Clinical trial NCT02256683: Resolution of Left Atrial-Appendage Thrombus - Effects of Dabigatran in Patients With AF
Official title: Effects of Dabigatran in Patients With AF - A Prospective, Randomized, Open-label, Explorative, Blinded-endpoint Trial to Compare the Efficacy of Dabigatran With Phenprocoumon for the Resolution of LAA Thrombus in Patients With AF
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Atrial Fibrillation or Atrial Flutter
Thrombosis of Left Atrial Appendage
Keywords: atrial fibrillation
atrial flutter
Atrial-Appendage Thrombus
Thrombus resolution
Dabigatran
Phenprocoumon
Transesophageal Echocardiography
Lead sponsor: Johannes Gutenberg University Mainz
Sponsor class: OTHER
Collaborators: name: Boehringer Ingelheim
name: Atrial Fibrillation Network
First posted: 2014-10-06
Enrollment: 64
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The primary objective of this study is to assess whether Dabigatran leads to a faster complete left atrial appendage (LAA) thrombus resolution as compared to Phenprocoumon. The secondary objectives of this trial are to assess the impact of Dabigatran versus Phenprocoumon on complete LAA thrombus resolution rate until week 6 and change in LAA thrombus volume under treatment as well as to assess and compare safety and tolerability of both drugs. A total of 110 patients with atrial fibrillation and LAA thrombus will be randomized to receive either Dabigatran (150 mg bid) or Phenprocoumon (INR 2-3) for a least three weeks. Thrombus resolution will be determined by transoesophageal echocardiography (TEE) 3 weeks after start of study treatment and subsequently at week 4 and 6 if necessary, i.e. LAA thrombus has not yet resolved. The study is terminated for each patient with the resolution of the LAA thrombus. For those patients whose thrombus still exists after 6 weeks treatment, the study is also terminated. Further treatments will be decided at the discretion of the treating physician.

Detailed description: BACKGROUND Dabigatran etexilate, a direct thrombin inhibitor and new oral anticoagulant (NOAC), has been shown to effectively prevent thromboembolic events in patients with atrial fibrillation (AF). However, there is a paucity of data on the antithrombotic efficacy and safety of dabigatran in the resolution of left atrial appendage (LAA) thrombi in AF patients.

OBJECTIVE The primary objective of the RE-LATED trial is to assess whether treatment with dabigatran results in a faster complete LAA thrombus resolution as compared to vitamin-K antagonist phenprocoumon. Secondary objectives are to assess the impact of dabigatran on complete LAA thrombus resolution rate during treatment of 6 weeks, and change in LAA thrombus volume under treatment. Furthermore, this study aims to assess and compare safety and tolerability of dabigatran vs. phenprocoumon.

METHODS The study is designed as a prospective, multicenter, randomized, open-label, controlled, explorative, blinded endpoint (PROBE) trial. Patients with AF and left atrial appendage thrombus confirmed by transesophageal echocardiography (TEE) will be randomized to receive either dabigatran (150 mg bid) or phenprocoumon (INR 2-3) for the resolution of LAA thrombus formation for at least 21 days. Thrombus resolution will be determined by TEE 3 weeks after treatment initiation and subsequently at week 4 and 6, if the primary study endpoint (LAA thrombus resolution) has not yet been achieved. A total of 110 patients are planned to get randomized.

CLINICAL CONTEXT This is the first controlled trial that investigates the safety and efficacy of a NOAC for the resolution of a LAA thrombus in patients with AF.

Eligibility criteria: Inclusion Criteria:

* Patients with documented non-valvular AF or atrial flutter (12-lead ECG)
* Newly diagnosed or confirmed LAA thrombus in TEE (time of detection ≤ 28 days)
* Patients 18 years old
* CHA2DS2-VASc Score 1
* CrCL 30 mL/min (Cockcroft-Gault)
* Women with childbearing potential have to practice a medically accepted contraception
* Ability of patient to understand the character and the individual consequences of the clinical trial
* Signed and dated informed consent before start of any specific trial procedures

Exclusion Criteria:

* Patients \> 80 years
* Low body weight (\< 50 kg)
* Previous failure of LAA thrombus resolution with a VKA or factor Xa antagonist
* Occurrence of LAA thrombus under long-term treatment (\> 3 months) with vitamin K antagonists with an exception in the case of continued INR out of the target range
* Contraindications for oral anticoagulation therapy (see current Fachinformation for Pradaxa® (150 mg) and Marcumar® (3 mg))
* History of heart valve disorder (i.e., prosthetic valve or hemodynamically relevant valve disease)
* Valvular heart disease requiring intervention (including mechanical valves)
* Acute myocardial infarction or MI within the last 26 weeks
* Acute coronary syndrome (e.g. instable angina pectoris, STEMI, NSTEMI)
* Chronic Heart Failure (\> NYHA IIIa)
* Previous haemorrhagic stroke
* TIA within the last 90 days
* Clinical relevant bleeding within the last 26 weeks
* Acute and subacute bacterial endocarditis
* Recurrent pulmonary embolism
* Esophagitis, gastritis and gastroesophageal reflux
* Thrombocytopenia or functional platelet defects
* Congenital or acquired coagulation or haemorrhagic disorders
* Liver diseases (liver enzymes \>2 ULN)
* Renal insufficiency (CrCL below 30 mL/min)
* Pre-treatment with Dabigatran in doses higher than 110 mg bid
* Concomitant treatment with rivaroxaban, apixaban, and in case of approval during the course of the trial, also edoxaban
* Concomitant treatment with irreversible cyclooxygenase inhibitors (e.g. ASA) at doses \> 100 mg/d.
* Concomitant treatment with high doses of Adenosine diphosphate (ADP) receptor inhibitors (e.g. clopidogrel) at doses \> 75 mg/d
* Combined treatment with Adenosine diphosphate (ADP) receptor inhibitors (e.g. clopidogrel) and irreversible cyclooxygenase inhibitors (e.g. ASA) in any dose combination
* Planned treatment with long-term oral anticoagulants for alternative indications
* Concomitant treatment with P-glycoprotein (P-gp) inhibitors, i.e. verapamil.
* Need for continued treatment with ticlopidine, ticagrelor, prasugrel, systemic ketoconazole, itraconazole, posaconazole, cyclosporine, tacrolimus, dronedarone, rifampicin, phenytoin, carbamazepine, St. John's Wort or any cytotoxic/myelosuppressive therapy
* Concomitant treatment with medication not permitted
* Planned surgical intervention during expected study participation or previous surgical interventions within the last 30 days
* Other significant risk factors for bleeding complications (e.g. malignancy)
* Pregnancy and lactation.
* History of hypersensitivity to the investigational medicinal product or to any drug with similar chemical structure or to any excipient present in the pharmaceutical form of the investigational medicinal product.
* Participation in other clinical trials during the present clinical trial or within the last 90 days.
* Medical or psychological condition that would not permit completion of the trial or signing of informed consent.

Primary outcomes:
measure: Time to complete left atrial appendage (LAA) thrombus resolution
timeFrame: 3 up to 6 weeks
Secondary outcomes:
measure: Complete LAA thrombus resolution until week 6 (yes/no)
timeFrame: 3 up to 6 weeks
measure: Change in LAA thrombus volume under treatment
timeFrame: 3 up to 6 weeks
measure: Occurrence of any adverse event
timeFrame: 3 up to 6 weeks
measure: Occurrence of major bleedings
timeFrame: 3 up to 6 weeks
measure: Occurrence of strokes (all-type, haemorrhagic, ischemic) ascertained by CCT or cMRT
timeFrame: 3 up to 6 weeks
measure: Occurrence of transient ischaemic attacks (TIAs)
timeFrame: 3 up to 6 weeks
measure: Occurrence of cardiovascular events requiring hospitalization
timeFrame: 3 up to 6 weeks
measure: Occurrence of other thromboembolic events
timeFrame: 3 up to 6 weeks
Other outcomes:
Locations:
city: Bad Krozingen
country: Germany
facility: University Heart Center; Department of Cardiology and Angiology II
city: Berlin
country: Germany
facility: Charité Universitätsmedizin Berlin
city: Berlin
country: Germany
facility: Vivantes Clinical Center Am Urban; General Internal Medicine and conservative intensive care
city: Coburg
country: Germany
facility: Klinikum Coburg GmbH
city: Dresden
country: Germany
facility: University Heart Center; Department of Invasive Electrophysiology
city: Hamburg
country: Germany
facility: University Heart Center; Department of Cardiology, Electrophysiology
city: Hannover
country: Germany
facility: Hannover Medical School; Department of Cardiology and Angiology
city: Karlsruhe
country: Germany
facility: Städtisches Klinikum Karlsruhe
city: Köln
country: Germany
facility: University Heart Center; Department of Cardiology
city: Leipzig
country: Germany
facility: Universitätsmedizin Leipzig
city: Mainz
country: Germany
facility: University Hospital Mainz, II. Medical Clinic, Dept. of Electrophysiology
city: Münster
country: Germany
facility: University Medical Center
city: Paderborn
country: Germany
facility: St. Vincenz-Hospital GmbH
city: Rostock
country: Germany
facility: Rostock University Hospital; Rhythmology and Clinical Electrophysiology
Study officials:
affiliation: University Medical Center of the Johannes Gutenberg-University Mainz
name: Thomas Rostock, MD
role: PRINCIPAL_INVESTIGATOR
References: