Clinical trial NCT03539055: Efficacy of Short Term Dabigatran Etexilate Followed by Aspirin Monotherapy After LAA (Left Atrial Appendage) Device Closure (the DEA-LAA Study).
Official title: Efficacy of Short Term Dabigatran Etexilate Followed by Aspirin Monotherapy After LAA (Left Atrial Appendage) Device Closure (the DEA-LAA Study).
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Atrial Fibrillation
Device Related Thrombus
Left Atrial Appendage Thrombosis
Watchman LAA Closure Device
Keywords: DRT
Device related thrombus
Dabigatran etexilate
Aspirin
Watchman
Lead sponsor: Vanderbilt University Medical Center
Sponsor class: OTHER
Collaborators: name: Boehringer Ingelheim
First posted: 2018-05-29
Enrollment: 100
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: Prospective single arm intervention of dabigatran etexilate with aspirin for 90 days following Watchman LAA device closure to prevent device related thrombus (DRT)
Primary purpose: PREVENTION

Brief summary: Single arm, prospective unblinded study on post Watchman LAA closure device implant anti-coagulation management at a primary center (Vanderbilt Medical Center) and up to 5 additional high volume LAA implant centers. This trial will be designed to evaluate the use of dabigatran for 90 days post implantation of an LAA closure device (Watchman LAA Closure Device, Boston Scientific Inc.) to prevent device related thrombus.

Detailed description: Single arm, prospective unblinded study on post Watchman LAA closure device implant anti-coagulation management at a primary center (Vanderbilt Medical Center) and up to 5 additional high volume LAA implant centers. This trial will be designed to evaluate the use of dabigatran for 90 days post implantation of an LAA closure device (Watchman LAA Closure Device, Boston Scientific Inc.).

The drug will be initiated on the morning following device implantation, taken BID per package insert dosing and until follow-up 90-day post implant TEE. Aspirin monotherapy will be utilized in conjunction at 81 mg for up to 12 months, after which the patients will be exited from the study and further treatment decisions will be made by the following physician (see Schedule of Study Procedures at end of protocol). The objective of this trial is to evaluate safety and efficacy of a 90-day period of dabigatran etexilate following LAA closure to prevent device associated thrombus, while minimizing adverse bleeding by eliminating the need for clopidogrel.

This is a single arm pilot study with the option (pending collaboration with additional funding source) to expand to a full single arm non-inferiority trial design with 80% power to detect a 1.4% difference with the non-inferiority margin 1% in absolute rate of DAT (control rate 3.9%).

Prospective, non-randomized single arm study. Comparison will be made to historical controls based on published one year DAT rates from PROTECT-AF, PREVAIL clinical trials, and EWOLUTION, and ACP/Amulet registries.

Echocardiography (TEE) will be performed at 90 days (3 months, +/- 2-week window), and again at 1-year post implant (+/- 4 weeks). Selected images will be interpreted by echo lab at coordinating center in an anonymous fashion (patient data de-identified). Ideal imaging will incorporate 0, 45, 90 and 135 degree angled views on the device at follow up.

Drug will be dispensed as part of the clinical trial supplied from the sponsor and each patient will receive a complete 90 days' supply up front. They will have a drug visit on the day of TEE with the research coordinator to hand back any remaining dabigatran, with clear instruction to stop the drug and only take ASA following confirmation of closure on TEE (no peri-device leak on Doppler of \>5mm). A decision to continue anti-coagulation post closure 90day TEE will be made by the physician discretion based on TEE findings. If thrombus is found at the 90 days TEE, anti-coagulation may be extended another 6 weeks with repeat TEE imaging to confirm clot resolution at the discretion of the investigator. In the unlikely event of embolization or Doppler leak \>5mm, decision on extending anti-coagulation, or re-implanting a device will be made by the following physician.

Additional baseline data collection: Patient demographics, medical history, age, sex, and prior use of anti-coagulants or anti-platelet medications will be collected. CHADS 2 Vasc, and HAS-BLED score calculated. Main indication for LAA closure must be documented. Baseline CBC and BMP required on day of implant or up to 1 week pre-procedure (typical standard of care labs at time of implant). This will include a recent calculation of Creatinine Clearance (using Cockroft Gault and using patients actual body weight) and dosing of study drug will be made in accordance (see below). Repeat PCV or hematocrit on the morning after Watchman LAAC implantation will be per hospital standard. PCV or hematocrit value pre-implant and at the post 90-day visit will be analyzed.

