Summary of key evidence on transcatheter tricuspid valve annuloplasty for tricuspid regurgitation

Study 1 Montalto C (2020)

Study details

Study type	Systematic review and meta-analysis
Country	Not reported for individual studies (3 were described as international)
Recruitment period	Search date: September 2019
Study population and number	n=454 (7 studies); 30 annular reduction, 15 bicuspidalisation by pledget-plication, 47 increased leaflet coaptation surface, 362 edge-to-edge leaflet plasty
Age and sex	Mean 76.7 years; 41% (188/454) male
Patient selection criteria	Studies were eligible if they fulfilled all the following criteria: 1) they included patients with at least moderate tricuspid regurgitation (adjudicated using a semiquantitative method) and treated with transcatheter repair devices; and 2) they reported at least 1 of the primary outcomes of interest at a minimum follow-up point of 30 days. Case reports, letters and studies that did not clearly report the numbers and rates of patients alive at follow-up were excluded from the analysis. Studies in which severe tricuspid regurgitation was treated using transcatheter implantation of prosthetic valves were also excluded.
Technique	Transcatheter tricuspid valve repair. Devices included Cardioband (Edwards Lifesciences, US; n=30), FORMA (Edwards Lifesciences; n=47), MitraClip (Abbott Vascular, US; n=334), PASCAL (Edwards Lifesciences; n=28), and Trialign (Mitralign, US; n=15).
Follow up	range 30 days to 1 year
Conflict of interest/source of funding	None for authors of the review.

Analysis

Follow-up issues: Studies were only included if they had a minimum of 30 days follow up for at least 1 of the primary outcomes of interest.

Study design issues: The review was done in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses and Meta-Analysis of Observational Studies in Epidemiology guidelines. All included studies were interventional, multicentre, single arm, and prospective. The primary endpoints of the analysis were the rate reduction of severe tricuspid regurgitation and NYHA functional class 3 or 4 at longest follow up available. Procedural success definition included at least successful device implantation because of the varying definitions in the studies. Pooled risk ratios and standardised mean differences with 95% CIs were used as summary statistics for outcomes of interest and were calculated using a random-effects model. Heterogeneity was considered to be low when I² was less than 25%, moderate when I² was less than 75%, and high when I² was more than 75%. No publication bias was identified by visually inspecting funnel plots and by mathematical testing.

Study population issues: Of the 454 patients, only 45 had a procedure that fits the remit of this overview. The remaining patients had a procedure that fits the remit for a separate overview titled 'Transcatheter tricuspid valve leaflet repair for tricuspid regurgitation'.

Patients were at high surgical risk, with a mean EuroSCORE 2 score of 6.8% (95% CI 5.4% to 8.1%). Tricuspid aetiology was mostly functional (90%; 95% CI 82% to 99%), and 90% (95% CI 82% to 100%) of patients were in NYHA functional class 3 or 4.

Studies included the following named trials: TRI-REPAIR, Trivalve, TRILUMINATE and SCOUT.

Key efficacy findings

Number of patients analysed: 454
Procedural success: 86% of patients (95% CI 78% to 95%)
All-cause mortality rate (weighted mean follow up 265 days): 9% (95% CI 5% to 16%)
The sensitivity analysis revealed that no study significantly changed the relative risk of being in NYHA functional class 3 or 4 at follow-up, as stepwise study omission did not result in a shift of the point estimate out of the 95% CI.
The random-effect subgroup analysis revealed that at follow-up, the proportion of patients in NYHA functional class 3 or 4 and of patients with tricuspid regurgitation graded severe or worse were reduced regardless of the device used.

Functional and echocardiographic parameters at baseline and after transcatheter tricuspid valve repair

Parameter	Baseline value, incidence or pooled mean (95% CI)	No. of studies	RR or MD	Follow up: RR or MD (95% CI)	p value	I² (%)	p for hetero-geneity
Incidence of NYHA class 3 or 4	90% (82% to 99%)	7	RR	0.23 (0.16 to 0.33)	0.004	39	0.13
Mean 6-minute walk distance, metres	245.4 (215.8 to 275.0)	6	MD	64.6 (41.3 to 87.9)	<0.0001	0	0.78
Mean left ventricular ejection fraction, %	57 (52.9 to 61.0)	6	MD	1.2 (-0.5 to 2.8)	0.16	0	0.99
Mean tricuspid annular plane systolic excursion, mm	15.1 (14.3 to 15.9)	6	MD	-0.09 (-1.2 to 0.98)	0.85	64	0.02
Incidence of tricuspid regurgitation severe or greater	95% (87% to 100%)	4	RR	0.38 (0.2 to 0.7)	0.004	90	0.0001
Mean EROA, mm	0.9 (0.7 to 1.0)	6	MD	-3.1 (-4.4 to -1.9)	<0.0001	54	0.06
Mean tricuspid valve annular diameter, mm	44.6 (42.5 to 46.7)	7	MD	-3.0 (-4.7 to -1.4)	0.0004	63	0.01
Mean systolic pulmonary artery pressure, mmHg	41.7 (38.4 to 45.0)	4	MD	-1.6 (-4.9 to 1.7)	0.33	53	0.09

Key safety findings

No safety outcomes were reported.

