth, only the TriClip was used is this study, and other repair devices are currently available.
Conclusions
T-TEER + OMT reduces tricuspid regurgitation severity and improves the composite clinical outcome comprising NYHA class, PGA, and major cardiovascular events at 12 months, driven by improved patient-reported outcome measures (NYHA class and PGA) in patients with severe, symptomatic tricuspid regurgitation.
Revised Trial Protocol and Statistical Analysis Plan
Supplemental Material eTable 1. Demographic and Clinical Characteristic of the Patients at Baseline
eTable 2. Biological Assessment at Baseline
eTable 3. Kansas City Cardiomyopathy Questionnaire Score Baseline Measurements
eTable 4. Medication Evolution
eTable 5. Echocardiographic Measurements Through 1-Year Follow-Up
eTable 6. Procedural Data and Major Adverse Events for TriClipTM Device Insertion Group
eTable 7. Components of the Hierarchical Clinical Composite (Within One Year)
eTable 8. Subgroup Analyses for the Primary Endpoint According to the Mechanism of TR
eTable 9. Evolution in 6-Minute Walk Test Over Time
eTable 10. Adjudicated Serious Adverse Events
eTable 11. Serious Adverse Events
eTable 12. Association Between Residual Tricuspid Regurgitation at 1 Year in the TEER Group and Primary Endpoint and Some Secondary Endpoints
eFigure 1. Analysis of the Clinical Composite Score
eFigure 2. Distribution of the Hierarchical Clinical Composite at 1-Rear Follow-Up
eFigure 3. Distribution Over Time of Tricuspid Regurgitation Grade
eFigure 4. KCCQ Overall Summary Score Evolution Over Time
eFigure 5. Distribution of the Patient Global Assessment (3-Level Result) at 1-Year Follow-Up
eFigure 6. Kaplan–Meier Estimate of Percentage of Patients Free From Major Acute Cardiovascular Event at 1 Year
eFigure 7. Kaplan–Meier Estimate of Cardiovascular Death at 1 Year
eFigure 8. New York Heart Association Functional Class Evolution Over Time
Data Sharing Statement
References
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Revised Trial Protocol and Statistical Analysis Plan
Supplemental Material eTable 1. Demographic and Clinical Characteristic of the Patients at Baseline
eTable 2. Biological Assessment at Baseline
eTable 3. Kansas City Cardiomyopathy Questionnaire Score Baseline Measurements
eTable 4. Medication Evolution
eTable 5. Echocardiographic Measurements Through 1-Year Follow-Up
eTable 6. Procedural Data and Major Adverse Events for TriClipTM Device Insertion Group
eTable 7. Components of the Hierarchical Clinical Composite (Within One Year)
eTable 8. Subgroup Analyses for the Primary Endpoint According to the Mechanism of TR
eTable 9. Evolution in 6-Minute Walk Test Over Time
eTable 10. Adjudicated Serious Adverse Events
eTable 11. Serious Adverse Events
eTable 12. Association Between Residual Tricuspid Regurgitation at 1 Year in the TEER Group and Primary Endpoint and Some Secondary Endpoints
eFigure 1. Analysis of the Clinical Composite Score
eFigure 2. Distribution of the Hierarchical Clinical Composite at 1-Rear Follow-Up
eFigure 3. Distribution Over Time of Tricuspid Regurgitation Grade
eFigure 4. KCCQ Overall Summary Score Evolution Over Time
eFigure 5. Distribution of the Patient Global Assessment (3-Level Result) at 1-Year Follow-Up
eFigure 6. Kaplan–Meier Estimate of Percentage of Patients Free From Major Acute Cardiovascular Event at 1 Year
eFigure 7. Kaplan–Meier Estimate of Cardiovascular Death at 1 Year
eFigure 8. New York Heart Association Functional Class Evolution Over Time
Data Sharing Statement
