https://orcid.org/0000-0002-6613-519X
Abstract
For patients with symptomatic, severe tricuspid regurgitation (TR), early results of transcatheter tricuspid valve (TV) intervention studies have shown significant improvements in functional status and quality of life associated with right-heart reverse remodelling. Longer-term follow-up is needed to confirm sustained improvements in these outcomes.
The prospective, single-arm, multicentre TRISCEND study enrolled 176 patients to evaluate the safety and performance of transcatheter TV replacement in patients with ≥moderate, symptomatic TR despite medical therapy. Major adverse events, reduction in TR grade and haemodynamic outcomes by echocardiography, and clinical, functional, and quality-of-life parameters are reported to one year.
Enrolled patients were 71.0% female, mean age 78.7 years, 88.0% ≥ severe TR, and 75.4% New York Heart Association classes III–IV. Tricuspid regurgitation was reduced to ≤mild in 97.6% (P < .001), with increases in stroke volume (10.5 ± 16.8 mL, P < .001) and cardiac output (0.6 ± 1.2 L/min, P < .001). New York Heart Association class I or II was achieved in 93.3% (P < .001), Kansas City Cardiomyopathy Questionnaire score increased by 25.7 points (P < .001), and six-minute walk distance increased by 56.2 m (P < .001). All-cause mortality was 9.1%, and 10.2% of patients were hospitalized for heart failure.
In an elderly, highly comorbid population with ≥moderate TR, patients receiving transfemoral EVOQUE transcatheter TV replacement had sustained TR reduction, significant increases in stroke volume and cardiac output, and high survival and low hospitalization rates with improved clinical, functional, and quality-of-life outcomes to one year. Funded by Edwards Lifesciences, TRISCEND ClinicalTrials.gov number, NCT04221490.
One-year results of transcatheter tricuspid valve replacement in patients with ≥ moderate tricuspid regurgitation. The TRISCEND study demonstrated the following for patients treated with the EVOQUE system: 9.1% all-cause mortality and 10.2% HF hospitalization; significant TR reduction to grade ≤ mild in 97.6% of patients; and marked improvement in functional and quality-of-life outcomes, including a 25.7-point increase in KCCQ, 56.2-m increase in 6MWD, and 93.3% of patients in NYHA class I/II. 6MWD, six-minute walk distance; HFH, heart failure hospitalization; KCCQ, Kansas City Cardiomyopathy Questionnaire; NYHA, New York Heart Association; TR, tricuspid regurgitation.
See the editorial comment for this article ‘From TriValve to TRILUMINATE to TRISCEND: what have we learned?’, by S.W. Bienstock and G.W. Stone, https://doi.org/10.1093/eurheartj/ehad622.
Introduction
Moderate or greater tricuspid regurgitation (TR) affects ∼4% of elderly adults,1–4 with increasingly severe TR associated with higher morbidity and mortality.5–8 However, treatment options are limited: surgery is rarely elected due to high in-hospital mortality of 10%–12% for isolated tricuspid valve (TV) surgery,9,10 and medical treatment fails to stem long-term disease progression.11–13
Transcatheter TV interventions (TTVI) have grown exponentially to accommodate the unmet need of patients with symptomatic, severe TR.14 A reduction in TR severity may result in right-heart reverse remodelling and improvements in forward stroke volume and survival.15 To that end, tricuspid transcatheter edge-to-edge repair (TEER) devices received commercial approval in Europe and led to positive changes in ESC/EACTS guideline recommendations for use of TTVI.16 Tricuspid TEER remains an important treatment option. However, rates of residual TR ≥ severe range from 43%–48%17,18 and may contribute to adverse outcomes in some patients.19,20 Thus, the prospect of eliminating TR has led to development of transcatheter TV replacement (TTVR) to further expand treatment options.
Early experiences with TTVR devices have demonstrated significant TR reduction to 98% ≤ mild21 and associated improvements in functional status and quality of life.21–24 To address a paucity of longer-term data in larger cohorts, we report interim one-year clinical and echocardiographic outcomes of the EVOQUE TV replacement system (Edwards Lifesciences, Irvine, CA) from the global, multicentre, prospective, single-arm TRISCEND study.
Methods
Patient selection and study conduct
The TRISCEND study evaluates the safety and performance of the EVOQUE system in patients with ≥moderate symptomatic TR despite medical therapy who are deemed appropriate for TTVR by the multidisciplinary local heart team and confirmed by a central screening committee and echocardiographic core laboratory (core lab).
Key exclusion criteria were TV anatomy precluding device placement or function, haemodynamic instability, severe pulmonary hypertension [pulmonary artery systolic pressure (PASP) > 70 mmHg or >2/3 systemic with pulmonary vascular resistance > 5 WU after vasodilator challenge], severe right ventricular (RV) dysfunction, refractory heart failure (HF) requiring advanced intervention, and need for emergent surgery or planned cardiac surgery within the next 12 months. Additional exclusion criteria were left ventricular (LV) ejection fraction < 25% and severe renal insufficiency with estimated glomerular filtration rate ≤ 25 mL/min/1.73 m2 or requiring chronic renal replacement therapy.
Patients who had a transtricuspid valve pacing lead implanted in the last three months were excluded from the study. Patients who had a lead implanted more than three months prior could be enrolled, although those who were pacemaker dependent needed to qualify for an alternative pacing option in case of lead failure post-procedure. Removing leads prior to the procedure was not required, although lead location across the annulus was factored into procedure planning to avoid adverse interactions between the lead and the device. Transoesophageal echocardiography (TEE), transthoracic echocardiography (TTE), and computed tomography (CT) were used for anatomic and functional screening and baseline assessments. Transoesophageal echocardiography was required for intraprocedural guidance, and TTE was assessed at discharge and follow-up. Clinical and echocardiographic follow-up were conducted at 30 days, six months, and one year, and will continue annually to five years.
The TRISCEND study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments, Good Clinical Practice principles, and ISO 14155. The protocol was approved by the Institutional Review Board or Ethics Committee at each participating centre. All patients provided written informed consent. Per protocol, the sponsor funded all trial-related activities and performed site selection, data collection and monitoring, and statistical analysis. The principal investigator monitored all aspects of on-site trial conduct and had access to source data. An echocardiographic core lab (Baylor Scott and White Research Institute Cardiac Imaging Core Laboratory, Dallas, TX) analysed all echocardiograms. A data safety monitoring board and clinical events committee oversaw and adjudicated events, respectively. Edwards Lifesciences sponsored the study, registered at ClinicalTrials.gov (NCT04221490).
EVOQUE tricuspid valve replacement system
The transcatheter EVOQUE system (Figure 1, Supplementary data online, Video S1) comprises a trileaflet bovine pericardial tissue valve implant available in 44 mm, 48 mm, and 52 mm diameters; a 28 Fr percutaneous delivery system; a dilator kit; and a loading system, stabilizer, stabilizer base, and stabilizer plate. The implant features a nitinol frame, nine anchors for implantation stability, and a sealing skirt to minimize paravalvular leak. The 28 Fr delivery system has three planes of flexion for precise steering and positioning.
The Edwards EVOQUE transcatheter tricuspid valve replacement system.
The EVOQUE valve is delivered to the right ventricle via transfemoral venous access and positioned within the native TV under real-time TEE visualization. Once in position, the anchors are exposed to engage the native leaflets, subvalvular anatomy, and annulus in a procedure previously described.21
Study endpoints
The safety endpoint was a 30-day composite of major adverse events (MAEs): cardiovascular mortality, stroke, myocardial infarction, renal complications requiring unplanned dialysis or renal replacement therapy, severe bleeding (major, extensive, life threatening, or fatal as defined by the Mitral Valve Academic Research Consortium25), non-elective TV re-intervention, major access site and vascular complications, major cardiac structural complications, and device-related pulmonary embolism.
Performance endpoints were device success (analysed per device and defined as successful device deployment and delivery system retrieval at the patient’s exit from the catheterization laboratory), procedural success (analysed per patient and defined as device success without clinically significant paravalvular leak by TTE at discharge as determined by the core lab), and clinical success (analysed per patient and defined as procedural success without MAEs at 30 days).