Study 2 Nickenig G (2021)

Study details

Study type	Single arm (TriBAND study)
Country	13 European centres
Recruitment period	July 2019 to December 2020
Study population and number	n=61 Patients with symptomatic functional tricuspid regurgitation despite diuretic therapy
Age and sex	Mean 78.6 years; 75% (46/61) female
Patient selection criteria	Key inclusion criteria were chronic symptomatic (moderate or worse) functional tricuspid regurgitation confirmed by echocardiographic core laboratory and heart failure symptoms with NYHA functional Class 2 to 4 despite optimal medical therapy including diuretic therapy. Patients were deemed candidates for transcatheter tricuspid repair by the multidisciplinary local Heart Team. Key exclusion criteria were left ventricular ejection fraction less than 25%; pulmonary arterial systolic pressure higher than 70 mmHg by echocardiography or right heart catheterisation; tricuspid PISA EROA at least 2 cm²; severe right ventricular dysfunction; tricuspid valve anatomy precluding proper device deployment and function; previous tricuspid valve repair or replacement; presence of trans-tricuspid valve pacemaker or defibrillator leads impinging on the tricuspid valve leaflets as evaluated by echocardiography; and renal insufficiency needing dialysis or severe kidney renal disease with an estimated glomerular filtration rate 25 mL/min/1.73 m² or lower.
Technique	Device: Cardioband tricuspid valve reconstruction system (Edwards Lifesciences, US). The Cardioband implant was deployed through transfemoral venous access using a delivery system under transoesophageal echocardiography and fluoroscopic guidance. Intraprocedural coronary angiography was done periodically to assess the proximity of the right coronary artery.
Follow up	30 days
Conflict of interest/source of funding	The study was funded by Edwards Lifesciences. 7 authors have received speakers' honoraria or travel/grant support from Edwards Lifesciences. 4 authors have received research funding, educational grants, honoraria for lectures of advisory boards or participated in clinical trials from companies including the Deutsche Forschungsgemeinschaft, the Federal Ministry of Education and Research, the European Union, Abbott, AGA Medical, AstraZeneca, Bayer, Berlin Chemie, BioSensus, Biotronik, Bristol-Myers Squibb, Boehringer Ingelheim, Daiichi Sankyo, Edwards Lifesciences, Medtronic, Novartis, Pfizer, Sanofi, St. Jude Medical, Cardiovalve, Amgen, BMS, Boston Scientific, Cardinal Health, CSL Behring, Johnson & Johnson, Querbet, Polares, Terumo, Sinomed, Abiomed, MedAlliance, V-Wave, Xeltis, Philips Healthcare and Navigate.

Analysis

Follow-up issues: 30-day follow up was done in 85% (52/61) of patients. One patient died before the visit, 1 patient exited from the study after an abandoned procedure, and 7 patients had missed or pending visits.

Study design issues: European single-arm, multicentre, prospective post-market clinical follow up study. This study included the first 61 patients to be enrolled. The primary endpoint was reduction in tricuspid regurgitation severity between baseline and discharge. Secondary endpoints included tricuspid regurgitation severity, NYHA functional class, EQ-5D-5L, and overall Kansas City Cardiomyopathy Questionnaire at 30 days follow up. The safety endpoint was a composite of major adverse events, defined as cardiovascular mortality, myocardial infarction, stroke, pericardial effusion needing intervention, coronary artery injury needing percutaneous or surgical intervention, arrhythmia and conduction disorders needing permanent pacing, new need for renal replacement therapy, severe bleeding, nonelective tricuspid valve reintervention (percutaneous or surgical), major access-site and vascular complications, and major cardiac structural complications. Device success was defined as the device deployed and the delivery system successfully retrieved as intended at the time of the patient's exit from the cardiac catheterisation laboratory (per device). Procedural success was defined as device success with 30% tricuspid regurgitation reduction in PISA EROA relative to baseline, and without the need for intervention before discharge (per patient). Clinical success was defined as procedural success with no major adverse events at 30 days (per patient). Analysis was done on the intention-to-treat population.

Study population issues: 85% of patients were in NYHA functional Class 3 to 4. Mean EuroSCORE 2 was 6.8% and Society of Thoracic Surgeons predicted risk of mortality score was 7.1%. All 61 patients had severe or worse functional tricuspid regurgitation based on their site evaluated qualifying echocardiograms; of the 53 patients who were assessed by the echocardiographic core laboratory, 94% had severe or worse tricuspid regurgitation at baseline. Mean NT-pro BNP level was 2,072 pg/mL.

