Clin Res Cardiol DOI 10.1007/s00392-015-0883-7

ORIGINAL PAPER

Rationale and design of the RE-LATED AF—AFNET 7 trial: REsolution of Left atrial-Appendage Thrombus—Effects of Dabigatran in patients with Atrial Fibrillation Marion Ferner1 • Daniel Wachtlin1 • Torsten Konrad2 • Oliver Deuster1 Thomas Meinertz3 • Stephan von Bardeleben2 • Thomas Mu¨nzel2 • Monika Seibert-Grafe1 • Gu¨nter Breithardt4,5 • Thomas Rostock2

•

Received: 19 March 2015 / Accepted: 9 June 2015 Ó Springer-Verlag Berlin Heidelberg 2015

Abstract Background Dabigatran etexilate, a direct thrombin inhibitor and non-vitamin K antagonist oral anticoagulant (NOAC), has been shown to effectively prevent thromboembolic events in patients with non-valvular 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 AF trial is to assess whether 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 within 6 weeks of treatment and change in LAA thrombus volume under treatment. Furthermore, this study aims to assess and compare safety and tolerability of dabigatran vs. phenprocoumon.

& Marion Ferner [email protected] 1

Interdisciplinary Center for Clinical Trials (IZKS) at the University Medical Center of the Johannes GutenbergUniversity Mainz, Langenbeckstrasse 1, 55131 Mainz, Germany

2

2nd Clinic for Internal Medicine at the University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany

3

Deutsche Herzstiftung, Frankfurt Am Main, Germany

4

Department of Cardiovascular Medicine, University Hospital Mu¨nster, Mu¨nster, Germany

5

Competence Network on Atrial Fibrillation, Mu¨nster, Germany

Methods The study is designed as a prospective, randomized, open-label, controlled, explorative, blinded endpoint (PROBE) trial. Patients with AF and left atrial appendage thrombus confirmed by transoesophageal 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 weeks 4 and 6, if the LAA thrombus has not been resolved before. A total of 110 patients are planned to be randomized. Conclusion This is the first prospective, multicentre, randomized controlled clinical trial investigating safety and efficacy of a NOAC for the resolution of LAA thrombi in patients with non-valvular AF. Keywords Atrial fibrillation
Atrial Appendage Thrombus
Thrombus Resolution
Dabigatran
NOAC
Anticoagulants

Introduction Left atrial appendage (LAA) thrombus formation is an adverse event in patients with atrial fibrillation (AF) not being on oral anticoagulation or even being on non-sufficient anticoagulation. The prevalence of LAA thrombus in patients with AF varies between 0.5–14 %, depending on anticoagulation status and CHA2DS2-VASc score [1–4]. Patients with documented LAA thrombus formation have a high risk of thromboembolic events. The annual embolic event rate has been reported to be at 14 % [5]. The state-ofthe-art treatment of LAA thrombi is bridging with lowmolecular heparin and initiation of oral anticoagulation

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with vitamin K antagonists (VKA) for at least 3 weeks within the therapeutic range between INR 2.0–3.0 [6]. Particularly in patients with an organized LAA thrombus, conventional VKA therapy may fail in the attempt to resolve the thrombus, even with long-term anticoagulation. Although used in clinical practice, a more aggressive anticoagulation regimen with higher INR levels or combination of oral anticoagulation and antiplatelet agents is not proven to result in higher rates of LAA thrombus resolution. For a long period of time, VKAs have been the mainstay of stroke prevention therapy in patients with AF [6, 7]. The antithrombotic effect of VKAs has been attributed to their anticoagulant effect, which is mediated by the reduction of four vitamin K-dependent coagulation factors [8]. Despite their effectiveness, VKAs have numerous limitations and disadvantages, e.g., various food/drug interactions, variable effectiveness due to genetic polymorphisms and need for regular anticoagulation monitoring [9]. Recent epidemiologic data show low treatment adherence for VKAs among patients with atrial fibrillation [10]. In addition, VKAs have a small therapeutic window: over-anticoagulation increases the risk of bleeding, while insufficient anticoagulation is associated with an increased risk for thromboembolism. Non-vitamin K antagonist oral anticoagulants (e.g., dabigatran, rivaroxaban or apixaban) (NOAC) are recommended for prevention of stroke in patients with nonvalvular atrial fibrillation in the current ESC guidelines [11], since they offer similar (or better) effectiveness, safety and a better patient convenience as compared with dose-adjusted VKA (INR 2–3) [12–14]. Also, under treatment with direct oral anticoagulants (dabigatran and rivaroxaban), the prevalence of intracardiac thrombi in patients with atrial fibrillation or flutter was lower as compared to therapy with phenprocoumon [15]. Due to the low incidence of LAA thrombi, structured data on thrombus resolution with oral anticoagulants are limited. Considering treatment with VKAs, in several observational studies [16–18] with relatively small patient numbers, a wide range of resolution rates was reported. In one study, thrombus resolution was successful in 55 % of 55 patients after 4 weeks of warfarin treatment with increased INR (3–3.5) [16]. In two other studies with small patient numbers, resolution rates of [80 % were reported after 4 weeks of treatment with warfarin with a target INR C21 [7, 18]. However, due to differences in patient populations, anticoagulant treatment duration, effective INR levels, and thrombus visualization by TEE, it is difficult to compare these studies[18–21]. Data on Non-VKA oral anticoagulants [22] being used for the treatment of LAA thrombi are still limited and consist of single case reports or case series on LAA