The echocardiographic endpoint was reduction in TR grade from screening or baseline TTE compared with discharge TTE. Two-dimensional TTE with Doppler was performed to assess TR using the five-grade scheme proposed by Hahn and Zamorano.26 Additional TTE parameters included TV mean gradient, cardiac output, stroke volume, right atrial volume, LV ejection fraction, inferior vena cava (IVC) diameter and respiratory variations, RV end-diastolic diameter, PASP, tricuspid annular plane systolic excursion (TAPSE), RV fractional area change (FAC), and hepatic vein flow reversal.
Clinical, functional, and quality-of-life endpoints were assessed at baseline, 30 days, six months, and one year, and will continue annually to five years. These include New York Heart Association (NYHA) classification, Kansas City Cardiomyopathy Questionnaire (KCCQ), Short Form Health Survey (SF-36) version 2, and six-minute walk distance (6MWD). All-cause mortality, HF hospitalization, and non-elective TV re-intervention were assessed at one year and will continue annually to 5 years.
Echocardiographic assessment
The independent core lab analysed all echocardiograms, including screening echocardiograms for inclusion and exclusion criteria, using American Society of Echocardiography standards.27 Two-dimensional Doppler echocardiography was used to assess chamber size and function and valvular regurgitation, and proximal isovelocity surface area method (PISA) was used to measure effective regurgitant orifice area (EROA) and regurgitant volume.
Medical therapy
Medical therapy was administered at the investigator’s discretion, with diuretic medications at stable doses for 30 days prior to the procedure unless the patient had a documented history of intolerance. Study guidelines recommended maintaining patients on a pre-procedure diuretic regimen for three months post-implant. Anticoagulation was recommended for up to six months post-procedure.
Statistical analysis
Continuous variables are reported as mean ± standard deviation or median [interquartile range (IQR)], with P-values calculated by paired Student’s t-test. Categorical variables are summarized with patient count and percentage, with paired change from baseline P-values calculated by Wilcoxon signed rank test. Event rate denominators for MAEs (including cardiovascular mortality) include patients who had been in the trial for at least the specified timepoint or had an event. All-cause mortality and HF hospitalization observed rates are calculated using the denominator of all patients enrolled in the study, and Kaplan–Meier estimates for time to first event are reported. Annualized HF hospitalization compares site-reported data from 12 months before implant to clinical events committee-adjudicated hospitalization 12 months after implant. SAS software version 9.4 (SAS Institute) was used for statistical analysis.
Results
Baseline characteristics
Among 176 patients enrolled at 20 centres in North America and Europe, 71.0% were female, mean age 78.7 years, Society of Thoracic Surgeons mortality scores of 7.4% (mitral valve repair) and 10.0% (mitral valve replacement), and EuroSCORE II 5.1% (Table 1). Tricuspid regurgitation grade was ≥severe in 88.0%, with aetiologies of secondary (68.2%), mixed (14.2%), primary (9.7%), indeterminate (5.1%), and pacer related (2.8%). Three-quarters (75.4%) of patients were in NYHA class III or IV, and significant comorbidities included atrial fibrillation (92.0%), hypertension (84.1%), pulmonary hypertension (75.0%), dyslipidaemia or hyperlipidaemia (65.3%), renal insufficiency or failure (58.5%), and ascites (22.2%). At baseline, 32.4% had a pre-existing cardiac implantable electronic device, 37.5% had a history of valve surgery or intervention, and 16.5% had prior coronary artery bypass grafting (Table 1). Baseline medications included diuretics (92.0%), anticoagulants (84.1%), beta blockers (72.7%), and antiplatelets (40.3%).
Baseline characteristics (n = 176)a
| Variable | |
|---|---|
| Age, years | 78.7 ± 7.33 |
| Female sex | 71.0 (125) |
| TR grade ≥ severe | 88.0 (154/175) |
| TR aetiology | |
| Primary | 9.7 (17) |
| Secondary | 68.2 (120) |
| Mixed | 14.2 (25) |
| Pacer related | 2.8 (5) |
| Indeterminate | 5.1 (9) |
| STS mortality score, % | |
| MV repair | 7.4 ± 5.8 (174) |
| MV replacement | 10.0 ± 5.3 (127) |
| EuroSCORE II, % | 5.1 ± 4.0 |
| NYHA classes III–IV | 75.4 (132/175) |
| Katz ADL score | 5.7 ± 0.7 |
| Hypertension (treated) | 84.1 (148) |
| Dyslipidaemia/hyperlipidaemia | 65.3 (115) |
| Renal insufficiency | 58.5 (103) |
| Diabetes | 20.5 (36) |
| Coronary artery disease ≥ 50% stenosis | 20.5 (36) |
| Coronary artery bypass grafting | 16.5 (29) |
| Prior myocardial infarction | 8.0 (14) |
| Carotid artery stenting/surgery | 1.7 (3) |
| Prior stroke | 13.6 (24) |
| Peripheral arterial disease | 6.3 (11) |
| Cancer/malignancy | 28.4 (50) |
| Cirrhosis | 13.1 (23) |
| Ascites | 22.2 (39) |
| LVEF, % | 55.3 ± 10.4 (158) |
| Cardiomyopathy | 10.2 (18) |
| Heart failure hospitalization in last 12 months | 40.9 (72) |
| Pulmonary hypertension within past year | 75.0 (132) |
| Valve surgery/intervention | 37.5 (66) |
| Aortic valve | 18.8 (33) |
| Mitral valve | 26.1 (46) |
| Tricuspid valve | 1.7 (3) |
| Atrial fibrillation | 92.0 (162) |
| Pacemaker | 32.4 (57) |
| Right bundle branch block | 22.2 (39) |
| Left bundle branch block | 3.4 (6) |
| Gastrointestinal or oesophageal bleeding | 16.5 (29) |
| Laboratory values | |
| Albumin, g/dL | 4.0 (3.7, 4.2) |
| Alanine transaminase, U/L | 18.0 (13.0, 25.0) |
| Aspartate transaminase, U/L | 26.0 (20.0, 35.0) |
| Alkaline phosphatase, U/L | 110.0 (81.0, 146.0) |
| Gamma-glutamyl transferase, U/L | 75.0 (36.0, 137.0) |
| Brain natriuretic peptide, pg/mL | 332.0 (189.0, 580.0) |
| Prothrombin time, s | 16.6 (14.4, 22.2) |
| INR | 1.4 (1.2, 2.0) |
| eGFR, mL/min/1.73 m2 | 52.0 (39.5, 60.0) |
| NT-proBNP, pg/mL | 1465.0 (972.0, 2495.0) |
| Creatinine, mg/dL | 1.1 (0.9, 1.4) |
| Uric acid, mg/dL | 7.0 (5.3, 9.2) |
| Variable | |
|---|---|
| Age, years | 78.7 ± 7.33 |
| Female sex | 71.0 (125) |
| TR grade ≥ severe | 88.0 (154/175) |
| TR aetiology | |
| Primary | 9.7 (17) |
| Secondary | 68.2 (120) |
| Mixed | 14.2 (25) |
| Pacer related | 2.8 (5) |
| Indeterminate | 5.1 (9) |
| STS mortality score, % | |
| MV repair | 7.4 ± 5.8 (174) |
| MV replacement | 10.0 ± 5.3 (127) |
| EuroSCORE II, % | 5.1 ± 4.0 |
| NYHA classes III–IV | 75.4 (132/175) |
| Katz ADL score | 5.7 ± 0.7 |
| Hypertension (treated) | 84.1 (148) |
| Dyslipidaemia/hyperlipidaemia | 65.3 (115) |
| Renal insufficiency | 58.5 (103) |
| Diabetes | 20.5 (36) |
| Coronary artery disease ≥ 50% stenosis | 20.5 (36) |
| Coronary artery bypass grafting | 16.5 (29) |
| Prior myocardial infarction | 8.0 (14) |
| Carotid artery stenting/surgery | 1.7 (3) |
| Prior stroke | 13.6 (24) |
| Peripheral arterial disease | 6.3 (11) |
| Cancer/malignancy | 28.4 (50) |
| Cirrhosis | 13.1 (23) |
| Ascites | 22.2 (39) |
| LVEF, % | 55.3 ± 10.4 (158) |
| Cardiomyopathy | 10.2 (18) |
| Heart failure hospitalization in last 12 months | 40.9 (72) |
| Pulmonary hypertension within past year | 75.0 (132) |
| Valve surgery/intervention | 37.5 (66) |
| Aortic valve | 18.8 (33) |
| Mitral valve | 26.1 (46) |
| Tricuspid valve | 1.7 (3) |
| Atrial fibrillation | 92.0 (162) |
| Pacemaker | 32.4 (57) |
| Right bundle branch block | 22.2 (39) |
| Left bundle branch block | 3.4 (6) |
| Gastrointestinal or oesophageal bleeding | 16.5 (29) |
| Laboratory values | |
| Albumin, g/dL | 4.0 (3.7, 4.2) |
| Alanine transaminase, U/L | 18.0 (13.0, 25.0) |
| Aspartate transaminase, U/L | 26.0 (20.0, 35.0) |
| Alkaline phosphatase, U/L | 110.0 (81.0, 146.0) |
| Gamma-glutamyl transferase, U/L | 75.0 (36.0, 137.0) |
| Brain natriuretic peptide, pg/mL | 332.0 (189.0, 580.0) |
| Prothrombin time, s | 16.6 (14.4, 22.2) |
| INR | 1.4 (1.2, 2.0) |
| eGFR, mL/min/1.73 m2 | 52.0 (39.5, 60.0) |
| NT-proBNP, pg/mL | 1465.0 (972.0, 2495.0) |
| Creatinine, mg/dL | 1.1 (0.9, 1.4) |
| Uric acid, mg/dL | 7.0 (5.3, 9.2) |
Values are given as % (n), mean ± SD (n), or median (interquartile range).