Key efficacy findings

Number of patients analysed: 61
In 1 patient, the procedure was abandoned because the right coronary artery was perforated by the guidewire before the device was inserted.
Device success=96.7% (58/60); 2 patients did not have the device inserted because of partial deployment of anchors leading to inability to contract the implant (n=1) and poor visibility along with right coronary artery proximity and steep atrial wall (n=1).
Procedural success=83.9% (26/31; EROA unreadable for 30 patients)
Clinical success=54.1% (20/37)
Mean fluoroscopy time=67.1 minutes
Mean length of hospital stay=6.5 days
Proportion of patients with at least 1 grade reduction in triscuspid regurgitation at discharge=78%
Proportion of patients with at least 1 grade reduction in triscuspid regurgitation at 30 days=85%
Proportion of patients with at least 2 grades reduction in triscuspid regurgitation at discharge=59%
Proportion of patients with at least 2 grades reduction in triscuspid regurgitation at 30 days=59%

Improvements in tricuspid regurgitation severity from baseline to 30 days (proportion of patients)

Severity	Qualifying echocardiogram, n=61	Baseline, n=53	Discharge, n=54	30 days, n=42
None/trace	0	0	6%	5%
Mild	0	0	20%	31%
Moderate	0	6%	33%	33%
Severe	31%	26%	24%	14%
Massive	25%	28%	4%	12%
Torrential	44%	40%	13%	5%
p value	-	-	<0.001	<0.001

Echocardiographic variables at baseline, discharge, and 30 days, mean (SD) or % (n/N)

Variable	Base-line	n	Discharge	n	Change	p value	30 days	n	Change	p value
Tricuspid annular septolateral diameter, mm	45.5 (4.5)	52	36.7 (5.0)	54	-8.7 (3.6)	<0.001	36.1 (5.0)	42	-8.9 (5.1)	<0.001
PISA EROA, cm²	0.76 (0.48)	41	0.39 (0.35)	36	-0.44 (0.37)	<0.001	0.34 (0.27)	37	-0.45 (0.36)	<0.001
Mean vena contracta, cm	1.5 (0.56)	48	0.89 (0.55)	50	-0.67 (0.44)	<0.001	0.79 (0.52)	37	-0.70 (0.43)	<0.001
Mid-right ventricle end-diastolic diameter, cm	4.0 (0.8)	50	3.7 (0.7)	51	-0.3 (0.6)	0.007	3.6 (0.6)	41	-0.4 (0.7)	0.005
Left ventricular ejection fraction, %	53.3 (7.6)	49	54.5 (7.5)	48	2.0 (4.7)	0.01	54.8 (8.2)	41	1.6 (5.9)	0.123
Right ventricle tricuspid annular plane systolic excursion, cm	1.6 (0.3)	52	1.4 (0.3)	53	-0.2 (0.3)	<0.001	1.5 (0.4)	42	-0.1 (0.3)	0.01
Systolic pulmonary artery pressure, mmHg	33.1 (11.0)	52	41.0 (14.2)	54	7.6 (14.0)	<0.001	38.4 (9.6)	41	3.5 (10.2)	0.045

Improvements in functional and clinical measurements from baseline to 30 days

Outcome	n	Baseline	n	30 days	p value
Proportion of patients with NYHA functional class 1 or 2	61	15%	50	74%	<0.001
Overall Kansas City Cardiomyopathy Questionnaire score, mean (SD)	60	50 (21)	53	69 (23)	<0.001
EQ-5D-5L score, mean (SD)	61	60 (17)	53	44 (19)	0.313

Key safety findings

All-cause mortality=1.6% (1/61) (the patient died from procedure related renal failure on postoperative day 18)
Cardiovascular mortality=0% (0/61)
Myocardial infarction=1.6% (1/61) (transient intraprocedural occlusion of the right coronary artery, resolved spontaneously)
Stroke=0% (0/61)
Pericardial effusion needing intervention=1.6% (1/61)
Coronary artery injury needing intervention=6.6% (4/61)
Arrhythmia and conduction disorders needing permanent pacing=1.6% (1/61)
New need for renal replacement therapy=3.3% (2/61)
Severe bleeding=11.5% (7/61) (all 7 were on anticoagulation or antiplatelet therapy for pre-existing atrial fibrillation or flutter)
Non-elective tricuspid valve reinterventions=0% (0/61)
Major access-site and vascular complications=6.6% (4/61)
Major cardiac structural complications=0% (0/61)
Composite major adverse event rate=19.7% (12/61)

Study 3 Nickenig G (2021b)

Study details

Study type	Single arm (TRI-REPAIR study)
Country	France, Germany, Italy (8 sites)
Recruitment period	October 2016 to July 2017
Study population and number	n=30 Patients with moderate or greater functional tricuspid regurgitation for whom surgery posed an unacceptable risk
Age and sex	Mean 75.2 years; 73% (22/30) female
Patient selection criteria	Key eligibility criteria included NYHA functional class 2 to 4a, moderate or greater chronic functional tricuspid regurgitation, symptomatic despite stable medical treatment at minimum on a diuretic regimen, tricuspid annular diameter 40 mm or larger, and surgery precluded as a treatment option. Key exclusion criteria included left ventricular ejection fraction less than 30%, systolic pulmonary artery pressure higher than 60 mmHg, echocardiographic evidence of severe right ventricular dysfunction, and recent myocardial infarction or known unstable angina within 30 days before the index procedure.
Technique	Device: Cardioband tricuspid valve reconstruction system (Edwards Lifesciences, US).
Follow up	Mean 604 days
Conflict of interest/source of funding	The study was funded by Edwards Lifesciences. 8 authors have received speakers' honoraria or travel and grant support from Edwards Lifesciences. 4 authors are employees of Edwards Lifesciences. 1 author reported speaker honoraria from Baylis Medical, Edwards Lifesciences and Medtronic, consulting for Abbott Structural, Edwards Lifesciences, Medtronic, Navigate and Philips Healthcare, and being the Chief Scientific Officer for the Echocardiography Core Laboratory at the Cardiovascular Research Foundation for multiple industry-sponsored trials, for which she receives no direct industry compensation.