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thrombus resolution with rivaroxaban, dabigatran and apixaban [23–30]. The rationale and design of a prospective study investigating the efficacy of rivaroxaban on the outcome of left atrial or LAA thrombi in patients with non-valvular atrial fibrillation has recently been published [31]. Trial rationale Patients with AF require at least temporarily anticoagulant treatment when an LAA thrombus is identified. Usually they would need long-term anticoagulation therapy. However, continued effective anticoagulation with VKAs may not prevent thromboembolic events in patients with permanent AF and prevalent LAA thrombi. In a prospective and serial study in 43 patients with AF and LAA thrombi, an increased risk for cerebral embolism and/or death was observed (16 % during a follow-up period of 12 months), even in patients on effective anticoagulation with phenprocoumon [32]. Furthermore, up to 40 % of LAA thrombi persist in patients under VKA treatment. Moreover, VKAs appear to have a poor capability to resolve large intracardiac thrombi [26]. Dabigatran etexilate, the orally bioavailable prodrug of dabigatran, is a synthetic, direct thrombin inhibitor. Following oral administration, dabigatran etexilate is rapidly converted to the active moiety dabigatran, which is a nonpeptidic, highly potent, competitive, and reversible inhibitor of thrombin. Dabigatran etexilate is registered for use in more than 100 countries for the prevention of VTE in patients undergoing elective hip or knee replacement surgery. It is approved since October 2010 in the US and in August 2011 in Europe for stroke prevention and prevention of systemic embolism in patients with non-valvular AF. Approval for treatment of deep venous thrombosis (DVT) and pulmonary embolism (PE), and prevention of recurrent DVT and PE was obtained by the FDA in April 2014 and by the EMA in June 2014. The pharmacological properties of dabigatran suggest a potential thrombolytic effect [33], but no systematic, controlled investigation on the effectiveness of dabigatran on LAA thrombus resolution in patients with AF has been published so far. In a post hoc analysis of patient data from the RE-LY trial, only the incidence of LAA thrombi under treatment with warfarin vs. dabigatran was analysed retrospectively; however, thrombus resolution was not considered [30]. The assumption of the efficacy of dabigatran is supported by several anecdotal reports on LAA thrombus resolution in patients with AF [23–25]. Thereof, in two case studies, LAA thrombus resolution was successful after switch of treatment from warfarin to dabigatran [23, 25].In another

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case report on three patients with persistent AF and newly detected LAA thrombus without a history of anticoagulation therapy, disappearance of thrombus evaluated by TEE was confirmed 19, 25, and 27 days after the initiation of treatment with dabigatran [24]. Therefore, the hypothesis that dabigatran is effective in resolving LAA thrombi and may even result in faster thrombus resolution than VKAs is worth being investigated. In this randomized multicentre clinical trial, dabigatran and phenprocoumon are investigated regarding their properties on resolution of LAA thrombus in patients with AF. This article presents the study design, statistical considerations and planned analyses for this study. Trial objectives and endpoints Due to its fast onset of action and low intra-individual variability of pharmacodynamic effects, the hypothesis is that dabigatran will result in a faster LAA thrombus resolution than phenprocoumon. Therefore, the primary objective of the study is to assess whether dabigatran leads to a faster LAA thrombus resolution as compared to phenprocoumon. The primary endpoint is the time to complete LAA thrombus resolution. Patients will be censored after 6 weeks of treatment if thrombus was classified as unresolved by then. The secondary objectives of this trial are to compare LAA thrombus resolution rate until week 6 and change in LAA thrombus volume of dabigatran and phenprocoumon. In addition, safety and tolerability of both drugs are compared, in particular regarding the occurrence of major bleedings, according to the ISTH major bleeding definition of Schulman and Kearon [34]. Further safety endpoints are the occurrence of strokes (all-type, ischaemic, haemorrhagic), transient ischaemic attacks (TIAs), cardiovascular events requiring hospitalization (e.g., myocardial

