Prevention of Silent Cerebral Thromboembolism by Oral Anticoagulation With Dabigatran After Pulmonary Vein Isolation for Atrial Fibrillation (ODIn-AF)

Oral anticoagulation treatment (OAC) following clinically successful catheter abla-tion of atrial fibrillation (AF) is controversial. Recent guidelines recommended con-tinuation of OAC in all patients with CHA2DS2VASc score ≥2 even if there is no evidence of recurrent AF (Camm JA et al., Eur Heart J 2012). The net clinical ben-efit of OAC after successful ablation in these patients remains to some extent un-clear. As OAC bears the risk of bleeding events, the ODIn-AF study aims to evalu-ate the positive effect of OAC on the incidence of silent cerebral embolic events in patients with a high risk for embolic events, free from AF after successful pulmo-nary vein ablation. ODIn-AF aims to determine that continued administration of dabigatran is superior in the preven-tion of silent cerebral embolism to discontinuation of OAC after 3 months in pa-tients free from symptomatic AF-episodes with a CHA2DS2VASc score ≥2 after the first pulmonary vein ablation for paroxysmal AF.

Study Overview

• Status: Completed
• Conditions: Atrial Fibrillation; Oral Anticoagulation; Cardioembolic Events
• Intervention / Treatment: Drug: Dabigatran

• Study Type: Interventional
• Enrollment (Actual): 200
• Phase: Phase 4

Contacts and Locations

Study Locations

• Germany
  • Bad Krozingen, Germany, 79189
    • Heart Center Freiburg University Bad Krozingen
  • Bad Neustadt An Der Saale, Germany, 97616
    • Heart Center Bad Neustadt-Saale
  • Bielefeld, Germany, 33604
    • Bielefeld Clinical Centre
  • Bonn, Germany, D-53105
    • Dept. of Medicine-Cardiology University Clinic Bonn
  • Cologne, Germany, 50937
    • University Hospital Cologne
  • Gießen, Germany, 35392
    • University Hospital Gießen
  • Gottingen, Germany, 37075
    • University Hospital Göttingen
  • Hannover, Germany, 30625
    • Hannover Medical School
  • Kaiserslautern, Germany, 67655
    • Westpfalz-Clinic GmbH Kaiserslautern
  • Karlsruhe, Germany, 76133
    • Municipal Clinical Center Karlsruhe
  • Karlsruhe, Germany, 76137
    • St. Vincentius Hospital
  • Leipzig, Germany, 04289
    • Heart Center Leipzig
  • Ludwigshafen, Germany, 67063
    • Ludwigshafen Hospital
  • Lüdenscheid, Germany, 58515
    • Hospital Lüdenscheid
  • Mannheim, Germany, 68167
    • University Hospital Mannheim
  • Munich, Germany, 81379
    • Peter Osypka Heart Center
  • Tübingen, Germany, 72076
    • University Hospital Tübingen
  • Villingen Schwenningen, Germany, 78050
    • Schwarzwald-Baar Hospital Villingen Schwenningen
  • Wuppertal, Germany, 42117
    • Helios Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion criteria:

1. Written informed consent
2. Patients undergoing circumferential antral PV ablation for non-valvular (mitral regurgitation less than moderate- severe insufficiency; no relevant mitral stenosis with a mean pressure gradient >5mmHg) symptomatic, paroxysmal AF or persistent AF (duration < 12 months) with risk factors resulting in a CHA2DS2VASc score ≥2, using a cooled tip RF-, laser- or cryo-balloon-catheter.
3. CHA2DS2VASc score ≥2

Randomization criteria:

1. Sinus rhythm (as assessed by 72h Holter ECG) following the 3 months blanking and 3 months observation period after first or second pulmo-nary vein ablation procedure
2. No clinical evidence of recurrent AF after completing 3 months blanking and 3 months observation period as assessed by symptoms
3. No other relevant contraindication for OAC assessed by randomization MRI of the brain

Exclusion criteria:

1. Severe mental retardation or psychiatrical disorder resulting in incapabil-ity to adequately understand nature, significance, implications and risks of study parcipitation (i.e. bipolar disorders, severe depression, suicidal tendencies, among others) as judged by the local physician, ongoing drug or alcohol addiction (> 8 drinks/week)
2. Pregnancy /breast feeding
3. Severely impaired renal function, GFR < 30 ml/min
4. Impaired liver function (ALT/AST transaminase count 3fold higher than normal values) or liver disease with reduced life expectancy <1 year
5. Valvular AF (moderate- severe mitral insufficiency; relevant mitral steno-sis with a mean pressure gradient >5mmHg)
6. Long standing persistent (>12 months) and permanent AF
7. NSTEMI/STEMI/implantated drug eluting stent with indication for dual antiplatelet therapy within 12 months before enrolment
8. History of complex left atrial ablation procedures. One previous PVI al-lowed.
9. Clinical indication for extended left atrial ablation procedures (CFAE-, rotor-ablation)
10. History or presence of left atrial or ventricular thrombus
11. History of stroke / TIA independent from etiology
12. Acute major bleedings
13. Lesion or condition, if considered a significant risk factor for major bleeding. This may include current or recent gastrointestinal ulceration, presence of malignant neoplasms at high risk of bleeding, recent brain or spinal injury, recent brain, spinal or ophthalmic surgery, recent intracranial haemorrhage, known or suspected oesophageal varices, arteriovenous malformations, vascular aneurysms or major intraspinal or intracerebral vascular abnormalities
14. Need for concomitant anitcoagulation in addition to dabigatran
15. History of previous surgery resulting in contraindication for OAC
16. History of malignoma resulting in contraindication for OAC
17. Mechanical prosthetic heart valve or other indication for permanent OAC
18. Contraindication for MRI (i.e. metal implants unsuitable for MRI, wearing of magnetic or metallic objects that cannot be removed from the body (such as body piercing, implanted electrodes, contraceptive coil), inabil-ity to lie on the back for an extended period of time, uncontrollable claustrophobia, hypersensitivity to noise etc.). Pacemaker and ICD-patients may be included at the discretion of the local investigators/radiologists if MRI is warranted
19. Hypersensitivity against dabigatran or other ingredients of the medical product
20. Concomitant medication with dronedarone, ketoconazole, itraconazole, cyclosporine, tacrolimus or other interacting drugs as specified in the drug information
21. Simultaneous participation in any clinical trial involving administration of an investigational medicinal product within 30 days prior to clinical trial beginning
22. Females of childbearing potential, who are not using or not willing to use medically reliable methods of contraception for the entire study duration (such as oral, injectable, or implantable contraceptives, or intrauterine contraceptive devices) unless they are surgically sterilized / hysterectomized or there are any other criteria considered sufficiently reliable by the investigator in individual cases
23. Conditions which interfere with the study treatment at the discretion of the investigator

