Clinical trial NCT04676880: Left Atrial Appendage Occlusion for AF Patients Unable to Use Oral Anticoagulation Therapy
Official title: Comparing Effectiveness and Safety of Left Atrial Appendage Occlusion for Non-valvular Atrial Fibrillation Patients at High Stroke Risk Unable to Use Oral Anticoagulation Therapy
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: NA
Conditions: Atrial Fibrillation
Anticoagulants and Bleeding Disorders
Keywords: Atrial fibrillation
Anticoagulation
Left atrial appendage occlusion
Left atrial appendage
Occluder
Stroke
Lead sponsor: R&D Cardiologie
Sponsor class: OTHER
Collaborators: name: ZonMw: The Netherlands Organisation for Health Research and Development
First posted: 2020-12-21
Enrollment: 609
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: This trial is set-up as an open-label, national multicentre, superiority randomized controlled trial where patients will be randomized in a 2:1 fashion to the device arm or the usual care arm.
Primary purpose: PREVENTION

Brief summary: Up to 5% of Atrial Fibrillation (AF) patients may have or develop contraindications to use oral anticoagulation (OAC). Randomized controlled trial (RCT) data suggest that Left Atrial Appendage Occlusion (LAAO) may provide a non-inferior alternative for cardioembolic stroke protection in patients tolerant to OAC. However, RCT data for LAAO is lacking in patients with contra-indications to OAC using antiplatelet (APT) or no therapy as usual care. The hypothesis underlying this trial is to demonstrate that LAAO is superior to usual care for the prevention of stroke.

Detailed description: Stroke risk for non-valvular AF is estimated with the CHA2DS2-VASc score. When patients have no risk factors, no anticoagulation 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). Platelet inhibitor monotherapy is prohibited with a Class III, loe-A. Patients that have or develop a long-term contra-indication for oral anticoagulation have no class I guideline accepted alternative. Instead it is recommended to modify conditions or interrupt anticoagulants (Class IIB, loe-B). Resumption of oral anticoagulants should be guided by a multidisciplinary team that weighs the risks and benefits of such a course of action (class IIA, loe-C). In patients after an intracranial haemorrhage (ICH), it is recommended to initiate or resume anticoagulation after 2-4 weeks (class IIA, loeC) choosing an agent with low intracranial bleeding risk.

There is insufficient data to support the choice of anticoagulant and no evidence at all for avoiding stroke prevention altogether, which has led to wide variations in restarting oral anticoagulation often after several months of abstinence. Over 60% does not even resume therapy after anticoagulation-associated ICH.

As the LAA is the dominant source for cardioembolic stroke, mechanical percutaneous endocardial occlusion procedures have been developed. The WATCHMAN and AMULET (both FDA- and CE approval) are the most used but others are emerging. Basically, a cardiac catheterization is performed from the Femoral Vein, passing a 14F catheter through the Inferior Caval Vein and the interatrial septum to the left atrium. The delivery system is then positioned in the LAA ostium, and the device is deployed blocking the entrance and eliminating the LAA from the circulation. The implant procedure is usually guided by trans-esophageal echo imaging to assess device size and determine optimal position before it can be released. Adequate closure is achieved in 99% of patients nowadays, with a low and manageable procedural risk of 2.5%. To avoid device-related thrombus during reendothelialization patients are treated with dual antithrombotic agents, aspirin and clopidogrel in the first 3 months, which is narrowed down to aspirin until 1 year after which time it may be discontinued.

The 5-year follow up of PROTECT-AF and PREVAIL showed that LAAO was non-inferior to vitamin K antagonist (VKA) for the primary endpoint of stroke/ TIA/systemic embolism/death (HR 0.82, p-value 0.3), while VKA-patients had significantly more major bleeding events after the implant (HR 0.48, p=0.0003). WATCHMAN LAAO is CE and FDA approved and worldwide almost 100.000 WATCHMAN implantations have now been performed. Currently no RCT outcome data are available comparing WATCHMAN LAAO to any type of NOAC. For 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) 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.

The COMPARE-LAAO trial studies the effectiveness and safety of LAAO as an alternative means for stroke prevention, to establish whether outcomes in The Netherlands are comparable to literature. In the setting of a randomized controlled trial, LAA will be compared to usual care of anti-platelet therapy or nothing based on individual physician's assessment. Cost-effectiveness will be studied by comparing the additional cost of the procedure to cost of usual care, and the differences in cost between both arms for complications due to stroke and other embolism.

Eligibility criteria: Inclusion Criteria:

1. Documented non-valvular AF (paroxysmal or non-paroxysmal) and
2. CHA2DS2-VASc score of 2 or more and
3. Unsuitable for long-term use of oral anticoagulation as determined by the referring physician team as well as the multidisciplinary team in the study hospital and
4. Suitable for dual APT for at least 3 months and single APT from 3 until at most 12 months and
5. At least 18 years of age, and willing and able to provide informed consent and adhere to study rules and regulations and follow-up

The decision of suitability for LAAO should be made by a multidisciplinary team consisting of at least an echocardiographist, an implanting cardiologist, and a cardiac surgeon. The decision of unsuitability for oral anticoagulation by the referring and implanting centers will be clearly and extensively documented in the study charts. This should include the support of physicians other than the referring and implanting cardiologist. These physicians should be specialists in the field where the contra-indication arises such as neurology, gastro-enterology, internal medicine, urology, or other specialties. In many cases the contra-indication may be due to (repeated) major bleeding.Bleeding will be classified according to the BARC criteria as major with a score of 3 or more. The risk of recurrent bleeding should be established by a multidisciplinary team, as well as the decision that the risk of bleeding recurrence outweighs the benefit of restarting oral anticoagulation, which will be documented in the charts. Alternative reasons not to use anticoagulation should be major and irreversible. These may be highly variable and may include but are not limited to occupational or life-style hazards, drug side-effects, ineffectiveness, intolerance, renal or liver failure, falling hazards, vascular problems, cerebral amyloid deposition, and coagulation disorders.

Exclusion Criteria:

1. Any invasive cardiac procedure within 30 days prior to randomization and 90 days after LAAO that would interfere with the study follow-up and medication
2. Unsuitable LAA anatomy for closure or thrombus in the LAA at the time of procedure
3. Contraindications or unfavourable conditions to perform cardiac catheterization or TEE
4. Atrial septal malformations, atrial septal defect or a high-risk patient foramen ovale that may cause thrombo-embolic events
5. 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
6. LVEF\<31% and/or heart failure NYHA 3-4
7. Mitral valve regurgitation grade 3 or more
8. Mitral stenosis as this makes AF by definition valvular in nature
9. Aortic valve stenosis (AVA\<1.0 cm2 or Pmax\>50 mmHg) or regurgitation grade 3 or more
10. Planned cardiac surgery for any reason within 3 months
11. Stroke within the 3 months prior to inclusion, if not yet clinically stable, and/or without adequate diagnostic or prognostic evaluation, and/or in need of other interventions NL75209.100.20 COMPARE-LAAO Study protocol version 1.4 September 2020
12. Planned CEA for significant carotid artery disease
13. Major bleeding (BARC criteria\>type 2) within 1 month prior to inclusion or longer if it has not been resolved yet
14. Compelling medical reason to use VKA or NOAC (e.g. mechanical heart valve, pulmonary embolism, ventricular aneurysm)
15. Major contraindications for using aspirin or clopidogrel
16. (planned) pregnancy
17. Participation in any other clinical trial that interferes with the current study
18. Life expectancy of less than 1 year