ADL, activities of daily living; eGFR, estimated glomerular filtration rate; INR, international normalized ratio; MV, mitral valve; NT-proBNP, N-terminal pro-brain natriuretic peptide; NYHA, New York Heart Association; PASP, pulmonary artery systolic pressure; STS, Society of Thoracic Surgeons; TR, tricuspid regurgitation; LVEF, left ventricular ejection fraction.
an = 176 unless otherwise noted.
Baseline characteristics (n = 176)a
| Variable | |
|---|---|
| Age, years | 78.7 ± 7.33 |
| Female sex | 71.0 (125) |
| TR grade ≥ severe | 88.0 (154/175) |
| TR aetiology | |
| Primary | 9.7 (17) |
| Secondary | 68.2 (120) |
| Mixed | 14.2 (25) |
| Pacer related | 2.8 (5) |
| Indeterminate | 5.1 (9) |
| STS mortality score, % | |
| MV repair | 7.4 ± 5.8 (174) |
| MV replacement | 10.0 ± 5.3 (127) |
| EuroSCORE II, % | 5.1 ± 4.0 |
| NYHA classes III–IV | 75.4 (132/175) |
| Katz ADL score | 5.7 ± 0.7 |
| Hypertension (treated) | 84.1 (148) |
| Dyslipidaemia/hyperlipidaemia | 65.3 (115) |
| Renal insufficiency | 58.5 (103) |
| Diabetes | 20.5 (36) |
| Coronary artery disease ≥ 50% stenosis | 20.5 (36) |
| Coronary artery bypass grafting | 16.5 (29) |
| Prior myocardial infarction | 8.0 (14) |
| Carotid artery stenting/surgery | 1.7 (3) |
| Prior stroke | 13.6 (24) |
| Peripheral arterial disease | 6.3 (11) |
| Cancer/malignancy | 28.4 (50) |
| Cirrhosis | 13.1 (23) |
| Ascites | 22.2 (39) |
| LVEF, % | 55.3 ± 10.4 (158) |
| Cardiomyopathy | 10.2 (18) |
| Heart failure hospitalization in last 12 months | 40.9 (72) |
| Pulmonary hypertension within past year | 75.0 (132) |
| Valve surgery/intervention | 37.5 (66) |
| Aortic valve | 18.8 (33) |
| Mitral valve | 26.1 (46) |
| Tricuspid valve | 1.7 (3) |
| Atrial fibrillation | 92.0 (162) |
| Pacemaker | 32.4 (57) |
| Right bundle branch block | 22.2 (39) |
| Left bundle branch block | 3.4 (6) |
| Gastrointestinal or oesophageal bleeding | 16.5 (29) |
| Laboratory values | |
| Albumin, g/dL | 4.0 (3.7, 4.2) |
| Alanine transaminase, U/L | 18.0 (13.0, 25.0) |
| Aspartate transaminase, U/L | 26.0 (20.0, 35.0) |
| Alkaline phosphatase, U/L | 110.0 (81.0, 146.0) |
| Gamma-glutamyl transferase, U/L | 75.0 (36.0, 137.0) |
| Brain natriuretic peptide, pg/mL | 332.0 (189.0, 580.0) |
| Prothrombin time, s | 16.6 (14.4, 22.2) |
| INR | 1.4 (1.2, 2.0) |
| eGFR, mL/min/1.73 m2 | 52.0 (39.5, 60.0) |
| NT-proBNP, pg/mL | 1465.0 (972.0, 2495.0) |
| Creatinine, mg/dL | 1.1 (0.9, 1.4) |
| Uric acid, mg/dL | 7.0 (5.3, 9.2) |
| Variable | |
|---|---|
| Age, years | 78.7 ± 7.33 |
| Female sex | 71.0 (125) |
| TR grade ≥ severe | 88.0 (154/175) |
| TR aetiology | |
| Primary | 9.7 (17) |
| Secondary | 68.2 (120) |
| Mixed | 14.2 (25) |
| Pacer related | 2.8 (5) |
| Indeterminate | 5.1 (9) |
| STS mortality score, % | |
| MV repair | 7.4 ± 5.8 (174) |
| MV replacement | 10.0 ± 5.3 (127) |
| EuroSCORE II, % | 5.1 ± 4.0 |
| NYHA classes III–IV | 75.4 (132/175) |
| Katz ADL score | 5.7 ± 0.7 |
| Hypertension (treated) | 84.1 (148) |
| Dyslipidaemia/hyperlipidaemia | 65.3 (115) |
| Renal insufficiency | 58.5 (103) |
| Diabetes | 20.5 (36) |
| Coronary artery disease ≥ 50% stenosis | 20.5 (36) |
| Coronary artery bypass grafting | 16.5 (29) |
| Prior myocardial infarction | 8.0 (14) |
| Carotid artery stenting/surgery | 1.7 (3) |
| Prior stroke | 13.6 (24) |
| Peripheral arterial disease | 6.3 (11) |
| Cancer/malignancy | 28.4 (50) |
| Cirrhosis | 13.1 (23) |
| Ascites | 22.2 (39) |
| LVEF, % | 55.3 ± 10.4 (158) |
| Cardiomyopathy | 10.2 (18) |
| Heart failure hospitalization in last 12 months | 40.9 (72) |
| Pulmonary hypertension within past year | 75.0 (132) |
| Valve surgery/intervention | 37.5 (66) |
| Aortic valve | 18.8 (33) |
| Mitral valve | 26.1 (46) |
| Tricuspid valve | 1.7 (3) |
| Atrial fibrillation | 92.0 (162) |
| Pacemaker | 32.4 (57) |
| Right bundle branch block | 22.2 (39) |
| Left bundle branch block | 3.4 (6) |
| Gastrointestinal or oesophageal bleeding | 16.5 (29) |
| Laboratory values | |
| Albumin, g/dL | 4.0 (3.7, 4.2) |
| Alanine transaminase, U/L | 18.0 (13.0, 25.0) |
| Aspartate transaminase, U/L | 26.0 (20.0, 35.0) |
| Alkaline phosphatase, U/L | 110.0 (81.0, 146.0) |
| Gamma-glutamyl transferase, U/L | 75.0 (36.0, 137.0) |
| Brain natriuretic peptide, pg/mL | 332.0 (189.0, 580.0) |
| Prothrombin time, s | 16.6 (14.4, 22.2) |
| INR | 1.4 (1.2, 2.0) |
| eGFR, mL/min/1.73 m2 | 52.0 (39.5, 60.0) |
| NT-proBNP, pg/mL | 1465.0 (972.0, 2495.0) |
| Creatinine, mg/dL | 1.1 (0.9, 1.4) |
| Uric acid, mg/dL | 7.0 (5.3, 9.2) |
Values are given as % (n), mean ± SD (n), or median (interquartile range).