infraction, acute coronary syndrome, severe tachyarrhythmia), or other thromboembolic events (e.g., deep vein thrombosis, pulmonary embolism).

Methods The RE-LATED AF study is a multicentre, prospective, explorative, randomized, open label, parallel group, blinded endpoint assessment, active comparator trial (PROBE design). Informed consent will be obtained from each patient. The study investigates dabigatran vs. the VKA phenprocoumon for thrombus resolution properties in patients with AF and a newly detected LAA thrombus. A total of 110 patients will be enrolled and randomly assigned to either treatment arm and subsequently treated for at least 3 up to a maximum of 6 weeks. All patients will be followed until 1 week after the end of treatment in order to monitor adverse events. The study design is presented in Fig. 1. Study management and ethics approval The RE-LATED AF study is an Investigator-Initiated Trial (IIT) with the University Medical Center (UMC) Mainz as Sponsor according to EU directive and German Drug Law. The study is conducted in 15 German clinical trial centres. A clinical coordinating centre at the UMC Mainz is responsible for study management as well as sponsor tasks, e.g., regulatory procedures, quality assurance and data processing. Two core echocardiographic laboratories will verify all TEEs for the correctness of diagnosis of LAA thrombus and for thrombus size assessment. An independent data monitoring board is responsible for continuous assessment of safety data and risk-benefit relationship. A Steering Committee was installed to supervise the study.

LAA thrombus resolution: EOT and telephone follow-up after 7 days

Study enrolment, randomization (N=110)

V3

V2

V1

V4

Dabigatran

3 weeks

TEE

1 week

TEE

2 weeks

TEE EOT

Phenprocoumon

3 weeks

TEE

1 week

TEE

2 weeks

TEE EOT

telephone follow-up after 7 days

LAA thrombus resolution: EOT and telephone follow-up after 7 days

Fig. 1 RE-LATED AF study design. Phenprocoumon arm: INR 2-3 (intermittent bridging with enoxaparin until INR C2). Dabigatran arm: 150 mg bid. Visit1 (V1): day 1. Visit 2 (V2): day 21 ± 3. Visit 3

(V3): day 28 ? 4. Visit 4 (V4): day 42 ± 3. EOT end of treatment, INR international normalized ratio, LAA left atrial appendage, TEE transoesophageal echocardiography

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The clinical trial has been approved by the responsible Ethics Committee of Rhineland-Palatinate, Mainz, Germany, and by the German Competent Authority (BfArM); all local authorities responsible for the participating trial sites have been informed. The study was registered at the EU Clinical Trials Register (EudraCT No 2013-005364-26) and at ClinicalTrials.gov (Identifier: NCT02256683). The study protocol conforms to the ethical guidelines of the 1975 Declaration of Helsinki. Patient selection Inclusion and exclusion criteria for this study are presented in Table 1. To be eligible for RE-LATED AF, patients have to show documented non-valvular AF or atrial flutter (12-lead ECG) and a newly diagnosed and confirmed LAA thrombus formation in TEE (time of detection less than 7 days). Further inclusion criteria are age C18 years, CHA2DS2-VASc Score C1, creatinine clearance CrCL C50 mL/min (Cockcroft-Gault), and ability of the patient to understand the character and the individual consequences of the clinical trial. Women with childbearing potential have to practice a medically accepted contraception during the trial and a negative pregnancy test (serum and urine) should be existent before inclusion. Patients excluded from the study are those who are [80 years old, with low body weight (\50 kg), previous failure of LAA thrombus resolution with a VKA or factor Xa antagonist, occurrence of LAA thrombus under longterm treatment ([3 months) with VKAs, or contraindications for oral anticoagulation therapy. Also excluded are patients with a history of valvular heart disease (i.e., prosthetic valve or hemodynamically relevant valve disease), valvular heart disease requiring intervention (including mechanical valves), acute myocardial infarction (MI) or MI within the last 26 weeks, acute coronary syndrome (e.g., instable angina pectoris, STEMI, NSTEMI), and chronic Heart Failure ([NYHA IIIa). Further exclusion criteria are thrombocytopenia, bleeding, (haemorrhagic) stroke, renal insufficiency (CrCL below 50 mL/min), liver diseases (liver enzymes [2 ULN), acute and subacute bacterial endocarditis, recurrent pulmonary embolism, esophagitis, gastritis and gastroesophageal reflux disease. After obtaining informed consent and evaluation of inclusion and exclusion criteria, patients will be randomly assigned to the treatment groups to avoid selection bias. Randomization will be performed online through a secure web interface. Randomization is conducted by blocks of variable length. No stratification is intended for the study. The treatment allocation ratio is 1:1 (balanced design).

