Aims: Tricuspid regurgitation (TR) is a detrimental disease frequently diagnosed in patients with right-sided heart failure (HF). While transcatheter tricuspid valve interventions (TTVI) effectively reduce TR and improve quality of life (QoL) in earlier stages of the disease, their effect on reducing HF hospitalizations (HFH) and improving survival remains unclear.

Methods: TRIC-I-HF-DZHK24 is an investigator-initiated, prospective, randomized, open-label, multi-center strategy trial. Approximately 360 patients with severe TR and manifest right-sided HF will be enrolled. In contrast to previous trials, subjects with increased risk for HFH will be selected as facilitated by specific inclusion criteria: HFH in the previous year, or presence of cardio-renal syndrome, or evidence for cardio-hepatic syndrome. Subjects will be randomized 2:1 to TTVI and optimal medical therapy (OMT) or continuation of OMT alone. All CE-marked transcatheter repair devices including tricuspid transcatheter edge-to-edge repair (T-TEER) or transcatheter tricuspid annuloplasty can be used for TTVI. The participating 29 study sites are highly experienced in T-TEER. The primary outcome will be assessed at one year. First, a composite of all-cause mortality, HFH, and QoL improvement will be tested hierarchically. If positive, the combination of hard clinical endpoints including all-cause mortality and HFH will be tested. Patients will be followed for a total of 3 years. The safety outcome comprises complications of TTVI, life threatening bleeding and death.

Conclusions: The TRIC-I-HF-DZHK24 trial will define the role of TTVI in patients with severe TR and right-sided HF.

Study design and study aims:

TRIC-I-HF-DZHK24 (TRICuspid Intervention in Heart Failure) is an investigator-initiated, prospective, nationwide, multi-center, randomized, controlled, open label strategy trial in patients with TR and significant right-sided HF. The trial is conducted in 29 German high-volume heart valve centers and will assess whether OMT plus transcatheter tricuspid valve repair in HF patients with severe TR is more effective than OMT alone. TRIC-I-HF-DZHK24 will assess the strategy of TTVI using the individual optimal CE-marked repair device. The optimal TTVI device for the individual patient is determined by the local heart team. TTVI repair devices studied in the trial include devices for T-TEER and transcatheter tricuspid annuloplasty. Patients deemed for tricuspid valve replacement (orthotopic or heterotopic) are excluded from this trial. TRIC-I-HF-DZHK24 will specifically enroll patients with signs of manifest HF to test the impact of TTVI on mortality and HFH in a vulnerable patient cohort with an increased risk for decompensation of HF. Previous randomized-controlled trials enrolled patients without criteria for manifest right-sided HF and observed comparably low event rates for HFH and mortality.

TRIC-I-HF-DZHK24 is funded by the German Center for Cardiovascular Research (DZHK) and co-funded by the university hospital of Ludwig-Maximilians-University, Munich, Germany, and Edwards Lifesciences. An executive steering committee composed of a group of experienced cardiologists in the treatment of HF and TR supports the design and conduct of the study. The industry sponsor is not involved in trial design or conduct and has no direct access to data during the course of the trial. A Data and Safety Monitoring Board will periodically review trial progress and evaluate the accumulated study data for participant safety. An independent Clinical Event Committee will independently adjudicate all hospitalizations. The trial is supported by the Münchner Studienzentrum (MSZ, TUM School of Medicine and Health in Munich) serving as central research organization. The trial is conducted in accordance with Good Clinical Practice, and ethical principles consistent with the Declaration of Helsinki. TRIC-I-HF-DZHK24 has received approval from the responsible local ethics committees prior to inclusion of patients.

Intervention scheme and trial flow:

HF patients with underlying severe TR are screened for eligibility. If all inclusion criteria and none of the exclusion criteria are met and the subject is willing to participate, informed consent for study participation is obtained. Further baseline examination is performed. Randomization will be performed online using pre-defined randomization lists with a 2:1 allocation ratio in favor of the interventional arm. Randomization is stratified by study center and by TR grade. To assure balanced group sizes a block-wise randomization is applied. If a participant is randomized into the control arm, OMT is continued at discharge and follow-up dates are scheduled. In the event of randomization into the interventional arm, TTVI should be scheduled as soon as possible within 14 days after randomization.

Optimal medical therapy: The OMT for the individual patient is defined by the treating physicians and the heart teams of the respective study sites. OMT in patients with chronic right-sided HF includes diuretic therapy titrated to the optimal individual dosage. OMT stability is considered when adequate diuretic therapy at the maximum tolerated dosage is given for at least 30 days. In patients with HFrEF, optimal medical therapy includes guideline-directed medical therapy as recommended by the guidelines for treatment of chronic heart failure.