ADL, activities of daily living; eGFR, estimated glomerular filtration rate; INR, international normalized ratio; MV, mitral valve; NT-proBNP, N-terminal pro-brain natriuretic peptide; NYHA, New York Heart Association; PASP, pulmonary artery systolic pressure; STS, Society of Thoracic Surgeons; TR, tricuspid regurgitation; LVEF, left ventricular ejection fraction.
an = 176 unless otherwise noted.
Procedural outcomes
Successful femoral access was achieved in 99.4% of patients (one case was aborted due to stenosis in right and left iliac veins), with a right-femoral-vein approach used in 93.8% of cases and pre-dilatation performed in 84.7%. The mean time from skin incision to closure was 121.4 ± 65.7 min, with 71.6 ± 31.4 min from delivery system insertion to removal and 34.4 ± 15.2 min of fluoroscopy. The median length of hospital stay was 3.0 (IQR: 2.0, 7.0) days, and 91.1% of patients were discharged to home (4.7% with organized home-health services). Device success was 94.4%, procedural success 93.0%, and clinical success 77.1%.
Safety outcomes
Thirty-day results
At 30 days, the composite MAE rate was 18.6% (Table 2). Cardiovascular mortality was 1.7%, and non-elective TV re-interventions occurred in 2.3%. These were a valve-in-valve implant during the index procedure after unsuccessful implantation due to challenging anatomy; two surgical explants for valve embolization, as previously reported;21 and a valve-in-valve intervention for a partially detached valve. No patient required RV mechanical support following TTVR.
Major adverse events adjudicated by the clinical events committee at 30 days and one year
| CEC-adjudicated MAEs | 30 days (n = 172)a | 1 year (n = 149)a |
|---|---|---|
| Cardiovascular mortality | 1.7 (3) | 9.4 (14) |
| Myocardial infarction | 0.0 (0) | 0.0 (0) |
| Stroke | 0.6 (1) | 1.3 (2) |
| Major cardiac structural complications | 0.0 (0) | 0.0 (0) |
| Renal complications requiring unplanned dialysis or renal replacement therapy | 1.7 (3) | 3.4 (5) |
| Non-elective tricuspid valve re-intervention | 2.3 (4) | 4.0 (6) |
| Major access site and vascular complications | 2.3 (4) | 2.7 (4) |
| Severe bleedingb | 16.9 (29)c | 25.5 (38)d |
| Major | 8.1 (14) | 10.7 (16) |
| Extensive | 7.0 (12) | 10.7 (16) |
| Life threatening | 1.7 (3) | 4.7 (7) |
| Fatal | 0.6 (1) | 0.7 (1) |
| Device-related pulmonary embolism | 0.0 (0) | 0.0 (0) |
| Composite MAEs | 18.6 (32)e | 30.2 (45)e |
| CEC-adjudicated MAEs | 30 days (n = 172)a | 1 year (n = 149)a |
|---|---|---|
| Cardiovascular mortality | 1.7 (3) | 9.4 (14) |
| Myocardial infarction | 0.0 (0) | 0.0 (0) |
| Stroke | 0.6 (1) | 1.3 (2) |
| Major cardiac structural complications | 0.0 (0) | 0.0 (0) |
| Renal complications requiring unplanned dialysis or renal replacement therapy | 1.7 (3) | 3.4 (5) |
| Non-elective tricuspid valve re-intervention | 2.3 (4) | 4.0 (6) |
| Major access site and vascular complications | 2.3 (4) | 2.7 (4) |
| Severe bleedingb | 16.9 (29)c | 25.5 (38)d |
| Major | 8.1 (14) | 10.7 (16) |
| Extensive | 7.0 (12) | 10.7 (16) |
| Life threatening | 1.7 (3) | 4.7 (7) |
| Fatal | 0.6 (1) | 0.7 (1) |
| Device-related pulmonary embolism | 0.0 (0) | 0.0 (0) |
| Composite MAEs | 18.6 (32)e | 30.2 (45)e |
Values are given as % (n).
CEC, clinical events committee; MAEs, major adverse events.
aDenominator includes patients who have been in the trial for at least the specified timepoint or have had an MAE, and number of patients who have had an event is shown.
bSevere bleeding as defined by the Mitral Valve Academic Research Consortium.
cMost common causes of bleeding up to 30 days were access/puncture-site related (n = 11) and gastrointestinal (n = 8).
dMost common cause of bleeding after 30 days was gastrointestinal (n = 8).
eComposite (bold) MAE n is counted as the number of patients experiencing at least one MAE. One-year counts are cumulative.
Major adverse events adjudicated by the clinical events committee at 30 days and one year
| CEC-adjudicated MAEs | 30 days (n = 172)a | 1 year (n = 149)a |
|---|---|---|
| Cardiovascular mortality | 1.7 (3) | 9.4 (14) |
| Myocardial infarction | 0.0 (0) | 0.0 (0) |
| Stroke | 0.6 (1) | 1.3 (2) |
| Major cardiac structural complications | 0.0 (0) | 0.0 (0) |
| Renal complications requiring unplanned dialysis or renal replacement therapy | 1.7 (3) | 3.4 (5) |
| Non-elective tricuspid valve re-intervention | 2.3 (4) | 4.0 (6) |
| Major access site and vascular complications | 2.3 (4) | 2.7 (4) |
| Severe bleedingb | 16.9 (29)c | 25.5 (38)d |
| Major | 8.1 (14) | 10.7 (16) |
| Extensive | 7.0 (12) | 10.7 (16) |
| Life threatening | 1.7 (3) | 4.7 (7) |
| Fatal | 0.6 (1) | 0.7 (1) |
| Device-related pulmonary embolism | 0.0 (0) | 0.0 (0) |
| Composite MAEs | 18.6 (32)e | 30.2 (45)e |
| CEC-adjudicated MAEs | 30 days (n = 172)a | 1 year (n = 149)a |
|---|---|---|
| Cardiovascular mortality | 1.7 (3) | 9.4 (14) |
| Myocardial infarction | 0.0 (0) | 0.0 (0) |
| Stroke | 0.6 (1) | 1.3 (2) |
| Major cardiac structural complications | 0.0 (0) | 0.0 (0) |
| Renal complications requiring unplanned dialysis or renal replacement therapy | 1.7 (3) | 3.4 (5) |
| Non-elective tricuspid valve re-intervention | 2.3 (4) | 4.0 (6) |
| Major access site and vascular complications | 2.3 (4) | 2.7 (4) |
| Severe bleedingb | 16.9 (29)c | 25.5 (38)d |
| Major | 8.1 (14) | 10.7 (16) |
| Extensive | 7.0 (12) | 10.7 (16) |
| Life threatening | 1.7 (3) | 4.7 (7) |
| Fatal | 0.6 (1) | 0.7 (1) |
| Device-related pulmonary embolism | 0.0 (0) | 0.0 (0) |
| Composite MAEs | 18.6 (32)e | 30.2 (45)e |
Values are given as % (n).
CEC, clinical events committee; MAEs, major adverse events.
aDenominator includes patients who have been in the trial for at least the specified timepoint or have had an MAE, and number of patients who have had an event is shown.
bSevere bleeding as defined by the Mitral Valve Academic Research Consortium.
cMost common causes of bleeding up to 30 days were access/puncture-site related (n = 11) and gastrointestinal (n = 8).
dMost common cause of bleeding after 30 days was gastrointestinal (n = 8).
eComposite (bold) MAE n is counted as the number of patients experiencing at least one MAE. One-year counts are cumulative.
New permanent pacemakers (not included in the pre-defined composite MAE definition) were implanted in 15 patients (13.3% of patients without a pre-existing pacemaker), all within 9 days post-procedure. No patients received a new pacemaker after 30 days. Of those receiving new pacemakers, 14 had baseline atrial fibrillation, eight with additional conduction disturbances (i.e. left bundle branch block, right bundle branch block, prolonged QT interval, and atrioventricular block).