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Study medication Dabigatran etexilate After randomization to the dabigatran arm, the patient will be treated with 150 mg dabigatran bid for at least three weeks. If the patient is already under oral anticoagulation (OAC) therapy (see above mentioned exclusion criteria), switch from previous OAC to dabigatran is performed and monitored by the patient’s treating physician. If the LAA thrombus persists after 3 weeks of treatment, dabigatran will be continued for a maximum of further 3 weeks. Patients will undergo a TEE at weeks 3, 4 and 6, respectively, for LAA thrombus assessment until thrombus resolution can be confirmed. In case of LAA thrombus resolution, study treatment is stopped. The further treatment of the patient after the trial will follow the patient’s individual needs at the discretion of the treating physician. The study is terminated for each patient with the demonstration of LAA thrombus resolution. For patients with a LAA thrombus persisting after 6 weeks of treatment, the study will also be terminated and further treatment strategies will be decided by the patient´s treating physician. Phenprocoumon Once a patient is randomized to the phenprocoumon arm, the phenprocoumon dose has to be adjusted to an INR of 2–3. If the patient received phenprocoumon before study enrolment, VKA treatment is continued and surveyed by the patient´s treating physician. To ensure INR adjustment to 2–3 during the trial, the INR will be measured additionally at the time of the study visits and phenprocoumon dose modifications can be done by the investigator, if indicated. Administration of phenprocoumon and dosing follows patient´s individual requirements in order to achieve INR adjustment to 2–3. Enoxaparin If the patient is randomized to phenprocoumon and has not been treated with phenprocoumon before the trial, he/she will receive in addition an initial bridging treatment with low-molecular weight heparin (LMWH) enoxaparin at 1 mg/kg bid until an international normalized ratio (INR) of C2.0 is achieved under phenprocoumon. Thereafter, phenprocoumon will be administered dose-adjusted aiming at an INR of 2–3. Assessment of efficacy The primary efficacy parameter is the time to complete LAA thrombus resolution assessed by TEE. The resolution

Clin Res Cardiol Table 1 Inclusion and exclusion criteria Inclusion criteria

Exclusion criteria

Patients with documented non-valvular AF or atrial flutter (12-lead ECG)

Patients [80 years

Newly diagnosed or confirmed LAA thrombus formation in TEE (time of detection less than 7 days)

Low body weight (\50 kg)

Patients C18 years old

Previous failure of LAA thrombus resolution with a VKA or factor Xa antagonist

CHA2DS2-VASc score C1

Occurrence of LAA thrombus under long-term treatment ([3 months) with vitamin K antagonists

CrCL C50 mL/min (Cockcroft-Gault)

Contraindications for oral anticoagulation therapy

Ability of the patient to understand the character and the individual consequences of the clinical trial

History of heart valve disorder (i.e., prosthetic valve or hemodynamically relevant valve disease)

Signed and dated informed consent of the patient must be available before start of any specific trial procedures

Valvular heart disease requiring intervention (including mechanical valves)

Women with childbearing potential have to practice a medically accepted contraception during the trial and a negative pregnancy test (serum and urine) should be existent before trial onset. In case of Phenprocoumon as study medication, a reliable contraception has to be continued 3 months after last intake of Phenprocoumon, due to the teratogenic potential of MarcumarÒ. Reliable contraceptive methods are systematic contraceptives (oral, implant, injection) and diaphragm or condoms with a spermicide. Women that are sterile by surgery or for more than 2 years postmenopausal can participate in the trial. The investigator has to discuss an adequate and reliable contraception method with the patient

