Primary ObjectiveThe goal of the study is to evaluate hemostasis (i.e. coagulation activation, platelet reactivity, overall thrombus formation and fibrinolysis) following LAAO in a longitudinal design for hypothesis-generating purposes. Several…
ID
Source
Brief title
Condition
- Cardiac arrhythmias
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
This study will capture the following (exploratory) primary endpoints:
• Coagulation activation: TAT (thrombin-antitrombin III complex), prothrombin
1+2, and factor XIIa
• Platelet reactivity as measured with multiple platelet function tests:
Multiplate and Pselectin
• Overall thrombus formation and clot lysis assessment using T-TAS (total
thrombus formation analysis system), TEG (thromboelastography), TGT (thrombin
generation test, fibrinopeptide A+B, fibrinogen, vWF (von Willebrand factor),
PT, APTT
• Fibrinolysis: d-dimer and plasmin inhibitor (i.e. alfa-2-antiplasmin)
• CYP2C19 polymorphism: carriers of one of the loss-of-function *2 and *3
alleles will be stratified as intermediate metabolizers, patients with 2
loss-of-function alleles will be stratified as poor metabolizers
Platelet function and thrombin generation testing will be performed in blood
samples collected before the procedure, directly after LAAO, and after 14 days,
3 months and 6 months. The goal of the study is to evaluate platelet inhibition
and thrombin generation after LAAO with regard to clinical endpoints and
patient characteristics such as CYP2C19 genotype and antithrombotic regimen.
Procedural characteristics such as type of device and echographic parameters
will also be taken into account.
Secondary outcome
In addition to coagulation endpoints and CYP2C19 genotype, secondary clinically
oriented endpoints during 12-month follow-up will include:
• The composite of stroke (ischemic or hemorrhagic), TIA, systemic embolism and
cardiovascular death.
• Ischemic stroke
• Disabling stroke
• Separate ischemic or hemorrhagic stroke, mortality (both cardiovascular and
all-cause), TIA, systemic embolism
• Major bleeding event rate (according to BARC criteria), both procedural up to
7 days, as well as total
• Minor bleeding event rate, both procedural up to 7 days, as well as total
• Procedural efficacy of LAAO up to 30 days
• Adverse events rate at 30 days, and from 30 days until end of follow up
• LAA sealing efficacy according to manufacturer*s definitions at all the
predefined LAA CT/TEE imaging moments
• Device related thrombus event rate
• Quality of life assessments at regular basis in follow up (SF-12, HADS,
EQ5D5L)
Background summary
Atrial fibrillation (AF) is prevalent in the Netherlands in around 300.000
patients. Cardio-embolic AF related stroke is assumed in around 7500 patients
annually. Stroke risk for non-valvular AF is estimated with the CHA2DS2-VASc
score. When patients have no risk factors, no oral anticoagulation (OAC) is
recommended with a Class III, loe B. With 1 risk factor in men and 2 in women,
anticoagulation should be considered (class IIA, loe-B). When the CHA2DS2-VASc
score is 2 or greater in men (3 or greater in women) anticoagulation is
recommended in all with a Class I, loe-A, preferably with a NOAC (class I,
loe-A). However, anticoagulant therapy is undesirable in a subgroup of patients
because of a high risk of (recurrent) bleeding.
Mechanical occlusion of the Left Atrial Appendage (LAAO), which is the main
source of cardio-embolism, has emerged strongly in the last decades as an
alternative to prevention of ischemic stroke. Percutaneous LAAO using the
Watchman device has been proven non-inferior to vitamin K antagonists regarding
thrombo-embolic prevention. Moreover, the possibility of cessation of OAC over
time after LAAO has a positive effect on major bleeding rates. In post hoc
analyses of PROTECT-AF, PREVAIL, and the CAP registries, it was observed that
after discontinuation of warfarin at 45 days, bleeding rates in the Watchman
arm were only half of those in the warfarin arm, and dropped another 50% after
discontinuation of DAPT. For AMPLATZER amulet and other LAAO devices there are
no published RCT compared to either VKA or NOAC. The EWOLUTION all-comers
registry data in over 1000 AF pts (73% unable to use (N)OAC, CHA2DS2-VASc 4.7)
after WATCHMAN LAAO showed stroke and bleeding rates 80% and 46% lower than
expected compared to historical data. In 2 similar AMPLATZER-AMULET LAAO
registries of >1000 AF patients, stroke and bleeding rates were 50-60% lower.
