PETRO Stroke Prevention in Patients With AF by Treatment With Dabigatran, With and Without Aspirin, Compared to Warfarin

Dose Exploration in Patients With Atrial Fibrillation

The purpose of this trial is to evaluate the safety of different doses of BIBR 1048, alone or in combination with acetylsalicylic acid (ASA), as determined by the rates of bleeding and other adverse events.

A secondary objective of this trial is to evaluate the anticoagulant effect of different doses of BIBR 1048, based on the reduction of plasma concentrations of D-dimer, a laboratory marker for activated coagulation in patients with atrial fibrillation (AF), and to correlate bleeding and other events with pharmacokinetic (PK) and pharmacodynamic (PD) data.

Inclusion criteria

1. Non-rheumatic atrial fibrillation.

2. Coronary artery disease (CAD), documented by previous myocard infarction (MI), angina, positive stress test, previous coronary intervention or bypass surgery, or atherosclerotic lesion(s) diagnosed by coronary angiography) is only considered as one of several possible qualifying risk factors. After recruitment of ca. 30%, a protocol amendment 4 was issued so that CAD was only considered as one of several possible qualifying risk factors, 2. see (3 f) below.

3. An additional risk factor for stroke, i.e. one or more of the following conditions/events:

   1. hypertension (defined as systolic bloodpressure (SBP) > 140 mmHg and/or diastolic bloodpressure (DBP) > 90 mm Hg) requiring antihypertensive medical treatment.
   2. diabetes mellitus (type I and II).
   3. symptomatic heart failure or left ventricular dysfunction (ejection fraction (EF) < 40%).
   4. a previous ischemic stroke or transient ischemic attack.
   5. age greater than 75 years.
   6. history of coronary artery disease (by amendment 4)

4. Treatment with warfarin or other vitamin K dependent anticoagulants for at least 8 weeks prior to inclusion. International normalised ratio (INR) should be within therapeutic range (i.e. INR 2.0 - 3.0) at visit 1 otherwise the visit should be rescheduled.

5. Age > = 18 years at entry.

6. Written, informed consent.

Exclusion criteria

1. Valvular heart disease.
2. Planned cardioversion.
3. Recent (=< 1 month) myocardial infarction, stroke or transient ischemic attack (TIA), or patients who have received a coronary stent within the last 6 months.
4. Intolerance or contraindications to acetylsalicylic acid (ASA).
5. Any contraindication to anticoagulant therapy.
6. Major bleeding within the last 6 months (other than gastrointestinal (GI) hemorrhage).
7. Severe renal impairment (estimated glomerular filtration rate (GFR) =< 30 mL/min).
8. Uncontrolled hypertension (SBP > 180 mmHg and/or DBP > 100 mmHg).
9. Abnormal liver function as defined by aspartat-aminotransferase (AST), alanin-aminotransferase (ALT), serum bilirubin or alkaline phosphatase (AP) above the reference range, or history of liver disease.
10. Women who are pregnant or of childbearing potential who refuses to use a medically acceptable form of contraception throughout the study.
11. Patients who have received an investigational drug within the last 30 days.
12. Patients scheduled for major surgery or invasive procedures which may cause bleeding, or those who have had major surgery or percutaneous coronary intervention (PCI) within 6 weeks.
13. Patients considered unreliable by the investigator.
14. Another indication for anticoagulant treatment.
15. Patients suffering from anemia.
16. Patients suffering from thrombocytopenia.
17. Any other condition which, in the discretion of the investigator, would not allow safe participation in the study.
18. Concomitant treatment with antiplatelet agents other than ASA.
19. Recent malignancy or radiation therapy (=< 6 month).