Analysis

Follow-up issues: Of the 30 patients, 5 died within the first year and 2 died during the second year of follow up. Two patients had a further intervention and 1 withdrew from the study, so 80% (24/30) of patients had a 1-year follow up and 67% (20/30) of patients had a 2-year follow up.

Study design issues: Single-arm, multicentre, prospective study. The primary efficacy endpoint for the study was successful access, deployment, and positioning of the tricuspid implant and reduction of the septolateral annular diameter at the end of the procedure and at discharge. The primary safety endpoint was the rate of major serious adverse events (a composite endpoint of death, myocardial infarction, cardiac tamponade, device-related cardiac surgery, and stroke) and serious adverse device effects at 30 days. These events were adjudicated by an independent clinical events committee. Changes were calculated for paired observations. The authors noted that some site-reported values differed from core laboratory assessments (1 patient had mild tricuspid regurgitation) and there was missing tricuspid regurgitation quantitation (PISA EROA) because of inadequate imaging.

Study population issues: Most patients (83%) were in NYHA Class 3 to 4. The mean EuroSCORE 2 was 4.1% and the Society of Thoracic Surgeons mortality score was 2.6%. Mean NT-proBNP level was 2,925 ng/L.

Other issues: Data from this trial was also included in the systematic review by Montalto et al. (2020)

Key efficacy findings

Number of patients analysed: 30
Technical success=100%
2-year survival estimate (Kaplan-Meier)=73%
Freedom from heart failure hospitalisation at 2 years (Kaplan-Meier)=56%

Improvements in tricuspid regurgitation severity from baseline to 2 years (proportion of patients)

Severity	Baseline, n=25	Discharge, n=22	1 year, n=16	2 years, n=11
Mild	4%	14%	13%	36%
Moderate	20%	41%	50%	36%
Severe	24%	18%	25%	9%
Massive	16%	9%	6%	9%
Torrential	36%	18%	6%	9%
p value	-	<0.001	0.007	0.016

Improvements in functional and clinical measurements from baseline to 2 years

Outcome	n	Baseline	n	1 year	p value	n	2 years	p value
Proportion of patients with NHYA functional class 1 or 2	30	17%	23	78%	<0.001	17	82%	0.002
Proportion of patients without oedema	30	37%	23	70%	0.073	17	88%	0.063
6-minute walk distance in metres, mean (SD)	26	248 (113)	19	296 (130)	<0.053	13	309 (119)	0.058
Overall Kansas City Cardiomyopathy Questionnaire score, mean (SD)	30	45 (23)	23	64 (23)	<0.001	20	63 (26)	0.046

Septolateral annular diameter (mm)

Baseline=41.9 (n=26)
Discharge=36.2 (n=22), p<0.001 compared with baseline
1 year=36.5 (n=19)
2 years=35.2 (n=14)

Echocardiographic variables at baseline, 1 year, and 2 years, mean (SD)

Variable	Base-line	n	1 year	n	Change	p value	2 years	n	Change	p value
Left ventricular ejection fraction, %	57.5 (10.8)	28	59.3 (6.4)	21	2.5 (8.3)	0.206	57.7 (7.0)	16	0.2 (7.6)	0.907
Estimated systolic pulmonary artery pressure, mmHg	35.9 (10.5)	29	38.1 (9.0)	23	1.4 (9.9)	0.513	39.5 (10.9)	15	4.4 (11.2)	0.150
PISA EROA, cm²	0.78 (0.49)	25	0.37 (0.18)	16	-0.36 (0.40)	0.004	0.34 (0.23)	11	-0.57 (0.47)	0.004
Mean vena contracta, cm	1.23 (0.40)	25	0.85 (0.30)	18	-0.36 (0.41)	0.005	0.79 (0.51)	10	-0.55 (0.40)	0.004
tricuspid valve annulus mid-diastolic septolateral diameter, mm	43.4 (5.0)	30	36.9 (4.0)	21	-6.8 (4.5)	<0.001	34.2 (4.4)	12	-9.8 (4.2)	<0.001
tricuspid valve annulus end-diastolic septolateral diameter, mm	41.9 (4.6)	26	36.5 (4.6)	19	-5.7 (3.2)	<0.001	35.2 (4.6)	14	-6.6 (6.7)	0.006
Right ventricle end-diastolic diameter (mid), cm	3.8 (0.6)	29	3.5 (0.5)	18	-0.1 (0.5)	0.294	3.2 (0.6)	15	-0.4 (0.6)	0.014
Fractional area change, %	35.8 (6.5)	29	35.4 (5.3)	16	-0.4 (5.7)	0.795	37.9 (6.9)	15	2.5 (6.2)	0.142
Right ventricle tricuspid annular plane systolic excursion, cm	1.4 (0.3)	22	1.4 (0.4)	22	-0.1 (0.3)	0.462	1.4 (0.4)	16	0.1 (0.2)	Not significant
Right atrial volume, mL	127 (45)	30	116 (46)	20	-14 (36)	0.103	104 (49)	15	-18 (41)	0.112

