The primary objective is to determine to what extent T-TEER on top of SOC reduce mortality and hospitalizations for heart failure, and improve QoL at 12 months, compared to SOC alone, in patients with severe symptomatic tricuspid valve regurgitation…
ID
Source
Brief title
Condition
- Cardiac valve disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary endpoint is defined as the hierarchical occurrence of all-cause
death, hospitalizations related to heart failure, and change in KCCQ at 12
months of follow-up.
Death and hospitalization due to heart failure are considered the most
significant clinical events that can occur due to TR and are therefore
incorporated into the primary endpoint. For the KCCQ-score a 5 point increase
is considered as clinically relevant.
Secondary outcome
Secundary endpoints (assessed at 12 months and at five years of follow-up):
- Composite endpoint of all-cause mortality, HFH, change in KCCQ-score
- Individual components of the primary outcome: all-cause mortality, HFH,
change in KCCQ score
- Freedom MAE (30 days and 12 months)
- Change in NYHA functional class
- Safety endpoints
- Success endpoints: procedural success and clinical success
- Urgent visit outpatient clinic for heart failure due to (impending)
decompensation with symptoms
- Change in EQ-5D-5L
- TR-reduction from at least severe to moderate or less
- Learning curve: procedural parameters (procedure time, number of devices),
procedural success (TR reduction), adverse events, clinical outcomes and
cost-effectiveness between the frist 8 and last 8 procedures per center.
- Cost-effectiveness: Quality Adjusted Life Years (QALY) and Incremental Cost
Effectiveness Ratios (ICERs), a formal cost-effectiveness- and budget impact
(BIA) analyses will be performed for TTVr. The iMCQ and iPCQ will be used to
calculate the in-hospital cost en costs outside the hospital, respectively.
Cost-effectiveness and acceptability curves will be made. The BIA comprises the
budgetary framework for health care (net-BKZ) perspective and the perspective
of the health insurer.
- Change in microcirculation
Background summary
Severe tricuspid regurgitation (TR) is a prevalent condition associated with a
poor quality of life (QoL), and an increased risk of heart failure and
mortality.
The prevalence of diagnosed moderate or severe TR in the community is estimated
at 0.55%, which would indicate 93,000 subjects in the Netherlands.
Only 2.6-10% of patients with symptomatic severe TR undergo surgical treatment,
reflecting the reservation to perform surgery, which is associated with high
peri-operative risk; the risks do not outweigh the potential benefits.
Moreover, there is no proven significant survival benefit of surgery when
compared to medical therapy alone.
The remaining patients depend on symptomatic medical therapy with mainly
diuretics. Despite SOC, a relevant group experiences symptoms of refractory
heart failure, leaving a relevant subgroup of patients with no treatment
options. This unmet clinical need prompted the development of less invasive,
Transcatheter Tricuspid Valve repair (TTVr) techniques.
Currently, several catheter-based techniques have been developed for treating
severe TR and are being evaluated for safety, efficacy and feasibility in
different studies and registries. The most experience regarding efficacy,
safety and feasbility has been gained with Tricuspid Transcatheter Edge-to-Edge
Repair (leaflet approximation), and is considered most most "mature". Moreover,
this technique is already frequently used for Mitral Transcatheter Edge-to-Edge
Repair (M-TEER). This technique aims to approximate the valve leaflets, with a
coaptation device, where there is insufficient leaflet coaption in a minimally
invasive manner, thereby reducing the valve leakage.
Currently, there are two devices with a CE-mark for T-TEER: the TriClip TTVr
system (Abbott vascular) and the PASCAL TTVr system (Edwards Lifesciences).
Only small single-arm studies for T-TEER have been conducted. In the largest
single-arm TRILUMINATE the 1-year mortality was low, 7.1%, and there was a
reduction in heart failure hospitalization of 40% compared to baseline and a
significant improvement in QoL. Moreover, patients with severe TR experience a
poor QoL with a 1-year mortality/hospitalization of 41%, eight times higher
than expected for age and sex.
T-TEER is considered breakthrough technology by the professional cardiology
associations worldwide and also the Dutch Society of Cardiology. However, data
from pivotal randomized controlled trials and data from the Netherlands are
missing.
This study will provide the data to evaluate the safety, efficacy and
cost-effectiveness of T-TEER in patients with severe symptomatic TR.
The principal hypothesis is that for patients with a symptomatic severe
tricuspid valve regurgitation, treatment with a T-TEER on top of SOC is
superior to SOC alone for the prevention of death, heart failure
hospitalizations and improvement in QoL.
