Primary Investigator: Greg Flaker, MD
Study Coordinator: Kathy Belew, CNS-BC
Purpose: The primary objective of this trial is to demonstrate that the efficacy and safety of two blinded doses (110 mg b.i.d. and 150 mg b.i.d.) of dabigatran etexilate in patients with non-valvular atrial fibrillation are non-inferior to warfarin treatment for the prevention of stroke and systemic embolism.
1. Patients with documented atrial fibrillation (AF) as follows:
a. ECG documented AF on the day of screening or randomization.
b. The patient has had a symptomatic episode of paroxysmal or persistent AF documented by 12 lead ECG within six months prior to randomization.
c. There is documentation of symptomatic or asymptomatic paroxysmal or persistent AF on two separate occasions, at least one day apart, one of which is within six months prior to randomization. In this case, AF may be documented by 12 lead ECG, rhythm strip, pacemaker/ICD electrogram, or Holter ECG. The duration of AF should be at least 30 seconds. Electrograms (not marker channels or mode switch episodes) from pacemakers and defibrillators can be used to document only one episode of paroxysmal or persistent AF.
2. In addition to documented AF, patients must have one of the following additional risk factors for stroke:
a. History of previous stroke, transient ischemic attack, or systemic embolism.
b. Left ventricular ejection fraction < 40% documented by echocardiogram, radionuclide or contrast angiogram.
c. Symptomatic heart failure, documented to be NYHA Class 2 or greater.
d. Age greater than or equal to 75 years.
e. Age greater than or equal to 65 years and one of the following additional risk factors:
- diabetes mellitus on treatment
- documented coronary artery disease (any of: prior MI, positive stress exercise test, positive nuclear perfusion study, prior CABG surgery or PCI, angiogram showing greater than or equal to 75% stenosis in a major coronary artery
- Hypertension requiring medical treatment
3. Age greater than or equal to 18 years at entry.
4. Written, informed consent.
1. History of heart valve disorders (i.e., prosthetic valve or hemodynamically relevant valve disease).
2. Severe, disabling stroke within the previous 6 months, or any stroke within the previous 14 days.
3. Conditions associated with an increased risk of bleeding:
- Major surgery in the previous month
- Planned surgery or intervention in the next 3 months
- History of intracranial, intraocular, spinal, retroperitoneal or atraumatic intra-articular bleeding
- Gastrointestinal hemorrhage within the past year
Symptomatic or endoscopically documented gastroduodenal ulcer disease in the previous 30 days
Hemorrhagic disorder or bleeding diathesis
- Need for anticoagulant treatment for disorders other than atrial fibrillation
- Fibrinolytic agents within 48 hours of study entry
Uncontrolled hypertension (SBP > 180 mmHg and/or DBP > 100 mmHg)
- Recent malignancy or radiation therapy (< or equal to six months) and not expected to survive 3 years.
4. Contraindication to warfarin treatment.
5. Reversible causes of atrial fibrillation (e.g., cardiac surgery, pulmonary embolism, untreated hyperthyroidism).
6. Plan to perform a pulmonary vein ablation or surgery for cure of the AF.
7. Severe renal impairment (estimated creatinine clearance < or equal to 30 mL/minutes).
8. Active infective endocarditis.
9. Active liver disease, including but not limited to:
- Persistent ALT, AST, ELK Phos. > 2 x ULN
- Known active hepatitis C* (as evidenced by positive HCV RNA by sensitive PCR-based assay, such as Roche Monitor or Bayer TMA assay)
- Active hepatitis B* (HBs antigen +, anti HBc IgM+)
- Active hepatitis A
10. 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)
11. Anemia (hemoglobin <100 g/L) or thrombocytopenia (platelet count < 100 x 10 to the 9th/L)
12. Patients who have developed transaminase elevations upon exposure to ximelagatran
13. Patients who have received an investigational drug in the past 30 days
14. Patients considered unreliable by the investigator concerning the requirements for follow-up during the study and/or compliance with study drug administration, has a life expectancy less than the expected duration of the trial due to concomitant disease, or has any condition which in the opinion of the investigator, would not allow safe participation in the study (e.g., drug addiction, alcohol abuse).
*Patients with a known history of hepatitis B or C must undergo hepatitis serology for hepatitis B and C prior to inclusion in the study.
1. Determine if patient fits major study criteria.
2. Determine if patient is interested in joining a clinical trial.
3. Call Kathy Belew (beeper 573-499-8063) and/or on-call research nurse (on-call beeper 573-499-8084) or Dr. Flaker to complete screening of subject.