Long-term, Open-label Follow-up Treatment of Patients With A-fib Who Have Been Previously Treated With BIBR 1048

Study Overview
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Brief Summary
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To determine the long term safety and efficacy of BIBR 1048 in patients with chronic atrial fibrilla tion, with or without concomitant chronic treatment with acetylsalicylic acid (ASA).

Official Title
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Long-term, Open-label Follow-up Treatment of Patients With Atrial Fibrillation Who Have Been Previously Treated With BIBR 1048 in the PETRO Trial (Trial 1160.20 - NCT01227629). (PETRO Extension Trial: PETRO-Ex)

Conditions
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Stroke, Atrial Fibrillation

Intervention / Treatment
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* Drug: dabigatran etexilate
* Drug: dabigatran etexilate
* Drug: dabigatran etexilate
* Drug: dabigatran etexilate


Participation Criteria
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Eligibility Criteria
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Inclusion criteria Diagnosis and main criteria for inclusion: Paroxysmal, persistent, or permanent (chronic) non-rheumatic atrial fibrillation with a history of coronary artery disease (CAD) Inclusion Criteria: previous treatment with BIBR 1048 in PETRO (trial 1160.20- NCT01227629) and no premature discontinuation of therapy paroxysmal, persistent, or permanent (chronic) non-rheumatic atrial fibrillation, documented by electrocardiogram (ECG) at least twice prior to enrollment in PETRO concomitant coronary artery disease -an additional risk factor for stroke (one or more of the following conditions/events): hypertension, diabetes mellitus (DM), congestive heart failure (CHF) or Left ventricular dysfunction (LVD), previous ischemic stroke or transient ischemic attack) TIA, or age greater than 75 years. -age >= 18 years written, informed consent Exclusion criteria Exclusion Criteria: Valvular heart disease conferring significantly increased risk of thromboembolic events (e.g. clinically significant mitral stenosis or prosthetic valves). planned cardioversion while patients are in the study. contraindication to anticoagulant therapy (previous intracranial hemorrhage, gastro-intestinal (GI) hemorrhage within previous 3 months, previous severe hemorrhage with warfarin at therapeutic international normalized ratio (INR), regular use of non-steroidal anti-inflammatory drugs, hemorrhagic diathesis) major bleeding within the last 6 months (other than GI hemorrhage). severe renal impairment (estimated glomerular filtration rate [GFR] <= 30 mL/min). uncontrolled hypertension (systolic blood pressure [SBP] > 180 mm Hg and/or diastolic blood pressure [DBP] > 100 mmHg). Women who are pregnant or of childbearing potential who refuse to use a medically acceptable form of contraception throughout the study (note: a negative pregnancy test must be obtained for any woman of childbearing potential prior to entry into the study). Patients who have received an investigational drug other than BIBR 1048 within the last 30 days. Patients considered unreliable by the investigator concerning the requirements for follow-up during the study and/or compliance with study drug administration. Another indication for anticoagulant treatment (eg, deep vein thrombosis or pulmonary embolus). Clinically significant anemia (note: patients with mild-moderate anemia should only be enrolled after the possibility of a GI bleeding source has been evaluated, the etiology of the anemia identified, and appropriate action taken). Patients suffering from thrombocytopenia (platelets < 100,000/uL). Any other condition which, in the discretion of the investigator, would not allow safe participation in the study. Continuing or planned concomitant treatment with antiplatelet agents other than acetylsalicylic acid (ASA). Recent malignancy or radiation therapy (<= 6 months).