Study objective
The primary objective is to determine to what extent T-TEER on top of SOC
reduce mortality and hospitalizations for heart failure, and improve QoL at 12
months, compared to SOC alone, in patients with severe symptomatic tricuspid
valve regurgitation
The secondary objectives include the assessment of the individual components of
the primary outcome measure, cost-effectiveness, exercise capacity, functional
status (NYHA class), and echocardiographic parameters (quantitative and
qualitative).
Study design
The TRACE-NL is a national multicenter randomized controlled superiority trial
in the Netherlands with a 2:1 inclusion favoring the intervention arm. The
trial is preceded by a pre-trial phase to assess the learning curve. Both are
explained below:
1. Pre-trial phase (learning curve): To obtain experience, each participating
center (n=7) will perform 8 T-TEER procedures before including patients into
the RCT (n=56). Sufficient training plays a major role in an interventional
study. Therefore, the study includes a pre-trial phase, allowing each
implanting center to obtain experience by performing 8 cases. We expect that
the number of 8 procedures allows for sufficient training with the 2 different
devices for the following reasons:
- The systems used for T-TEER are very similar to those employed for M-TEER
(MitraClip or PASCAL), with only relative limited procedural and technical
differences.
- The participating heart centers have extensive experience with these devices,
treating hundreds of patients (with mitral valve regurgitation) per center in
the last decade.
- The main reason why T-TEER is more complex than mitral valve repair is the
periprocedural imaging (echocardiography) of the tricuspid valve anatomy. The
interventional imaging cardiologist can be trained in imaging of the tricuspid
valve during diagnostic transesophageal echo-investigations, the 8 pre-trial
procedures and during mitral valve procedures before the start of a T-TEER
program
- Each case will be proctored by an experienced device expert from the company
(Abbott Vascular or Edwards Lifesciences) providing the devices.
2. RCT: we chose to perform a national multicenter open label superiority RCT
(n=150) with a 2:1 inclusion rate favoring the intervention arm (n=100).
A randomized study makes guarantees that at the start of the study both groups
have the same probability reaching the main outcome. When all other factors
remain equal during the study, the difference in outcome can be attributed to
the intervention.
A total of 7 implanting centers will participate in the trial: UMC Groningen,
Amsterdam UMC, Erasmus MC, Leiden UMC, Maastricht UMC, Catharina Hospital en
St. Antonius Hospital. Other heart centers will be participating in the study,
screening the patients and referring to an implanting center.
Each participating center will receive a seperate randomization set. This will
serve the purpose that each participating center will have an equal number of
patients in both treatment arms. To complete the study in a timely manner there
will be a competative inclusion without a maximum number of patients per
center.
Intervention
T-TEER on top of SOC
The procedure attempts to repair coaptation (edge-to-edge) of the leafletes of
the tricuspid valve in a minimal invasive manner. All edge-to-edge repair
systems for TV are allowed in the study, as long as the device has a CE mark
and has demonstrated safety and efficacy. There are two edge-to-edge T-TEER
devices available: TriClip (Abbott Vascular) and PASCAL (Edwards Lifesciences).
Both systems received a CE mark for treating TR in a minimally invasive manner.
These CE marks are in accordance with the intentional use in the TRACE-NL
trial.
Study burden and risks
Baseline:
Prior to the inclusion all participants will receive a transthoracic and 3D
transesophageal echocardiography (TTE ad 3DTEE), to determine the TR grade, and
blood samples will be taken (liver & kidney function etc., at least <2 months
before the procedure. A CT scan is optional (overall cardiac screening, 6 mSv)
and a right-heart catheterization (4.5 mSv) for invasive right-sided cardiac
and pulmonary arterial pressure measurements, since these are important
selection (inclusion/exclusion) criteria. Last, all patients will be asked to
complete a 6 minute walk test (6MWT) and to complete the EQ-5D-5L, KCCQ, iMCQ
and iPCQ questionnaires at baseline. These tests require two visits to the
hospital.
Interventional arm:
All patients in the device arm will undergo T-TEER, under general anaesthesia,
with implantation of a CE-approved device (dedicated TV system) for
percutaneous transfemoral transcatheter leaflet approximation (T-TEER). The
trial will be preceded by a pre-trial phase at which each participating center
will perform eight procedures to gain experience with the devices. The device
will be implanted under three-dimensional (3D) transesophageal echo (3DTEE)
guidance (by an interventional imaging cardiologist) and fluoroscopy for
adequate positioning of the device, according to the device specific
instructions and recommendations. The procedure will be performed by a team of
two interventional cardiologist, an imaging cardiologist, and an
anesthesiologist. A proctor affiliated with the device company and with
in-depth knowledge of the device will attend the procedure.
Anticoagulants will be temporarily discontinued and resumed 24h after
implantation. After the procedure, all T-TEER patients will receive dual
antithrombotic therapy for at least three months, after which it is narrowed
down to single antithrombotic therapy until at least one year after the
procedure. After implantation patients will be shortly monitored for bleeding
and rhythm control, which generally means a one night stay in the hospital.
Procedure-related risk:
The procedure itself will include the following process steps with associated
risks and subsequent measures:
1. Screening/heart team meeting: 3D transesophegeal echocardiography and CT
scan (no relevant risk) and right heart catheterization for invasive pressure
measurement (low risk)
2. Intake/hospital admission: informed consent (IC), history, physical
examination and laboratory check to assess fitness for procedure (no relevant
risk).
3. Start procedure: time out to check patient identification, allergies,
medication, procedural details, and necessary equipment.
4. Procedure: anaesthesia, access site complications (risk reduction with echo
guided puncture, heparinization after puncture (consider antagonizing heparin
after procedure), pressure bandage after, in case of bleeding: follow sheath
removal protocol. Chordae rupture (valvular injury) due to device manipulation:
consider repair with device, bail out surgery despite high surgical risk and
prior obtained informed consent. Hemodynamic problems: close hemodynamic
monitoring and medical/mechanical management according to good clinical
practice. Thromboembolic complications: adequate heparinization guided by
activated clotting time (ACT). Infection: prophylactic antibiotic treatment
according to protocol. Respiratory problems (mainly with pulmonary disease):
reserving ICU bed.
Overall, procedural risk is reduced by adequate training/certification of the
whole team, and guidance of an experienced proctor of the device company.
5. Transfer to recovery room: complications such as bleeding, hemodynamic
problems: close monitoring of the patient (cardiac anaesthesiologist).
6. Aftercare on the ward: late bleeding complications (periodic groin checks by
nurse and physician according to protocol). Alarm system for timely
notification of staff.
7. Discharge: physical examination and laboratory check before discharge to
exclude complications.
Accurate periprocedural TV 3DTEE imaging of sufficient quality is crucial for
accurate placement of the device(s). An imaging cardiologist with experience in
the field and qualified for the procedure (with pre-trial phase and M-TEER)
will assist the implantation to enable successful repair. Inadequate placement
of the device can result in overcorrection of the regurgitant orifice area with
the ultimate consequence of tricuspid valve stenosis. However, this is
avoidable by closely monitoring the trans-tricuspid valve gradient and
tricuspid valve area during the procedure and before definite deployment of the
device.
Furthermore, inadequate grasping of the leaflets with subsequent single leaflet
device attachment (SLDA) may occur. However, this is often without clinical
consequence or urgent need for re-intervention, except technical failure of the
procedure. Careful selection of patients may help prevent this outcome;
predictors for increased risk of SLDA and procedural failure are leaflet
tethering and a large coaptation gap. The use of the device with larger
grasping arms (wide version) may also reduce the risk of SLDA.
Control arm:
The patients in the control arm will continue SOC (mainly diuretics) pursuing
good clinical practice (ESC 2021). There is no additional therapeutical
clinical burden for patients in the control group.
Follow-up:
For the intervention group TR grade will be assessed at 30 days, 6 months and
12 months of follow-up through TTE. TR grade of the control group is only
assessed at 6 months and 12 monhts of follow-up. Clinical testing at 12 months
of follow-up is part of the regular annual check (standard of care). At 30
days, 6 months and 12 months a blood test and ECG of all patients will be
obtained.
Moreover, all patients will be asked to complete the 6MWT at 30 days and 12
months, and the EQ-5D-5L, KCCQ, iMCQ and iPCQ questionnaires after 30 days, 6
months and 12 months of follow-up, requiring a total of three visits to the
hospital.
After 12 months an annual follow-up moment with clinical examination, TTE, ECG,
blood test, 6MWT and questionnaires is scheduled.
Clinical endpoints mortality, HHF, NYHA and major adverse event (MAE) will be
obtained from collected data and do not require patients to visit the hospital.
MAE and TR grade will also be assessed at 30 days of follow-up and 6 months of
follow-up and provides the DSMB with information regarding early safety
outcomes and provides data regarding technical success, respectively.
Justification:
The 1-year mortality rate for patients with severe TR is ranging from 17.8% to
42%%, due to heterogeneity in the TR population
The risks and benefits associated with T-TEER is based on previous small
single-arm studies evaluating the safety and efficacy of the procedure. The
largest clinical trial, TRILUMINATE (n=85), evaluating TriClip and reported a
1-year mortality and MACE rate of 7.1% for both and a hospitalization rate of
15% (40% reduction) for T-TEER. Moreover, the TRILUMINATE reported an increase
of 20 points (SD 21) after T-TEER.
Other relatively small single-arm studies reported a low mortality and
complication rate for T-TEER and good safety to perform the procedure.