Acute myocardial infarction or MI within the last 26 weeks Acute coronary syndrome (e.g., instable angina pectoris, STEMI, NSTEMI) Chronic heart failure ([ YHA 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 50 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/day Concomitant treatment with high doses of adenosine diphosphate (ADP) receptor inhibitors (e.g., clopidogrel) at doses [75 mg/day 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 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

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has to be as complete as it would be required for the conduct of cardioversion. Complete LAA thrombus resolution is defined as the absence of an echo-dense intracavitary mass in the LAA. LAA thrombi are being identified as a mobile or sessile, irregularly shaped, grey, textured density that is clearly separated from the lining of the atrial appendage. It is an echo-dense intracavitary mass that is acoustically distinct from the endocardium [35]. Special care has to be taken to exclude artefacts from the rim to the left superior pulmonary vein. In doubt, application of contrast medium is indicated. Spontaneous echo contrast is a risk factor but distinct from thrombi and can be graded in a score from 0 to 4 according to the classification of Fatkin et al. [36]. Low LAA emptying peak flow velocities below 30 or 25 cm/s indicate high-risk populations for thrombi. Flow velocities within each RR cycle are averaged over a minimum of 5 heart cycles. The confirmation of a LAA thrombus will be done by TEE before inclusion of a patient in the trial. TEE will be performed by a clinician who is in charge of TEE examination in the clinical department of the trial site. Assessment of the TEE results, and especially the diagnosis and resolution of a LAA thrombus as well as its documentation in the patient file, will be done according to the established usual procedures in the respective institution. All TEE images will be validated by either of two independent core laboratory facilities after the end of trial for each patient. Before patient recruitment, the trial sites will be randomly assigned to one of the two Core Laboratories. Images will be blinded regarding the study treatment (rater-blinded study) and the TEE assessments of the study centres. LAA analysis includes LAA size and area in 45°–60° and 135° as a minimum for at least 5 heart cycles. For LAA size determination, the lengths of two axes in two orthogonal layers have to be measured. The estimation of the LAA thrombus volume will be calculated by the TEE software. Complete thrombus resolution is defined as the absence of any echo-dense intracavitary mass in the LAA. In cases the LAA thrombus evaluation of the study centres differs from the evaluation of the core laboratory, the evaluation of the core laboratory will be accounted for the analyses.

Treatment with vitamin K antagonists is recommended for 3–6 weeks with an INR between 2.0 and 3.0 according to current AF guidelines [6]. Due to the faster onset of action of dabigatran and a more predictable action profile as compared to phenprocoumon, we assume a median time to complete LAA thrombus resolution of 4 weeks, based on data from case reports [24, 25], under treatment with dabigatran and of 5 weeks under phenprocoumon treatment [19]. In order to detect a difference in time to complete LAA thrombus resolution between treatment groups, a two-sided log-rank test (alpha = 5 %) comprising 55 patients per group will achieve a power of 14.9 %. With a 20 % drop out rate until week 6, power turns out as 14.0 %. With these assumptions, the expected number of complete LAA thrombus resolutions will be 36 and 31 for the dabigatran and phenprocoumon treatment groups, respectively.

Statistical considerations

Efficacy analyses

Sample size

The primary population for the analyses of efficacy is the mITT population. The time to complete LAA thrombus resolution will be compared using the two-sided log-rank test at a significance level of 5 %. The analysis will be based on the modified intention-to-treat population. Kaplan–Meier curves will be presented for both groups. A sensitivity analysis will be performed in the per protocol population. In the primary analysis, patients with missing

The below calculated power based on 55 patients per group is regarded as sufficient to gain first data with respect to the differences in time to complete LAA thrombus resolution under the two treatments. The sample size required to achieve 80 % power was not calculated for this explorative trial.

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Analysis populations All patients who signed informed consent are considered as enrolled patients. All patients who were assigned to a randomization number are considered as randomized patients, even if they did not receive any trial treatment. All randomized patients, except for those for whom LAA thrombus existence is not confirmed by the core laboratory, will be included in the modified Intention-totreat (mITT) population. This population is the primary analysis population. Within mITT population analyses, patients will be assigned to the treatment to which they were randomized. The Per Protocol population (PP) comprises all mITT patients with a minimum of protocol adherence (no unallowed concomitant medication, treatment compliance of at least 90 % measured by drug accountability, visits performed according to the trial schedule, no refusals of planned TEE). The safety population comprises all patients who received at least one dose of trial treatment. In analyses of the safety population, patients will be assigned to the treatment which they actually received. The analysis populations will be defined prior to database closure.