Both in the 2020 ESC and the 2019 AHA/ACC guidelines, LAAO has received a Class
IIb, loe-B recommendation for stroke prevention in patients with AF that have
non-reversible contra-indications for long-term anticoagulation. Randomized
controlled trials comparing LAAO to direct oral anticoagulants (DOACs) are
currently running. LAAO may also be a suitable option based on patient
preference or AF-related ischemic events under OAC.
Administering OAC after LAAO procedure in the selection of patients ineligible
for OAC is undesirable for obvious reasons. There is still no consensus on
optical medical treatment after LAAO, despite multiple observational studies.
In the Netherlands, dual antiplatelet therapy (DAPT) with acetylsalicylic acid
(ASA) and clopidogrel (CLOP) has emerged as the standard of care treatment
directly after LAAO. However, this strategy is only based on expert opinion and
no randomized controlled trials have been conducted regarding optimal medical
approach to anticoagulation and platelet inhibition after LAAO.
Moreover, device-related thrombus (DRT) remains prevalent among patients
undergoing LAAO. In the randomized Watchman device arms of the PROTECT-AF and
PREVAIL combined with CAP-I and CAP-II registries, DRT occurred in 3.7% of 1739
patients. Similar numbers were found in the European EWOLUTION trial (2.5%)
and the Asian-Pacific WASP registry (2.5%). For the Amplatzer device, similar
DRT rates were found in the ACP registry, showing a DRT rate of 2.7%. In both
devices an association of DRT and ischemic stroke, TIA, or systemic embolism
have been reported. In a registry by Fauchier et al., risk factors for thrombus
formation on the device included older age and previous ischemic stroke, while
DAPT and OAC at discharge showed significantly lowered hazard ratios for DRT
(0.10 (0.01-0.76) and 0.26 (0.09-0.77), respectively).Furthermore, suboptimal
LAA occlusion, lower left ventricular ejection fraction (LVEF), larger LA size,
greater spontaneous echocardiogram contrast (SEC) and lower peak LAA emptying
velocity have been mentioned as possible risk factors.
The mechanism behind DRT remains uncertain. In the EWOLUTION registry, 34 of
835 patients with LAA imaging showed DRT. In these patients, no clear relation
could be found regarding type of anticoagulation regimen. Both platelet
activation and coagulation cascade could play a role in the pathogenesis of
DRT. Rodés-Cabau et al. showed elevated biomarkers for coagulation activation 7
days after device implantation, without significant elevation of biomarkers for
platelet activation. This suggests the possible importance of coagulation
cascade above platelet activation in DRT.
Clopidogrel resistance might also play a role in observed DRT rates after LAAO.
The efficacy of a genotype-based approach taking this phenomenon into account
in primary percutaneous intervention in myocardial infarction has recently been
described by Claassens et al. In this study, genetic clopidogrel resistance
testing was performed in 1240 patients, of which 31% were intermediate to poor
metabolizers based on genetic testing. A genotype-based approach to
antiplatelet therapy was non-inferior with regard to thrombotic events and
resulted in a lower incidence of bleeding. After LAAO, less data regarding
clopidogrel resistance is available. In a case series by Ketter et al., 4/46
LAAO patients developed DRT. Of these DRT patients, 3 (75%) showed resistance
to clopidogrel after platelet function testing. This suggests possible under
treatment of a proportion of patients receiving clopidogrel.
Multiple tests have been developed regarding quantification of hemostasis.
Prothrombin 1+2 and thrombin-antithrombin III complex (TAT) have proven to be
valuable markers for coagulation activation.Platelet reactivity and aggregation
can be assessed using flowcytometry for measuring the percentage platelet bound
P-selectin expression. Whole blood multiple electrod aggregometry (MEA) is
useful for measuring the magnitude of platelet reactivity by several agonist
such as Adenosine Diphosphate- and Arachidonic Acid-induced platelet
aggregation (ADP and AA), yielding information about the effectiveness of
P2Y12-inhibitors (e.g. clopidogrel, ticagrelor) and acetylsalicylic acid (ASA)
and the risk of ischemic events. Furthermore, thromboelastography (TEG), total
thrombus formation analysis (T-TAS) and thrombin generation test (TGT) can help
clarify several hemostatic processes.
The aim of this study is to analyze changes in coagulation activation and
platelet reactivity after LAAO in several subgroups in a hypothesis-generating
manner.
Study objective
Primary Objective
The goal of the study is to evaluate hemostasis (i.e. coagulation activation,
platelet reactivity, overall thrombus formation and fibrinolysis) following
LAAO in a longitudinal design for hypothesis-generating purposes. Several
factors will be taken into account, such as type of implantation device,
CYP2C19 polymorphism and antithrombotic regimen.