Given the reported low adverse event rates and almost no necessity for surgical
bail out in early outcomes of previous studies, we expect the procedure will be
safe
Considering the high mortality rates in TR patients, the fact there is no
effective treatment option to adequately address TR and the promising early
outcomes, we think that T-TEER is a safe and effective treatment option for
selected patients with severe symptomatic TR, otherwise left untreated.
Koekoekslaan 1
Nieuwegein 3435 CM
NL
Koekoekslaan 1
Nieuwegein 3435 CM
NL
Listed location countries
Age
Inclusion criteria
1. The patient is symptomatic (NYHA Functional Class II, III or ambulatory
class IV) despite Standard Of Care (SOC). The Central Screening Committee (CSC)
will assess whether the patient is receiving Standord Of Care (SOC), which for
TR is limited to symptomatic treatment with diuretics. The CSC will also ensure
that in case of the presence of atrial fibrillation, left sided heart valve
disease (not requiring intervention) or coronary artery disease, these
conditions are treated adequately with medication and/or intervention/device
therapy.
2. The patient suffers from >= grade 3 isolated TR as determined by the
assessment of a qualifying TTE and 3DTEE and confirmed by the CSC, according to
PCR Tricuspid Focus Group consensus document (in press). Note: If cardiac
procedure(s) occur after eligibility was determined, TR grade will be
re-assessed 30 days after the procedure.
3. The cardiac surgeon of the sites* local heart team concurs that the patient
is at high estimated risk for mortality or morbidity with TV surgery.
4. The patient is >=18 years of age at time of consent.
5. The patient must provide written IC prior to any trial related procedure.
Exclusion criteria
1. Systolic pulmonary artery pressure (sPAP) > 70 mmHg or fixed pre-capillary
pulmonary hypertension as assessed by RHC. Severe uncontrolled hypertension
Systolic Blood Pressure (SBP) >= 180 mmHg and/or Diastolic Blood Pressure (DBP)
>= 110 mmHg.
2. Any condition that would interfere with a TTVr procedure, such as prior
tricuspid valve repair or tricuspid valve leaflet anatomy which may preclude
device implantation (e.g. calcification in grasping area, a severe coaptation
defect of the tricuspid leaflets (non-clippable), pacemaker or Implantable
Cardioverter Defibrillator (ICD) leads that would prevent appropriate placement
or visualization of TTVr devices, Ebstein Anomaly (normal annulus position, but
valve leaflets attached to walls and septum of RV), tricuspid valve anatomy non
evaluable by echo, known allergy or hypersensitivity to dual antiplatelet
therapy AND anticoagulant therapy or to device materials, femoral venous mass
or thrombus or vegetation.
3. Indication for left-sided (e.g. severe aortic stenosis, severe mitral
regurgitation) or pulmonary valve correction within prior 60 days. Note:
concomitant mitral valve disease (e.g. mitral regurgitation) will be treated
first and patients will be reassessed for the trial after 60 days.
4. Tricuspid valve stenosis - Defined as a tricuspid valve orifice of <= 1.0 cm2
and/or mean gradient >=5 mmHg.
5. Left Ventricular Ejection Fraction (LVEF) <=20%
6. Active endocarditis, active rheumatic heart disease, other ongoing infection
requiring antibiotic therapy (enrolment possible 30 days after discontinuation
of antibiotics with no active infection) or leaflets degenerated from
rheumatic disease (i.e. noncompliant, perforated)
7. Myocardial infarction known unstable angina, or percutaneous coronary
intervention within prior 30 days.
8. Hemodynamic instability defined as systemic systolic pressure <90 mmHg with
or without afterload reduction, cardiogenic shock or the need for inotropic
support or hemodynamic support device (e.g. intra-aortic balloon pump).
9. Cerebrovascular Accident (CVA) within prior 90 days
10. Chronic dialysis
11. Bleeding disorders or hypercoagulable state, inability to use dual
antithrombotic therapy due to contraindication, allergy or hypersensitivity
12. Active peptic ulcer or active gastrointestinal (GI) bleeding
13. Life expectancy of less than 12 months
14. Subject currently participating in another clinical trial (not yet
completed primary endpoint) or in another clinical investigation for valvular
heart disease.
15. Pregnant or nursing patients or those who plan pregnancy during the course
of the trial. Women of childbearing age are required to have a negative
pregnancy test 7 days prior to baseline visit. Women of childbearing age should
be instructed to use safe contraception or have a sterilized regular
partner.
16. Presence of anatomic or comorbid conditions, or other medical, social or
psychological conditions that, in the eye of the investigator, limits the
subject*s ability to participate in the clinical investigation or comply with
follow-up requirements, or impact the scientific soundness of the investigation
results.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| CCMO | NL81645.100.22 |