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complete LAA thrombus resolution status at week 6 will be censored at the time of last LAA thrombus evaluation (including the baseline visit). Analysis of secondary endpoints Complete LAA thrombus resolution rates until week 6 will be calculated and compared between treatment groups by an explorative two-sided Chi-square test. Change in LAA thrombus volume under treatment will be analysed descriptively by supplying distributional parameters (mean, standard deviation, minimum, median, maximum) separately for each visit and treatment. If sufficient measurements are available, explorative analyses using generalized estimating equations (GEE) will be performed. In analogy to the analysis of the primary endpoint, the core laboratory assessments overrule the LAA thrombus assessments (resolution status and volume) at the trial sites in case of discrepancies. This may lead to missing information concerning LAA thrombus resolution at week 6 for single patients. Frequencies of patients experiencing at least one adverse event (AE) will be displayed by body system and preferred term according to MedDRA terminology. Detailed information for each AE will include a description of the event, its duration, whether the AE was serious, intensity, relationship to trial treatment, action taken and clinical outcome. Summary tables will present the number of patients observed with AEs and the corresponding percentages. A patient listing of all AEs will be prepared. All other secondary endpoints will be analysed by absolute and relative frequencies for each treatment arm. All analyses of secondary endpoints will be interpreted in an explorative way.

thromboembolic events in case of sub-therapeutic doses. Concerning the benefit of the use of dabigatran, there is a scientifically based assumption that it exerts thrombus resolving effects on LAA thrombi as supported by the pharmacological profile and individual case reports [23–26]. In conclusion, this trial is addressing an important issue in patients with LAA thrombus who are definitely in need of oral anticoagulant therapy by assessing the thrombus resolution effects of the non-vitamin K antagonist direct factor IIa inhibitor dabigatran and the vitamin K antagonist phenprocoumon. Acknowledgments RE-LATED AF is an investigator-initiated trial (IIT) and supported by a grant of Boehringer Ingelheim Pharma GmbH & Co. KG to and by an additional research grant provided by the University Medical Center of the Johannes Gutenberg-University Mainz. This clinical trial is performed under the patronage of the German Competence Network on Atrial Fibrillation (AFNET e.V.; http://www.kompetenznetz-vorhofflimmern.de/en/home) as RELATED AF – AFNET 7 and in close collaboration with AFNET e.V. members and its clinical trial sites. Principal investigator: Thomas Mu¨nzel, Mainz. Members of the Steering Committee: Gu¨nter Breithardt, Mu¨nster (Chairman), Lars Eckardt, Mu¨nster, Thomas Rostock, Mainz, Monika Seibert-Grafe, Mainz. Independent Data Monitoring Committee: Dietrich Andresen, Berlin, Wolfgang Ko¨pcke, Mu¨nster. Core Laboratories: Andreas Hagendorff, Leipzig, Stephan von Bardeleben, Mainz. We would like to thank all members of these committees as well as all investigators for their contribution to the trial. We would also like to thank members of the BMBF-funded IZKS (Funding No.: 01KN1103) for regulatory work, monitoring, data and safety management. Conflict of interest G. Breithardt has previously received educational funds for the AFNET from Boehringer Ingelheim, and he has been on advisory boards of this company. In addition, he has been on advisory boards of Bayer Health Care, Johnson & Johnson, BMS/ Pfizer, MSD, Portola, and has received research grants from Meda Pharma, Biosense, St. Jude Medical, Sanofi-Aventis, BMS/Pfizer, and Daiichi-Sankyo, all either provided to the Westfa¨lische WilhelmsUniversita¨t for work done by AFNET or directly to AFNET e.V., Mu¨nster, Germany.