Key safety findings

Adverse events

Event	1 year, n (%)	2 years, n (%)
Death	5 (16.7)	8 (26.7)
Stroke	1 (3.3)	2 (6.7)
Myocardial infarction	0	0
Bleeding complications (extensive, life-threatening, or fatal)	6 (20.0)	7 (23.3)
Coronary complications	3 (10.0)	3 (10.0)
Device-related secondary intervention	1 (3.3)	2 (6.7)
Device-related cardiac surgery	0	0
Renal failure	1 (3.3)	1 (3.3)
Conduction system disturbance	1 (3.3)	2 (6.7)
Ventricular arrhythmia	3 (10.0)	3 (10.0)

Of the 8 deaths, there were 6 non-cardiovascular deaths beyond 30 days (progression of chronic lymphatic leukaemia, respiratory failure, worsening of chronic renal failure, multifactorial reasons primarily pulmonary artery embolism, acute renal failure, and metastatic liver cancer).

Study 4 Körber M (2021)

Study details

Study type	Case series
Country	Germany
Recruitment period	October 2018 to February 2020
Study population and number	n=60 Patients with severe secondary tricuspid regurgitation
Age and sex	Median 76 years; 62% (37/60) female
Patient selection criteria	Patients with symptomatic, at least severe tricuspid regurgitation and secondary aetiology were eligible for inclusion. All patients were discussed in an interdisciplinary heart team and deemed inoperable because of high surgical risk. Exclusion criteria included: annular dimensions more than 128 mm device length (cardiac CT), heavily calcified annulus or leaflets, and proximity of right coronary artery less than 6.5 mm in more than 40% of the perimeter. The latter was amended to less than 5 mm in more than 3 segments mid-2019 and was omitted in 2020. Patients who had already participated in the TRI-REPAIR trial were excluded from this study
Technique	Device: Cardioband tricuspid valve reconstruction system (Edwards Lifesciences, US) The largest implant size was used for most patients.
Follow up	Median clinical follow up was 92 days (IQR 43 to 203 days).
Conflict of interest/source of funding	5 of the 11 authors have received research grants and speaker honoraria from Edwards Lifesciences Services, Germany.

Analysis

Follow-up issues: Vital status for the 30 day periprocedural period was available for all 60 patients. During this period, 4 patients died. Information on survival status at 6-month follow up was available for 37 patients (62%).

Study design issues: Retrospective case series of the first 60 patients to have the procedure at 4 high-volume centres. The primary efficacy end point (procedural success) was defined as technical success and tricuspid regurgitation reduction of 2 or more grades at discharge. Tricuspid regurgitation severity was graded using a 5‑class grading scheme: mild, moderate, severe, massive, and torrential. Technical success was defined as successful delivery, deployment and positioning of device, absence of procedural mortality, and freedom from emergency surgery related to the device. Device success at follow up was defined as the absence of procedural mortality or stroke, proper placement of device, freedom from unplanned surgery or interventional procedures related to the device, improvement of at least 1 grade in tricuspid regurgitation, absence of device-specific technical failure or complications (specifically damage to tricuspid leaflets, pericardial effusion, and coronary complications), and without significant tricuspid valve stenosis. In the context of device success, only coronary complications with a potentially persistent damage (vessel perforation with active bleeding because of anchor penetration) or needing therapy were considered. The primary safety end point was the overall rate of major adverse events, defined as a composite end point of death, myocardial infarction, need for urgent cardiothoracic surgery, and stroke through postprocedural day 30. Clinical and functional outcome measures comprised cause specific mortality and change in NYHA functional class.

Study population issues: The median EuroScore 2 was 3.9% (IQR 2.2 to 8.1) and the mean was 6.3%. At baseline, 98% of patients were taking diuretics and 41% were taking an aldosterone antagonist. Most patients (82%) were in NYHA class 3 or 4 and 80% had peripheral oedema. The mean coaptation gap was 6.9 mm. The mean NT-proBNP level at baseline was 2,769 ng/L.

Key efficacy findings

Number of patients analysed: 60
Technical success=96.7% (58/60)
Procedural success=45.0% (27/60)
Technical success and reduction of tricuspid regurgitation of 1 grade or more=88.3% (53/60)
Patients who met the primary efficacy end point presented with greater vena contracta diameter at baseline (14.9 compared with 11.3 mm, p=0.004) and more often with torrential tricuspid regurgitation (44.4% compared with 3%, p<0.001) but did not differ in other baseline characteristics.
The septolateral diameter of the tricuspid annulus was reduced by a mean of 10.5 mm.
The mean coaptation gap after cinching was 1.4 mm, representing a mean reduction of 5.5 mm.
Device success at 30 days=73.2% (41/56)

Improvements in tricuspid regurgitation severity (echocardiographic paired analyses at baseline, discharge, and 30 days), proportion of patients, p<0.001

Severity	Baseline, n=59	Discharge, n=59	Baseline, n=43	30 days, n=43
Mild	0	8.5%	0	20.9%
Moderate	0	52.5%	0	46.5%
Severe	47.5%	35.6%	53.5%	30.2%
Massive	30.5%	1.7%	23.3%	0
Torrential	22%	1.7%	23.3%	2.3%

Improvements in NYHA functional class (paired analysis of functional improvement after 30 days), proportion of patients, n=48, p<0.001