Transcatheter tricuspid valve intervention: TTVI should be scheduled as early as possible after randomization to the interventional arm to reduce the risk of adverse events before the intervention has been performed. The heart teams decide on the selection of the individual optimal repair device used for TTVI. For study participation, patients need to be treated with CE-marked devices. At the time of study initiation, CE-marked devices for TTVI included T-TEER by PASCAL®, PASCAL ACE® (both Edwards Lifesciences) or TriClip® (Abbott Cardiovascular) as well as direct transcatheter tricuspid annuloplasty by CARDIOBAND® (Edwards Lifesciences). Orthotopic or heterotopic tricuspid valve replacement devices are not studied in this trial. Experience of study sites was set to a minimum of 20 TTVI cases for the desired device before treatment within the trial.

Data Collection:

Baseline evaluation: Diagnostic procedures required for study screening are performed as standard of care. This includes TTE, TEE, right heart catheterization and assessment of the NYHA functional class. If a subject is determined as eligible study candidate and informed consent was obtained, several baseline examinations need to be performed. This baseline evaluation includes information on demographics and past medical history, electrocardiogram (ECG), physical assessment, medication, laboratory results, and assessment of standardized 6-minute walking distance test. QoL is assessed by the standardized Kansas City Cardiomyopathy Questionnaire (KCCQ). In collaboration with the DZHK, a predefined set of biosamples is taken and included into a central biobank, if the subject agrees and specific informed consent was obtained.

Echocardiographic image acquisition and central image analysis: A comprehensive TTE exam is required for screening and should be performed or repeated within one week (maximum of four weeks) before patient enrollment. All TTE images (screening TTE, discharge TTE in the event of randomization to the interventional arm, follow-up TTEs after 1 month, 1 year, 2 years and 3 years) are uploaded to a central image laboratory for further image assessment. Pseudonymization, image transfer, and image quality checks are performed by the respective core facilities at the DZHK (German Center for Cardiovascular Research). Additional TEE imaging is performed during the screening visit to evaluate the anatomy of the tricuspid valve and right heart. This anatomic information is required for clinical decision making and is used to assess eligibility for study participation.

Follow-up assessment: Follow-up evaluations are performed at 1 month (assessing procedural safety) and at 1 year, 2 years, and 3 years (assessing procedural efficacy) after randomization (control arm) or after discharge of TTVI procedure (interventional arm). All follow-up evaluations should be performed on-site and include assessment of the NYHA functional class, TTE, ECG, physical assessment, medication, laboratory results, 6-minute walking distance test, and KCCQ. Events of hospitalization are specifically enquired, if not reported earlier. Adverse events and severe adverse events are documented immediately throughout the course of the study. Follow-up TTEs are sent to the central image laboratory for independent analysis.

The following inclusion criteria were defined to assure generalizability of the population to be studied:

• Subject is symptomatic due to severe TR despite being on stable OMT for at least 30 days based on judgment of the local heart team.
• Subject is at intermediate or greater estimated risk of morbidity and mortality, defined as a) hospitalization for heart failure during the previous 12 months, or b) cardio-renal syndromea or c) cardio-hepatic syndrome
• New York Heart Association (NYHA) Functional Class II, III or IVa
• Femoral vein access and valve anatomy are determined to be feasible for interventional treatment (including sufficient quality of TTE and TEE imaging)
• Age ≥ 18 years at time of consent
• Subject must provide written informed consent prior to any trial related procedure

The following exclusion criteria were selected to define a representative study cohort:

• Presence of severe aortic, mitral or pulmonary valve disease OR surgical/interventional treatment at the aortic, mitral or pulmonary valves prior 60 days
• Right heart catheterization (mandatory) with systolic pulmonary artery pressure > 70 mmHg or substantial pre-capillary pulmonary hypertension (defined as mean pulmonary artery pressure (mPAP) >30 mmHg plus transpulmonary gradient (TPG) >17 mmHg or pulmonary vascular resistance (PVR) >5 wood units)
• Tricuspid valve stenosis (tricuspid mean gradient > 5 mmHg)
• Pacemaker or ICD leads that would prevent appropriate TTVT
• Prior tricuspid valve procedures or tricuspid valve leaflet anatomy that would interfere with appropriate TTVT (e.g. calcification, Ebstein anomaly, coaptation defect > 8mm for planned leaflet- and annuloplasty-based therapy)
• Chronic renal failure requiring dialysis
• Tricuspid valve anatomy not evaluable by TTE and TEE
• Myocardial infarction or cerebrovascular accident within prior 90 days
• Life expectancy of less than 12 months