Primary outcomes:
measure: Time to first occurrence of ischemic or hemorrhagic or undetermined stroke.
timeFrame: Minimal follow up is 1 year, maximum follow up +/- 5 years
measure: Time to first occurrence of the composite of stroke (ischemic or hemorrhagic or undetermined), TIA and systemic embolism.
timeFrame: Minimal follow up is 1 year, maximum follow up +/- 5 years
measure: Incidence of procedural complications
timeFrame: Procedure up to 30 days
Secondary outcomes:
measure: The composite event rate of stroke (ischemic or hemorrhagic), TIA, systemic embolism and cardiovascular death.
timeFrame: Through study completion, an average of 3 years
measure: Ischemic stroke event rate
timeFrame: Through study completion, an average of 3 years
measure: Disabling stroke event rate
timeFrame: Through study completion, an average of 3 years
measure: Hemorrhagic stroke event rate
timeFrame: Through study completion, an average of 3 years
measure: TIA event rate
timeFrame: Through study completion, an average of 3 years
measure: Systemic embolism (SE) event rate
timeFrame: Through study completion, an average of 3 years
measure: Mortality (cardiovascular) event rate
timeFrame: Through study completion, an average of 3 years
measure: Mortality (all-cause) event rate
timeFrame: Through study completion, an average of 3 years
measure: Major bleeding event rate (according to BARC criteria)
timeFrame: both procedural up to 7 days, as well as total (through study completion, an average of 3 years)
measure: Minor bleeding event rate
timeFrame: both procedural up to 7 days, as well as total (through study completion, an average of 3 years)
measure: Number of patients with successful device deployment
timeFrame: procedural up to 7 days
measure: Adverse events rate
timeFrame: at 30 days, and from 30 days until end of follow up (max. 5 years, avarage of 3 years)
measure: Device related thrombus event rate
timeFrame: Through study completion, an average of 3 years
measure: Net-clinical benefit of efficacy and safety endpoint (calculated as the difference in time to first occurence of stroke, TIA and SE in both arms in comparison to the 30-day rate of procedural complications in both groups)
timeFrame: Through study completion, an average of 3 years
measure: Patient-reported health quality assessed by the SF12 questionnaire
timeFrame: baseline, 3, 6, 12 months, after that on a yearly base (until the end of the study, max follow up +/- 5 years)
measure: Anxiety and depression assessed by the HADS questionnaire
timeFrame: baseline, 3, 6, 12 months, after that on a yearly base (until the end of the study, max follow up +/- 5 years)
measure: Generic health status assessed by the EQ5D5L questionnaire (in order to perform a cost-effectiveness analysis)
timeFrame: Through study completion, an average of 3 years. Questionnaires will be send on a half yearly basis.
measure: Medical consumption (in order to perform a cost-effectiveness analysis)
timeFrame: Through study completion, an average of 3 years. Questionnaires will be send on a half yearly basis.
measure: Productivity losses (in order to perform a cost-effectiveness analysis)
timeFrame: Through study completion, an average of 3 years. Questionnaires will be send on a half yearly basis.
Other outcomes:
Locations:
city: Leeuwarden
country: Netherlands
facility: Medical Center Leeuwarden
state: Friesland
city: Nijmegen
country: Netherlands
facility: Radboud UMC
state: Gelderland
city: Maastricht
country: Netherlands
facility: Maastricht UMC
state: Limburg
city: Nieuwegein
country: Netherlands
facility: St Antonius Hospital
state: Noord Holland
city: Breda
country: Netherlands
facility: Amphia Hospital
state: Noord-Brabant
city: Amsterdam
country: Netherlands
facility: OLVG
state: Noord-Holland
city: Amsterdam
country: Netherlands
facility: Amsterdam UMC
state: Noord-Holland
city: Enschede
country: Netherlands
facility: Medical Spectrum Twente
state: Overijssel
city: Zwolle
country: Netherlands
facility: Isala Clinics
state: Overijssel
city: Den Haag
country: Netherlands
facility: Haga Hospital
state: Zuid Holland
city: Leiden
country: Netherlands
facility: Leiden UMC
state: Zuid-Holland
city: Rotterdam
country: Netherlands
facility: Erasmus MC
state: Zuid-Holland
city: Groningen
country: Netherlands
facility: UMC Groningen
city: Utrecht
country: Netherlands
facility: UMC Utrecht
Study officials:
affiliation: St Antonius Ziekenhuis Nieuwegein
name: Lucas VA Boersma, Prof. Dr.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Huijboom M, Maarse M, Aarnink E, van Dijk V, Swaans M, van der Heijden J, IJsselmuiden S, Folkeringa R, Blaauw Y, Elvan A, Stevenhagen J, Vlachojannis G, van der Voort P, Westra S, Chaldoupi M, Khan M, de Groot J, van der Kley F, van Mieghem N, van Dijk E, Dijkgraaf M, Tijssen J, Boersma L. COMPARE LAAO: Rationale and design of the randomized controlled trial "COMPARing Effectiveness and safety of Left Atrial Appendage Occlusion to standard of care for atrial fibrillation patients at high stroke risk and ineligible to use oral anticoagulation therapy". Am Heart J. 2022 Aug;250:45-56. doi: 10.1016/j.ahj.2022.05.001. Epub 2022 May 7.