NYHA functional class	Baseline	30 days
1	2.1%	22.9%
2	18.8%	58.3%
3	70.8%	18.8%
4	8.3%	0

Key safety findings

30-day events

Primary safety end point (death, myocardial infarction, need for urgent cardiothoracic surgery, stroke)=6.7% (4/60).
- 1 patient needed surgical thoracotomy for intramural bleeding.
- 1 patient needed open heart surgery because of accidental puncture of the right ventricle during pericardiocentesis for pericardial effusion. Pericardial effusion was present before the intervention but progressed afterward with need for intervention 2 days after the procedure.
- 2 patients died in hospital. One patient with poor left ventricular function at baseline needed persistent vasopressor support after the procedure, which was first attributed to pharyngeal bleeding associated with transoesophageal echocardiography and tracheal tube. Four days after the procedure, the patient developed pulseless electric activity and resuscitation efforts were unsuccessful. The other patient died on postoperative day 10. The patient had a laryngeal injury related to general anaesthesia and transoesophageal echocardiography and had to stay ventilated after the procedure. The patient developed pneumonia and enteritis leading to toxic megacolon and died from septic shock shortly after having abdominal surgery. There was no indication of device malfunction.
Death=3.3% (2/60)
- 1 patient died 15 days after the procedure in a palliative setting after being discharged.
- 1 patient died 3 weeks after the procedure because of a severe acute respiratory syndrome–coronavirus disease 2019 (COVID-19) infection.
Haemodynamically relevant arrhythmia=11.7% (7/60)
Need for new pacemaker=3.3% (2/60)
Acute renal failure=11.7% (7/60)
Access site-related bleeding=1.7% (1/60)

Bleeding complications

Overall=11.7% (7/60)
Major bleeding=5.0% (3/60)
Extensive bleeding=5.0% (3/60)
Life-threatening bleeding=1.7% (1/60)
Fatal bleeding=0
Blood transfusion=20.0% (12/60)
Device-related open heart surgery=1.7% (1/60)
Need for urgent open heart surgery=3.3% (2/60)

Coronary complications (patients may have had more than 1)

Right coronary artery perforation=5.0% (3/60) (2 were treated conservatively)
Right coronary artery stent implantation=11.7% (7/60)
Cardiac tamponade=3.3% (2/60)
Myocardial infarction=1.7% (1/60)
Stroke/transient ischaemic attack=0

Study 5 Davidson C (2021)

Study details

Study type	Case series
Country	US
Recruitment period	August 2018 to November 2019
Study population and number	n=30 Patients with severe or greater symptomatic functional tricuspid regurgitation
Age and sex	Mean 77 years; 80% (24/30) female
Patient selection criteria	Patients aged 18 years or over with moderate or greater chronic functional tricuspid regurgitation who were symptomatic despite medical therapy including diuretics were included in the study. The multidisciplinary local heart team determined whether transcatheter tricuspid reconstruction was clinically appropriate for the patient. The criteria for exclusion were tricuspid valve anatomy precluding proper device deployment and function including primary tricuspid valve disease, previous tricuspid valve repair or replacement, presence of transtricuspid pacemaker or defibrillator leads that impinge the tricuspid valve leaflets as evaluated by echocardiography or were implanted within the last 90 days, left ventricular ejection fraction less than 25%, severe right ventricular dysfunction as assessed by the echocardiography core laboratory, kidney dysfunction with estimated glomerular filtration rate 25 ml/min/1.73 m² or less or chronic dialysis, and chronic anaemia not corrected by transfusion.
Technique	Device: Cardioband tricuspid valve reconstruction system (Edwards Lifesciences, US) Most patients had the largest available implant size.
Follow-up	30 days
Conflict of interest/source of funding	Study was funded by Edwards Lifesciences. 5 authors have received grant support or consulting fees from Edwards Lifesciences. 1 has served as a speaker and consultant for Edwards Lifesciences and is the Chief Scientific Officer for the Echocardiography Core Laboratory at the Cardiovascular Research Foundation for multiple industry sponsored trials, for which she has received no direct industry compensation. 4 authors are employees of Edwards Lifesciences.

Analysis

Study design issues: Single-arm, multicentre, prospective early feasibility study. The safety endpoint was major adverse events at 30 days defined as a composite of cardiovascular mortality, myocardial infarction, stroke, tamponade, right coronary artery perforation, conduction disorders needing a new permanent pacemaker, new need for renal replacement therapy, severe bleeding, reintervention related to study device, and major access site and vascular complications that needed intervention. Device success was defined as device deployed as intended and the delivery system successfully retrieved as intended at the time of the patient's exit from the cardiac catheterisation laboratory.

Study population issues: At baseline, NYHA functional class was 3 or 4 in 21 (70%) patients. Comorbidities included atrial fibrillation or flutter (97%), pulmonary hypertension (73%), hypertension (62%), prior pacemaker, implantable cardioverter defibrillator or cardiac resynchronisation therapy (23%), prior myocardial infarction (13%), diabetes (30%) and kidney dysfunction (37%). All patients had at least severe tricuspid regurgitation including 73% massive or torrential tricuspid regurgitation with average tricuspid septolateral diameter of 45.2 mm and left ventricular ejection fraction of 58.4%.