One-year results
Major adverse event rates at one year are presented in Table 2. The all-cause cause mortality rate (n = 176) was 9.1%, and the rate of hospitalization for HF was 10.2%. Kaplan–Meier estimates for all-cause mortality and HF hospitalization were 9.9 ± 2.3% and 11.6 ± 2.6%, respectively (Figure 2), and there was a 74.9% relative reduction in the rate of HF hospitalization in the 12 months before vs. after the procedure (P < .001; Figure 3).
Kaplan–Meier estimates for all-cause mortality and heart failure (HF) hospitalizations to one year. Kaplan–Meier curves show time to first events.
Patients experienced a 74.9% annualized reduction in heart failure hospitalizations between the 12 months before and 12 months after EVOQUE implantation. HF, heart failure.
Echocardiographic outcomes
In paired analysis from baseline to one year, 97.6% of implanted patients had TR ≤ mild, with 69.0% having no or trace TR (P < .001) (Figure 4). All patients (100%) experienced at least one grade reduction in TR severity, 97.6% had ≥two grade reductions, and 33.3% ≥four grade reductions. The majority (88.2%) of patients had no or trace paravalvular leak, with 10.6% mild and 1.2% moderate. Changes from baseline to one-year follow-up TTE (Table 3) included reductions in RV mid-ventricular end-diastolic diameter (−6.3 ± 9.5 mm, P < .001) and IVC diameter at end-expiration (−7.2 ± 5.9 mm, P < .001). In the setting of a stable LV ejection fraction (P = .197), there were significant increases in LV outflow tract stroke volume (10.5 ± 16.8 mL, P < .001) and cardiac output (0.6 ± 1.2 L/min, P < .001). Several parameters associated with RV systolic function decreased, including RV FAC (−8.4 ± 13.8%, P < .001) and TAPSE (−2.8 ± 6.5 mm, P = .006). Pulmonary artery systolic pressure also decreased (−6.8 ± 13.6 mmHg, P = .003). The TAPSE/PASP ratio was 0.48 mm/mmHg at baseline with an insignificant decrease at one year (−0.07 ± 0.36 mm/mmHg, P = .439).
One-year results of transfemoral tricuspid valve replacement with the EVOQUE valve showed significant improvements in tricuspid regurgitation severity, New York Heart Association (NYHA) functional class, Kansas City Cardiomyopathy Questionnaire (KCCQ) score, and six-minute walk distance (6MWD) in paired analysis. The Sankey diagram, top right, shows the flow of TR grade changes among patients who completed every echocardiographic follow-up visit; the width of the arcs between time points represents the proportion of patients who experienced a specific grade change (e.g. severe to none/trace). aP-values calculated by Wilcoxon signed rank test. bP-values calculated by paired t-test. Error bars show standard deviation. TR, tricuspid regurgitation.
Paired changes observed on transthoracic echocardiogram at baseline and one-year follow-up
| Baseline | One year | Δ One year—baseline P-valuea | |
|---|---|---|---|
| RV end-diastolic mid diameter, mm | 41.4 ± 8.8 (69) | 35.0 ± 7.4 (69) | −6.3 ± 9.5 −6.0 (−12.0, .0) P < .001 |
| RV fractional area change, % | 38.7 ± 10.1 (59) | 30.3 ± 10.6 (59) | −8.4 ± 13.8 −10.0 (−17.0, −2.0) P < .001 |
| TAPSE, mm | 15.3 ± 5.2 (46) | 12.5 ± 4.2 (46) | −2.8 ± 6.5 −2.0 (−5.0, 1.0) P = .006 |
| RA volume systolic, mL | 144.4 ± 54.1 (73) | 140.5 ± 53.8 (73) | −3.9 ± 42.3 −2.0 (−27.8, 25.0) P = .434 |
| IVC diameter (expiration), mm | 27.6 ± 7.7 (76) | 20.4 ± 5.1 (76) | −7.2 ± 5.9 −7.0 (−11.0, −3.0) P < .001 |
| LVEF, % | 54.1 ± 11.2 (70) | 55.6 ± 10.9 (70) | 1.5 ± 9.7 2.0 (−5.0, 7.0) P = .197 |
| Cardiac output (LVOT), L/min | 4.0 ± 1.1 (81) | 4.5 ± 1.1 (81) | .6 ± 1.2 .4 (−.1, 1.2) P < .001 |
| Stroke volume (LVOT), mL | 54.8 ± 15.8 (81) | 65.3 ± 17.6 (81) | 10.5 ± 16.8 9.0 (1.0, 14.0) P < .001 |
| RA pressure systolic, mmHg | 12.0 ± 4.8 (75) | 8.7 ± 4.7 (75) | −3.3 ± 5.9 .0 (−7.0, .0) P < .001 |
| IVC respiratory variation (derived), % | 30.2 ± 16.9 (74) | 40.5 ± 17.3 (74) | 10.3 ± 24.2 10.0 (−5.0, 28.0) P < .001 |
| PASP, mmHg | 39.3 ± 12.8 (40) | 32.5 ± 11.0 (40) | −6.8 ± 13.6 −5.2 (12.9, 1.8) P = .003 |
| TAPSE/PASP | 0.48 ± 0.26 (22) | 0.41 ± 0.21 (22) | −.07 ± .36 −.04 (−.3, .1) P = .439 |
| TV mean gradient, mmHg | 1.7 ± 1.0 (82) | 3.4 ± 1.4 (82) | 1.7 ± 1.6 1.7 (.8, 2.8) P < .001 |
| LVOT VTI | 18.0 ± 4.3 (81) | 18.9 ± 4.2 (81) | .9 ± 4.3 1.0 (−2.0, 2.6) P = .054 |
| Hepatic vein flow reversal | n = 49 | n = 49 | P < .001b |
| S-dominant | 0 (0) | 26.5 (13) | |
| D-dominant | 4.1 (2) | 63.3 (31) | |
| S-reversal | 95.9 (47) | 10.2 (5) |
| Baseline | One year | Δ One year—baseline P-valuea | |
|---|---|---|---|
| RV end-diastolic mid diameter, mm | 41.4 ± 8.8 (69) | 35.0 ± 7.4 (69) | −6.3 ± 9.5 −6.0 (−12.0, .0) P < .001 |
| RV fractional area change, % | 38.7 ± 10.1 (59) | 30.3 ± 10.6 (59) | −8.4 ± 13.8 −10.0 (−17.0, −2.0) P < .001 |
| TAPSE, mm | 15.3 ± 5.2 (46) | 12.5 ± 4.2 (46) | −2.8 ± 6.5 −2.0 (−5.0, 1.0) P = .006 |
| RA volume systolic, mL | 144.4 ± 54.1 (73) | 140.5 ± 53.8 (73) | −3.9 ± 42.3 −2.0 (−27.8, 25.0) P = .434 |
| IVC diameter (expiration), mm | 27.6 ± 7.7 (76) | 20.4 ± 5.1 (76) | −7.2 ± 5.9 −7.0 (−11.0, −3.0) P < .001 |
| LVEF, % | 54.1 ± 11.2 (70) | 55.6 ± 10.9 (70) | 1.5 ± 9.7 2.0 (−5.0, 7.0) P = .197 |
| Cardiac output (LVOT), L/min | 4.0 ± 1.1 (81) | 4.5 ± 1.1 (81) | .6 ± 1.2 .4 (−.1, 1.2) P < .001 |
| Stroke volume (LVOT), mL | 54.8 ± 15.8 (81) | 65.3 ± 17.6 (81) | 10.5 ± 16.8 9.0 (1.0, 14.0) P < .001 |
| RA pressure systolic, mmHg | 12.0 ± 4.8 (75) | 8.7 ± 4.7 (75) | −3.3 ± 5.9 .0 (−7.0, .0) P < .001 |
| IVC respiratory variation (derived), % | 30.2 ± 16.9 (74) | 40.5 ± 17.3 (74) | 10.3 ± 24.2 10.0 (−5.0, 28.0) P < .001 |
| PASP, mmHg | 39.3 ± 12.8 (40) | 32.5 ± 11.0 (40) | −6.8 ± 13.6 −5.2 (12.9, 1.8) P = .003 |
| TAPSE/PASP | 0.48 ± 0.26 (22) | 0.41 ± 0.21 (22) | −.07 ± .36 −.04 (−.3, .1) P = .439 |
| TV mean gradient, mmHg | 1.7 ± 1.0 (82) | 3.4 ± 1.4 (82) | 1.7 ± 1.6 1.7 (.8, 2.8) P < .001 |
| LVOT VTI | 18.0 ± 4.3 (81) | 18.9 ± 4.2 (81) | .9 ± 4.3 1.0 (−2.0, 2.6) P = .054 |
| Hepatic vein flow reversal | n = 49 | n = 49 | P < .001b |
| S-dominant | 0 (0) | 26.5 (13) | |
| D-dominant | 4.1 (2) | 63.3 (31) | |
| S-reversal | 95.9 (47) | 10.2 (5) |
Results reported that data are given as mean ± SD (n), % (n), or median (IQR).