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Non-Randomized
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: dabigatran etexilate, 150 mg once daily<br>dosage used at study start | Drug: dabigatran etexilate<br>* dosage used at study start<br>|
| Experimental: dabigatran etexilate, 150 mg twice daily<br>dosage used at study start | Drug: dabigatran etexilate<br>* dosage used at study start<br>|
| Experimental: dabigatran etexilate, 300 mg once daily<br>dosage used at study start | Drug: dabigatran etexilate<br>* dosage used at study start<br>|
| Experimental: dabigatran etexilate, 300 mg twice daily<br>dosage used at study start | Drug: dabigatran etexilate<br>* dosage used at study start<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Yearly Event Rate for Composite Endpoint of Stroke, Transient Ischaemic Attacks, System Thromboembolism, Myocardial Infarction, Other Major Adverse Cardiac Events and Mortality. | Time to first occurrence of stroke, transient ischaemic attacks, system thromboembolism, myocardial infarction, other major adverse cardiac events and mortality. Yearly event rate (%) = number of subjects with event / subject-years * 100. Subject years = sum (date of end of treatment - date of start of treatment) of all entered subjects / 365.25 | 5 years | 
| Yearly Event Rate for Major Bleeding | Time to first occurrence of fatal or life-threatening, retroperitoneal, intracranial, intraocular, or intraspinal bleeding, which required surgical treatment, led to a transfusion of a minimum of 2 units of packed cells or whole blood, or led to a fall in hemoglobin of 20g/L or less. Yearly event rate (%) = number of subjects with event / subject-years * 100. Subject years = sum (date of end of treatment - date of start of treatment) of all entered subjects / 365.25 | 5 years | 
| Yearly Event Rate for Major + Minor/Relevant Bleeding | Time to first occurrence of either major or minor/relevant bleeding. Yearly event rate (%) = number of subjects with event / subject-years * 100. Subject years = sum (date of end of treatment - date of start of treatment) of all entered subjects / 365.25 | 5 years | 
| Yearly Event Rate for Any Bleeding | Time to first occurrence of any bleeding event. Yearly event rate (%) = number of subjects with event / subject-years * 100. Subject years = sum (date of end of treatment - date of start of treatment) of all entered subjects / 365.25 | 5 years | 
| Yearly Event Rate for Minor Bleeding | Time to first occurrence of minor bleeding. A minor bleeding event is any bleed that does not qualify as a major bleed. All minor bleeding events not fulfilling one of the criteria for clinically relevant were classified as nuisance bleeds. Clinically-relevant was defined as spontaneous skin hematoma ≥25 cm², spontaneous nose bleed >5 min, macroscopic hematuria spontaneous or lasting longer than 24 hours if associated with an intervention, spontaneous rectal bleeding, gingival bleeding >5 min, leading to hospitalization, leading to a transfusion of <2 units of packed cells or whole blood and any other bleeding event considered clinically relevant by the investigator. Yearly event rate (%) = number of subjects with event / subject-years * 100. Subject years = sum (date of end of treatment - date of start of treatment) of all entered subjects / 365.25 | 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Yearly Event Rate for Stroke | Time to first occurrence of any fatal or non-fatal stroke. Yearly event rate (%) = number of subjects with event / subject-years * 100. Subject years = sum (date of end of treatment - date of start of treatment) of all entered subjects / 365.25 | 5 years | 
| Yearly Event Rate of Ischaemic Stroke | Time to first occurrence of any ischaemic stroke. Yearly event rate (%) = number of subjects with event / subject-years * 100. Subject years = sum (date of end of treatment - date of start of treatment) of all entered subjects / 365.25 | 5 years | 
| Yearly Event Rate of Haemorrhagic Stroke | Time to first occurrence of any haemorrhagic stroke. Yearly event rate (%) = number of subjects with event / subject-years * 100. Subject years = sum (date of end of treatment - date of start of treatment) of all entered subjects / 365.25 | 5 years | 
| Yearly Event Rate for Transient Ischaemic Attacks | Time to first occurrence of any transient ischaemic attacks. Yearly event rate (%) = number of subjects with event / subject-years * 100. Subject years = sum (date of end of treatment - date of start of treatment) of all entered subjects / 365.25 | 5 years | 
| Yearly Event Rate for Systemic Thromboembolism | Time to first occurrence of any non-central nervous system systemic thromboembolism. Yearly event rate (%) = number of subjects with event / subject-years * 100. Subject years = sum (date of end of treatment - date of start of treatment) of all entered subjects / 365.25 | 5 years | 
| Yearly Event Rate of Myocardial Infarction | Time to first occurrence of any myocardial infarction. Yearly event rate (%) = number of subjects with event / subject-years * 100. Subject years = sum (date of end of treatment - date of start of treatment) of all entered subjects / 365.25 | 5 years | 
| Yearly Event Rate of Other Major Adverse Cardiac Events | Time to first occurrence of any other major adverse cardiac events. Yearly event rate (%) = number of subjects with event / subject-years * 100. Subject years = sum (date of end of treatment - date of start of treatment) of all entered subjects / 365.25 | 5 years | 
| Yearly Event Rate of Death | Time to death of any cause. Yearly event rate (%) = number of subjects with event / subject-years * 100. Subject years = sum (date of end of treatment - date of start of treatment) of all entered subjects / 365.25 | 5 years | 
| Yearly Event Rate for Composite Secondary Endpoint of Ischaemic Stroke, Transient Ischaemic Attacks, Non-central Nervous System Systemic Thromboembolism, Myocardial Infarction, Other Major Adverse Cardiac Events and All-cause Mortality | Time to first occurrence of ischaemic stroke, transient ischaemic attacks, non-central nervous system systemic thromboembolism, myocardial infarction, other major adverse cardiac events and all-cause mortality. Yearly event rate (%) = number of subjects with event / subject-years * 100. Subject years = sum (date of end of treatment - date of start of treatment) of all entered subjects / 365.25 | 5 years | 
| Severe Adverse Event | Frequency of patients with severe adverse events. | 5 years | 
| Laboratory Analyses | Frequency of patients with possible clinically significant abnormalities, i.e. with values out of normal range. Normal ranges are defined as: Alanine aminotransferase (ALT): 5-45 [U/L] Aspartate aminotransferase (AST): 10-40 [U/L] Bilirubin, total: 0.2-1.0 [mg/dL] | 5 years |