Calculation for dabigatran dosing:

CCr={ (l40-age) x weight in kg)/(72 x SCr) } x 0.85 (if female)

Implant procedure variables to collect include access site, sheath used for deployment (WAS), device size at implant and number of implant attempts. LA pressure mean if available. Presence of angiography contrast or Doppler Echo leak, thrombus, or pericardial effusion post implant will be recorded. At 90 days, TEE report findings and image review (standard of care) with drug dosing visit with research coordinator and return of any remaining study drug.

1 year TEE (standard of care) with a research exit visit with MD, physician extender, or research coordinator, with documentation of ASA tolerance, dosing, and any late bleeding episodes or hospitalizations (typically should be reported as AE/SAE when first knowledge of event is determined). TEE images will be sent to the primary study site (Vanderbilt University Medical Center) and core TEE lab will review to confirm presence or absence of DAT. In cases of CTA utilized for follow up, similarly images will be reviewed by chest radiology team at Vanderbilt.

Medication administration with 90 days of dabigatran to be dispensed by pharmacy ideally one time (180 capsules).

Eligibility criteria: Inclusion Criteria:

1. Male or female sex, age \>18 years.
2. CHADS2 Vascular score of 3-9 and HAS BLED score 2 or higher meeting CMS coverage criteria for Watchman LAA closure device implantation.
3. Able to give informed consent.
4. Life expectancy of \> 1year in the judgment of the implanting physician and shared decision-making physician.

Exclusion Criteria:

1. Unable to give informed consent
2. History of confirmed allergy to dabigatran etexilate
3. Active cerebral bleeding, or active non-cerebral bleeding requiring blood transfusions (any absolute contra-indications to anti-coagulation).
4. History of intraocular, spinal, retroperitoneal or a traumatic intra-articular bleeding unless the causative factor has been permanently eliminated or repaired (e.g. by surgery)
5. Gastrointestinal (GI) haemorrhage within one month prior to screening, unless, in the opinion of the Investigator, the cause has been permanently eliminated (e.g. by surgery)
6. Major bleeding episode (reduction in the haemoglobin level of at least 2g/dL, transfusion of at least two units of blood, or symptomatic bleeding in a critical area or organ) including life-threatening bleeding episode (symptomatic intracranial bleeding, bleeding with a decrease in the haemoglobin level of at least 5g/dL or bleeding requiring transfusion of at least 4 units of blood or inotropic agents or necessitating surgery) in one month prior to screening visit
7. Intolerance to dabigatran, if medication naïve, or other contra-indications as per the USPI, including ESRD on hemodialysis or GFR \< 15ml/min, or concomitant use of rifampin.
8. History of non-compliance, inability to follow-up.
9. Pre-menopausal women (last menstruation ≤ 1 year prior to screening) who are not surgically sterile.
10. Ischemic stroke or hemorrhagic stroke within 90 days of LAA placement.
11. Anatomy unsuitable for LAA closure (incomplete surgical LAA ligation without suitable anatomy for Watchman placement. LAA ostial measurements \>31mm, or \<17mm in all views).
12. Requires long-term oral anticoagulation therapy for a condition other than atrial fibrillation.
13. ASA allergy, or confirmed allergy to nickel.
14. Prior PFO or ASD closure device or prosthetic or mechanical heart valve.
15. Acute MI within 90 days.
16. Platelets \<50,000 at time of Watchman LAAC implantation.
17. Active endocarditis.
18. Planning for endocardial catheter AF or left atrial ablation within 90 days of Watchman implantation.

Primary outcomes:
measure: Device Related Thrombus (DRT) at 90 Days
timeFrame: Baseline to 90 days
measure: Device Related Thrombus (DRT) at 1 Year
timeFrame: 90 days to 1 year
Secondary outcomes:
measure: Includes Ischemic Stroke, Peripheral Thrombo-embolic Events and Major Bleeding Events
timeFrame: Baseline to 90 days
Other outcomes:
Locations:
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
Study officials:
affiliation: Vanderbilt University Medical Center
name: Arvindh N Kanagasundram, MD
role: STUDY_DIRECTOR
References:
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citation: Bergmann MW, Ince H, Kische S, Schmitz T, Meincke F, Schmidt B, Foley D, Betts TR, Grygier M, Protopopov AV, Stein KM, Boersma LVA. Real-world safety and efficacy of WATCHMAN LAA closure at one year in patients on dual antiplatelet therapy: results of the DAPT subgroup from the EWOLUTION all-comers study. EuroIntervention. 2018 Apr 20;13(17):2003-2011. doi: 10.4244/EIJ-D-17-00672.