Secondary Objective(s
In addition to coagulation endpoints, secondary clinically oriented endpoints
during 12-month follow-up will include:
* Minor and major bleeding
* Device-related thrombus incidence
* Stroke, TIA, and systemic embolism
Study design
We propose a prospective observational study to identify the state of
coagulation and platelet activity in patients after LAAO. Subjects may be on
dual antiplatelet therapy (DAPT), single antiplatelet therapy (SAPT), oral
anticoagulation (OAC) or use no anti-thrombotic agents at all. This will be at
the discretion of the treating physician. Blood samples will be taken prior to
LAAO, shortly after LAAO, and 14 days, 3 months and 6 months after the
procedure. Genotype testing for CYP2C19 will be performed in all patients at
baseline to asses prevalence of clopidogrel *non-responders* in the LAAO
population. Implantations will be mainly be performed using the Watchman (FLX)
device or AMULET device, but other devices are emerging and not excluded from
this study. Subjects will receive quality of life questionnaires at baseline, 3
months, 6 months and 12 months after the procedure. Study follow-up will take
place during 1 year per patient, followed by follow-up conform current standard
of care. The total study duration is estimated to be 4 years.
We propose a prospective observational study to identify the state of
coagulation and platelet activity in patients after LAAO. Subjects may use a
wide variation of antithrombotic medication, including but not limited to dual
antiplatelet therapy (DAPT), single antiplatelet therapy (SAPT), oral
anticoagulation (OAC) or no anti-thrombotic agents at all. This will be at the
discretion of the treating physician. When the medication of choice differs
from the current standard of care after LAAO (ascal+clopidogrel), the reason
for deviation will be assessed. Blood samples will be taken prior to LAAO,
shortly after LAAO, and 14 days, 3 months and 6 months after the procedure.
Genotype testing for CYP2C19 will be performed in all patients at baseline to
asses prevalence of clopidogrel *non-responders* in the LAAO population.
Implantations will be mainly be performed using the Watchman (FLX) device or
AMULET device, but other devices are emerging and not excluded from this study.
Subjects will receive quality of life questionnaires at baseline and 3 months,
6 months and 12 months after the procedure.Study follow-up will take place
during 1 year per patient, followed by follow-up conform current standard of
care. The total study duration is estimated to be 4 years.
Study burden and risks
Study-related risks involve multiple venepunctures for diagnostic testing in an
observational study-design. Potential risks of venepuncture involve
bleeding/hematoma formation, infection, nerve damage and syncope.
Koekoekslaan 1
Nieuwegein 3435 CM
NL
Koekoekslaan 1
Nieuwegein 3435 CM
NL
Listed location countries
Age
Inclusion criteria
- The subject is aged 18 years or older
- The subject is accepted/scheduled for left atrial appendage closure
- The subject has a CHA*DS*-VASc Score >=2 (male) or >=3 (female)
- The subject or legal representative is able to understand and is willing to
provide written informed consent to participate in the trial.
Exclusion criteria
- Unable or unwilling to return for required follow-up visits and examinations
- Mechanical heart valves or valvular disease requiring surgery or
interventional procedure
- Ongoing major bleeding or complicated or recent (<72hours) major surgery
- Known large oesophageal varices or decompensated liver disease (unless a
documented positive opinion of a gastro-enterologist)
- Severe thrombocytopenia (<50,000/ml)
- High likelihood of being unavailable for follow-up or psycho-social condition
making study participation impractical.
- Woman with child bearing potential who do not use an efficient method of
contraception.
- Positive serum or urine pregnancy test for woman with child bearing potential
- Pregnancy or within 48 hours post-partum
- unsuitable LAA anatomy for closure or thrombus in the LAA at the time of
procedure
- contraindications or unfavourable conditions to perform cardiac
catheterization or TEE
- atrial septal malformations, atrial septal defect or a high-risk patient
foramen ovale that may cause thrombo-embolic events
- atrial septal defect repair or closure device or a patent foramen ovale
repair or any other anatomical condition as this may preclude an LAAO procedure
- Mitral valve regurgitation grade 3 or more
- Aortic valve stenosis (AVA<1.0 cm2 or Pmax>50 mmHg) or regurgitation grade 3
or more
- Planned CEA for significant carotid artery disease
- Life expectancy of less than 1 year
Design
Recruitment
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 | NL75530.100.20 |