Atrial Fibrillation
Conditions
Keywords
atrial fibrillation, stroke, systemic embolism, bleeding, oral anticoagulant
Brief summary
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.
Detailed description
1. participants 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
Interventions
DRUGDabigatran etexilate
this drug is administered twice per day for the entire study period
DRUGRivaroxaban
this drug is administered once per day for the entire study period
DRUGApixaban
this drug is administered twice per day for the entire study period
Sponsors
Tainan Municipal Hospital
E-DA Hospital
National Cheng-Kung University Hospital Dou-Liou Branch
Ministry of Health and Welfare, Taiwan
National Cheng-Kung University Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
20 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Known AF (paroxysmal or persistent/ permanent) who are suitable and ready for NOAC treatment plus at least one of the following criteria * Prior ischemic stroke, transient ischemic accident or systemic embolism * Left ventricular ejection fraction ≤40% (documented by echocardiography or contrast ventriculography) * Symptomatic congestive heart failure (≥ New York Heart Association Functional Class 2) within 6 months before screening * Age ≥75 years * Age ≥65 but \<75 years with diabetes mellitus, hypertension or coronary artery disease
Exclusion criteria
Subjects are excluded if they have at least one of the following situations before screening: * Known severe (i.e. hemodynamically significant) mitral stenosis regardless of having received operation * Time elapsed from the onset of stroke ≤7 days * Bleeding tendency * Creatinine clearance rate ≤30 mL/min * Known active liver disease (persistent elevation of alanine aminotransferase, aspartate transaminase or alkaline phosphatase ≥3 × upper normal limit; or advanced liver cirrhosis ≥Pugh B) * Pregnancy * Recent documented active malignancy or radiation therapy (≤6 months) and not expected to survive 3 years * Unwilling to give informed consent * Conditions other than AF that required anticoagulation * Anemia (hemoglobin level \<90 g/L) or thrombocytopenia (platelet count \<100 × 109/L) * Persistent uncontrolled hypertension (systolic blood pressure \>180 mmHg or diastolic blood pressure \>100 mmHg) * Active infective endocarditis * Patients considered unreliable by the investigator or have a life expectancy less than the expected duration of the trial because of concomitant disease, or has any condition which in the opinion of the investigator, would not allow safe participation in the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to the occurrence of the major embolic events | up to 36 months | a composite of stroke (ischemic or hemorrhagic), transient ischemic attack or systemic embolism |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to the occurrence of all clinically relevant bleeding events | up to 36 months | a composite of major bleeding or clinically relevant non-major bleeding events |
| Time to the occurrence of the major embolic events and death | up to 36 months | a composite of all stroke (including hemorrhagic), systemic embolism, and death |
| Time to the occurrence of the major embolic and vascular events | up to 36 months | a composite of all stroke, systemic embolism, pulmonary embolism, acute myocardial infarction, and vascular death |
Other
| Measure | Time frame | Description |
|---|---|---|
| Time to the occurrence of death | up to 36 months | all-cause death includes vascular and non-vascular causes |
| Time to the occurrence of pulmonary embolism | up to 36 months | clinical diagnosis of pulmonary embolism should be confirmed by an image study |
| Time to the occurrence of acute myocardial infarction | up to 36 months | acute myocardial infarction is defined in accordance with the universal definition proposed in 2012 |
| Time to the occurrence of vascular death | up to 36 months | sudden cardiac death, fatal stroke, fatal myocardial infarction, any other death for which there is no clearly documented non-vascular cause, and death from bleeding |
| Time to the occurrence of hospitalization for congestive heart failure | up to 36 months | decompensated congestive heart failure requiring hospitalization for stabilization |
| Time to the occurrence of advanced chronic kidney disease | up to 36 months | defined as estimated glomerular filtration rate \<30 mL/min/1.73m2 confirmed by 2 separate laboratory tests within 3 months |
| Time to the occurrence of cardiogenic shock | up to 36 months | symptoms and signs of organ hypoperfusion (e.g. cool peripheries, oliguria) plus one of the following parameters: systolic blood pressure 90 mmHg or less, hypotension requiring inotropic/vasopressor therapy remaining after fluid challenge, heart rate of at least 60 bpm, or a cardiac index of 2.2 L/min/m2 or less |
| Time to the occurrence of any revascularization for peripheral artery disease | up to 36 months | percutaneous transluminal angioplasty or bypass surgery for low extremity artery disease |
| Time to the occurrence of any revascularization for coronary artery disease | up to 36 months | percutaneous coronary intervention or coronary artery bypass grafting for obstructive coronary artery disease |
| Time to occurrence of any revascularization for carotid or vertebral artery stenosis | up to 36 months | endovascular therapy, endarterectomy or bypass surgery for carotid or vertebral artery stenosis |
| Time to the occurrence of major bleeding events | up to 36 months | defined as bleeding to cause a drop in hemoglobin level \>= 2g/dL, fatal bleeding, life-threatening bleeding, or symptomatic bleeding at critical sites (including intracranial, retroperitoneal, intraocular, or intrapericardial) |
| Time to the occurrence of life-threatening bleeding events | up to 36 months | defined as fatal bleeding, symptomatic intracranial hemorrhage, bleeding to cause a drop in hemoglobin level \>=5g/dL, bleeding requiring transfusion with \>=4u blood component, bleeding requiring vasopressor administration, or bleeding needing surgery for hemostasis |
| Time to the occurrence of minor bleeding events | up to 36 months | non-major or non-life-threatening bleeding events |
| Time to the occurrence of clinically relevant non-major bleeding events | up to 36 months | clinically overt bleeding that does not satisfy the criteria for major bleeding and that leads to hospital admission, physician-guided medical or surgical treatment, or a change in antithrombotic therapy |
| Time to the occurrence of major or minor bleeding events | up to 36 months | major or minor bleeding |
| Time to the occurrence of all stroke | up to 36 months | stroke is defined as a focal loss of neurological function caused by an ischemic or hemorrhagic event with residual symptoms at least 24 hours after onset or leading to death |
| Time to the occurrence of systemic embolism | up to 36 months | embolic events excluding stroke, pulmonary embolism or venous thromboembolism |
| Time to the occurrence of transient ischemic attack | up to 36 months | a transient focal loss of neurological function caused by an ischemic event with complete recovery within 24 hours after onset |
Countries
Taiwan
Contacts
Primary ContactTing-Hsing Chao, MD
Outcome results
None listed