Key efficacy findings

Number of patients analysed: 30
Device success=93.3% (28/30); 2 patients did not receive the device as intended because of anchor disengagements that happened during contraction with no clinical sequelae.
Mean length of hospital stay=4.6 days
The end-diastolic tricuspid septolateral annular diameter statistically significantly decreased from 45.2 mm to 38.8 mm at discharge (p<0.001) and was stable at 30 days to 39.5 mm (p<0.001) in paired analysis.
At 30 days, 85% of patients had at least 1 grade reduction and 56% of patients had at least a 2 grade reduction in tricuspid regurgitation.
Kansas City Cardiomyopathy Questionnaire score results improved from 53 points at baseline to 69 points at 30 days (p<0.001).
The proportion of patients with NYHA functional class 1 or 2 improved from 32% at baseline to 75% at 30 days (p<0.001).
The 6-minute walk distance at baseline was 245.8 metres and remained unchanged at 30 days (247.0 metres; p=0.926).

Echocardiographic results, paired analyses, mean (SD)

Variable	Baseline	30 days	n	p value
Left ventricular ejection fraction, %	58.6 (5.8)	58.5 (7.1)	27	0.904
Systolic pulmonary artery pressure, mmHg	37.8 (10.9)	40.3 (12.0)	27	0.259
PISA EROA, cm²	0.84 (0.39)	0.55 (0.41)	21	<0.001
Mean vena contracta, cm	1.48 (0.48)	0.91 (0.44)	25	<0.001
Right ventricle end-diastolic diameter (mid), cm	4.1 (0.5)	3.7 (0.5)	26	<0.001
Right ventricle end-diastolic diameter (base), cm	5.6 (0.6)	5.2 (0.7)	27	<0.001
Right ventricular fractional area change, %	41.6 (5.2)	38.1 (7.2)	26	0.011
Right atrial volume, mL	134.6 (41.6)	105.7 (42.5)	28	<0.001
Inferior vena cava diameter, cm	2.8 (0.8)	2.4 (0.9)	27	0.002

Improvements in tricuspid regurgitation severity from baseline to 30 days, proportion of patients, p<0.001

Severity	Baseline, n=27	30 days, n=27
Mild	0	15%
Moderate	0	30%
Severe	26%	33%
Massive	19%	11%
Torrential	56%	11%

Key safety findings

Major adverse events at 30 days (adjudicated by Clinical Events Committee)

Cardiovascular mortality=0
Myocardial infarction=0
Stroke=0
Cardiac tamponade=3.3% (1/30)
Right coronary artery perforation=0
Arrhythmia and conduction disorders needing permanent pacing=0
New need for renal replacement therapy=0
Severe bleeding=23.2% (7/30)
- Fatal=0
- Life-threatening=2
- Extensive=1
- Major=4
Major access site and vascular complications needing intervention=0
Reintervention on the previously implanted study device=0

Other events

All-cause mortality=0

Study 6 Hahn R (2017)

Study details

Study type	Case series (SCOUT trial)
Country	US (4 sites)
Recruitment period	November 2015 to June 2016
Study population and number	n=15 Patients with NYHA functional class 2 or higher and at least moderate functional tricuspid regurgitation
Age and sex	Mean 73.6 years; 86.7% (13/15) female
Patient selection criteria	Inclusion criteria: patients with NYHA functional class 2 or higher and greater than or equal to moderate functional tricuspid regurgitation, with no indication of left-sided valve surgery. Exclusion criteria included older than 85 years, pacemaker implantation, systolic pulmonary artery pressure above 60 mm Hg, left ventricle ejection fraction less than 35%; tricuspid annular plane systolic excursion less than 13 mm; or tricuspid EROA greater than 1.2 cm².
Technique	Device: Trialign system (Mitralign Inc., US)
Follow-up	30 days
Conflict of interest/source of funding	The first author is a speaker for Edwards Lifesciences, Abbott Vascular, Boston Scientific, and GE Medical; is an unpaid national principal investigator for the SCOUT Trial; and is an uncompensated director of Echo Core for multiple industry-sponsored trials. Seven authors are consultants, proctors or have received research grants or support from companies including Medtronic, Boston Scientific, Edwards Lifesciences, Abbott Vascular, St. Jude Medical, Siemens Healthcare, GE Medical, Dura Biotech and Atricure. One author is a speaker for Medtronic, Edwards Lifesciences, and Abbott Vascular; and holds stock/ownership in BayLabs. One author is an employee of and holds ownership stock in Mitralign. One author holds equity in Thubrikar Aortic Valve and BioTrace.

Analysis

Study design issues: Prospective, single-arm, multicentre, early feasibility study. The primary safety and performance endpoint was technical success at 30 days. Patient quality of life was assessed by using NYHA functional class assessment, 6-minute walk test results, and Minnesota Living with Heart Failure Questionnaire responses.

Study population issues: All patients were symptomatic and in NYHA functional class 2 (33%) or 3 (67%). Most patients had a history of hypertension (80%) or pulmonary hypertension (60%) or had a previous mitral valve intervention (67%) and were in atrial fibrillation (67%). All patients were taking diuretic agents, and most (93%) were also taking a betablocker agent.

Other issues: The device used in this study is no longer available. This study is included in the systematic review by Montalto et al. (2020).

