Resolution of Left Atrial-Appendage Thrombus - Effects of Dabigatran in Patients With AF

NCT ID: NCT02256683

Last Updated: 2019-07-26

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE2
• Total Enrollment: 64 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2014-07-31
• Study Completion Date: 2018-05-31

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.

Conditions

Atrial Fibrillation or Atrial Flutter; Thrombosis of Left Atrial Appendage

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: SINGLE

Study Groups

Dabigatran

Dabigatran etexilate (Pradaxa®) 150 mg capsule by mouth twice daly for 3 up to 6 weeks depending on treatment response

Group Type: EXPERIMENTAL

Dabigatran etexilate

Intervention Type: DRUG

After inclusion of the patients with LAA thrombus, they are treated according to the randomization either with Pradaxa® (150 mg bid) or Marcumar® (INR 2-3) for at least three weeks. Thrombus resolution will be determined by transesophageal echocardiography (TEE) 3 weeks after start of 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 or after 6 weeks of study treatment.

Phenprocoumon

Phenprocoumon (Marcumar®) 3 mg capsule by mouth according to INR (2-3) for 3 up to 6 weeks depending on treatment response

Group Type: ACTIVE_COMPARATOR

Phenprocoumon

Intervention Type: DRUG

After inclusion of the patients with LAA thrombus, they are treated according to the randomization either with Pradaxa® (150 mg bid) or Marcumar® (INR 2-3) for at least three weeks. Thrombus resolution will be determined by transesophageal echocardiography (TEE) 3 weeks after start of 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 or after 6 weeks of study treatment.

Interventions

Dabigatran etexilate

After inclusion of the patients with LAA thrombus, they are treated according to the randomization either with Pradaxa® (150 mg bid) or Marcumar® (INR 2-3) for at least three weeks. Thrombus resolution will be determined by transesophageal echocardiography (TEE) 3 weeks after start of 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 or after 6 weeks of study treatment.

Intervention Type: DRUG

Phenprocoumon

After inclusion of the patients with LAA thrombus, they are treated according to the randomization either with Pradaxa® (150 mg bid) or Marcumar® (INR 2-3) for at least three weeks. Thrombus resolution will be determined by transesophageal echocardiography (TEE) 3 weeks after start of 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 or after 6 weeks of study treatment.

Intervention Type: DRUG

Other Intervention Names

Pradaxa®; Marcumar®

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.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 80 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Boehringer Ingelheim

INDUSTRY

Sponsor Role: collaborator

Atrial Fibrillation Network

OTHER

Sponsor Role: collaborator

Johannes Gutenberg University Mainz

OTHER

Sponsor Role: lead

Responsible Party

Thomas Rostock

Univ.-Prof. Dr. med.

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Thomas Rostock, MD

Role: PRINCIPAL_INVESTIGATOR

University Medical Center of the Johannes Gutenberg-University Mainz

Locations

University Heart Center; Department of Cardiology and Angiology II

Bad Krozingen, , Germany

Charité Universitätsmedizin Berlin

Berlin, , Germany

Vivantes Clinical Center Am Urban; General Internal Medicine and conservative intensive care

Berlin, , Germany

Klinikum Coburg GmbH

Coburg, , Germany

University Heart Center; Department of Cardiology

Cologne, , Germany

University Heart Center; Department of Invasive Electrophysiology

Dresden, , Germany

University Heart Center; Department of Cardiology, Electrophysiology

Hamburg, , Germany

Hannover Medical School; Department of Cardiology and Angiology

Hanover, , Germany

Städtisches Klinikum Karlsruhe

Karlsruhe, , Germany

Universitätsmedizin Leipzig

Leipzig, , Germany

University Hospital Mainz, II. Medical Clinic, Dept. of Electrophysiology

Mainz, , Germany

University Medical Center

Münster, , Germany

St. Vincenz-Hospital GmbH

Paderborn, , Germany

Rostock University Hospital; Rhythmology and Clinical Electrophysiology

Rostock, , Germany

Countries

Germany

Other Identifiers

2013-005364-26

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

2013-008

Identifier Type: -

Identifier Source: org_study_id