IVC, inferior vena cava; LV, left ventricle; LVEF, LV ejection fraction; LVOT VTI, LV outflow tract velocity time integral; PASP, pulmonary artery systolic pressure; RA, right atrium; RV, right ventricle; TAPSE, tricuspid annular plane systolic excursion; TV, tricuspid valve.
aP-values calculated by paired t-test, unless otherwise noted.
bP-values calculated by Wilcoxon signed rank test.
Bold values are statistically significant.
Paired changes observed on transthoracic echocardiogram at baseline and one-year follow-up
| Baseline | One year | Δ One year—baseline P-valuea | |
|---|---|---|---|
| RV end-diastolic mid diameter, mm | 41.4 ± 8.8 (69) | 35.0 ± 7.4 (69) | −6.3 ± 9.5 −6.0 (−12.0, .0) P < .001 |
| RV fractional area change, % | 38.7 ± 10.1 (59) | 30.3 ± 10.6 (59) | −8.4 ± 13.8 −10.0 (−17.0, −2.0) P < .001 |
| TAPSE, mm | 15.3 ± 5.2 (46) | 12.5 ± 4.2 (46) | −2.8 ± 6.5 −2.0 (−5.0, 1.0) P = .006 |
| RA volume systolic, mL | 144.4 ± 54.1 (73) | 140.5 ± 53.8 (73) | −3.9 ± 42.3 −2.0 (−27.8, 25.0) P = .434 |
| IVC diameter (expiration), mm | 27.6 ± 7.7 (76) | 20.4 ± 5.1 (76) | −7.2 ± 5.9 −7.0 (−11.0, −3.0) P < .001 |
| LVEF, % | 54.1 ± 11.2 (70) | 55.6 ± 10.9 (70) | 1.5 ± 9.7 2.0 (−5.0, 7.0) P = .197 |
| Cardiac output (LVOT), L/min | 4.0 ± 1.1 (81) | 4.5 ± 1.1 (81) | .6 ± 1.2 .4 (−.1, 1.2) P < .001 |
| Stroke volume (LVOT), mL | 54.8 ± 15.8 (81) | 65.3 ± 17.6 (81) | 10.5 ± 16.8 9.0 (1.0, 14.0) P < .001 |
| RA pressure systolic, mmHg | 12.0 ± 4.8 (75) | 8.7 ± 4.7 (75) | −3.3 ± 5.9 .0 (−7.0, .0) P < .001 |
| IVC respiratory variation (derived), % | 30.2 ± 16.9 (74) | 40.5 ± 17.3 (74) | 10.3 ± 24.2 10.0 (−5.0, 28.0) P < .001 |
| PASP, mmHg | 39.3 ± 12.8 (40) | 32.5 ± 11.0 (40) | −6.8 ± 13.6 −5.2 (12.9, 1.8) P = .003 |
| TAPSE/PASP | 0.48 ± 0.26 (22) | 0.41 ± 0.21 (22) | −.07 ± .36 −.04 (−.3, .1) P = .439 |
| TV mean gradient, mmHg | 1.7 ± 1.0 (82) | 3.4 ± 1.4 (82) | 1.7 ± 1.6 1.7 (.8, 2.8) P < .001 |
| LVOT VTI | 18.0 ± 4.3 (81) | 18.9 ± 4.2 (81) | .9 ± 4.3 1.0 (−2.0, 2.6) P = .054 |
| Hepatic vein flow reversal | n = 49 | n = 49 | P < .001b |
| S-dominant | 0 (0) | 26.5 (13) | |
| D-dominant | 4.1 (2) | 63.3 (31) | |
| S-reversal | 95.9 (47) | 10.2 (5) |
| Baseline | One year | Δ One year—baseline P-valuea | |
|---|---|---|---|
| RV end-diastolic mid diameter, mm | 41.4 ± 8.8 (69) | 35.0 ± 7.4 (69) | −6.3 ± 9.5 −6.0 (−12.0, .0) P < .001 |
| RV fractional area change, % | 38.7 ± 10.1 (59) | 30.3 ± 10.6 (59) | −8.4 ± 13.8 −10.0 (−17.0, −2.0) P < .001 |
| TAPSE, mm | 15.3 ± 5.2 (46) | 12.5 ± 4.2 (46) | −2.8 ± 6.5 −2.0 (−5.0, 1.0) P = .006 |
| RA volume systolic, mL | 144.4 ± 54.1 (73) | 140.5 ± 53.8 (73) | −3.9 ± 42.3 −2.0 (−27.8, 25.0) P = .434 |
| IVC diameter (expiration), mm | 27.6 ± 7.7 (76) | 20.4 ± 5.1 (76) | −7.2 ± 5.9 −7.0 (−11.0, −3.0) P < .001 |
| LVEF, % | 54.1 ± 11.2 (70) | 55.6 ± 10.9 (70) | 1.5 ± 9.7 2.0 (−5.0, 7.0) P = .197 |
| Cardiac output (LVOT), L/min | 4.0 ± 1.1 (81) | 4.5 ± 1.1 (81) | .6 ± 1.2 .4 (−.1, 1.2) P < .001 |
| Stroke volume (LVOT), mL | 54.8 ± 15.8 (81) | 65.3 ± 17.6 (81) | 10.5 ± 16.8 9.0 (1.0, 14.0) P < .001 |
| RA pressure systolic, mmHg | 12.0 ± 4.8 (75) | 8.7 ± 4.7 (75) | −3.3 ± 5.9 .0 (−7.0, .0) P < .001 |
| IVC respiratory variation (derived), % | 30.2 ± 16.9 (74) | 40.5 ± 17.3 (74) | 10.3 ± 24.2 10.0 (−5.0, 28.0) P < .001 |
| PASP, mmHg | 39.3 ± 12.8 (40) | 32.5 ± 11.0 (40) | −6.8 ± 13.6 −5.2 (12.9, 1.8) P = .003 |
| TAPSE/PASP | 0.48 ± 0.26 (22) | 0.41 ± 0.21 (22) | −.07 ± .36 −.04 (−.3, .1) P = .439 |
| TV mean gradient, mmHg | 1.7 ± 1.0 (82) | 3.4 ± 1.4 (82) | 1.7 ± 1.6 1.7 (.8, 2.8) P < .001 |
| LVOT VTI | 18.0 ± 4.3 (81) | 18.9 ± 4.2 (81) | .9 ± 4.3 1.0 (−2.0, 2.6) P = .054 |
| Hepatic vein flow reversal | n = 49 | n = 49 | P < .001b |
| S-dominant | 0 (0) | 26.5 (13) | |
| D-dominant | 4.1 (2) | 63.3 (31) | |
| S-reversal | 95.9 (47) | 10.2 (5) |
Results reported that data are given as mean ± SD (n), % (n), or median (IQR).
IVC, inferior vena cava; LV, left ventricle; LVEF, LV ejection fraction; LVOT VTI, LV outflow tract velocity time integral; PASP, pulmonary artery systolic pressure; RA, right atrium; RV, right ventricle; TAPSE, tricuspid annular plane systolic excursion; TV, tricuspid valve.
aP-values calculated by paired t-test, unless otherwise noted.
bP-values calculated by Wilcoxon signed rank test.
Bold values are statistically significant.
Clinical, functional, and quality-of-life outcomes
Patients experienced significant and sustained improvements in clinical, functional, and quality-of-life outcomes in paired analyses compared with baseline (Figure 4). At one year, 93.3% of patients were in NYHA class I or II, compared with 25.8% at baseline (P < .001). The mean KCCQ overall summary score increased from 46.0 ± 21.8 points to 71.7 ± 22.0 points (P < .001), with 54.9% of patients improving by at least 20 points and 21.6% by 10–19 points; 50.0% had scores in the range of 75 to 100 points at one year. SF-36 mental scores improved by 5.7 ± 12.4 points (P < .001) and physical scores by 7.4 ± 9.5 points (P < .001) (Figure 5). There was also a significant improvement in mean 6MWD, which increased by 56.2 ± 117.0 m (P < .001). Patients lost body weight by a mean of 1.8 ± 6.3 kg (P = .005), and the proportion of patients with absent or grade 1 + oedema (assessed by standard pitting) improved from 63.9% at baseline to 86.6% at one year (P < .001). Changes in right and left ankle circumference were insignificant.
Short Form Health Survey (SF-36) scores improved significantly for mental and physical domains on paired analysis. P-values calculated by paired t-test; error bars represent standard deviation.
Discussion
This study represents the largest cohort with one-year follow-up of patients undergoing TTVR for symptomatic TR. At one year, the TRISCEND study demonstrated the following for patients treated with the EVOQUE system: (i) device and procedural success of 94.4% and 93.0%, respectively; (ii) 9.1% all-cause mortality; (iii) 10.2% HF hospitalization rate with 74.9% annualized reduction; (iv) sustained TR reduction to grade ≤ mild in 97.6% of patients; (v) right-heart reverse remodelling with improvement in forward stroke volume and cardiac output; and (vi) marked improvement in functional and quality-of-life outcomes (Structured Graphical Abstract).
To place these results into context, recent natural history studies of comparable patients with symptomatic severe TR despite optimal medical therapy have shown one-year mortality rates between 36% and 42%, compared with 9.1% in this study.5,28 The TriValve Registry showed that, compared with propensity-matched medically treated patients, TTVI in selected high-risk patients with symptomatic severe TR is associated with lower one-year mortality (23 ± 3% vs. 36 ± 3%; P = .001) and hospitalization rates (26 ± 3% vs. 47 ± 3%; P < .0001).28 Surgical replacement carries a 10%–12% in-hospital mortality rate,10,29 and other TTVR therapies have reported short-term mortality rates of 13%–17%.22,24 The one-year mortality and HF hospitalization rates in the TRISCEND study are the lowest reported for transcatheter replacement therapies in this otherwise high-risk, comorbid population. The estimated 74.9% reduction in annualized HF hospitalization, if confirmed by randomized controlled trials, is not only impactful for patients but also for healthcare systems.
The MAE rate in this study was primarily driven by severe bleeding events. Of these, all but one patient were on an antiplatelet and/or anticoagulation regimen at baseline, elevating the risk for bleeding complications. Moreover, patients had multiple comorbidities that increase the risk for bleeding, including renal insufficiency, liver dysfunction, and past medical history of bleeding.30,31 In medically managed TR patients, of whom >80% are on chronic anticoagulation and >20% have cirrhosis, gastrointestinal bleeding rates are reportedly high, exceeding 15 per 100 patient-years.32 Bleeding rates in the TRISCEND study are thus consistent with the patient population and may not be device specific. Although not defined as an MAE, 15 patients required new pacing; however, the 13.3% rate of new pacemaker implants at 30 days is similar to the reported rates of 10%–14% following TV surgery.10,33
Of the attempted device implants, 5.6% were unsuccessful, with half of these procedures aborted due to insufficient imaging and/or unfavourable patient anatomy. Intraprocedural imaging should improve with increased experience and the development of formal acquisition protocols and advanced imaging tools for TV replacement.34 This early experience with TTVR provided insights into potential anatomical challenges, including sizing, RV dimensions and function, and IVC-to-annulus offset, that are important to consider when planning interventions. Future learnings will help elucidate best approaches for diverse patient anatomies.
A general concern with TTVR therapies is an anticipated reduction in RV function and RV stroke volume when TR is alleviated.35–37 A recent meta-analysis of TTVI studies suggests that, for any transcatheter device therapy, a reduction in TR is associated with a reduction in echocardiographic measures of RV function yet is also associated with right-heart reverse remodelling with an increase in forward stroke volume.15 The echocardiographic findings from the TRISCEND study are consistent with evidence of right-heart reverse remodelling (i.e. reduction in mid-RV dimensions and IVC diameter) and increases in both stroke volume and cardiac output, despite a reduction in standard measures of RV function. Right ventricular-pulmonary artery coupling, which indexes RV function to afterload, may be a more physiologic measure of RV function and has been shown to predict outcomes in transcatheter device therapies.35,38 Baseline high RV-pulmonary artery coupling, as well as a decline in coupling measurements (suggesting RV-pulmonary artery coupling ‘reserve’), are independently associated with reduced all-cause mortality following TTVI.35 Patients in the TRISCEND study had a high baseline ratio of TAPSE/PASP and a decline at one year (although insignificant), consistent with normal RV-pulmonary artery coupling at baseline, and RV functional reserve at one year. Importantly, TAPSE/PASP at both baseline and one year suggest that RV function remains appropriately coupled to the increase in effective afterload associated with TR reduction.
The recent publication of the TRILUMINATE Pivotal trial39 on TEER raises questions about the clinical benefit of TR reduction. TRILUMINATE randomized patients to tricuspid TEER or medical therapy with a 12-month primary hierarchical outcome of (i) mortality or TV surgery, (ii) HF hospitalization, and (iii) quality-of-life improvement ≥ 15 points assessed using the KCCQ. The primary endpoint results favoured the TEER group (P = .02), driven mainly by significant improvement in KCCQ, without a difference in mortality, TV surgery, or HF hospitalization, despite significant reduction in TR after the TEER implant. Interestingly, patients who derived the most benefit in symptomatic improvement had the greatest reduction in TR, suggesting that degree of TR reduction is important in transcatheter therapy. The reasons for lack of differences in these important endpoints are unknown and deserve further investigation.
There are important differences in TRILUMINATE and TRISCEND patient populations. Patients in the TRISCEND study likely had more advanced disease with more patients presenting in NYHA class III/IV (75.4% in TRISCEND vs. 59.4% in TRILUMINATE), with renal disease (58.5% vs. 35.4%), and with prior year HF hospitalization (40.9% vs. 25.1%). The TRILUMINATE trial showed a graded response of the KCCQ overall score to TR reduction, and the nearly complete elimination of TR in the TRISCEND study [2.4% residual moderate TR (0.0% ≥ severe) in TRISCEND vs. 50.3% residual moderate or greater TR in TRILUMINATE] may be why, compared to TEER, TTVR resulted in marked improvement in the KCCQ (25.7 points vs. 12.3 points) and 6MWD (+56.2 m vs. −8.1 m).39 Because the signs and symptoms of severe chronic TR are related to low cardiac output, the sustained reduction in TR and the improvement in forward stroke volume after TTVR likely explains the marked improvement in NYHA class, KCCQ, and 6MWD at one year. Indeed, the magnitude of improvements in symptoms, quality of life, and functional metrics are among the largest reported for any transcatheter valve therapy trials.17,40–42
Limitations
The main limitation of this study is the single-arm design without comparison to standard of care, which is under investigation in a randomized pivotal trial. In addition, these results reflect the treatment of a highly selected patient cohort in specialized centres with extensive experience in transcatheter valve intervention, and outcomes may not be generalizable. Additionally, as an interim analysis, not all enrolled patients had yet reached their one-year follow-up. Moreover, echocardiographic data were incomplete due to unmeasurable variables on some echocardiograms—a sign of the inherent challenges of TV imaging. Finally, TTVR is an evolving field and standardized criteria for data collection and clinical trial definitions continue to develop.