Conclusion To the best of our knowledge, RE-LATED AF is the first prospective, randomized clinical trial investigating the NOAC dabigatran vs. phenprocoumon for resolution of LAA thrombus in patients with non-valvular AF. The open label design is close to clinical practice and should therefore provide results allowing to draw conclusions on the potential benefits of using an NOAC-like dabigatran in comparison to a conventional VKA for management of patients with atrial thrombi. Due to the short treatment duration of a maximum of 6 weeks (compared to 6 months in the RE-COVER trial [37], and a mean of 2 years in the RE-LY trial [38] ) and the exclusion of patients at risk, there is no concern of unexpected harm for study participants. In addition, the diagnosis of LAA thrombus presents a clear indication for anticoagulation which implies the risk of bleeding and for

References 1. Wallace TW, Atwater BD, Daubert JP et al (2010) Prevalence and clinical characteristics associated with left atrial appendage thrombus in fully anticoagulated patients undergoing catheterdirected atrial fibrillation ablation. J Cardiovasc Electrophysiol 21:849–852 2. Khan MN, Usmani A, Noor S et al (2008) Low incidence of left atrial or left atrial appendage thrombus in patients with paroxysmal atrial fibrillation and normal EF who present for pulmonary vein antrum isolation procedure. J Cardiovasc Electrophysiol 19:356–358 3. Klein AL, Grimm RA, Murray RD et al (2001) Use of transesophageal echocardiography to guide cardioversion in patients with atrial fibrillation. N Engl J Med 344:1411–1420 4. Wasmer K, Kobe J, Dechering D et al (2013) CHADS(2) and CHA(2)DS (2)-VASc score of patients with atrial fibrillation or flutter and newly detected left atrial thrombus. Clin Res Cardiol Off J German Cardiac Soc 102:139–144

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Clin Res Cardiol 5. Stoddard MF, Singh P, Dawn B, Longaker RA (2003) Left atrial thrombus predicts transient ischemic attack in patients with atrial fibrillation. Am Heart J 145:676–682 6. European Heart Rhythm A, European Association for CardioThoracic S, Camm AJ et al (2010) Guidelines for the management of atrial fibrillation: the task force for the management of atrial fibrillation of the European society of Cardiology (ESC). Eur Heart J 31:2369–2429 7. Hohnloser SH, Oldgren J, Yang S et al (2012) Myocardial ischemic events in patients with atrial fibrillation treated with dabigatran or warfarin in the RE-LY (randomized evaluation of long-term anticoagulation therapy) trial. Circulation 125:669–676 8. Hirsh J, Fuster V, Ansell J, Halperin JL (2003) American Heart Association/American College of Cardiology F. American Heart Association/American College of Cardiology Foundation guide to warfarin therapy. J Am Coll Cardiol 41:1633–1652 9. Lip GY, Ramsay SG (2012) Insights from the RCPE UK consensus conference on approaching the comprehensive management of atrial fibrillation. Exp Rev Cardiovasc Ther 10:697–700 10. Skeppholm M, Friberg L (2014) Adherence to warfarin treatment among patients with atrial fibrillation. Clin Res Cardiol Off J German Cardiac Soc 103:998–1005 11. Camm AJ, Lip GY, De Caterina R et al (2012) 2012 focused update of the ESC Guidelines for the management of atrial fibrillation: an update of the 2010 ESC Guidelines for the management of atrial fibrillation. Developed with the special contribution of the European Heart Rhythm Association. Eur Heart J 33:2719–2747 12. Caldeira D, Costa J, Ferreira JJ, Lip GY, Pinto FJ (2015) Nonvitamin K antagonist oral anticoagulants in the cardioversion of patients with atrial fibrillation: systematic review and metaanalysis. Clin Res Cardiol Off J German Cardiac Soc. doi:10. 1007/s00392-015-0821-8 13. Nielsen PB, Lane DA, Rasmussen LH, Lip GY, Larsen TB (2015) Renal function and non-vitamin K oral anticoagulants in comparison with warfarin on safety and efficacy outcomes in atrial fibrillation patients: a systemic review and meta-regression analysis. Clin Res Cardiol Off J German Cardiac Soc 104:418–429 14. Ruff CT, Giugliano RP, Braunwald E et al (2014) Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. Lancet 383:955–962 15. Zylla MM, Pohlmeier M, Hess A et al (2015) Prevalence of intracardiac thrombi under phenprocoumon, direct oral anticoagulants (dabigatran and rivaroxaban), and bridging therapy in patients with atrial fibrillation and flutter. Am J Cardiol 115:635–640 16. Seidl K, Rameken M, Drogemuller A et al (2002) Embolic events in patients with atrial fibrillation and effective anticoagulation: value of transesophageal echocardiography to guide direct-current cardioversion. Final results of the Ludwigshafen Observational Cardioversion Study. J Am Coll Cardiol 39:1436–1442 17. Collins LJ, Silverman DI, Douglas PS, Manning WJ (1995) Cardioversion of nonrheumatic atrial fibrillation. Reduced thromboembolic complications with 4 weeks of precardioversion anticoagulation are related to atrial thrombus resolution. Circulation 92:160–163 18. Corrado G, Tadeo G, Beretta S et al (1999) Atrial thrombi resolution after prolonged anticoagulation in patients with atrial fibrillation. Chest 115:140–143 19. Jaber WA, Prior DL, Thamilarasan M et al (2000) Efficacy of anticoagulation in resolving left atrial and left atrial appendage thrombi: a transesophageal echocardiographic study. Am Heart J 140:150–156 20. Saeed M, Rahman A, Afzal A et al (2006) Role of transesophageal echocardiography guided cardioversion in patients

123

21.