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Oral Anticoagulation with Dabigatran; The recommended daily dose of Pradaxa is 300 mg taken as one 150 mg capsule twice daily. For the following patients the recommended daily dose of Pradaxa is 220 mg taken as one 110 mg capsule twice daily: Patients aged 75 years or above; Cr-Cl 30-50 ml/min; Patients who receive concomitant verapamil For the following groups, the daily dose of Pradaxa of 300 mg or 220 mg should be selected based on an individual assessment of the thromboembolic risk and the risk of bleeding: Patients with moderate renal impairment; Patients with gastritis, esophagitis or gastroesophageal reflux; Other patients at increased risk of bleeding	Drug: Dabigatran; Antral pulmonary vein ablation for patients with AF; left atrial fibrosis/electrical scar assessment by electroanatomical mapping; followed by 6 months OAC (3 months blanking period + 3 months observation period); in case of AF-recurrence in month 4-6: re- pulmonary vein ablation; followed again by 6 months OAC (3 months blanking period + 3 months observation period) AF-free patients as assessed by 72h Holter ECG and symptoms wil be random-izedals to the following two interventional arms: Experimental arm (group A): OAC with dabigatran for 12 months; Control arm (group B): No OAC (no placebo medication) for 12 months - Cerebral MRI at randomisation and 12 months later
No Intervention: No Oral Anticoagulation

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Incidence of new micro- and macro-embolic lesions on cerebral MRI incl. flare and diffusion weighted imaging 12 months after randomization compared to baseline MRI (3 months after AF catheter ablation)	12 months

Secondary Outcome Measures

Outcome Measure	Time Frame
Location, size and number of new micro- and macro-embolic lesions on cerebral MRI	12 months
Incidence of clinically evident cardio-embolic events (stroke, TIA, systemic embolism)	12 months
Severity of neurological deficits assessed by Modified Rankin Scale	12 months
Incidence of other thrombotic or thrombo-embolic events (myocardial in-farction, deep vein thrombosis, pulmonary embolism)	12 months
Life-threatening / major / minor bleedings	12 months
Hemorrhagic cerebral infarction	12 months
All-cause mortality / Cardiovascular mortality	12 months
Correlation of cardio-embolic events to method used for PVI (cryo-balloon versus RF)	12 months
Correlation of cardio-embolic events with arrhythmia recurrence (atrial fi-brillation or atrial flutter post ablationem with ECG documentation or symp-toms)	12 months
Quality of life questionnaire (AF-specific symptoms, SF36)	12 months
Neuropsychological questionnaire (RBANS A&B)	12 months
Assessment of neurocognitive deficits: Minimental Test	12 months

Other Outcome Measures

Outcome Measure	Time Frame
Major / minor bleeding events	12 months
Clinically evident cardio-embolic events	12 months
Serious Adverse Events	12 months

Collaborators and Investigators

• Sponsor: Georg Nickenig
• Collaborators: Boehringer Ingelheim

Publications and helpful links

General Publications

• Schrickel JW, Linhart M, Bansch D, Thomas D, Nickenig G. Rationale and design of the ODIn-AF Trial: randomized evaluation of the prevention of silent cerebral thromboembolism by oral anticoagulation with dabigatran after pulmonary vein isolation for atrial fibrillation. Clin Res Cardiol. 2016 Feb;105(2):95-105. doi: 10.1007/s00392-015-0933-1. Epub 2015 Oct 29.

Study record dates

Study Major Dates

• Study Start: August 1, 2015
• Primary Completion (Actual): September 15, 2020
• Study Completion (Actual): September 15, 2020

Study Registration Dates

• First Submitted: February 18, 2014
• First Submitted That Met QC Criteria: February 18, 2014
• First Posted (Estimate): February 20, 2014

Study Record Updates

• Last Update Posted (Actual): November 7, 2022
• Last Update Submitted That Met QC Criteria: November 4, 2022
• Last Verified: November 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Embolism and Thrombosis; Arrhythmias, Cardiac; Atrial Fibrillation; Thromboembolism; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protease Inhibitors; Antithrombins; Serine Proteinase Inhibitors; Anticoagulants; Dabigatran
• Other Study ID Numbers: MED2-201301; 2013-003492-35 (EudraCT Number)