A Dose Response Study of Dabigatran Etexilate(BIBR 1048) in Pharmacodynamics and Safety in Patients With Non-valvular Atrial Fibrillation in Comparison to Warfarin

• Frequency (Occurrence Rates) of Major Bleeding Event [ Time Frame: Treatment period: from the first dose of study medication and ending 6 days after the last dose of study medication ] [ Designated as safety issue: Yes ]
  The percentage of patients with major bleeding event
• Frequency (Occurrence Rates) of Clinically Relevant Bleeding Event [ Time Frame: Treatment period: from the first dose of study medication and ending 6 days after the last dose of study medication ] [ Designated as safety issue: Yes ]
  The percentage of patients with clinically relevant bleeding event
• Frequency (Occurrence Rates) of Nuisance Bleeding Event [ Time Frame: Treatment period: from the first dose of study medication and ending 6 days after the last dose of study medication ] [ Designated as safety issue: Yes ]
  The percentage of patients with nuisance bleeding event

• Incidence of major bleeding event [ Time Frame: Treatment period: from the first dose of study medication and ending 6 days after the last dose of study medication ] [ Designated as safety issue: Yes ]
• Incidence of clinically relevant bleeding event [ Time Frame: Treatment period: from the first dose of study medication and ending 6 days after the last dose of study medication ] [ Designated as safety issue: Yes ]
• Incidence of nuisance bleeding event [ Time Frame: Treatment period: from the first dose of study medication and ending 6 days after the last dose of study medication ] [ Designated as safety issue: Yes ]

• Frequency (Occurrence Rates) of a Composite Clinical Endpoint. [ Time Frame: Treatment period: from the first dose of study medication and ending 6 days after the last dose of study medication ] [ Designated as safety issue: No ]
  Percentage of patients with the composite clinical endpoint (ischemic or haemorrhagic stroke (fatal or non-fatal), transient ischemic attacks, systemic embolism, myocardial infarction (fatal or non-fatal), other major adverse cardiac events, and death)
• Frequency (Occurrence Rates) of Ischemic or Haemorrhagic Stroke (Fatal or Non-fatal) [ Time Frame: Treatment period: from the first dose of study medication and ending 6 days after the last dose of study medication ] [ Designated as safety issue: No ]
  The percentage of patients with ischemic or haemorrhagic stroke (fatal or non-fatal)
• Frequency (Occurrence Rates) of Transient Ischemic Attack [ Time Frame: Treatment period: from the first dose of study medication and ending 6 days after the last dose of study medication ] [ Designated as safety issue: No ]
  The percentage of patients with transient ischemic attack
• Frequency (Occurrence Rates) of Systemic Embolism [ Time Frame: Treatment period: from the first dose of study medication and ending 6 days after the last dose of study medication ] [ Designated as safety issue: No ]
  The percentage of patients with systemic embolism
• Frequency (Occurrence Rates) of Myocardial Infarction (Fatal or Non-fatal) [ Time Frame: Treatment period: from the first dose of study medication and ending 6 days after the last dose of study medication ] [ Designated as safety issue: No ]
  The percentage of patients with myocardial infarction (fatal or non-fatal)
• Frequency (Occurrence Rates) of Other Major Adverse Cardiac Events [ Time Frame: Treatment period: from the first dose of study medication and ending 6 days after the last dose of study medication ] [ Designated as safety issue: No ]
  The percentage of patients with other major adverse cardiac events
• Frequency (Occurrence Rates) of Death [ Time Frame: Treatment period: from the first dose of study medication and ending 6 days after the last dose of study medication ] [ Designated as safety issue: No ]
  The percentage of patients with death

• A composite clinical endpoint including the incidence of ischemic or haemorrhagic stroke (fatal or non-fatal), transient ischemic attacks, systemic embolism, myocardial infarction (fatal or non-fatal), other major adverse cardiac events, and death [ Time Frame: Treatment period: from the first dose of study medication and ending 6 days after the last dose of study medication ] [ Designated as safety issue: No ]
• The incidence of ischemic or haemorrhagic stroke (fatal or non-fatal) [ Time Frame: Treatment period: from the first dose of study medication and ending 6 days after the last dose of study medication ] [ Designated as safety issue: No ]
• The incidence of transient ischemic attack [ Time Frame: Treatment period: from the first dose of study medication and ending 6 days after the last dose of study medication ] [ Designated as safety issue: No ]
• The incidence of systemic embolism [ Time Frame: Treatment period: from the first dose of study medication and ending 6 days after the last dose of study medication ] [ Designated as safety issue: No ]
• The incidence of myocardial infarction (fatal or non-fatal) [ Time Frame: Treatment period: from the first dose of study medication and ending 6 days after the last dose of study medication ] [ Designated as safety issue: No ]
• The incidence of other major adverse cardiac events [ Time Frame: Treatment period: from the first dose of study medication and ending 6 days after the last dose of study medication ] [ Designated as safety issue: No ]
• The incidence of death [ Time Frame: Treatment period: from the first dose of study medication and ending 6 days after the last dose of study medication ] [ Designated as safety issue: No ]

The primary objective was to evaluate the safety of dabigatran etexilate(BIBR 1048) administered orally at doses of 110 and 150 mg, twice daily, for 12 weeks in patients with non-valvular atrial fibrillation (paroxysmal, persistent or permanent) in comparison with warfarin.

• Drug: Dabigatran etexilate
  Dabigatran etexilate 110 mg capsule, twice a day, oral administration
• Drug: Dabigatran etexilate
  Dabigatran etexilate 150 mg capsule, twice a day, oral administration
• Drug: Warfarin
  Dose-adjusted warfarin based on target INR values

• Experimental: Dabigatran etexilate 220 mg daily
  Dabigatran etexilate 110 mg capsule, twice a day, oral administration
  Intervention: Drug: Dabigatran etexilate
• Experimental: Dabigatran etexilate 300 mg daily
  Dabigatran etexilate 150 mg capsule, twice a day, oral administration
  Intervention: Drug: Dabigatran etexilate
• Active Comparator: Warfarin
  Dose-adjusted warfarin based on target INR values
  Intervention: Drug: Warfarin

Inclusion criteria Inclusion criteria

1. Patients with non-valvular atrial fibrillation (paroxysmal, persistent or permanent)

2. Patients who had additional risk factor for thromboembolism; one or more of the following conditions/events:

   • Hypertension
   • Diabetes mellitus
   • Left-side heart failure
   • A previous ischemic stroke or transient ischemic attack
   • Age 75 years or older
   • A history of coronary artery diseases

Exclusion criteria Exclusion criteria

1. Patients diagnosed as having a valvular heart disease by echocardiography, or patients who had a history of prosthetic valve replacement or valve surgery
2. Patients who were to receive electric defibrillation or pharmacological defibrillation during the study period
3. Patients who developed stroke or transient ischemic attack within 30 days before the date of informed consent
4. Patients who developed myocardial infarction or were admitted to hospital due to acute coronary syndrome or for percutaneous transluminal coronary angioplasty within 3 months before the date of informed consent or patients underwent coronary stenting within 6 months before the date of informed consent
5. Patients with atrial myxoma or left ventricular thrombosis
6. Patients with contraindication to anticoagulant therapies
7. Patients scheduled for major surgery or invasive procedure
8. Patients having major bleeding from non-gastrointestinal organs within 6 months before the date of informed consent
9. Patients with uncontrolled hypertension