22.

23. 24.

25. 26.

27.

28. 29.

30.

31.

32.

33.

34.

35. 36.

37.

38.

with atrial fibrillation, previous left atrial thrombus and effective anticoagulation. Int J Cardiol 113:401–405 Fukuda S, Watanabe H, Shimada K et al (2011) Left atrial thrombus and prognosis after anticoagulation therapy in patients with atrial fibrillation. J Cardiol 58:266–277 Husted S, de Caterina R, Andreotti F et al (2014) Non-vitamin K antagonist oral anticoagulants (NOACs): no longer new or novel. Thromb Haemost 111:781–782 Vidal A, Vanerio G (2012) Dabigatran and left atrial appendage thrombus. J Thromb Thrombolysis 34:545–547 Nagamoto Y, Shiomi T, Sadamatsu K (2013) Thrombolytic action of dabigatran in patients with acute pre-existing atrial thrombus. Europace European pacing, arrhythmias, and cardiac electrophysiology. J Working Groups Cardiac Pacing Arrhythmias Cardiac Cell Electrophysiol Eur Soc Cardiol 15:1608 Morita S, Ajiro Y, Uchida Y, Iwade K (2013) Dabigatran for left atrial thrombus. Eur Heart J 34:2745 Hammerstingl C, Potzsch B, Nickenig G (2013) Resolution of giant left atrial appendage thrombus with rivaroxaban. Thromb Haemost 109:583–584 Kawakami T, Kobayakawa H, Ohno H, Tanaka N, Ishihara H (2013) Resolution of left atrial appendage thrombus with apixaban. Thrombosis J 11:26 Dobashi S, Fujino T, Ikeda T (2014) Use of apixaban for an elderly patient with left atrial thrombus. BMJ Case Rep 2014 Takasugi J, Yamagami H, Okata T, Toyoda K, Nagatsuka K (2013) Dissolution of the left atrial appendage thrombus with rivaroxaban therapy. Cerebrovasc Dis 36:322–323 Nagarakanti R, Ezekowitz MD, Oldgren J et al (2011) Dabigatran versus warfarin in patients with atrial fibrillation: an analysis of patients undergoing cardioversion. Circulation 123:131–136 Lip GY, Hammerstingl C, Marin F et al (2015) Rationale and design of a study exploring the efficacy of once-daily oral rivaroxaban (X-TRA) on the outcome of left atrial/left atrial appendage thrombus in nonvalvular atrial fibrillation or atrial flutter and a retrospective observational registry providing baseline data (CLOT-AF). Am Heart J 169(464–71):e2 Bernhardt P, Schmidt H, Hammerstingl C et al (2004) Fate of left atrial thrombi in patients with atrial fibrillation determined by transesophageal echocardiography and cerebral magnetic resonance imaging. Am J Cardiol 94:801–804 Ammollo CT, Semeraro F, Incampo F, Semeraro N, Colucci M (2010) Dabigatran enhances clot susceptibility to fibrinolysis by mechanisms dependent on and independent of thrombin-activatable fibrinolysis inhibitor. JTH 8:790–798 Schulman S, Kearon C (2005) Subcommittee on control of anticoagulation of the S, Standardization Committee of the International Society on T, Haemostasis. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. JTH 3:692–694 Otto C (2002) The practice of clinical echocardiography, 2nd edn. WB Saunders Co, Philadelphia Fatkin D, Loupas T, Jacobs N, Feneley MP (1995) Quantification of blood echogenicity: evaluation of a semiquantitative method of grading spontaneous echo contrast. Ultrasound Med Biol 21:1191–1198 Schulman S, Kearon C, Kakkar AK et al (2009) Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med 361:2342–2352 Connolly SJ, Ezekowitz MD, Yusuf S et al (2009) Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 361:1139–1151