1. The recent development of novel oral anticoagulants (NOACs), including direct thrombin inhibitor (dabigatran) and factor Xa inhibitors (rivaroxaban, apixaban, and edoxaban), could potentially overcome many drawbacks of warfarin, and might provide a safer, and even more effective and convenient alternative approach to warfarin in non-valvular atrial fibrillation (NVAF), especially in Asians.
2. According to the results of a meta-analysis comparing Asians and non-Asians, NOACs are preferentially indicated in Asians in terms of both efficacy and safety.
3. There is no randomized controlled trial with sufficient power to directly compare the efficacy and safety among NOACs in NVAF, not to speak of Asians and Chinese.
4. Indirect comparisons are only based on observation with a lot of limitations such as heterogeneous background characteristics, difference in study design, and diversity in time within therapeutic range in control group. The findings from indirect comparisons are not conclusive but only hypothesis-generating.
5. This investigator-initiated prospective randomized open blinded end-point clinical trial will directly compare the efficacy and safety among 3 NOACs in patients with NVAF in Taiwan. We hypothesize that rivaroxaban or apixaban is non-inferior to dabigatran in terms of the efficacy.
a. eligible participants are randomly assigned to dabigatran, rivaroxaban, or apixaban with allocation ratio of 1:1:1
- Patients are randomly assigned to receive dabigatran (110 or 150 mg twice daily), rivaroxaban (15 or 20 mg daily), or apixaban (5 mg twice daily) with dosage and frequency approved by the Ministry of Health and Welfare, Taiwan. Reduced doses (dabigatran 110 mg twice daily, rivaroxaban 10 or 15 mg daily, or apixaban 2.5 mg twice daily) are allowed in a subset of patients with one or more of the following criteria: an age of at least 80 years, a body weight of no more than 60 kg, a serum creatinine level ≥1.5 mg per deciliter (133 μmol per liter) or creatinine clearance around 30 to 49 ml per minute)
2. blood sampling, genotyping, and measurement of biomarkers
a. bood samples (13 mL) from peripheral veins in all study subjects at baseline and 10 mL 3 months later, and stored for enzyme-linked immunosorbent assay as well as genotyping
3. outcome follow-up a. clinical follow-up is performed and clinical outcomes are obtained by clinic visit, telephone call or direct contact with participants or subjects' family quarterly after treatment for 2 times, then every 6 months
- Rivaroxaban Drug
Intervention Desc: this drug is administered once per day for the entire study period ARM 1: Kind: Experimental Label: Rivaroxaban Description: oral rivaroxaban film-coated tablet 15 or 20 mg (10 or 15 mg in specific population) qd for entire study period
- Apixaban Drug
Other Names: BMS-562247 Intervention Desc: this drug is administered twice per day for the entire study period ARM 1: Kind: Experimental Label: Apixaban Description: oral apixaban 5 mg (2.5 mg in specific population) bid for entire study period
- Dabigatran etexilate Drug
Intervention Desc: this drug is administered twice per day for the entire study period ARM 1: Kind: Experimental Label: Dabigatran Description: oral dabigatran etexilate capsule 110 or 150 mg (110 mg in specific population) bid for entire study period
- Allocation: Randomized
- Masking: Open Label
- Purpose: Treatment
- Endpoint: Efficacy Study
- Intervention: Parallel Assignment
|Type||Measure||Time Frame||Safety Issue|
|Primary||Time to the occurrence of the major embolic events||up to 36 months||No|
|Secondary||Time to the occurrence of the major embolic events and death||up to 36 months||No|
|Secondary||Time to the occurrence of the major embolic and vascular events||up to 36 months||No|
|Secondary||Time to the occurrence of all clinically relevant bleeding events||up to 36 months||Yes|