Conclusions
In patients with significant, symptomatic TR, TTVR with the transfemoral EVOQUE system in the TRISCEND study demonstrated high procedural success and sustained TR reduction to mild or none at one year. A high burden of comorbidities contributed to risk of bleeding and new pacemakers and underscore both the challenges and need for treatment options for this high-risk group of patients. In this study representing the largest one-year follow-up of patients undergoing TTVR for symptomatic TR, patients experienced marked improvements in symptoms and functional and quality-of-life outcomes with low mortality and reduced hospitalization rates. The TRISCEND II randomized pivotal trial is currently enrolling (ClinicalTrials.gov, NCT04482062).
Acknowledgements
The authors thank the staff and patients of the study centres who participated in the TRISCEND study. In addition, they thank Edwards Lifesciences TMTT members for their support of this publication: Ted Feldman, MD; Suzanne Y. Gilmore, MPIA; Ann Krzmarzick, MBC; Laura Gerik, MS; Minji Lee, PhD; and Youping Cao, MPH.
Supplementary data
Supplementary data are available at European Heart Journal online.
Declarations
Disclosure of Interest
S.K. reports institutional research grants from Edwards Lifesciences, Medtronic, Abbott, Boston Scientific, and JenaValve; he is a consultant to Admedus, TriCares, TriFlo, X-Dot, MicroInterventional Devices, Supira, Adona, Tioga, Helix Valve Repair, and Moray Medical and serves on advisory boards for Dura Biotech, Thubrikar Aortic Valve Inc., Phillips, Medtronic, and Boston Scientific. R.T.H. reports speaker fees from Abbott Structural, Baylis Medical, Edwards Lifesciences, and Philips Healthcare; she has institutional consulting contracts for which she receives no direct compensation with Abbott Structural, Edwards Lifesciences, Medtronic, and Novartis; she is Chief Scientific Officer for the Echocardiography Core Laboratory at the Cardiovascular Research Foundation for multiple industry-sponsored tricuspid valve trials, for which she receives no direct industry compensation. Ra.M. is a consultant to and has received research grants from Edwards Lifesciences, Abbott, Medtronic, and Boston Scientific. M.M. is a consultant to Abbott Vascular, Boston Scientific, and Edwards Lifesciences. C.J.D. reports research grant support from Edwards Lifesciences and Abbott and is a consultant to Philips Healthcare and uncompensated consultant to Edwards Lifesciences. J.J.P. reports honoraria from Edwards Lifesciences and Abbott Structural. F.Z. reports institutional research and educational grants from Edwards Lifesciences, Siemens, and Medtronic and personal consultation fees from Edwards Lifesciences and Medtronic. S.C. is a consultant to Edwards Lifesciences and Medtronic and receives grant support from GE HealthCare. N.F. is a consultant to Edwards Lifesciences, Abbott, and Cardiovalve. G.O. reports speaker fees from Abbott. P.Y. reports institutional grants from Abbott, Edwards Lifesciences, Boston Scientific, Medtronic, HighLife, and JenaValve and personal consulting and speaker fees from Abbott, Edwards Lifesciences, and Boston Scientific. V.T. is an advisor or researcher for Artivion, Atricure, Abbott Vascular, Boston Scientific, Edwards Lifesciences, JenaValve, and Shockwave. M.V. reports research grants and speaker’s honorarium, for which he receives no direct compensation, from Abbott, Medtronic, and Edwards LifeSciences. W.W.O. reports grant support from Edwards, Medtronic, BSCI, and Abiomed and consultant fees from Abiomed. D.D.W. is a consultant to Edwards Lifesciences, Abbott, and Boston Scientific; she reports a research institutional grant from Boston Scientific. D.T. reports consulting fees from Edwards Lifesciences. N.D. reports consultancy fees from Abbott Vascular, Boston Scientific, Edwards Lifesciences, and Medtronic. L.B. and L.L. have received fees from GE HealthCare. R.S. reports honoraria for speaking and teaching from Medtronic, Artivion, and Intuitive as well as institutional grant support from Edwards Lifesciences, Artivion, and Medtronic. P.A.G. reports research grants from Abbott Structural, Boston Scientific, Cardiovalve, Edwards Lifesciences, Medtronic, Neochord, W.L. Gore, and 4C Medical; he receives advisory board honoraria from Abbott Structural, Cardiovalve, Edwards Lifesciences, Medtronic, Neochord, W.L. Gore, and 4C Medical. R.P.S. is a consultant, speaker, and clinical proctor for Edwards Lifesciences, Abbott, Medtronic, and Boston Scientific. C.H. is a consultant and speaker for Edwards Lifesciences. V.B. is a consultant to Edwards Lifesciences and reports equity in Transmural Systems. P.T.G. reports institutional grant support from Edwards Lifesciences, Medtronic, Abbott Vascular, and Boston Scientific. S.E. serves as a consultant to and receives institutional research support from Edwards Lifesciences and Medtronic. I.I.-A. reports educational grants from Edwards Lifesciences and Medtronic and consulting fees from Edwards Lifesciences, Medtronic, Boston Scientific, and W.L. Gore. H.C.H. reports institutional research grants from Abbott Structural, Boston Scientific, Edwards Lifesciences, Highlife, Medtronic, and W.L. Gore; he reports personal consulting fees from Medtronic, Wells Fargo, and W.L. Gore and equity in Microinterventional Devices. Sc.L. reports institutional research grants from Abbott, Boston Scientific, Corvia, Edwards Lifesciences, Medtronic, and V-Wave; he reports personal consulting fees from LagunaTech, Philips, Valgen, and Venus. J.G.W. is a consultant to Edwards Lifesciences. Ro.M. is a consultant to Edwards Lifesciences and has received speaker fees and travel support from Abbott. T.M. reports grant support and consultant fees from Edwards, Medtronic, and Abbott. St.L. consults for Abbott, Pfizer, GE HealthCare, and Philips. A.L. reports institutional research grants from Abbott, Boston Scientific, Edwards Lifesciences, and Medtronic; he reports personal consulting fees from Medtronic, Abbott, Boston Scientific, NeoChord, Philips, and Valgen. E.H. reports an institutional consulting contract with GE Healthcare for which he does not receive direct compensation; he is an advisor to Neochord, Inc., and Valgen. P.S. reports honoraria from Edwards Lifesciences and educational grants from Medtronic, Abbott, and Edwards Lifesciences; he is on an advisory board for Xenter. J.R.-C. reports institutional research grants and speaker fees from Edwards Lifesciences. M.J.M. reports consulting fees and research grants from Edwards Lifesciences. M.B.L. reports institutional clinical research grants from Abbott, Boston Scientific, Edwards Lifesciences, and Medtronic. S.W. reports research, travel, or educational grants to the institution from Abbott, Abiomed, Amgen, Astra Zeneca, Bayer, Biotronik, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cardinal Health, CardioValve, Corflow Therapeutics, CSL Behring, Daiichi Sankyo, Edwards Lifesciences, Guerbet, InfraRedx, Janssen-Cilag, Johnson & Johnson, Medicure, Medtronic, Merck Sharp & Dohm, Miracor Medical, Novartis, Novo Nordisk, Organon, OrPha Suisse, Pfizer, Polares, Regeneron, Sanofi-Aventis, Servier, Sinomed, Terumo, Vifor, and V-Wave. S.W. serves as advisory board member and/or member of the steering/executive group of trials funded by Abbott, Abiomed, Amgen, Astra Zeneca, Bayer, Boston Scientific, Biotronik, Bristol Myers Squibb, Edwards Lifesciences, Janssen, MedAlliance, Medtronic, Novartis, Polares, Recardio, Sinomed, Terumo, and V-Wave and Xeltis with payments to the institution but no personal payments. He is also member of the steering/executive committee group of several investigator-initiated trials that receive funding by industry without impact on his personal remuneration. Y.G., J.P., F.E.S., N.B., A.S., D.F., E.B., and C.N. have no disclosures to report.
Data Availability
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.
Funding
The TRISCEND Study is funded by Edwards Lifesciences (Irvine, CA, USA).
Ethical Approval
The TRISCEND study was conducted in compliance with the Declaration of Helsinki (2008), was approved by Institutional Review Boards of all participating sites, and all patients provided written informed consent. Study oversight included an independent clinical events committee, a data safety monitoring board, and an echocardiography core laboratory.
Pre-registered Clinical Trial Number
The pre-registered clinical trial number is ClinicalTrials.gov/NCT04221490.