Key efficacy findings

Number of patients analysed: 15
All devices were implanted in the correct position, with successful plication.
Overall technical success at 30 days=80.0% (12/15); in 3 patients, there was echocardiographic evidence of a single pledget detachment from the annulus. The pledgets stayed attached to the remaining pledgeted suture and did not need reintervention or result in adverse events.
No unplanned or emergency surgery or reintervention related to the device or access procedure within 30 days=93.3% (14/15)

Quality of life outcomes for intention-to-treat patients (n=15)

Outcome	Baseline	30 days	Change	p value
NYHA class 1, n (%)	0 (0)	7 (46.7)	-	0.001
NYHA class 2, n (%)	5 (33.3%)	8 (53.3)	-
NYHA class 3, n (%)	10 (66.7%)	0 (0)	-
NYHA class 4, n (%)	0 (0)	0 (0)	-
Minnesota Living with Heart Failure Questionnaire score, mean (SD)	47.4 (17.6)	20.9 (14.8)	-26.5 (20.4)	<0.001
6-minute walk test (metres), mean (SD)	245.2 (110.1)	298.0 (107.6)	52.9 (72.6)	0.008

In the 3 patients with single-pledget detachment,there were no statisticallysignificant differences between baselineand 30 day values for NYHA functional class, Minnesota Living with Heart Failure Questionnaire score and 6MWT.

Echocardiographic results in the intention-to-treat group, mean (SD)

Variable	Baseline	30 days	change	n	p value
Left ventricular ejection fraction, %	59.9 (11.5)	59.7 (11.9)	0.4 (7.6)	13	0.853
Right ventricular tricuspid annular plane systolic excursion, cm	1.6 (0.4)	1.6 (0.4)	0 (0.6)	12	0.456
left ventricular outflow tract Doppler stroke volume, ml	67.1 (18.1)	72.8 (23.2)	8.5 (13.4)	13	0.041
Tricuspid regurgitation vena contracta, cm	1.3 (0.3)	1.1 (0.4)	-0.2 (0.4)	14	0.133
Estimated systolic pulmonary artery pressure, mmHg	43.6 (9.3)	40.9 (9.5)	-2.7 (7.0)	15	0.222
PISA EROA, cm²	0.51 (0.16)	0.41 (0.27)	-0.11 (0.3)	15	0.192
Tricuspid valve annular diameter, cm	4.0 (0.5)	3.9 (0.5)	-0.2 (0.4)	15	0.017
Tethering distance, cm	0.7 (0.2)	0.6 (0.1)	-0.1 (0.2)	15	0.037
2-dimensional tricuspid valve annulus area, cm²	12.3 (2.8)	11.5 (2.5)	-0.7 (1.4)	15	0.061
Tricuspid regurgitant volume, ml	86.0 (21.3)	78.7 (53.3)	-2.7 (39.5)	13	0.811
Quantitative Doppler tricuspid regurgitation EROA, cm²	0.93 (0.27)	0.93 (0.74)	0 (0.56)	14	0.530

Change from baseline to 30 days computed using paired data

Echocardiographic results in the as treated group, mean (SD)

Variable	Baseline	30 days	change	n	p value
Left ventricular ejection fraction, %	59.8 (12.7)	59.1 (12.9)	-0.3 (7.3)	11	0.904
Right ventricular tricuspid annular plane systolic excursion, cm	1.7 (0.4)	1.6 (0.2)	-0.1 (0.4)	10	0.308
left ventricular outflow tract Doppler stroke volume, ml	63.6 (17.9)	71.5 (25.7)	11.7 (13.2)	10	0.021
Tricuspid regurgitation vena contracta, cm	1.3 (0.4)	1.0 (0.3)	-0.3 (0.3)	11	0.022
Estimated systolic pulmonary artery pressure, mmHg	44.1 (10.2)	42.0 (9.5)	-2.1 (6.6)	12	0.327
PISA EROA, cm²	0.51 (0.18)	0.32 (0.18)	-0.2 (0.25)	12	0.02
Tricuspid valve annular diameter, cm	4.0 (0.5)	3.8 (0.6)	-0.2 (0.4)	12	0.038
Tethering distance, cm	0.7 (0.1)	0.6 (0.1)	-0.1 (0.2)	12	0.116
2-dimensional tricuspid valve annulus area, cm²	12.3 (3.1)	11.3 (2.7)	-1.0 (1.3)	12	0.019
Tricuspid regurgitant volume, ml	79.6 (17.5)	57.1 (29.0)	-18.1 (27.2)	10	0.065
Quantitative Doppler tricuspid regurgitation EROA, cm²	0.85 (0.22)	0.63 (0.29)	-0.22 (0.29)	11	0.045

Change from baseline to 30 days computed using paired data

Key safety findings

There werenodeaths, strokes, bleeding, tamponade, or valve reintervention.
In 1 patient, the completion angiogram showed tenting of the distal right coronary artery in the region of the plication with narrowing confirmed by fractional flow reserve of 0.57, which was associated with ST-segment elevations on electrocardiogram. These changes resolved with right coronary stent placement with post-procedure peak troponin concentration of 1.79 mg/l, which decreased to 0.7 mg/l.

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Interventional procedure overview of transcatheter tricuspid valve annuloplasty for tricuspid regurgitation